Huntsman Cancer Institute goal of this course is to provide a comprehensive review and update on the ... Department of Internal Medicine, and Huntsman Cancer Institute, University

Huntsman Cancer Institute Eighth Annual

Hematology Review

A review of advances in benign and malignant hematology

Saturday, February 24, 2018

Contents Introduction ................................................................................................................................................................................... 1

Accreditation ................................................................................................................................................................................. 2

Speaker and Planning Committee Disclosure Summary ............................................................................................. 3

Grant Support ................................................................................................................................................................................ 5

Instructions for Claiming and Printing Your Certificate ............................................................................................. 6

Agenda.............................................................................................................................................................................................. 7

Faculty .............................................................................................................................................................................................. 8

Growing UP: Treatment of Young Adults with ALL ................................................................................................................ 9 Wendy Stock, MD

Update on Coagulation ........................................................................................................................................................................ 31 George Rodgers, MD, PhD

Multiple Myeloma: A Year in Review .................................................................................................................................. 41 Douglas Sborov, MD

New Therapeutic Options for AL Amyloidosis........................................................................................................................... 56 Tibor Kovacsovics, MD

Acute Leukemias .................................................................................................................................................... 70 Paul Shami, MD

Cancer Survivorship .............................................................................................................................................................................. 84 Paul Thielking, MD; Rachel Montague, APRN, FNP-C; Brighton Loveday, APRN, ANP-BC; Jacyln Piper-Williams, APRN, FNP-C

Differential Diagnosis of Polycythemias and New Clinical Data on Ph-negative MPNs ....................................... 108 Josef Prchal, MD

Advances in the Treatment of Lymphoma and CLL ............................................................................................................... 124 Martha Glenn, MD

Huntsman Cancer Institute

Eighth Annual Hematology Review

Salt Lake City, Utah

Welcome to the eighth Huntsman Cancer Institute Annual Hematology Review. The goal of this course is to provide a comprehensive review and update on the state-of- the-art management of benign and malignant hematologic diseases. This academic course will provide an opportunity t o learn about new approaches for the diagnosis, prognostication, treatment, and care of these diseases.

The lectures are provided by speakers with expertise in each covered discipline. We welcome your feedback regarding the organization and content. This will help us in planning future meetings.

Course Director

Paul J. Shami, MD

Professor, Division of Hematology and Hematologic Malignancies Huntsman Cancer Institute

University of Utah Salt L ake City, Utah

This conference is supported by an educational grant from Novartis.

Exhibitors include: Adaptive Biotech, Amgen, ARIAD, Brisol-Myers Squibb, Genentech, Gilead, Incyte, Janssen Biotech, Merck, Onyx, Pfizer, Novartis and Takeda

Huntsman Cancer Institute Eighth Annual Hematology Review 1

Huntsman Cancer Institute 8th Annual Hematology Review February 24, 2017

Huntsman Cancer Institute – Eccles Auditorium

Accreditation: The University of Utah School of Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

AMA Credit: The University of Utah School of Medicine designates this live activity for a maximum of 7.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Nondiscrimination and Disability Accommodation Statement: The University of Utah does not exclude, deny benefits to or otherwise discriminate against any person on the basis of race, color, national origin, sex, disability, age, veteran’s status, religion, gender identity/expression, genetic information, or sexual orientation in admission to or participation in its programs and activities. Reasonable accommodations will be provided to qualified individuals with disabilities upon request, with reasonable notice. Requests for accommodations or inquiries or complaints about University nondiscrimination and disability/access policies may be directed to the Director, OEO/AA, Title IX/Section 504/ADA Coordinator, 201 S President’s Circle, RM 135, Salt Lake City, UT 84112, 801-581-8365 (Voice/TTY), 801-585-5746 (Fax).

Acknowledgment of Commercial Support: We would like to thank the following commercial interest company for the generous grant in support of our conference: Novartis.


Instructions for Course Coordinators:

Copy & paste the information below into an email. This will go to all participants registered for your course. This information MUST be given to participants before your course begins. If it does not go out before your course as an email, this information must be printed and given to every participant.

Please include [email protected] in your email so we have documentation this was sent. Please have a few hard copies on hand at your course to give to any ‘walk-ins’.

Please feel free to add any additional information to this email (parking instructions, directions, etc.).

Thank you for registering for the:

8th Annual HCI Hematology Course February 24th, 2018

HCI

Accreditation: The University Of Utah School Of Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

AMA Credit: The University of Utah School of Medicine designates this live activity for a maximum of 7.00 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

NONDISCRIMINATION AND DISABILITY ACCOMMODATION STATEMENT: The University of Utah does not exclude, deny benefits to or otherwise discriminate against any person on the basis of race, color, national origin, ethnicity, sex, disability, age, veteran’s status, religion, gender identity, gender expression, genetic information, or sexual orientation in admission to or participation in its programs and activities. Reasonable accommodations will be provided to qualified individuals with disabilities upon request, with reasonable notice. Requests for accommodations or inquiries or complaints about University nondiscrimination and disability/access policies may be directed to the Director, OEO/AA, Title IX/Section 504/ADA Coordinator, 201 S President’s Circle, RM 135, Salt Lake City, UT 84112, 801-581-8365 (Voice/TTY), 801-585-5746 (Fax).

Speaker and Planning Committee Disclosure Summary: The University Of Utah School Of Medicine Continuing Medical Education Office meets the ACCME expectations regarding the identification and resolution of conflicts of interest that arise from financial relationships with commercial interests.

Financial relationships are those relationships in which the individual benefits by receiving a salary, royalty, intellectual property rights, consulting fee, honoraria, ownership interest (e.g., stocks, stock


mailto:[email protected]

options or other ownership interest, excluding diversified mutual funds), or other financial benefit. Financial benefits are usually associated with roles such as employment, management position, independent contractor (including contracted research), consulting, speaking and teaching, membership or advisory committees or review panels, board membership, and other activities from which remuneration is received, or expected. We consider relationships of the person involved in the CME activity to include financial relationships of a spouse or partner.

Everyone in control of content, including all speakers and planners are expected to disclose any relevant financial relationships in any amount within the past 12 months. Speakers are also expected to openly disclose intent to discuss any off-label, experimental, or investigational use of drugs, devices, or equipment in their presentations.

No one in The University of Utah Continuing Medical Education Office in control of content for the course has any relevant financial relationship with commercial products or services discussed during this conference.

Your Name Role Role Role

Relevant Financial Relationships

Commercial Interest & Role/Nature of Relationship

Nicole Felkel Planner No

Wendy Stock Speaker Yes pfizer, advisory board; jazz, advisory boardDeidre Moore Planner NoMartha Glenn Planner Speaker No

Paul Shami Planner Speaker Moderator Yes Pfizer - Advisory Board Meeting.Sarah Stice-Goff Planner NoMarie Asay Planner No

George Rodgers Speaker Yes Novartis-consultingPaul Thielking Speaker NoJosef Prchal Speaker NoBrighton Loveday APRN Planner Speaker NoRachel Montague Planner Speaker No

Tibor Kovacsovics Speaker YesProthena, research support; Janssen, research support

Douglas W Sborov MD MS Speaker NoJaclyn Piper-Williams Speaker No


HUNTSMAN CANCER INSTITUTE EIGHTH ANNUAL HEMATOLOGY REVIEW

A REVIEW OF ADVANCES IN BENIGN AND MALIGNANT HEMATOLOGY

SPONSORED BY The Division of Hematology and Hematologic Malignancies, Department of Internal Medicine,

and Huntsman Cancer Institute, University of Utah

GRANT SUPPORT NOVARTIS


Instructions for Course Coordinators:

Copy & paste the instructions below into an email. This will need to go to all participants once your course is complete. Include [email protected] in your email so we have documentation that this has been sent. Have a few hard copies on hand at your course to give to any registrants who might request this.

The link below will ask participants to complete an evaluation of your course, as well as claim their credit for participating. If participants do not “claim their credit, they will not be awarded the credit and will not receive a certificate.

Please feel free to add any additional information to your email.

8th Annual HCI Hematology Course February 24th, 2018

HCI Thank you for your participation in our course! Please complete the short course evaluation by following the link below. The evaluation should take less than 5 minutes.

Once you complete the evaluation, the link will prompt you to claim your CME credit for this course. Thank you!

Instructions for Claiming Credit and Printing Your Certificate:

(Note: There will be a series of screens please follow the directions on each screen).

1. To complete a short evaluation, claim your credit and print your course certificate please go tothe following link:

http://goo.gl/nrJKrN

2. When prompted enter your email address. If you are a new user, select “new user” andcomplete some short identifying information about yourself.

3. Enter the password; if you do not have a password you will be able to create one.4. Enter the following CME Activity code: 438135. Complete the short evaluation6. Enter the number of credits commensurate with your participation in the activity, up to 7.00

which is the number of AMA PRA Category 1 Credit(s)TM credits this activity is certified for.7. If you encounter any problems please call the UUCME office at 801-581-6886.


mailto:[email protected]

http://goo.gl/nrJKrN

Huntsman Cancer Institute Seventh Annual Hematology Review Huntsman Cancer Institute Eccles Auditorium

February 24, 2018

Agenda

7:15 a.m. Registration and Breakfast

7:55 a.m. Welcome Paul J. Shami, MD

8:00 a.m. ALL AYA Wendy Stock, MD Keynote Speaker

9:00 a.m. Coagulation George Rodgers, MD, PhD

9:45 a.m. Break

10:00 a.m. Multiple Myeloma Douglas Sborov, MD

10:45 p.m. Amyloidosis Tibor Kovacsovics, MD

11:30 a.m. Acute Leukemias Paul Shami, MD

12:15 p.m. Lunch

1:15 p.m. Survivorship Rachel Montague, APRN Brighton Loveday, APR Jaclyn Piper-Williams APRN Paul Thielking, MD

2:45 p.m. Break

3:00 p.m. MPD Josef Prchal, MD

3:45 p.m. Lymphoma Martha Glenn, MD

4:30 p.m. Wrap-up and Evaluations Paul J. Shami, MD


Faculty

Keynote Speaker: Wendy Stock, MD Anjuli Seth Nayak Professor in Leukemia, University of Chicago School of Medicine

Martha Glenn, MD Professor, Division of Hematology and Hematologic Malignancies, University of Utah

Tibor Kovacsovics, MD Professor, Division of Hematology and Hematologic Malignancies, University of Utah

Brighton Loveday, APRN Rachel Montague, APRN Jaclyn Piper-Williams, APRN Nurse Practitioners, Supportive Oncology and Survivorship, Huntsman Cancer Institute

Josef Prchal, MD Professor, Division of Hematology and Hematologic Malignancies, University of Utah

George Rodgers, MD, PhD Professor, Division of Hematology and Hematologic Malignancies, University of Utah

Douglas Sborov, MD, MS Assistant Professor, Division of Hematology and Hematologic Malignancies, University of Utah

Paul Shami, MD Professor, Division of Hematology and Hematologic Malignancies, University of Utah

Paul Thielking, MD Assistant Professor, Department of Psychiatry, University of Utah



Hematology Review

Growing UP: Treatment of Young Adults with ALL

Wendy Stock, MD


Growing UP: Treatment of Young Adults with ALL

Striving towards PRECISION MEDICINEImproving Outcomes

Wendy Stock, MDUniversity of Chicago Medicine

Disclosures

• Research funding: Sigma Tau (Baxalta)

• Advisory Boards: Amgen, Pfizer, SeattleGenetics

• Honoraria: Up to Date

• Service honoraria:, NCI (CTEP leukemiasteering committee), American Society ofHematology

Jim Nachman, 2011

“Pediatricians know best!”……how to treat ALL!”


Survival Differences in ALL are Dramatic: Depends on which “door” you enter

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 2 4 6 8 10 12 14

Log Rank p<.0001

Ages 16-20

Pediatric Adult

US France NetherlandsUK

CCG (pediatric group); EFS = 64%

CALGB; EFS = 36%

Survival of Adolescents/Young Adults (AYA), Ages 16-20 years

Blood 112:1646, 2008

Pediatric Adult

What Accounts for these Differences?

Treatment?

Disease Biology?

The People – Docs and Patients?

ALL of the ABOVE!

Comparison of Dose Intensity duringPost-Remission Therapy

CCG-BFM CALGB

Dexamethasone 210 mg/m2 140 mg/m2

Vincristine 22.5 mg/m2 14 mg

L-Asparaginase 90,000 u/m2 48,000 u/m2

Doxorubicin 75 mg/m2 90 mg/m2

Cyclophosphamide 3000 mg/m2 3000 mg/m2

IT-Methotrexate

Cranial RT

132 mg + RT or 216 mg, no RT

105 mg

2400 cGy


Cytogenetics of ALL as Function of Patient Age

Moorman et al, Brit J Haemat 10.1111,1365, 2008

????

Proportion of Patients Treated at NCICCC/COG Sites

63% 63%

70%74%

34%30%

51%

42%

10% 8%12%

16%

0%

10%

20%

30%

40%

50%

60%

70%

80%

NHL HL ALL AML

1‐14y 15‐21y 22‐39y

p<0.0001

Wolfson J et al, Cancer Epidemiol Biomarkers Prev; 26(3); 312–20. ©2017

Goals of US Intergoup Trial (10403)

• Estimate feasibility and DFS using a successful COG regimen in adult cooperative group setting in USA– Flow sheets to evaluate compliance with doses/schedule ofchemotherapy

• Obtain insights into age‐specific molecular pathogenesis and toidentify prognostic markers– MRD studies: characterize patients likely to relapse– Partnership with COG/St. Jude for GWAS studies

• New knowledge of psycho‐social and socio‐economic issues of AYA population – Patient survey at three treatment time‐points


US Intergroup study for AYAs 16- 39 years old: C-10403

I DIC MIM

T-ALL patients receive prophylactic RT after DIMaintenance therapy continues for 2 (F) – 3 (M) years

DNRVCRPredPeg-AspIT-MTXIT-AraC

CycloVCRDexPeg-AspAra-C6MPIT-MTX

MTXVCRPeg-ASPIT-MTX

DOXCycloDexPeg-AspAra-C6-TGIT-MTX

DEXVCR6MPMTXIT-MTX

Accrual completed on 9/15/12 (n = 300)

C10403 Patient Population

• 318 patients entered on 10403;– 22 withdrew prior to Rx (exclusion of Ph+ ALL)

• 295 eligible patients enrolled from 11/07– 9/12– on schedule accrual

• Median age: 25 years– <20 years: 25%– 20-29 years: 49%– 30-39 years: 27%

• 75% Caucasian, 10% African American– Ethnicity: 16% Hispanic / Latino

• 61% Male; 39% Female

C10403 Toxicities: Induction Only

• 2% induction mortality rate (identical to0232)

C10403 COG 0232

Hyperglycemia 29.3% 22.0%

Hyperbilirubinemia 15.9% 6.7%

Anaphylaxis 0.4% 0.8%

Pancreatitis 1.1% 0.5%

Thrombosis 2.9% 1.5%

Febrile neutropenia (indn)

19.2% 7.0%


No significant differences in toxicity at later time‐points in treatment

Hepatic 10403 0232

Liver failure 1.0 1.9

ALT 50.0 48.7

AST 30.2 22.2

Bilirubin 22.9 24.7

Pancreatitis 4.2 3.8

Low overall treatment related mortality of 3%; identical to COGAALL0232 AYAs

10403: Event‐free and Overall Survival

All Patients

3 yr EFS = 61%

3 year OS = 73%

Obesity Associated with Poor Survival

p = 0.0003


Multivariable model

p = 0.62

p = 0.02

p = 0.15

Univariate Analyses : Event Free Survival

Undetectable MRD following induction associated with excellent DFS, OS

HR = 0.25, p = 0.0006

3 yr DFS = 85%

3 yr DFS = 56%

C10403: Conclusions

• 3 year EFS of 62% and OS of 73% is asignificant improvement compared to 36%EFS historical controls in CALGB

– Low treatment related mortality (3%); toxicities manageable

• Outcomes similar to other prospectiveinternational studies of pediatric regimen inAYAs – Ribera, J Clin Oncol 2008,26:1843; Huguet, J Clin Oncol 2009

27:911; Deangelo, Leukemia 2014 ; Gokbuget ASH 2013, abstract 839


DFCI Consortium: Pediatric regimen for adults with ALL

• Applied DFCI standard pediatric regimen toprospective study in adults 18‐50 years oldwith newly diagnosed ALL

– 92 adults treated in 13 centers

• Tolerable – increasing toxicities with age

• Median follow‐up 4.5 years: DFS is 67% and OSat 4 yrs is 70%

Deangelo et al, Leukemia 2014

Disease-free survival (n=78): DFCI regimen

4-yr = 69%Median f/u = 4.5 yrs

Deangelo et at, Leukemia 2014

AlloSCT vs Pediatric Regimen in CR1 for Ph‐ ALLLarge IBMTR analysis

• Patients age: 18‐50 years old

• Dana‐Farber Cancer Institute (DFCI) Adult ALLconsortium phase II trials between 06/02 and12/2011 who achieved CR1 (N=108)

• 1st HCT for Ph/bcr‐abl neg ALL between

• 06/2002 to 12/2011 (n=422)– HLA‐identical sib (42%)

– Unrelated donor with 8/8 (40%), 7/8 (18%)

– MA (94%, 85% with TBI) or RIC/NMA regimens

Seftel et al, Am J Hematol 2016


Overall Survival Superior for Chemo vsAlloSCT in CR1

22

100

0

20

40

60

80

Probab

ility, %

Years since CR1

HR=3.12 (1.99-4.90); P < 0.0001

Chemo (N=107)

HCT (N=422)

0 2 64 531

Considerations for Transplant in CR1

• Adverse Cytogenetics– Hypodiploid

– 11q23 (MLL rearranged): e.g. t(4;11)

• High risk molecular features– Ph‐like ALL (BCR‐ABL1 like) ; IKZF1 (IKAROS)

• Persistence of MRD at early timepoints– Requires standardized, reproducible assay

– And, although transplant viable option, outcomes still not good if MRD+

SCT in CR1 beneficial for poor MRD responders

GRAAL 2003/2005 (N=955)

Patients eligible for allo‐SCT:High‐risk patients <56 years in CR1 (N=522)

SCT cohort (N=283) No‐SCT cohort (N=239)

Dhedin et al, Blood 2015:125:2486

P=0.04 for interaction

According to the MRD1 level(post-induction)

Benefit of SCT in patientswith MRD1 ≥10-4

No benefit of SCTin the whole high-risk population

MRD<10‐4

MRD≥10‐4


NEXT STEPS: INTEGRATING NEW TREATMENT STRATEGIES, NEW BIOLOGIC INSIGHTS

The melding of biology and therapy

What’s Next for AYA ALL ?

• Integrate biology/new targets: Eradicate MRD– Antibodies/Targeted kinase inhibitors/CAR‐Ts

• Rituximab – GRAALL Phase III trial : EFS and OS advantage

• Blinatumomab (frontline for older adults – E1910)

– Can addition of inotuzumab ozogamycin (InO) eradicate MRD and improve survival in AYA ALL?

– Can novel antibodies also improve outcome of patients with Ph‐like ALL?

– Use 10403 backbone and add new targeted therapies to eradicate MRD

• Insights, adjustments to reduce toxicities

•Patients with newly-diagnosed previouslyuntreated Ph-negative B-cell precursor (BCP)ALL 18-59 years old

– With ≥ 20% bone marrow non-Burkitt ALL blasts

•Positive for CD20 expression– Defined as 20% or more CD20+ leukemic blasts

•Patients could receive allogeneic transplant inCR1

Phase III Trial of Intensive BFM-like regimen+\- Rituximab: GRAALL-R 2005

Maury et al, NEJM 2016


Improved EFS for CD20+ ALL: GRAALL‐R

• After censoring at SCT in CR1: HR, 0.59 [0.37-0.93]; p= 0.021

Median follow-up, 30 months

Maury et al, NEJM 9.16

Inotuzumab Phase III trial: INOVATE

Ara‐C=cytarabine; FLAG=fludarabine/ara‐C/granulocyte colony‐stimulating factor; HIDAC=high‐dose ara‐C; Ph=Philadelphia chromosome

• Relapsed/refractory CD22+ ALL

• Due for salvage 1 or 2 therapy

• Ph– or Ph+

1:1 Randomization(N=326)

Inotuzumab ozogamicin (InO)

•Starting dose 1.8 mg/m2/cycle

•0.8 mg/m2 on day 1;0.5 mg/m2 on days 8 and 15 of a 21–28 day cycle (≤6 cycles)

Standard of Care (SOC)

• FLAG or

• Ara‐C plus mitoxantrone or

• HIDAC

• ≤4 cycles

Stratifications:

• Duration of 1st remission ≥12 vs <12 mo

• Salvage 2 vs 1

• Aged ≥55 y vs <55 y

326 patients randomized at 117 sites in 19 countries (INO‐VATE ALL; NCT01564784)

InO dose was reduced to 1.5 mg/m2/cycle once the patient achieved CR/CRi

Kantarjian et al, N Engl J Med, 6/2016

Inotuzumab vs Standard of CareINOVATE: Relapsed ALL

InO Standard of care1-Sided P Value

Na 109 96

CR/CRi,% (95% CI)

80.7 (72−88) 33.3 (24−44) <0.0001

CR 35.8 (27−46) 19.8 (12−29) 0.0056

CRi 45.0 (35−55) 13.5 (7−22) <0.0001

MRD-negativity among responders, n (%) [95% CI]

CR/CRi 69/88 (78.4) [68−87] 9/32 (28.1) [14−47] <0.0001

CR 35/39 (89.7) [76−97] 6/19 (31.6) [13−57] <0.0001

CRi 34/49 (69.4) [55−82] 3/13 (23.1) [5−54] 0.0034Kantarjian et al, NEJM, 2016


A041501 for AYAs 18-39: Opened to accrual fall 2017

Ph‐negCD22+16‐40

C10403Induction

R

NoINO

2 Cycles INO

C10403Consol.Maint.

Stratification*:Age

LDA‐cardCD20

Primary Endpoint:3‐yr EFS

*Based on GRAALL data , we will incorporate rituximab in non‐random fashion for all CD20+ patients

US Intergroup study for AYA: A041501 Randomized Phase III trial

I DIC MIM

*CD20+ Patients will Receive Rituximab with C, IM, DIMaintenance therapy continues for 2 (F) – 3 (M) years

DNRVCRDexPeg-AspIT-MTXIT-AraC

CycloVCRDexPeg-AspAra-C6MPIT-MTX

Rituximab

MTXVCR

Peg-ASPIT-MTX

Rituximab

DOXCycloDexPeg-AspAra-C6-TGIT-MTXRituximab

DEXVCR6MPMTXIT-MTX

Inotuzumab

Can we reduce treatment toxicity?

• More work needed to optimize PEG‐aspdosing in AYAs with ALL– Reduce dose but still achieve adequate depletion?

• May be most important during induction cycle• Cap dose?

• Obesity related toxicity

– Important insights will be obtained in the A041501 from study of asparaginase levels

• Now routinely available as CLIA/CAP approved test

• Will also detect silent inactivation if it occurs


Pharmacogenomics

• Pharmacogenomics: genetic polymorphismsaffect metabolism, impact toxicity– Myelosuppression – TPMT (6-MP)

– Osteonecrosis (glucocorticoids, asparaginase)• Karol et al, Blood 127;2016

– Pancreatitis -CPA2 (glucocorticoids,asparaginase)

• Liu et al, J Clin Oncol 34; 2015– Hepatotoxicity –SOD2 (asparaginase)

• Alachkar et al, Pharmacogenomics J. 2016, PMID27019981

– Neuropathy CEP72 (vincristine)• Diouf et al JAMA. 2015;313(8):815‐23

An Inherited Genetic Variant in CEP72 Promoter Predisposes to Vincristine‐Induced Peripheral Neuropathy in Adults with ALL

Clinical Pharmacology & Therapeuticspages 391‐395, 16 NOV 2016 DOI: 10.1002/cpt.506http://onlinelibrary.wiley.com/doi/10.1002/cpt.506/full#cpt506‐fig‐0001

‐CEP72 involved in mitotic spindle formation

‐CEP72 risk allele (T) results in decreased CEP72 expression

‐Knockdown of CEP72 results in increased sensitivity to vincristine (iPS model)

IMPLICATION‐Suggests that it may be possible to reduce dose of vincristine, decrease neuro‐tox, without compromise of efficacy

The rs4880 SOD2 SNP genotype frequencies in adults with ALL:CC genotype is associated with higher rates of hepatotoxicity

Alachkar et al, Pharmacogenomics 2017, 17:274

CC genotype is more common among self‐reported Hispanic ethnicity


Modulating Asparaginase Toxicity?

• Pilot study of 41 pts (median age of 43);– 15 received reduction in Peg‐Asp dosing with goal of achieving therapeutic asparaginase level and assessment of hepatic toxicity

• Dose ‐ 1000U/m2 IV vs standard dose of 2750U/m2

– Further dose reduction to 500 U/m2 if BMI>30, Age> 50,Baseline LFT abnormalities, Diabetes

• Goal was ≥ 0.1 IU/mL, measured weekly after dose• 80% achieved therapeutic levels with lower dose• Overall, trend towards decreased hepatotoxicity with

significant decrease in grade 3/4 hyperbilirubinemia– Occurred in 12 (46%) standard dose vs 1 (7%), p=0.014

Streck et al, ASCO 2017

BCR‐ABL1 like or Ph1‐like ALL:Important, new biological Subset

• 26 year old man: New diagnosis of ALL

• B‐ALL; CD19+,CD10+, Tdt+; 28% circulatinglymphoblasts

• Cytogenetics, 46 XY

• Initial CSF – clear

• Induction according to 10403

• Induction course uncomplicated

• Day 14 marrow: hypocellular (10%), with residualALL (40‐50% Tdt+)

• Day 28 marrow……..

(BM biopsy, Images courtesy of Dr. SandeepGurbuxani, UChicago)

Post‐induction Bone Marrow Biopsy

Day 29 of Induction:

Hypercellular Marrow

Gross Residual Disease


Discovery of Novel Subset of ALL:“BCR‐ABL1‐Like” or “Ph‐like” ALL

• “Ph‐like” ALL or “BCR‐ABL1‐like” ALL:– ≥ 10‐15% childhood ALL– Gene expression profile similar to BCR‐ABL1 ALL

• den Boer, Lancet Oncol 2009:10

– Very poor treatment outcome • Mullighan NEJM 2009; Harvey/Chen Blood 2010;

Loh, Blood 2013

– 50% have CRLF2 alterations, the majority have JAK mutations

– Remaining 50% have cryptic translocations or small deletions in genes encoding tyrosine kinases or genes deregulating kinase signaling: ABL1/2, CSF1R, EPOR, IL7R, JAK2, PDGFRB

• Roberts, Cancer Cell 2012

21 3 87654

0 1 2 3 4 5 6

0.0

0.2

0.4

0.6

0.8

1.0

Years

Pro

ba

bili

ty o

f RF

S

Kinase Fusions Retain Intact Tyrosine Kinase domains: Targets!

Childhood H

R

Adolesc

ent (

16-2

1 yr

s)

Young adult

(21-

39 y

rs)

% c

ases

Kathryn Roberts, NEJM, 2014

High proportion of JAK alterations in AYA Ph‐like ALL

Kinase gene TKI % of children % of AYAs

ABL1, ABL2, CSFR1, PDGFRB

Dasatinib 17% 6‐9%

CRLF2, JAK2, EPOR,IL2RB, TSLP

JAK2 inhibitor 68% 74‐87%

Others Crizotinib, TYK2 inhibitor, FAK inhibitor, unknown

15% 6‐17%


BCR-ABL1 like signature occurs in 28% of 10403 patients and is associated with poor EFS

3 yr OS = 81%

3 yr OS = 63%

Aberrant CRLF2 associated with worse outcomes among Ph‐like ALL

CRLF2 Subgroup of Ph‐like ALL:Worst Outcomes

Ph‐like ALL

Courtesy, Nitin Jain


Gene Expression “Chip” Identifies Ph‐Like ALL

• The COG (Willman et al) developed a CLIA‐approved adaptable screening assay to identifyPh+‐like ALL using 8 gene “chip array”

Reshmi et al, Blood. 2017 Jun 22;129(25):3352-3361.

Event-Free Survival Overall Survival

Ph+‐like

Not Ph+‐like

Current diagnostic pipeline for Ph‐like cases at UChicago

Flow cytometry for CRLF2 expression

FISH panel for Ph‐like associated most recurrent rearrangements

Chromosomal Microarray Analysis

Targeted RNA seq (not ready for prime time)Yap et al, Leukemia and Lympohoma, 58, 2017

Ph‐like ALL FISH panel: UChicago(3’ regions of the genes are involved in fusion event)

• CRLF2 break‐apart probe (Kreatech)

• IGH break‐apart probe (Vysis)

• ABL2 break‐apart probe (Empire genomics)

• CSF1R break‐apart probe (Empire)

• PDGFRB break‐apart probe (Vysis)

• JAK2 break‐apart probe (Kreatech)

• BCR/ABL1 (Vysis) – NUP214‐ABL

Expected pattern: break‐apart of a fusion signal in case of translocation or loss of 5’region signal in case of intrachromosomal deletions

CRLF2 Break-apart

Courtesy, G. Raca, M. Sukhanova


Post-induction Post-dasatinib + chemo

(BM biopsy, Images courtesy of Dr. S. Gurbuxani, UChicago)

day 29 consolidation

Dasatinib added to consolidation therapy:

CR , MRD neg

Clinical trials for Ph‐like ALL

• Ongoing: MDACC: HyperCVAD + Kinase inhibitor (KI) forrelapsed disease

• Ongoing COG Frontline trial adding appropriate TKI to COG backbone; Phase I study of Ruxolitinib for JAK (up to age 18)

• Planned: approved and to initiate in March, 2018– UChicago consortium: Ruxolitinib Phase I with 10403 backbone for frontline JAK mutant AYAs

• Emily Curran, PI

• Will combination TKI + Chemo eradicate MRD and obviatethe need for allo‐SCT in CR1?

Other Considerations: CAR‐T cells for frontline?

Ref T cellEngager

Population Response CRS

Maude et al.NEJM 2014

Anti-CD19CART4-1BB

N=30Peds&Adults

CR=90% 100% CRS27% Severe

Davila et al.SciTrMed2014

Anti-CD19CARTCD28

N=44Adults

CR=82% 43% Severe

Lee et al.Lancet 2015

Anti-CD19CARTCD28

N=21Peds&AYA

CR=67% 76% CRS28% Severe

Turtle et al.JCI 2016

Anti-CD19CART4-1BB

N=30Adults

CR=93% 83%CRS

Shah et al,ASH, 2017,Abstract 888

Anti‐CD19 N=22Adults

CR/CRi=82% 25%>Grade 365% neurotox >Grade 3


Overcoming Treatment Resistance: Targeting Survival Pathways

Phase I Trial of Venetoclax/Navitoclax +/‐ Chemotherapy for Relapsed Refractory ALL in children and young adults up to age 45 years

44 year old man: Resistant to 10403 induction, Resistant to Blinatumomab, Resistant to Inotuzumab, Finally CR with CAR‐T followed by MRD alloSCT‐ RELAPSE day 150 post allo‐SCT and enrolled on Phase I trial of Venetoclax/Navitoclax

Pre‐treatment: 11/27/17 Day 8: 12/12/17 Day 36: 1/9/18

CREATION OF YOUNG ADULT CANCER CLINIC

Providing comprehensive care for the young adult with cancer

The AYA Psyche and Adherence

• Lower levels of well‐being than patients withcancer in other age groups

– Higher levels of isolation, depression

• Nonadherence in adolescents and youngadults with cancer are high, ranging from 27‐60%

– Associated with higher rates of morbidity and lower survival rates

– 39% considered stopping treatment

Kroenke et al, JCO 22:1849, 2004; Kondryn et al; Lancet Oncology 12:100, 2011; Bleyer et al, CA Cancer J Clin 57;242, 2007; Kondryn et al Psychooncology 18; 1327, 2009


“It takes a village”: Creation of AYA clinic

GOALS:

• Comprehensivetherapeutic, physical andpsychosocial support;improved patient well-being and alliance withmedical team

• Improving treatmentcompliance leading tobetter outcomesTrevino et al, JCO 31; 1683,2013

UCHICAGO AYA TEAM 2017

AYA Clinic InitiativesStudy of post‐traumatic stress in AYA patients completing treatment for malignancies

‐Lori Muffly, MD; Cancer, 2016

Study of risky behaviors in AYA receiving treatment

‐Tara Henderson,MD

Piloting tools for assessment of the patient/caregiver (MD/Nursing) “alliance” and treatment complicance

37

17

29

11

35

31

27

12

0 10 20 30 40 50

AnyImpairment

Anxiety

Depression

PTSD

% Impaired

On‐Treatment

Early Survivor

P= 0.99

P= 0.89

P= 0.21

P= 0.84

Frequency of Psychological Impairments Amongst AYAs with Hematologic Malignancies

Muffly et al, Cancer 2016


Treatment should be at site with expertise in ALL management

• ALL regimens: Compliance, adherence is key– Arduous regimens– More than three years of treatment

• Requires expertise on part of health care team• Requires appropriate support, motivation forpatient and their caregivers

• Emerging data support improved outcomes whenAYAs with ALL treated at NCI cancercenter/cooperative group sites– J Wolfson et et al, Cancer Epidemiol Biomarkers Prev;2017, 26(3); 312–20.

Summary: Treatment of ALL in Young Adults

• Progress made when patients enrolled onclinical trials

• Clinical expertise required

• Psycho‐social support crucial

– Adherence, compliance facilitated

• Exciting time for future progress!

– Building upon a successful “backbone” with addition of novel agents

Thanks to our patients – they are our inspiration


Faculty/FellowsAndy Artz, MDJane Churpek, MDEmily Curran, MDMichael Drazer, MDLucy Godley, MD, PhDAndrew Hantel, MDTara Henderson, MDSatya Kosuri, MDRichard Larson, MDHongtao Liu, MD, PhDJennifer McNeer, MDToyosi Odenike, MDWendy Stock, MDMichael J. Thirman, MDJoe Wynne, MD, PhDRandy Knoebel, PharmDJenn Anderson, PharmD

HematopathologyJohn Anastasi, MDJason Cheng, MDSandeep Gurbuxani, MD, PhDElizabeth Hyjek, MDGarish Venkataraman, MDJames W. Vardiman, MDDan Arber, MD

Clinical SpecialistsNancy Glavin, RNPeggy Green, RNRebecca Pape, APNJean Ridgeway, APNLauren Ziskind, APNStock LabNoreen Fulton, BSHouda Alachkar, PhDBart Eisfelder, PhD

Cytogenetics and Molecular Genetics

Michelle M. Le Beau, PhDMegan McNerney, MD,PhDY. Lynn Wang, MD, PhD

Madina Sukhanova, PhDJeremy P. Segal, MD, PhD

The Leukemia Program: UC Medicine

ClinicalResearch GroupHowie Weiner, LeaderKristy Johnson, BAMelissa Fridstein, BABelen Aguado, BSChris Ott, BSJudith Murray, BAAlliance LeukemiaRichard Stone, MDJohn Byrd, MD Clara Bloomfield, MDECOG: Selina Luger MDSWOG: Anjali Advani MDCOG/St. JudeCharles Mullighan, MDMary Relling, PharmDBill Evans, PharmDCheryl Willman, MDRichard Harvey, PhDI-Ming Chen, DVM, MS



Hematology Review

Update on Coagulation

George Rodgers, MD


UPDATE ON COAGULATION

George M. Rodgers, MD

TOPICS

• NOACs vs LMWH in cancer-associated VTE

• Incidental VTE in cancer patients

• Thrombocytopenia in pregnancy

• Thrombopoietic drugs

• Cost analysis

• Benefit-risk comparison

• Chemotherapy – induced thrombocytopenia

• A novel treatment for hemophilia

TRIAL OF EDOXABAN VS LMWH IN CANCER VTE

• LMWH is considered to be treatment of choice

• Guidelines recommend six months LMWH therapy

• A NOAC (edoxaban) was compared with LMWH (dalteparin) in cancer VTE for 12 months of therapy

• 1050 patients in total randomized; 525 patients per group

• Non-inferiority trial; primary outcome – composite of first recurrent VTE or major bleeding event over 12 months

• 53% of patients had metastatic disease

Raskob GE, et al. ASH LBA-6, 2017 (NEJM 2017)


TRIAL OF EDOXABAN VS LMWH IN CANCER VTE

Raskob GE, et al. ASH LBA-6, 2017 (NEJM 2017)

Recurrent VTE

Major Bleeding

TRIAL OF EDOXABAN IN CANCER PATIENTS WITH VTE

• Rate of recurrent VTE lower with edoxaban (p = 0.09)

• Rate of major bleeding higher with edoxaban (p = 0.04)

• Frequency of severe major bleeding was similar with both drugs

• Major bleeding in edoxaban group was primarily GI, in patients with GI cancer

• Mortality from any cause was similar with both drugs

Raskob GE, et al. ASH LBA-6, 2017


RIVAROXABAN VS LMWH IN CANCER VTE

• A prospective British trial compared rivaroxaban vs dalteparin in cancer VTE between 2013-2016

• 203 patients in each treatment arm; 59% had metastatic disease

• 53% had incidental PE; 47% had symptomatic PE or DVT

• After six months treatment, VTE recurrence rates were: 11% dalteparin; 4% rivaroxaban

• Major bleeding rates were similar: 3% dalteparin; 4% rivaroxaban

• A larger phase III trial is pending

Young A, et al. ASH abstract #625, 2017

REAL-WORLD EFFICACY AND SAFETY OF RIVAROXABAN IN CANCER PATIENTS WITH

VTE

• US Truven Market Scan claims data and NCI-SEER data: cancer patients who developed VTE and were prescribed rivaroxaban were identified

• 949 patients were started on rivaroxaban following their index VTE

• The 180-day cumulative incidence estimate was 4% for recurrent VTE, 2.7% for major bleeding, and 11% for mortality

• These results are similar to prior studies using LMWH therapy

Kohn CG, et al. ASH abstract #3717

REAL-WORLD EFFICACY AND SAFETY OF RIVAROXABAN IN CANCER PATIENTS WITH VTE

Kohn CG, et al. ASH abstract #3717


INCIDENTAL VTE IN CANCER PATIENTS

• Approximately, 50% of VTE events in cancer patients are found incidentally

• In general, the prognosis of incidental VTE in cancer patients is similar to that of symptomatic VTE with comparable high rates of recurrent VTE

• Clot location may determine whether anticoagulation is necessary

Di Nisio M, Carrier M. 2017 ASH Education Book, p. 121

INCIDENTAL VTE IN CANCER PATIENTS

Di Nisio M, Carrier M. 2017 ASH Education Book, p. 121

THROMBOCYTOPENIA IN PREGNANCY

Cines DB, Levine LD. 2017 ASH Education Book, p. 144


THROMBOCYTOPENIA IN PREGNANCY

Practical Points

• Gestational thrombocytopenia is not apparent before mid-second trimester

• First trimester thrombocytopenia is likely to be ITP

• Platelet counts in GT rarely are less than 50,000/mcL

• GT does not respond to steroids or IvIgG

• ITP is the most common cause of platelet count below 50,000/mcL in first or second trimesters

• Preeclampsia is the most common cause of a platelet count below 50, 000/mcLin third trimester


TREATMENT OF ITP IN PREGNANCY

• Guidelines suggest a minimum platelet count of 80,000/mcL for neuraxialanesthesia

• Steroids are preferred later in pregnancy; daily prednisone is preferred overpulse dexamethasone because of placental transfer concerns

• If treatment is necessary early in pregnancy, IvIgG is recommended

• Romiplostim has been used in anecdotal cases

• Pregnancy-associated TTP or aHUS should be treated with plasma exchange or eculizumab, respectively


CATARACT INCIDENCE IN ITP PATIENTS TREATED WITH ELTROMBOPAG

• Clinical trials with eltrombopag reported cataract development or worsening in 7% of both treated and placebo patients

• An eltrombopag extension trial looked at the long-term risks of cataracts

• The rate of cataract development was low (9%) and no higher than that expected in a general adult population with other risk factors (steroid use, diabetes, and smoking)

WONG RSM, ET AL. ASH ABSTRACT # 1053, 2017


A COST-CONSEQUENCE MODEL: ELTROMBOPAG VS ROMIPLOSTIM

IN PEDIATRIC ITP PATIENTS

• Data was extracted from phase III clinical trials – platelet count response, bleeding events, and adverse events. Costs include

drugs and administration, routine care, rescue medications, bleeding-related

adverse events, mortality.

Tremblay G, et al . ASH abstract # 2146, 2017; Tremblay G, et al. ASH abstract # 3410, 2017

BENEFIT-RISK COMPARISON IN ITP PATIENTS RECEIVING ELTROMBOPAG OR

ROMIPLOSTIM

• Electronic data from 26 hospitals was analyzed to compare adult ITP patients treated with two drugs

• The proportion of patients who experienced bleeding events, rescue medication use, platelet transfusions, and adverse events were calculated overthe first 12 months of treatment

• Incidence proportions of patients with all bleeding events, rescue medication use, and most adverse events were lower in patients receiving eltrombopag

• Eltrombopag appears to have advantages over romiplostim in ITP

Forsythe A, et al. ASH abstract # 3409, 2017

BENEFIT-RISK COMPARISON IN ITP PATIENTS RECEIVING

ELTROMBOPAG OR ROMIPLOSTIM

Forsythe A, et al. ASH abstract # 3409, 2017

*

*

*

*

*


ROMIPLOSTIM FOR CHEMOTHERAPY-INDUCED THROMBOCYTOPENIA

• Chemotherapy-induced thrombocytopenia (CIT) may delay or cause dose-reduction of treatment

• First prospective trial of romiplostim in CIT

• Phase II open-label trial of solid tumor patients with at least four weeks ofthrombocytopenia (<100,000/mcL) despite dose-reduction or delay in chemotherapy

• Two groups: romiplostim vs observation

• 40 patients, approximately 90% had metastatic disease; 55% had GI cancer

• Observation arm was discontinued after interim analysis

Soff GA, et al. ASH abstract #289, 2017

ROMIPLOSTIM FOR CHEMOTHERAPY-INDUCED

THROMBOCYTOPENIA

Results

• Of 32 romiplostim up-front patients, 84% corrected thrombocytopenia within three weeks

• Mean effective romiplostim dose was 2.5 mcg/kg

• Four of 32 romiplostim patients experienced thrombosis (all VTEs); all had metastatic or locally-advanced pancreas, colorectal, or liver cancer

Soff GA, et al. ASH abstract #289, 2017

THROMBOPOIETIC DRUGS

Nursing Aspects

• Eltrombopag (Promacta®)

Oral; 25-75 mg daily

Adverse events- Liver toxicity, thrombosis, rebound thrombocytopenia

Monitoring- Platelet counts and LFTs

• Romiplostim (Nplate®)

S.C. ;1-10 mcg/kg weekly

Adverse events- 10% patients have variable PK, thrombosis, rebound

thrombocytopenia

Monitoring- Platelet counts

When these drugs are discontinued, consider “bridging therapy” with steroids or IVIgG to avoid rebound thrombocytopenia and bleeding


A NOVEL TREATMENT FOR HEMOPHILIA A

Standard Hemophilia A Therapy

• Patients without inhibitors – factor VIII replacement

• Patients with inhibitors – immune tolerance therapy

“bypass therapy” – factor VIIₐ


A NOVEL TREATMENT FOR HEMOPHILIA A

• Emicizumab is now approved to treat hemophilia patients with inhibitors

• Larger trials are ongoing in non-inhibitor patients

• Additional “non-factor” therapies for hemophilia are under investigation

SUMMARY

• For cancer-associated VTE patients, edoxaban and rivaroxaban are goodtreatment options (vs LMWH)

• Most cancer patients with incidental VTE should be anticoagulated

• Thrombopoietic drugs

• Eltrombopag has advantages over romiplostim

• Early clinical trial data with romiplostim to treat chemotherapy-induced thrombocytopenia is encouraging

• Emicizumab is a breakthrough therapy for hemophilia A patients



Hematology Review

Multiple Myeloma: A Year in Review

Douglas Sborov, MD


8th ANNUAL HCI HEMATOLOGY UPDATE

Multiple myeloma: A year in review

Douglas W. Sborov, MD MSAssistant Professor

Division of Hematology & Hematologic MalignanciesUniversity of Utah – Huntsman Cancer Institute

24-Feb-2018


• No financial disclosures

Disclosures


• Newly diagnosed MM (NDMM)– Transplant ineligible not fit for RVd

– Transplant eligible

• Relapsed refractory MM (RRMM)– Carfilzomib- and Daratumumab-based regimens

– New promising therapeutics• CAR-T, BiTE, and SINE

Outline



• Clonal BMPCs > 10% or biopsy-proven bony orextramedullary plasmacytoma

AND

• CRAB (Calcium, Kidney (Renal), Anemia, Bone)

• BMPCs > 60%

• sFLC > 100

• > 1 focal lesion (> 5 mm) on MRI

New diagnostic criteria include some asymptomatic patients

Rajkumar et al, Lancet Oncol, 2014


Staging tells us about how well our drugs work

Stage ISS Cytogenetics LDH5-year OS

(%)

1 I Standard NL 82

2 Not Stage 1 or 3 62

3 III High-risk High 40

Palumbo et al, JCO, 2015


Steroids

Proteasome InhibitorsVelcade

CarfilzomibIxazomib

IMiDsThalomid

LenalidomidePomalidomide Antibodies

DaratumumabElotuzumab

VenetoclaxSelinexor

CAR T-cellsBiTE antibodiesAntibody-drug

conjugates

Other Novel Therapeutics in

Clinical InvestigationMyeloma Cell

The Myeloma toolbox continues to growMelphalan

Cyclophosphamide

HDACiPanobinostat



NDMM – A simple treatment algorithm

VRd or clinical trial

Transplant ineligible unable to tolerate SOC

VRd lite

Transplant eligible

AutoHSCT

Maintenance

Rd


FIRST line treatment of elderly or frail patients

Rd Continuous REVLIMID + low-dose dexarm (n = 535) until progression

Rd18 arm REVLIMID + low-dose dex(n = 541) up to 18 cycles

MPT arm Melphalan + prednisone + (n = 547) thalidomide up to 12 cycles

Ra

nd

om

izat

ion

Benboubker et al, NEJM, 2014


Continuous Rd is safe and effective

Benboubker et al, NEJM, 2014

Outcome Rd continuous Rd18 MPT

Safety (G3/4)> 1 AE

NeutropeniaInfection

DVT +/- PE

85%28%29%8%

80%26%22%6%

89%45%17%5%

ResponseORR

> VGPR75%44%

73%43%

62%28%

SurvivalPFS

3-year OS4-year OS

25.5 m70%59%

20.7 m66%56%

21.2 m62%51%

SPMs 3% 6% 5%

Compared to MPT, continuous Rd significantly improves PFS and reduces the risk of death without compromising safety and tolerability



VRd lite may be an option for more fit transplant ineligible patients

Induction(35-day cycle x 9)

LEN 15 mg d1-21Vel 1.3 mg/m2 SQ d1,8,15,22Dex 40 vs. 20 (> 75 years) weekly

• Phase 2 trial (n = 53) treated with above for 9 cycles followed by 6 cycles of consolidation• Minimal G3 toxicities – mostly G1/2 including 74% fatigue (74%) and neuropathy (66%)• Response

– ORR 91.4% (after 4 cycles), 70% with VGPR or better– mPFS 35.1m– mOS not reached– Statistically significant improvement in QoL

Consolidation(35-day cycle x 6)

LEN 15 mg d1-21Vel 1.3 mg/m2 SQ d1,15

O’Donnell, ASH, 2017


4-drug combinations may be feasible in transplantineligible NDMM (ALCYONE)

3Mateos, NEJM, 2018

NDMMTransplant ineligible

N = 706

VMP (42d x 9 cycles)

Vel 1.3 mg/m2 SQC1: Twice weeklyC2-9: Once weekly

MEL 9 mg/m2 PO d1-4Pred 60 mg/m2 PO d1-4

D-VMP (9 cycles)

VMP – same scheduleDara 16 mg/m2 IV

C1: WeeklyC2-9: q3weeks

Daratumumab

Q4weeks until PD

ENDPOINTSPRIMARY: PFSSECONDARY: ORR, OS, safety


ALCYONE – 4-drug therapy was safe + effective

3Mateos, NEJM, 2018

• Rates of G3/4 events were similar including cytopenias, diarrhea, and neuropathy, but more patients on the Dara-arm had pneumonias (11% vs. 4%)



VRd is SOC for all fit patients: SWOG S0777

NDMM s intent for immediate autoHSCT

Rd (n=232)

LEN 25 mg D1-21Dex 40 mg weekly

[6 x 28-day cycles]

VRd (n=242)

LEN 25 mg D1-14Dex 20 mg Vel 1.3 mg/m2 D1,4,8,11

[8 x 21-day cycles]Rd


[24‐day cycles until PD, unacceptable toxicity, or withdrawl of consent]

MAINTENANCE

Stratified by ISS & intent to transplant

INDUCTION

ENDPOINTSPRIMARY: PFSSECONDARY: ORR, OS, safety

Durie et al, Lancent Oncology, 2016


VRd + Rev maintenance is tolerated and significantly improves outcomes in NDMM

Durie et al, Lancent Oncology, 2016

Outcome VRd (n = 241) Rd (n = 226) p-value

Safety (G3/4 AE)Neurologic

PainInfection

GISPM

802934522

249

31174

ResponseORR

VGPR or better81.5%43.5%

71.5%31.8%

SurvivalPFSOS

43 m75 m

30 m64 m

p = 0.0018p = 0.0125


• KRd– P2 trials show exceptional activity1,2

– Ongoing randomized ENDURANCE trial – KRd vs VRd

• 4 drug combinations– VRd +/- Daratumumab (GRIFFIN)3

– KRd +/- Daratumumab4

– VRd +/- Elotuzumab5

We can likely do better than VRd induction… KRd or 4-drug induction

1Korde et al, JAMA Onc, 2015; 2Jakubowiak et al, Blood, 2012; 3Voorhes, ASH, 2017; 4XXXX, ASH, 2017; 5Usman et al, BCJ, 2015;



• Randomized phase 3 trial of VRd vs. KRd followed by limited (2 years) or indefinite Rev maintenance in NDMM

• ECOG-ACRIN Cancer Research Group: ENDURANCE

ENDURANCE should reveal the best 3-drug induction regimen


KRd may improve and deepen response

Pts < 65 yrs of agewith symptomatic

NDMM(N = 76)

Induction (4 cycles)Carfilzomib 20/36 mg/m² IV Days 1, 2, 8, 9, 15, 16

Lenalidomide 25 mg Days 1-21Dexamethasone 20 mg Days 1-2, 8-9, 15-16, 22-23

(Cycles 1-4)

Stem cell collection followed by high-dose melphalan 200 mg/m2

and ASCT

Consolidation (cycles 5-8)Carfilzomib 36 mg/m² IV Days 1, 2, 8, 9, 15, 16

Lenalidomide 15 mg Days 1-21Dexamethasone 20 mg Days 1-2, 8-9, 15-16, 22-23

(Cycles 5-8)

Maintenance KRd for 10 cycles (CFZ d1, 2, 15,16 LEN maintenance after C18

• Primary endpoint: sCR at completion of consolidation (cycle 8)

• Secondary endpoints: ORR at various points, MRD for pts with ≥ VGPR, safety/tolerability, PFS

Zimmerman, ASH, 2016


High overall and deep response rates

Zimmerman, ASH, 2016

Endpoint (n=46) After induction After ASCT Best response

sCR + CR 11 19 35 (76)

VGPR 25 18 7 (15)

> VGPR 36 37 42 (91)

ORR 42 40 46 (100)

20

69

82

0

10

20

30

40

50

60

70

80

90

100

Post-HSCT Post-consolidation Post-10 cycles KRd

Pat

ient

s (%

)

Timepoint

Percent patients with sCR at 3 time points



RVd +/- Daratumumab (P2 - GRIFFIN)

Voorhes, ASH, 2017

• Safety run-in: DLTs (n=3) included fatigue, gastroenteritis, and pneumonitis and hypotension• No new safety signals with 4-drug treatment

NDMMTransplant eligible

N ~ 200

RVd (4 – 21d cycles)

Vel 1.3 mg/m2 SQ d1,4,8,11LEN 25 mg d1-4Dex 40 mg weekly

D-RVd (4 cycles)

RVd – same scheduleDara 16 mg/m2 IV weekly

AutoHSCT

AutoHSCT

RVd x 2

Same schedule

D-RVd x 2

RVd – same scheduleDara 16 mg/m2 d1

Revlimid d1-2110 mg 15 mg

Revlimid + Dara q56 day

INDUCTION CONSOLIDATION MAINTENANCE


• Phase 1b study (n = 22) NDMM

• ORR 100% including > VGPR 90%; all patients alive at 1-year

• No new safety signals

KRd +/- Daratumumab

Chari, ASH, 2017

KRd + Daratumumab(13 – 28d cycles)

CFZ weekly20 mg/m2 C1D170 mg/m2 thereafter

LEN 25 mg d1-21Dex 40 mg weeklyDaratumumab 16 mg/m2 IV weekly

10091

57

43

0

10

20

30

40

50

60

70

80

90

100

> PR > VGPR > CR sCR

Best response (n=21)


Transplant remains standard of care

RVRd x 3 cycles VRd x 3 cycles

AutoHSCT

VRd x 2 cycles

LEN 12 months

VRd x 5 cycles

LEN 12 months

Attal et al, NEJM, 2017

IFM / DFCI 2009



IFM / DFCI 2009 trial

Attal et al, NEJM, 2017

Outcome VRd (n = 350) AutoHSCT (n = 350) p-value

CR rate by treatment phase (%)

After inductionAfter AutoHSCT or consolidation

End of maintenance

456976

477885

0.870.03

< 0.001

Response (%)VGPR or betterMRD negative

7765

8879

0.001< 0.001

mTTP / mPFS 36 m 50 m < 0.001

4 year OS (NR) 82% 81% 0.87

Autologous transplant was associated with significantly increased TTP and PFS but no benefit in OS


Single autoHSCT is SOC: P3 STaMINA trial

Eligible pts ≤ 70(N = 758)

Single ASCT (n=257)LEN Maintenance until PD

10 mg qday x 3 cycles 15 mg/day

Consolidation (n=254)VEL 1.3 mg/m² D1,4,8,11

LEN 15 mg D1-15Dex 40 mg D1,8,154 – 28-day cycles

LEN Maintenance until PD10 mg qday x 3 cycles

then 15 mg/day

Tandem ASCT (n=247)Melphalan 200 mg/m²

AutoHSCTMEL 200 mg/m2

• Primary endpoint: PFS at 38 mos

• Secondary endpoints: OS, ORR, CR conversion rate, safety, infections, tx-related mortality, QoL

Stadtmauer, ASH abstract, 2016


No significant difference in PFS or OS between the 3 arms

Stadtmauer, ASH abstract, 2016

PFS100

80

60

40

20

0

PF

S (

%)

0 12 24 38

Months From Randomization

OS100

80

60

40

20

0

OS

(%

)

0 12 24 38Months From Randomization



Revlimid maintenance leads to improved survival

Holstein et al, Lancet, 2017

• Revlimid– CALGB 100104

• Randomized phase 3 trial in 460 patients

• mTTP 57.3m vs. 28.9m (p < 0.0001)

• mOS 113.8m vs. 84.1m (p = 0.0004)

• 5 year OS was 76% vs. 64%

– Meta-analysis (CALGB 100104, IFM 2005-2,GIMEMA RV-209) demonstrated OS with LEN in all

• 26% reduction in risk of death

• Estimated 2.5 year OS benefit


Relapsed and refractory myeloma (RRMM)Progressive

disease

Off treatment*On maintenance*

Frail or indolentFit

IF REVLIMID MAINTENANCE

KPd, DVd DVd

IF VELCADE MAINTENANCE

DRd DRd or IRd

Frail or indolentFit

KRd or DRd DRd, DVd, ERd, IRd

* Always consider clinical trial; salvage autoHSCT for patients not previously transplanted; 2nd autoHSCT if > 18 months off treatment or > 36 months response on post-transplant maintenance


Daratumumab-, Carfilzomib-, and Pomalidomide-based regimens



Daratumumab + Revlimid or Velcade + Dex

Dimopoulos, NEJM, 2016; Palumbo, NEJM, 2016

POLLUXDRd vs. Rd [P3 (n=569)]

> 1 prior lines of therapy

CASTOR DVd vs. Vd[P3 (n=498)]

> 1 prior lines of therapy

RA

ND

OM

IZA

TIO

NR

AN

DO

MIZ

AT

ION

RdLEN days 1-21 + weekly Dex

DRdDara qweek x 8 q2w for 16 w monthly

LEN days 1-21 + weekly Dex

DVdDara qweek x 10 q3w for 24 w monthly

VEL days 1, 4, 8, 11 + Dex

VdVEL days 1, 4, 8, 11 + Dex


Daratumumab: POLLUX and CASTOR trials

Dimopoulos, NEJM, 2016; Palumbo, NEJM, 2016; Spencer, ASH, 2017; Dimopoulos, ASH, 2017

POLLUX CASTOR

Response DRd Rd p‐value DVd Vd p‐value

ORR 93% 76% p < 0.001 84% 63% p < 0.001

> VGPR 81% 49% p < 0.001 62% 29% p < 0.001

12 m PFS 83% 60% p < 0.0001 62% 29% p < 0.0001

MRD negativity (10‐4) 29% 8% p < 0.0001 13.5% 2.8% p < 0.0001


Daratumumab: POLLUX and CASTOR trials

Dimopoulos, NEJM, 2016; Palumbo, NEJM, 2016

POLLUX CASTOR

Most common G3/4 AE DRd Rd DVd Vd

Neutropenia 51.9% 27% 12.8% 4.2%

Anemia 12.4% 19.6% 14.4% 16.0%

Thrombocytopenia 12.7% 13.5% 45.3% 32.9%

Febrile neutropenia 5.7% 2.5%

Diarrhea 5.3% 3.2% 3.7% 1.3%

Fatigue 6.4% 2.5% 4.5% 3.4%

Infusion reactions*Any gradeGrade 3

47.7%5.3%

45.3%8.6%



Daratumumab + Pomalidomide + Dex (DPd)

DPd(28d cycles)

Daratumumab 16 mg/m2 IV Weekly C1-2Biweekly C3-6Monthly until PD

POM 4 mg d1-21Dex 40 mg weekly

• P1b (EQQLEUS) – DPd in patients (n = 103) treated with > 2 prior lines• AE profile similar to Pd with more neutropenia and infusion reactions• Time to response 1 – 3 months• mPFS 8.8m, mOS 17.5m

Chari, Blood, 2017


Daratumumab + Carfilzomib + Dex (DKd)

DKd(28d cycles)

Daratumumab 16 mg/m2 IV Weekly C1-2Biweekly C3-6Monthly until PD

CFZ 20/70 mg/m2 weeklyDex 40 mg weekly

Lonial, ASH, 2017

• P1b – DKd in patients (n=85),treated with 1-3 prior lines

• MC AE cytopenias, HTN

• No changes in mLVEF

• ORR 84%, 56% > VGPR


Carfilzomib + Revlimid + Dex (KRd) - ASPIRE

Endpoint KRd Rd

sCR + CR 31.8% 9.3%

mPFS 26.1m 16.6m

OS 48.3m 40.4m

ORR 42 40

KRd is associated with improved QoL

RRMM1-3 prior lines

N = 792

Rd


KRd

CFZ 20/27 d1,2,8,9,15,16LEN 25 mg d1-21Dex 40 mg weekly

After C12 – CFZ d1,2,15,16After C16 – CFZ stopped

Stewart, ASH, 2017



Pomalidomide + Cyclophosphamide + Dex (PCd)

PCd(28d cycles)

POM 4 mg d1-21Cy 300 mg weeklyDex 40 mg d1-4, 15-18

• P2– PCd at 1st relapse on theIFM / DFCI 2009

• MC AE – Cytopenias, fatigue,GI disorders, clot, infection

• After 4 cycles, ORR 85%,VGPR or better 34%

• 94% autoHSCT-naïve wentto transplant

Gardenet, ASH, 2017


Exciting new agents


bb2121 CAR-T cells show amazing promise

• Bb2121 is a 2nd generation CAR that targets BCMA (expressed on myeloma cells and some mature B-cells)

• P1 3+3 dose escalation study (CRB-401) in RRMM treatedwith > 3 prior lines (n=21)

• Lymphodepletion (3 days) Flu and Cy

Kochenderfer, ASH, 2017



bb2121 CAR-T cells

AEOveralln (%)

> G3n (%)

CRS 15 (71) 2 (10)

Neurotoxicity 5 (24) 0

Neutropenia 18 (86) 18 (86)

Thrombocytopenia 11 (52) 9 (43)

Anemia 14 (67) 12 (57)

27

6

47

33

27

56

0

20

40

60

80

100

04 MAY 2017 (N=15) 02 OCT 2017 (N=18)

ORR

CR/sCR

VGPR

PR

• 5 deaths – PD (3), cardiac arrest (1), MDS p treatment stopped (1)• ORR 94%, > VGPR 89%• MRD negative in 90% of evaluable patients• P2 KarMMa is open

Kochenderfer, ASH, 2017


• Humanized anti-BCMA IgG monoclonal antibody conjugated to the cytotoxic agent monomethyl auristatin-F - kills MM cells via ADC, ADCC, immune directed cell death, BCMA receptor signaling inhibition

• DREAMM-1 (Driving Excellence in Approaches to Multiple Myeloma)

• RRMM with at least 3 prior lines of treatment

BCMA antibody drug conjugate – GSK2857916

Trudel, ASH, 2017


Antibody-drug conjugate GSK2857916

Trudel, ASH, 2017

n (%)N = 35

Any Grade > G3

Thrombocytopenia 20 (57) 12 (34)

Vision blurred 16 (46) 0

Dry eye 12 (34) 1 (3)

Anemia 10 (29) 5 (14)

Nausea 8 (23) 0

Photophobia 8 (23) 0

Fever 8 (23) 0

Fatigue 7 (20) 0

RESPONSE

• ORR 60%

• In part 2, 51% of patientshad VGPR or better

• mPFS 7.9m



• Questions?

• Please do not hesitate to contact me:– [email protected]

Thank you


• Diagnosis and staging of multiple myeloma

• Common side effects associated with SOC and experimental regimens

• Understanding the differences between induction, relapsed, andexperimental treatments

RN considerations



Hematology Review

New Therapeutic Options for AL Amyloidosis

Tibor Kovacsovics, MD


New therapeutic options for AL amyloidosis

Tibor Kovacsovics, MDUtah Amyloidosis Program

Division of Hematology and Hematologic MalignanciesHuntsman Cancer Institute andUniversity of Utah

Utah Amyloidosis Program

Disclosures

• Research support:

‐ Janssen

‐ Prothena

• Off label use: all medications described in thistalk; there are no FDA approved drugs for ALamyloidosis

Outline

• diagnostic algorithm

• novel prognostic scores

• therapy:

‐ chemotherapy approaches

‐ transplant

• Direct amyloidosis targeting:

‐ agents destabilizing amyloid fibrils: doxicyclin

‐ monoclonal antibodies: NED001


Amyloidosis: a protein misfoldingdisease

• Amyloidosis is a protein disease, which resultsfrom the accumulation into amyloid fibrils ofmisfolded precursor proteins

• There are about 30 different amyloidosisprecursors proteins

• The amyloidosis accumulate into amyloidfibrils, which have a beta pleated sheet

The cascade of molecular events leading to amyloidosis.

Giampaolo Merlini et al. JCO 2011;29:1924-1933

©2011 by American Society of Clinical Oncology

Most Common Amyloidosis Types

PRECURSOR PROTEIN AMYLOIDOSIS TYPE SITE OF SYNTHESIS

Monoclonal light chain AL, acquired Bone marrow plasma cells

Mutant transthyretin TTR, hereditary Liver

WT transthyretin SSA (senile), acquired Liver

SAP AA (reactive), acquired Liver

LECT ALECT2, hereditary Liver


Mechanism of amyloid organ toxicity

• Mass effect in most organs

• Direct toxicity of AL light chains on the heart:

‐ discrepancy between the amount of amyloiddeposits in the heart and the level of heartfailure

‐direct toxicity of light chains in differentmodels

‐mediation by reactive oxygen species or bythe MAP kinase pathway

Clinical Presentation

CARDIAC RENAL NEURO GI MSK

Heart failureNephrotic syndrome

Polyneuropathy Hepatomegaly Shoulder pad

Conduction abnormalities

Peripheral edema

Autonomic dysfunction

Gastroparesis Macroglossia

Diarrhea Arthropathy

Malabsorption

Organ involvement varies with amyloidosis type

AMYLOID TYPE HEART KIDNEY LIVER PNS

AL amyloidosis ++ ++ + +

TTR amyloidosis ++ + ‐ ++

SSA (WT‐TTR) ++ ‐ ‐ ‐

AA (reactive) + ++ + ‐


Amyloidosis diagnosis

• Requires positive Congo Red staining• Tissue biopsy‐ fat pad biopsy is the best screening test‐ involved organ biopsy: kidney, heart, liver

• Requires confirmation of amyloidosis type‐ immunohistochemistry (Kappa/Lambda)‐ laser directed microdissection and massspectrometry‐ immunoelectron microscopy‐ DNA analysis for hereditary amyloidosis

Laser microdissection.

Nelson Leung et al. Blood 2012;120:3206-3213

©2012 by American Society of Hematology


Representative mass spectrometry data.

Nelson Leung et al. Blood 2012;120:3206-3213


AL amyloidosis prognosis in the Italian series

Pavia series, from Merlini 2014

Risk stratification in AL amyloidosis

• Two cardiac biomarkers: TNT and pro‐BNP, arethe best predictors of overall survival, but also oftreatment‐related toxicity

• They form the basis of the Mayo score

• A renal score has been recently published andrelies on

‐ 24‐hour proteinuria

‐ GFR

• Bone marrow plasma cell >10%


Risk stratification in AL amyloidosisMayo score

Dispenzieri, J Clin Oncol 22:3751, 2004

Risk stratification in renalAL amyloidosis

Palladini et al, Blood 124:2235, 2014

Therapeutic strategy in AL amyloidosis

• Reduction of free light chain burden byeradicating the plasma cells with anti‐myelomastrategies‐ standard dose chemotherapy‐ stem cell transplantation

• Overall survival correlates with quality ofhematologic response

• Organ function improves slowly• Limitations: toxicity, especially with transplantand in patient with poor heart function


Survival from the 3-month landmark based on hematologic response in the validation cohort of 374 patients with immunoglobulin light chain amyloidosis.

Giovanni Palladini et al. JCO 2012;30:4541-4549


Stem cell transplantation in AL amyloidosis

• High‐dose Melphalan, followed by anautologous stem cell transplantation, isassociated to the best response rates andlongest survival in AL amyloidosis

• It is also associated to a high mortality rate,especially in patients with cardiacinvolvement, and is limited to ~20% cases

Long‐term outcome of transplant in AL amyloidosis: the BU experience

Sanchorawala et al, Blood 2015


Impact of Mayo score on transplant‐related mortality

Gertz et al, Bone Marrow Transplantation 2013

Probabilities of (A) early mortality and (B) overall survival (OS) in light-chain amyloidosis after transplantation for all three time cohorts.

Anita D'Souza et al. JCO doi:10.1200/JCO.2015.62.4015


Trends in (A) overall survival (OS) for cardiac light-chain amyloidosis (AL); (B) OS for renal, noncardiac AL; (C) early mortality (EM) based on center experience; and (D) time trends in

improvement in EM among centers.

Anita D'Souza et al. JCO doi:10.1200/JCO.2015.62.4015



Chemotherapy

• Chemotherapy approaches have evolved overtime

• Melphalan‐Dexamethasone has been astandard for a long time

• Bortezomib‐based regimens are associated todeep and rapid responses, and represent anew standard

• CyBorD (Cyclophosphamide‐Bortezomib‐Dexamethasone) is the regimen of choice

Survival of 230 patients with AL amyloidosis treated with CyBorD.

Giovanni Palladini et al. Blood 2015;126:612-615


Transplant vs chemotherapy

• Transplant:

‐ pro: Deeper responses, long follow up

‐ con: high mortality rate

• Modern chemotherapy regimens:

‐ deep responses, low mortality

‐ durability of responses unknown


Mayo clinic algorith for AL amyloidosis management

Chemotherapy options for relapsed amyloidosis

• Ongoing clinical trials (relapse):

‐ Carfilzomib

‐ Izaxomib

‐ Bendamustine‐Dexamethasone

‐ Daratumumab

Novel approaches targeting the amyloid fibrils

• Chemotherapy: Daratumumab

• Anti amyloid agents:

‐ disruptors of amyloid fibrils: Doxicylin

‐ monoclonal antibodies targeting SAP, acomponent of the amyloid fibril

‐ NEOD001


Potential NEOD001 MOAs: Neutralizes Soluble Amyloid and Clears Insoluble Amyloid

1. Plasma cells overproduce lightchainsthat misfold, aggregate and become toxic amyloid

31

2. NEOD001neutralizes and disaggregatescirculating solubleamyloid

3. NEOD001 clears deposited insoluble amyloid by inducing macrophages to clear amyloid through phagocytosis

4. NEOD001recycled to continue neutralizing circulatingsoluble amyloid andclearing deposited insoluble amyloid

NEOD001 Phase 1/2 Trial Design

Primary objectives• Evaluate the safety and tolerability of NEOD001

(NCT01707264)• Determine MTD or recommended dose for future clinical study

of NEOD001

Secondary objectives

Exploratory objective • Evaluate organ response (eg, NT-proBNP, proteinuria)

• Evaluate the serum PK of NEOD001

• Assess the immunogenicity of NEOD001

Expansion phase

Additional patients with

cardiac, renal, and/or

peripheral neuropathy involvement

Multiple ascending dose (3+3)•27 patients with AL amyloidosis•Prior PC directed treatment and ongoing organ dysfunction•7 cohorts; IV q28 days; determine MTD/RP3D

†Maximum of 2500 mg per dose permitted – 24 mg/kg selected based on patient body weight

24 mg/kg†

16 mg/kg

8 mg/kg

4 mg/kg

0.5 mg/kg

1 mg/kg

2 mg/kg

IV, intravenous; MTD, maximum tolerated dose; NT-proBNP, N-terminal pro-brainnatriuretic peptide; PC, plasma cell; PK, pharmacokinetics; RP3D, recommendedphase 3 dose.

5 Unaudited interim data as of 2/28/15

Cardiac Biomarker ResponseBest Response Analysis

–90 –90

For patients with baseline NT-proBNP ≥650 pg/mL without progressive renal dysfunction1

•Response: >30% and 300 pg/mL decrease in NT-proBNP•Progression: >30% and 300 pg/mL increase in NT-proBNP•Stable disease: neither response nor progression

Evaluable (N = 14)8 responders

(57%)6 stable (43%)

All Patients (N = 27)

–60

–30

0

30

60

90

NT-

pro

BN

P%C

ha

ng

efr

om

bas

elin

e

–60

1. Comenzo R et al, 2012; Palladini et al, 2012.Unaudited interim data as of 2/28/15

11

–30

0

30

60

90

NT-

pro

BN

PC

ha

ng

efr

om

B

as

eli

ne

%


Renal Biomarker ResponseBest Response Analysis

For patients with baseline proteinuria ≥0.5 g/24 hours1

• Response: >30% decrease in proteinuria or a decrease in proteinuria to <0.5 g/24 hours inthe absence of renal progression

• Progression: >25% worsening in eGFR• Stable disease: neither response nor progression

All Patients (N =24)

Evaluable (N = 15)9 responders (60%)

6 stable (40%)100

80

60

40

20

0

–20

–40

–60

–80

–100

Pro

tein

uri

a

%C

ha

ng

efr

om

Ba

se

lin

e 100

80

60

40

20

0

–20

–40

–60

–80

–100

1. Palladini et al. 2014.Unaudited interim data as of 2/28/1513

Pro

tein

uri

afr

om

Ba

se

lin

e%

Ch

an

ge

Baseline NT-proBNP = 3312 Best NT-proBNP = 1275 (-61.5%)Time since last hematologic response = 9.63 months

Patient Case ProfilesImproved and Sustained Response Over Time

Cardiac Renal

Baseline protein = 5129Best protein level= 1241 (-76%)Time since last hematologic response = 40.33 months

60 60

30 30

0 0

–30 – 30

–60 – 60

–90 – 900 2 4 6 8 10 12 14 16 18

NEOD001 Treatment, month

90 90120403

%C

han

ge

inB

ase

line

0 2 4 6 8 10 12 14

NEOD001 Treatment, month

110601

35 Unaudited interim data as of 2/28/15

Phase 3: The Vital Study (NCT02312206)Patients must be treatment naive and have a confirmed diagnosis of AL amyloidosis with cardiac involvement

Eligibility Criteria• ≥18 years old• Treatment naive• Confirmed new diagnosis of

AL amyloidosis• Cardiac involvement

• NT-proBNP ≥650 pg/mL

Key Exclusion Criteria

• Non-AL amyloidosis

• Diagnostic criteria for symptomatic multiplemyeloma

• NT-proBNP >8500 pg/mL Primary end point: Time to composite of all-cause mortality or cardiac hospitalizationKey Secondary end points: SF-36 (QoL), 6MWT, cardiac, renal, nerve, and hepatic response

N = 236

NEOD001 (24 mg/kg IV) + SOCn = 118

Placebo (normal saline IV) + SOCn = 118

Every 28 days for up to 42 monthsEvent-based timeline

QoL, quality of life; 6MWT, Six-Minute Walk Test.


Conclusions

• diagnostic accuracy is essential

• novel prognostic scores

• therapy:

‐ chemotherapy approaches

‐ transplant

• novel anti amyloidosis agents:

‐ agents destabilizing amyloid fibrils: doxicyclin

‐ monoclonal antibodies: NED001

Utah Amyloidosis Program

Services

1. Hematology - Chemotherapy and Stem Cell Transplant

2. Cardiology - Heart Failure

3. Nephrology - Renal Failure

4. Neurology - Polyneuropathy

Regional Referral Center



Hematology Review

Acute Leukemias

Paul Shami, MD


Acute Leukemias

Paul J. Shami, M.D.

Division of Hematology and Hematologic Malignancies

Huntsman Cancer Center

University of Utah

Outline

• AML drugs approved in 2017:

- Midostaurin

- Liposomal Daunorubicin/Cytarabine (CPX-351)

- Gemtuzumab Ozogamicin

- Enasidenib

• ALL drug approved in 2017:

- Inotuzumab Ozogamicin

Acute Myeloid Leukemia- 21,380 new cases in 2017.- 10,590 deaths in 2017.- 26.9% 5-year survival.- Disease involving mainly middle aged and elderly.

- Therapeutic backbone of cytarabine/anthracyclinedeveloped around 40 years ago.

- Transplant limited to a minority of patients- Hypomethylating agents for frail patients- Most of the therapeutic advances up to this point were

due to improved supportive care.

THINGS CHANGED IN 2017!


FLT3 Overview• Type III transmembrane receptor tyrosine kinase

– Other subfamily members include KIT, FMS, and PDGFR-α/ 1

• FLT3 is highly expressed on hematopoietic progenitors and is required for proliferation and differentiation of myeloid progenitorcell.

• Mutations in the FLT3 gene cause constitutive activation of the FLT3 receptor.

• ITD and TKD mutations are found in about 30% of AML patients.

• ITD mutations are associated with a worse prognosis.

Midostaurin

• Multikinase inhibitory activity.

• Targets include PKC, PDGFR, CDK1, KIT, VEGFR.

• Inhibitor of FLT-3.

• Synergy with cytotoxic chemotherapy.

• Phase Ib study established safety when combinedwith standard AML chemotherapy.

5/ M‐PKC‐


RATIFYPhase 3, Randomized, Double-Blind, Placebo-Controlled Study

Primary endpoint: OSSecondary endpoint: EFS

Postconsolidation(up to 12 cycles)

Midostaurin(50 mg bid, days 1-28)

Placebo(bid, days 1-28)

Cytarabine(200 mg/m2/day, days 1-7)

Daunorubicin(60 mg/m2/day, days 1-3)



Cytarabine(200 mg/m2/day, days 1-7)

Daunorubicin(60 mg/m2/day, days 1-3)

High-dose cytarabine

(3 g/m2/day q12h, days 1, 3, and 5)

Consolidation(4 cycles)


High-dosecytarabine

(3 g/m2/day q12h, days 1, 3, and 5)


Induction(1-2 cycles) CR CR

R

Patients with newly diagnosed AML

aged≥ 18 to < 60 years

with activating FLT3mutationsa,b

Stratification by TKD and ITD

(ratio < 0.7 vs ≥ 0.7)

(N = 717)

Stone RM et al. N Engl J Med 2017;377:454‐464.

Summary of Grade 3, 4, or 5 Adverse Events.

Stone RM et al. N Engl J Med 2017;377:454‐464.

Overall Survival.


Midostaurin• OS of 51.4% vs. 44.3% (P = 0.009).

• Benefit with FLT3 low and high ITD ratio.

• Post-transplant survival was marginally better (P =0.07).

• Greater benefit in men vs. women.

• Approved in 2017 in combination withchemotherapy for FLT-3 mutated AML

• Need rapid screen to make treatment decision.

• Effect of NPM1 mutations.

CPX‐351

• Cytarabine:Daunorubicin molar ratios of 1:1 to10:1 are synergistic.

• Liposomal formulation of Cytarabine:Daunorubicinat a fixed ratio of 5:1.

• Enhanced drug concentration in the bone marrowand drug uptake by AML cells.

• Elimination T1/2 for Daunorubicin and Cytarabine of25 and 37 hours, respectively.

CPX‐351


CPX‐351

CPX‐351• Higher CR rate than 7+3 (47.7 vs. 33.3%) in patients with

antecedent hematologic disorders or t-AML.• Higher OSrate than 7+3 (9.56 vs. 5.95 months) in patients

with antecedent hematologic disorders or t-AML.• Longer cytopenias than 7+3.• FDA-approved for t-AML and AML with MDS-related

changes.• Younger patients and t-AML were not studied in the pivotal

trial.• Morphologic definition of MLD is subjective to a certain

extent.• Cytogenetic information may not be available at the time

of treatment decision.

Gemtuzumab Ozogamicin (GO)

• Antibody drug conjugate, directed at CD33 and linked to calicheamycin.

• Approved in 2000 for relapsed AML in olderpatients.

• Drug taken off in 2010 after findings in a SWOG randomized trial.

• European studies completed after withdrawalshowed benefit in subgroups of patients.


ALFA-0701 trial

• Phase 3 trial of the ALFA group in patients 55‐70.

• N=280.

• Design: patients with de novo AML randomized to 7+3 ± fractionated GO.

• Study showed same response rate but lowerrelapse risk in GO arm, especially in patients withfavorable risk AML (CBF AML).

Castaigne et al, Lancet 379:1508, 2012

ALFA-0701 trial

Castaigne et al, Lancet 379:1508, 2012

Hills meta-analysis

• Meta‐analysis of 4 randomized trials.

• GO in newly diagnosed AML in combination withchemotherapy.

• N=3325.

• Findings:

‐ the optimal dose of Mylotarg is 3 mg, in single or fractionated doses.

‐ CR rate is not increased but relapse risk is reduced.

‐ maximal benefit observed in favorable risk AML.

Hills et al, Lancet Oncol 15:986, 2014



Hills meta-analysis


Overall survival according to cytogenetic risk category

Gemtuzumab Ozogamicin (GO)• Only 50% of the calicheamicin payload is conjugated to the

Ab, raising concerns about toxicity and competition betweenunconjugated Ab and conjugated Ab.

• VOD is a concern, particularly if given close to transplant.

• Fractionated dosing improves safety profile withoutcompromising efficacy.

• FDA re‐approved the drug at a lower fractionated dose in 2017 with a broad spectrum of indications (newly diagnosed,R/R, combined with chemotherapy, single agent.

• Dosing and safety of fractionated GO in combination withHiDAC consolidation regimens needs to be established.


• IDH1 and IDH2 are enzymes of the citric acid cycle.

• Mutant IDH1 and IDH2 (mIDH1 and mIDH2) occurs in 8 and 12% ofpatients with AML.

• Result is production of 2-HG, which alters DNA methylation and leadsto a block in cellular differentiation.

• Enasidenib (AG-221) is a selective, oral, potent inhibitor of mIDH2 enzyme.

• Enasidenib induces differentiation of leukemic cells.

Isocitrate Dehydrogenase (IDH) Mutations as a Target in AML

22

EnasidenibPhase 1/2 Study Design

• Patients with relapsed/refractory AML (239) and mIDH2.

• Dose range of 50 – 650 mg/day.

• Dose of 100 mg/day selected for expansion cohort.

• Generally well tolerated.

• Grade 3 – 4 AEs included hyperbilirubinemia (12%).

• Differentiation syndrome (7%).

Stein et al, Blood 130(6):722; 2017

EnasidenibPhase 1/2 Study Design

• CR/CRi 26.6%.

• PR and morphologic leukemia-free state 12%.

• Median duration of response of 5.6 months.

• Overall Survival of 9.3 months.

• OS of 19.7 months if CR achieved.

• No marrow aplasia observed.



Evolution of response during treatment of responding patients (n = 71).

Eytan M. Stein et al. Blood 2017;130:722-731


Morphologic evidence of myeloid differentiation during enasidenib treatment.



Mean (± standard error) platelet count, absolute neutrophil count, hemoglobin, and bone marrow blasts over time in patients with relapsed/refractory AML treated with enasidenib.




Overall survival.



Enasidenib

• Differentiation rather than cytotoxic effect.

• Prolonged time for optimal response.

• Differentiation syndrome – Treat promptly with steroids.

• FDA approved in 2017 for R/R AML with mIDH2.

• Role in the first-line setting to be determined.


Venetoclax

• BCL2 inhibitor with modest single agent activity in AML (19% CR/CRi).

• Combined with hypomethylating agents or low dose cytarabine in elderly patients who are not eligible for intensive therapy.

• CR/CRi of 62 – 68%.

• 12-months survival of 50 – 70%.

• NOT FDA approved for this indication.

• Stay tuned.


AML 2018

• No longer one size fits all.

• Choices of therapies depending on multiple factors: history, chromosomal rearrangement, molecular findings.

• It is critically important to obtained comprehensive chromosomal and molecular studies in a timely fashion.

• More agents are coming.

• Cost of newly approved agents is a significant issue.

• Optimal management of MRD is still an open question.

AMLNCCN 2017

AML- NCCN 2018


Newly Diagnosed non-APL AML Fit for InductionHCI 2018

• Obtain molecular studies as soon as possible.

• Clinical trial preferred.

• CBF leukemia: Chemotherapy + GO.

• FLT3-mutated AML: Chemotherapy + Midostaurin followed by transplant if feasible.

• Secondary AML: CPX-351 followed by transplant if feasible.

ALLInotuzumab Ozogamicin (IO)

• CD22 is expressed on 90% of B-cell ALL cells.

• IO is a humanized anti-CD22 antibody conjugated to Calicheamicin.

• Adults (326) with R/R B-cell ALL randomize to IO vs. standard intensive chemotherapy.

• CR rate of 80.7% vs. 29.4% (P < 0.001).

• Median PFS of 5.0 vs. 1.8 months (P < 0.001).

• Median OS of 7.7 vs. 6.7 months (P = 0.04).

• VOD of 11% vs 1%.

• FDA approved in 2017 for R/R B-cell ALL.

Kantarjian et al, NEJM 375:740; 2016

Acute LeukemiaNursing Considerations

• It will often take longer to make treatment decisions for AML.

• Patients may be sent home without therapy pending results of molecular studies.

• During that time more intensive outpatient monitoring will be required with interventions that could include transfusions. During that time watch for any indication to re-admit the patient, especially infections (fever, etc…) and bleeding.

• Watch for liver toxicity, particularly VOD (abnormal liver function tests, jaundice, weight gain, ascites) with GO and IO.

• Watch for differentiation syndrome with enasidenib (fever, SOB, oxygen requirement).

• CPX-351 is associated with longer cytopenias than standard 7+3.


Suggested Reading

• Wei AH and Tiong IS. Blood 130(23):2469-2474;2017.

• Kantarjian et al. NEJM 375(8):740-753, 2016.

Acknowledgement

• Tibor Kovacsovics



Hematology Review

Cancer Survivorship

Paul Thielking, MD Rachel Montague, APRN, FNP-C

Brighton Loveday, APRN, ANP-BC Jaclyn Piper-Williams, APRN, FNP-C


Cancer SurvivorshipHCI Supportive Oncology & Survivorship Team

Paul Thielking, MD Brighton Loveday, APRN, ANP‐BCRachel Montague, APRN, FNP‐C Jaclyn Piper‐Williams, APRN, FNP‐C

HCH Supportive Oncology Team

Learning Objectives

Upon completion of this presentation, participants will be able to:

Identify the members and role of the Supportive Oncology team here at HCH

Define “survivorship” in cancer patients, with particular attention to those with hematologic cancers

Discuss the role of a Survivorship Care Plan

Describe the complex medical and psychosocial needs of survivors and ways to attend to those needs

Discuss some of the most common sequelae of cancer treatment


Survivorship – Who are “survivors”

National Coalition for Cancer Survivorship4

– Starting at the point of diagnosis and for the balance of life

ASCO Functional Definition3

– Individuals who have successfully completed curative treatment or those who have transitioned to maintenance or prophylactictherapy (acute, extended, permanent)

NCI & NCCN (National Comprehensive Cancer Network)6

– An individual is considered a cancer survivor from the time of diagnosis through the balance of his or her life. Family members, friends, and caregivers are also impacted.

Survivorship – Who are “survivors”

American Cancer Society1

Any person with a history of cancer, from the time of diagnosis through the remainder of their life

Three phases of “survival”: Time from diagnosis to end of initial treatment

Transition from treatment to extended survival

Long‐term survival

Encompasses a range of cancer experiences and trajectories

May be difficult to define in hematologic cancers where the “treatment” phase is more long‐term…

American Cancer Society, 2016


Survivorship ‐ What

Primary or secondary cancer prevention

Surveillance for cancer recurrence

Health promotion (intervention)

Symptom management of common and long‐term late effects (coordination)

Assessment of late psychosocial and medicaleffects

Survivorship ‐ Where

• Everywhere!

• Clinical settings – outpatient, inpatient,community

• Primary oncology team responsible forproviding Survivorship Care Plan which is thensupplied to community based care teams (PCP,specialists, etc)

• Once completed, found under “TreatmentSummary” in Problem List in EPIC

Survivorship ‐ When

Defined time period group specific

Generally within first year followingcompletion of treatment and transitioning into “surveillance” or “remission” phase

Acute/initial, extended, long‐term


Survivorship ‐ Why

As of January 1, 2016, more than 15.5 million cancer survivors in the U.S.1

– Expected to be 20.3 million by 2026– More than the populations of NYC, Houston, and Chicago combined

Longer lifespans, increasing survival rates At least 50% of survivors suffer late effects of cancer –

most commonly pain, depression, fatigue Survivors are remarkably resilient, but may have to

make physical, emotional, social, and spiritual adjustments to their lifestyle – in other words, to find a “new normal.”

Survivorship ‐ Why

Quality of life (QOL) is a broad multidimensional concept that considers a person’s physical, emotional, social, and spiritual well‐being

Individuals who have a history of more invasive and aggressive treatments tend to report poorer functioning and QOL

Healthy behaviors hugely important for survivors –nutrition, physical activity, smoking cessation, etc

Cancer not only affects survivors but also their family members and close friends

Role of Survivorship Care Plans

In 2006, IOM issued a report recommending that every cancer patient receive an individualized plan1

American College of Surgeons sets standards for percentage of delivered survivorship care plans – current goal is >50% ofeligible patients (reduced from 75%)2

Designed to provide patients and their clinicians with a treatment summary, information about possible late and long‐term effects, follow‐up care/surveillance guidelines,recommendations for healthy living, delineation of oncologist/PCP roles and timing of transfer of care if needed, and identification of supportive resources3


Example of Survivorship Care Plan

NCCN, 2018

References1. American Cancer Society. Cancer Treatment & Survivorship Facts & Figures 2016‐

2017. Atlanta: American Cancer Society; 2016.2. American College of Surgeons. (2017, December 13). Important information

regarding CoC Survivorship Care Plan Standard. Retrieved fromhttps://www.facs.org/quality‐programs/cancer/news/survivorship.

3. American Society of Clinical Oncology. (2018). About survivorship. Retrieved fromhttps://www.cancer.net/survivorship/about‐survivorship.

4. Center for Disease Control and Prevention. (2017). Cancer Survivorship. Retrieved from http://www.cdc.gov/cancer/survivorship/.

5. National Coalition for Cancer Survivorship. (2018). https://www.canceradvocacy.org/.

6. National Comprehensive Cancer Network. (2018). NCCN guidelines version 2.2017 survivorship. Retrievedhttps://www.nccn.org/professionals/physician_gls/pdf/survivorship.pdf.

7. Taylor, K., DipOnc, G., & Monterosso, L. (2015, May). Survivorship Care Plans and Treatment Summaries in Adult Patients With Hematologic Cancer: An Integrative Literature Review. In Oncology nursing forum (Vol. 42, No. 3).

Depression

and

Anxiety


Depression ‐ Prevalence1,2

Depression ‐ (DSM‐IV)3

Five or more of the following symptoms during a2‐week period with a change in functioning. Atleast one of the symptoms of either depressedmood or loss of interest/pleasure

– Depressed mood– Diminished interest– Weight loss/gain or appetite changes– Insomnia/hypersomnia– Psychomotor agitation/retardation– Fatigue/ loss of energy– Feelings of worthlessness/guilt– Diminished ability to think/concentrate– Recurrent thoughts of death

Depression ‐ Diagnosis4

“Exclusive” approaches attempt to exclude symptoms that overlap with physical illness such as fatigue or weight loss. Endicott proposed focusing on hopelessness, helplessness, worthlessness, guilt instead of somatic symptoms in cancer patients.

Anhedonia could be due to decreased functional status

Inclusive approaches include all symptoms in DSM. Risk of over‐diagnosis of depression in medically ill is small.

Benefits of treatment outweigh risks associated withfailure to treat.


Depression ‐ Assessment 1,4

Instruments validated and used often inmedically ill Hospital Anxiety and Depression Scale Patient Health Questionnaire (PHQ‐9) Single item “are you depressed?”

Two item “have you been depressed, and haveyou lost interest or pleasure?”

Beck Depression Inventory Hamilton Depression Scale

Depression ‐ Treatment1,5,6

Challenging if life expectancy is limited

Psychotherapy

Individual, Group, Family

Depression ‐ SSRIs

Paroxetine

Fluoxetine

Sertraline

Citalopram

Escitalopram


Depression ‐ SNRIs

Venlafaxine

Duloxetine

Depression ‐ Atypical Antidepressants

Buproprion

Mirtazapine

Olanzapine

Ketamine

Depression‐Tricyclic Antidepressants

Desipramine

Nortriptyline

Amitriptyline

Imipramine


Psychostimulants7

Methylphenidate is most commonly prescribed.

Augmentation therapy for depression

Counteracts sedation associated with opioid use.

CNS malignancies – may enhance cognitivefunction, stamina, motivation.

May help fatigue with neurodegenerativediseases and HIV.

Psychostimulants5,7

Methylphenidate is most commonly prescribed.

Augmentation therapy for depression

Counteracts sedation associated with opioid use.

CNS malignancies – may enhance cognitivefunction, stamina, motivation.

May help fatigue with neurodegenerativediseases and HIV.

Prognosis < 6 Months5

*Consider referral to psychiatrist if patient has suicidal ideation, treatment resistant depression, diagnostic uncertainty


Prognosis > 6 Months5

*patient preference, prior response to meds, primary relative response to meds, anticipated side effects, co‐occurring conditions, potential drug interactions, cost.**augmenting options include bupropion (Wellbutrin), buspirone (Buspar), T3 (Cytomel), lithium.

Anxiety8

Symptoms thought to occur in up to 70% ofmedically ill patients

Adjustment Disorder, Panic Disorder, GeneralizedAnxiety Disorder, PTSD most common

Distress may be related to physical, psychological,social, spiritual, practical, end‐of‐life, and lossissues

Fear of uncontrolled symptoms or dependency

Anxiety ‐ Treatment

Care Tenor Treating patients with compassion, respect, dignity.

Compassionate, patient‐centered care Frequent meetings with team, opportunity to be involved in decisions, information about diagnosis and prognosis, psychological support for patient and family

Combination of pharmacologic and non‐pharmacologic approaches usually is mosteffective


Anxiety ‐ Psychotherapy

Psychotherapies for Anxiety Supportive psychotherapy (emphatic, compassionate, non‐judgmental listening) CBT (focus on modifying dysfunctional thoughts, feelings, behaviors) Interpersonal Therapy (focus on role of social dysfunction in creating or maintaining distress)

Psychotherapies for Palliative Care Managing Cancer and Living Meaningfully (CALM) Dignity Therapy (Chochinov) Meaning Centered Therapy (Breitbart)

Anxiety ‐ Complementary Therapies

Music Therapy

Relaxation Training

Acupuncture

Meditation

Mind Body Skills Group

Aromatherapy

Massage

Art Therapy

Anxiety ‐ Other Interventions

Exercise

Decreased caffeine and alcohol consumption

Sleep hygiene

Psycho‐education


Anxiety ‐ Pharmacologic Interventions

SSRIs are drug of choice

SNRIs

Neuropathic Pain

Mirtazapine

Sedating

Buspirone


Benzodiazepines– Very short acting

• Midazolam 0.5‐5 mg/hr infusion

– Short acting • Lorazepam 0.5‐2 mg bid PO, SL, IV, IM

– Intermediate • Chlordiazepoxide 10‐50 mg tid‐qid PO, IM

– Long Acting • Clonazepam 0.25‐3 mg qd‐bid PO.

• Diazepam 2‐10 mg qd‐bid PO, IV, IM, PR


Other Anxiolytics

– Trazodone 25 mg q 1 hr, NTE 500 mg in 24 hr

– Gabapentin 100 mg q 1 hr, NTE 3600 mg in 24 hr

– Hydroxyzine 25‐100 mg q 6 hrs

– Lyrica


References

1. Ali Abbas AA, Wagle KC, et al. Depression in terminally ill patients: dilemmas in diagnosis and treatment. Journal of Pain and Symptom Management. May, 2013. 45(5);926‐933

2. Walker J, Hansen CH, et al. Prevalence of depression in adults with cancer: a systematic review. Ann Oncol.2013;24(4):895‐900.

3. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders.4th ed., 2000

4. Klopstein KG, Marin DB. How does one assess for psychiatric illness in patients with advanced disease? Evidence‐based practice of palliative medicine.2013. Chapter 35.176‐180.

5. Irwin SA, Block S. What treatments are effective for depression in the palliative care setting? Evidence Based Palliative Medicine. 2013. Chapter 33.

6. Strouse TB. Psychopharmacologic treatment of depression in patients with cancer: a 2013 update. FOCUS The Journal of Lifelong Learning in Psychiatry. Fall 2013; 482‐498.

7. Prommer E. Methylphenidate: established and expanding roles in symptoms management. American Journal of Hospice and Palliative Medicine. 2012;29(6:):483‐490.

8. Irwin SA, Montross, LP, Chochiov HM. What treatments are effective for anxiety in patients with serious illness? Evidence Based Palliative Medicine. 2013. Chapter 34.

Pain

Management

Part of a Bigger Picture

Majority of cancer patients will experience acutepain related to procedures, interventions, orcomplications

30‐50% of patients require opioid therapy forchronic pain during antineoplastic therapy, up to90% in those with advanced disease


Acetaminophen & NSAIDs

Effective for mild nociceptive or visceral cancer‐related pain

May be used as monotherapy, or in combinationwith opioids

Opioid‐sparing

NSAID contraindications: history of PUD, concurrent corticosteroid use, bleeding history,renal insufficiency, thrombocytopenia, orconcurrent anticoagulant use

NSAIDs Celecoxib

– Only available selective COX‐2 inhibitor in the US– Does not affect platelet aggregation, safer for concurrent anticoagulation or if

thrombocytopenic– ↓ GI toxicity, ↑ cardiovascular toxicity– May be cost‐prohibitive

Meloxicam– 7.5mg dose may be safely used with concurrent anticoagulation or

thrombocytopenia– Typically more affordable than celecoxib

Naproxen– ↓ Cardiovascular toxicity, ↑ GI toxicity– OTC and Rx strengths

* Consider addition of PPI for gastroprotection

Neuropathic Pain Gabapentinoids

– First line treatment in pts without co‐occurring depression– Pregabalin has simplified dosing but typically requires prior‐authorization– Gabapentin is typically less cost‐prohibitive, has large range of dosing– No known drug‐drug interactions– Most common side effects are somnolence and mental cloudiness

Duloxetine– Specifically studied in CIPN, analgesia noted at 30‐60mg daily– First line treatment if concurrent depression and CIPN– May be cost‐prohibitive

TCAs– Amitriptyline is least tolerated, has most bothersome side effect profile, ↑

anticholinergic– Nortriptyline and Desipramine have less side effects at lower doses– May also help with sleep– Affordable, on $4 drug list– Use with caution in elderly population


Topical Agents Diclofenac ‐ NSAID

– Voltaren gel 1%, must be applied 3‐4 times/daily• Best for localized nociceptive pain of superficial joints, non‐neuropathic

– Flector patch 1.3%, applied BID• Useful for musculoskeletal pain• May be cost‐prohibitive

Capsaicin– Derived from the chili pepper– Depletes substance P from afferent C fibers– Available OTC in cream or low‐dose patch– Weak to moderate analgesic effect for neuropathic pain– Most common side effect is burning at administration site

Lidocaine– 5% patches available with Rx only, may be cost‐prohibitive– 4% patches are OTC, more affordable– Available in creams, ointments, and gels for local pain relief, more affordable option– Weak evidence to support benefit for neuropathic pain– Clinical experience indicates modest benefit with limited side effects

Opioid Therapy

High dose = > 90mg OME Goal for gradual reduction of opioid therapy over time, due

to risks associated with chronic opioid use Opioids are first line for cancer‐related pain during active

cancer treatment, but not recommended for long‐term use Long‐term use is associated with fatigue, low testosterone,

immune suppression, dental problems due to decreased salivary gland production, physical and emotional dependence, addiction and opioid‐induced hyperalgesia.

Recommend use of adjunctive and alternative treatments in longer term survivorship

Opioid Therapy

Short‐acting opioids are indicated for acute painsyndromes– Tramadol, Norco, Morphine, Oxycodone, Hydromorphone

Long‐acting formulations are reserved forchronic management, not for first‐line therapy– MS Contin, Fentanyl Patch, OxyContin

– Cost may be prohibitive with certain agents

Consider move to long‐acting opioids if OME >90mg


Clinical Pearls

Avoid Morphine products with renal insufficiency– Oxycodone, Fentanyl, Hydromorphone safer options

Always consider adjunctive medications for opioid‐sparing benefits

Consideration for Interventional Pain evaluation– Neurolysis, corticosteroid injections, Intrathecal Pain Pump,

lidocaine infusion

Recommend regular Controlled Substance Database reviewof each patient, both in clinic and inpatient– Limit number of prescribers if possible

Always put your patients on a bowel regimen– Senna‐S and Miralax are first‐line agents

References

1. Portenoy, R. K., & MZ, A. E. (2010). Cancer pain management: General principles and risk management for patients receiving opioids. Uptodate.

2. Portenoy, R. K., Ahmed, E., & Keilson, Y. Y. (2012). Cancer pain management: use of acetaminophen and nonsteroidal anti‐inflammatory drugs. UpToDate, 18.

3. Portenoy, R. K., Ahmed, E., & Keilson, Y. Y. (2017). Cancer pain management: Adjuvant analgesics (coanalgesics). UpToDate.(Accessed on April 25, 2016.).

4. Portenoy, R. K., & Dhingra, L. K. (2017). Overview of cancer pain syndromes.

Cancer‐Related Fatigue

and

Wellness Services


Cancer‐Related Fatigue (CRF)

Fatigue is a common problem in cancer patients, both in those being actively treated and in cancer survivors.

CRF profoundly affects quality of life (QOL) of both patients and their families.

It is routinely identified by patients as one of the most distressing symptoms associated with cancer and its treatment.

Treatment of CRF is one of the major symptoms the supportive care focuses on.

Guidelines from Groups

ASCO Encourage all patient to engage in a moderate level of physical activity

after cancer treatment (eg, 150 minutes of moderate aerobic exercise such as fast walking, cycling, or swimming) per week with an additional 2‐3 strength training (such as wt. lifting) sessions per week unless contraindicated.

Walking programs are generally safe for most cancer survivors.

Survivors are at a higher risk of injury (those living with neuropathy, cardiomyopathy, or other long‐term effects of therapy) and patients with severe fatigue interfering with function should be referred to a PT or exercise specialist.

Guidelines from Groups

NCCN Provide information about patterns of fatigue during and after treatment (conservation, pacing, peak energy times).

Make use of local resources to increase exercise (Cancer centers, community programs focused on survivors).

For patients with fatigue interfering with function, consider referral to a physical therapist or physiatrist

Psychosocial interventions recommended (CBT, nutrition consultation, sleep hygiene, acupuncture, etc).

Consider psychostimulants


Impact on Quality of Life

Survivors of allo‐HSCT are at high risk for treatment‐related adverse events that may worsen physical capacity and may induce fatigue and disability.

Exercise capacity was reduced in most allo‐HSCT long‐term survivors1

– Because reduced exercise capacity was associated with fatigue, disability and decrease in QOL, recommendation was made for exercise testing in every patient who reports fatigue and disability.

1 Dirou, S., Chambellan, A., Chevallier, P., Germaud, P., Lamirault, G., Gourraud, P. A., ... & Peterlin, P. (2017).


Role of Exercise Programs

Supervised or prescribed exercise programs can reduce or reverse declines in physical fitness seen during and after medical treatment in cancer survivors2

Exercise programs increase strength, decrease fatigue.

Supervised exercise has been consistently shown to be safe in this population and is recommended by the National Comprehensive Cancer Network (NCCN) and the American College of Sports Medicine (ACSM) among others.

2 Marker, R. J., Cox‐Martin, E., Jankowski, C. M., Purcell, W. T., & Peters, J. C. (2017)

HCH Wellness Program ‐ Mission

To empower people affected by cancer to improve their quality of life, reduce treatment side effects, and increase strength for daily living through movement in a supportive atmosphere

HCH Wellness Program ‐ Overview

Physical assessments

Personalized exercise prescriptions

Supervised Individual training

Group Training sessions

Community‐based activities such as road biking, hiking, and

rowing

Many classes for patients, caregivers, and staff

Telemedicine Visits


Impact of Physical Activity

Improvements in: Fatigue Nausea Pain Insomnia/Sleep Depression Anxiety Quality of Life Emotional Wellbeing Cardiovascular Fitness Muscle Strength Body Composition And much more…

Mind‐Body Interventions

Mindfulness‐based stress reduction

Mind Body Skills Group here at Huntsman

Yoga

Acupuncture

Touch therapy, massage

Music therapy

Relaxation, Reiki and QiGong

Mindfulness‐Based Stress Reduction

There is evidence from randomized trials that mindfulness‐based approaches may relieve fatigue in cancer survivors.

In the largest trial, 229 women with early‐stage breast cancer after surgery, chemo, and radiotherapy were randomly assigned to an 8‐week program of mindfulness‐based stress reduction or usual care.

The intervention group had significant improvements at 8 wks.

3 Escalante, C.P. (2017)


Yoga

There is some evidence from randomizedtrials that mind‐body approaches such as yogamay improve sleep quality and fatigue.

– Four of the five trials have enrolled cancer survivors.

In the largest trial, 410 patients with breast cancer. After four weeks, yoga participants demonstrated greater improvements compared with baseline in global sleep quality, greater reduction in daytime dysfunction and reduced use of sleep medications.


Acupuncture

Benefits of acupuncture for CRF are unclear.

Major problem with interpreting study results is the lack of a sham acupuncture control group; at least in the setting of non‐cancer disease such as chronic pain, both acupuncture and sham acupuncture have been shown to have much greater efficacy than no treatment – suggesting a strong placebo effect.

Benefit from acupuncture has been suggested in at least four randomized trials, some conducted in cancer survivors and some in patients receiving active treatment.


Acupuncture

In the largest trial, 302 patients with non‐metastatic breast cancer who completed chemotherapy and were experiencing at least moderate fatigue were randomly assigned to usual care with and without acupuncture.– The usual care received a booklet with info about fatigue and its

management, while the acupuncture group received both the booklet and a once weekly treatment by an acupuncturist for 6 weeks.

– Acupuncture was of significant benefit, with an estimated difference in the week 6 general fatigue score and also significantly improved other fatigue aspects including physical and mental fatigue, anxiety and depression, and QOL.



Pharmacologic Management

For patients with severe fatigue during cancer therapy in whom non‐pharmacologic methods are not helpful, and anemia and other medical conditions and symptoms causing fatigue are controlled, a therapeutic trial of a psychostimulant or other wakefulness agent is suggested.– Methylphenidate, dexmethylphenidate, modafinil

Benefit for psychostimulants in patients with CRF was suggested in a year 2010 Cochrane review of five trials(four used methylphenidate).– There was a small but statistically significant improvement in

fatigue score relative to placebo.

References

1. Dirou, S., Chambellan, A., Chevallier, P., Germaud, P., Lamirault, G., Gourraud, P. A., ... & Peterlin, P. (2017). Deconditioning, fatigue and impaired quality of life in long‐term survivors after allogeneic hematopoietic stem cell transplantation. Bone marrow transplantation, 1.

2. Marker, R. J., Cox‐Martin, E., Jankowski, C. M., Purcell, W. T., & Peters, J. C. (2017). Evaluation of the effects of a clinically implemented exercise program on physical fitness, fatigue, and depression in cancer survivors. Supportive Care in Cancer, 1‐9.

3. Escalante, C.P. Cancer‐related fatigue:Treatment. 2017 December. Retrieved on 2/1/18 fromUpToDate; https://www.uptodate.com/contents/cancer‐related‐fatigue‐treatment

Understand all of our patients are at high risk for depression,

anxiety, pain, sleep disturbances, anorexia, fatigue, and many more

challenges throughout the course of cancer treatment and into

survivorship. Be sure to frequently assess not only the physical but

also the mental, emotional, and spiritual well‐being of your

patients and their families.

Encourage patients to explore services of the Wellness Center for

Power Program, complementary therapies, and other modalities

for ensuring quality of life. There are many here at HCH!

Feel free to contact SOS, both inpatient and outpatient, for

additional support with symptom management and coping needs

Nursing Considerations


Thank you!



Hematology Review

Differential Diagnosis of Polycythemias and New Clinical

Data on Ph-negative MPNs

Josef Prchal, MD


Differential Diagnosis of Polycythemias and new clinical data on Ph-negative MPNs.

Josef Prchal and Tsewang Tashi, University of Utah, Salt Lake City

Josef T. Prchal – Conflict of Interest

• Advisory Boards:

Agios ‐ “Therapy of Pyruvate Kinase Deficiency”. Not related to this topic

Ctibiopharma–” Phase 2 Study of Pacritinib, JAK2 inhibitor”. Will not discuss here.

Classification of Polycythemias/Erythrocytoses• Primary Polycythemias

• Due to acquired or congenital mutations expressed within hematopoietic progenitors causing increased proliferation/decreased apoptosis

Polycythemia Vera ‐acquiredPrimary Familial and Congenital Polycythemia (PFCP)‐inherited, autosomal dominant

• Secondary PolycythemiasDue to circulating factors driving erythropoiesis, e.g., erythropoietin

Hemoglobin mutations, 2,3 BPG deficiency

• Chuvash Polycythemia—inherited hypoxia sensing defects(& HIF2a and PHD2)

• Acquired Compensatory Physiological “Polycythemia”; in contrast natives of high altitude developing genetic determinants permitting adaptation to extreme hypoxia; Tibetans & Ethiopians versus Andean natives(Quechua and Aymara).


Primary Polycythemias‐Proliferative Defect of Erythroid Progenitors

• The progenitor cell (bone marrow or peripheralblood) undergo serial divisions which result in aformation of a colony, composed of lineage(s)specific, recognizable cells.

Prchal JF & Axelrad A, NEJM,1976

Sensitivity of BFU‐E to Epo

0%

25%

50%

75%

100%

0 30 60 125 250 3000

EPO (mU/ml)

PV (EEC)

PFCP

Normal

EEC

Primary Familial and Congenital Polycythemia

• Autosomal dominant inheritance

• Low serum EPO (lower than PV)

• Polyclonal hematopoiesis

• No transformation to MDS or acute leukemia

• Usually no splenomegaly

• Normal WBC, platelets, chromosomes

• Most misdiagnosed as PV

• In ~30% families denovo mutation

• ? increased thrombosis independent of Hct

Prchal&Goldwasser Blood1971,Emanuel et al Blood 1992, Sokol Exp Hemat1993, dela Chapelle PNAS 1993, SokolBlood 1995


STAT-5

Erythropoietin Receptor (EPOR)Primary familial and congenital polycythemia (PFCP)

STAT-5 HCPNegative Regulatory Domain

HCP

PO4 PO4

HCP

JAK-2 JAK-2

Secondary Polycythemias/ErythrocytosesHigh oxygen affinity hemoglobins and low 2,3DPG

Hb Oxygen Dissociation CurveHigh and Low Affinity Hbs

• Polycythemia associated Hbs

• Different phenotypes associated w:– Alpha globin– Beta globin– Gamma globin mutations

• Easy screen for from venous blood: N. Agarwal:Int J Med Sci. 2007 Oct 4;4(4):232-6

If you cannot get Hb/O2 dissociation curve

• ANNALS OF INTERNAL MEDICINE: ORIGINAL RESEARCH |1 MAY 1976

• Detection of Mutant Hemoglobins with Altered Affinity for Oxygen: ASimplified Technique

• MARSHALL A. LICHTMAN, M.D.; MARION S. MURPHY, B.S.; JOHN W.ADAMSON, M.D.

pO2(venous) 65

pH(venous) 7.378

sO2(venous) 89.8

p50= 28.32

Original Formula Converted by Excel


Hypoxia Sensing• EPO expression upregulated by hypoxia ~300

• HRE (Hypoxia Responsive element): oligo 16‐merGCCCTACGTGCTGTCTCACACAGCCTGTCTGACCICTCGACCTACCGGCC

• Many HRE in the genomes

• HIFs (Hypoxia Inducible Factors) ; HIF‐1, HIF‐2, HIF‐3

• Bind to HRE

• HIFs- dimers of hypoxia responsive) a and b

subunits

• HIF-1 ubiquitously expressed

• ~3% of genes controlled by HIF-1

• HIF-2 -tissue specific expression

Hypoxia Sensing

Hypoxia

HIF-1

CGTG

HIF -1HIF-1

EPO

VEGF

Glut1, PGK

Transferrin

…VHL

Normoxia

O2 O2

O2

O2

O2O2

OH

HIF-1

Pro.H

Fe

Degradation

HIF-1

Chuvash Polycythemia

• >100 pts with endemic polycythemia, most previously diagnosed and treated as PV

• Sib-pair analysis • 79 families, 339 siblings• 111 affected siblingsautosomal recessive inheritance

• Polyakovaʼs thesis rejected because of use of genetic methodology in then Soviet Union

• My lab: high EPO, normal p50, no linkage with EPO & EPOR

Lydia AndreyevnaPolyakova, MDDoctoral Thesis, 1977 Chuvash State UniversityCheboksary, Russia


Molecular Basis of Chuvash Polycythemia

VHLR200W Homozygosity

Up regulated HIF1 and HIF2 in normoxia

mortality- CVA- thrombosis- trauma (?bleed)- other

VHL Syndr. tumors- No evidence

Clinical picture‐ systemic BaP‐ pulmonary pressure‐ glucose levels‐ varicose veins‐ benign vertebral hemangiomas‐ silent cerebral ischemia‐ major thromboses and bleeding

Thrombosis and MortalityCP vs. Controls

a. b.


Phlebotomy Rx and Thrombosis in CP patients

• Enrollment• No phlebotomy: n = 27

• Remote phlebotomy: n = 36

• Phlebotomy past year: n = 65

• Follow‐up• Independent predictors of new thrombosis: age, gender, past thrombosis, Remote and recent phlebotomy

Hazards Ratio 2.0, 95% CI1.0 ‐ 4.0, P = 0.040

HIF2A M535V (EPAS1 A2019G) mutation family pedigree

HIF2A M535V(EAPS1 A2019G )

21yr stroke MI 27yr Spleen 29yr

Cerebral palsy

44yr stroke

+70sHeart failure

NR Acquired polycythemia

by smoking

PR NR PR MI 70+

NRPR 70+ Budd‐Chairi (+)

NR

Zhengping Zhuang, M.D., Ph.D., Chunzhang Yang, Ph.D.,

Felipe Lorenzo, M.D., Ph.D., Josef T. Prchal*, M.D., and Karel Pacak*, M.D., Ph.D.,

D.Sc.N Engl J Med 2012; 367:922-930

Peptide Sequencing in Samples Obtained from the Patients.

HIF2A (EPAS1) mutations in tumors

BUT NOT IN

Blood, mucosal, urine (renal), skin DNA. genetic mosaicism

Over 100 similar patients described with different EPAS1 (gain-of function mutaions

HIF2A (EPAS1) Gain-of-Function Mutations in

Pheochromocytomas/Paragangliomawith Congenital Polycythemia


Classical Myeloproliferative Disorders-Neoplasms(MPN)

• Chronic Myelogenous Leukemia -

increased leukocytes

• Polycythemia Vera- increased

erythrocytes; most common MPD

• Primary Myelofibrosis (PMF)-

variable increased or decreased

blood cells

• Essential Thrombocythemia-

increased platelets

• Acquired mutation in a

hematopoietic stem cell

• Clonal hematopoiesis

• Variable proliferation of

granulocytes, red cells and/or

platelets

• Variable rate of transformation to

incurable acute leukemias

2016 revised WHO classification for Myeloid Malignancies

Acute

Chronic

Acute Myeloid Leukemia

Myelodysplastic Syndromes

MPN/MDS

Myeloid/Lymphoid neoplasms associated with eosinophilia and with PDGFRa,PDGFRb,FGFR1 or

PCM1‐JAK2

Myeloproliferative Neoplasms

Mastocytosis

• Chronic Myeloid Leukemia (CML)• Chronic Neutrophilic Leukemia (CNL)• Polycythemia Vera (PV)• Essential Thrombocythemia (ET)• Primary Myelofibrosis

• Pre‐fibrotic – early stage• Overt fibrotic stage

• Chronic Eosinophilic Leukemia, NOS• MPN ‐ Unclassifiable

Arber D et al, Blood, 2016

Chronic Myelogenous Leukemia

Before Targeted Therapy

• Proliferation of granulocytes

• All stages of granulocyte maturation in peripheral blood

• Platelets may be elevated

• Splenomegaly, frequent

• Almost invariable transformation to fatal acute leukemia; ~2.5yrs after Dx


Mechanism of Action of Imatinib Mesylate (STI571)

Goldman JM, Melo JV. N Engl J Med. 2001. 344:1084-1086.

MPN

CMLPV ET

PMF

Ph+ Ph‐

JAK2

JAK2

JAK2cMPL

CALR

CALR

cMPL

JAK2, MPL and CALR in MPN

Polycythemia Vera

• Primary polycythemia, erythropoietin independent growth

• Clonal disorder

• Acquired somatic mutation of a hematopoietic stem cell


JAK2V617F mutation

• Gene encodes a cytoplasmic tyrosine kinase essential for erythroid maturation

• This mutation causes substitution of phenylalanine for valine at position 617

• The mutation occurs in “the pseudo-kinase (negative regulatory)domain” which leads to a gain of function mutation

• This increases JAK2 activity and leads to cytokine-independent cell line growth

• BUT not specific: 98% of PV, 60% of PMF, 50% E&, and in chronic neutrophilic leukemia and MDS-RS with high platelets

PV ComplicationsSymptoms

Aquagenic pruritusErythromelalgia

ThrombosesCorrelates with WBCNo correlation with increased platelet count.Correlated with JAK2 V617F allelic burden???effect of Hct

MyelofibrosisLeukemia

in most instances JAK2 V617F negative?same clone as PV from clonal pre- JAK2 V617F cells?

Erythromelalgia


Thrombosis in MPN

Arterial

Venous, including

unusual sites(BCS, PVT,

CVT)

MicrovascularErythromelalgia

HA, visual disturbance, TIA

At initial presentation11-25% in ET pts12 to 39% in PV pts

Risk persists after diagnosisPV:3.8/100 person yrsET:1.9/100 person yrs

Clear impact on prognosis

ET and PV management largely influenced by vascular risk

Falanga et al, Seminars in Thrombosis and Hemostasis 2014

Diagnostic Criteria (WHO) for PV

2016• Major Criteria

1. Hgb > 16.5 g/dl (Hct >49%) in men or 16 g/dl (Hct>48%) in women

2. Bone marrow biopsy – hypercellular for age with panmyelosis and pleomorphic mature megakaryocytes

3. Presence of JAK2 mutations

• Minor Criteria1. Low serum Erythropoietin

• Requires all 3 major or first 2 major + the minor

• Caveat – if sustained erythrocytosis, JAK2 positive and low EPO, then BMmay not be needed

Silver R et al, Blood, 2008

2008• Major Criteria

1. Hgb > 18.5 g/dl in men or 16.5 g/dl in women

2. Presence of JAK2 mutations

• Minor Criteria1. Bone marrow biopsy – hypercellular

for age with panmyelosis2. Low serum Erythropoietin3. Endogenous erythroid colonies

• Requires both major and 1 minor OR first major and 2 minor


Summary – 2016 revision in MPN• Decreased Hb/Hct threshold for PV

• but BM morphology as one of the major criteria

• Addition of CALR mutation for ET and PMF

• Distinction of Prefibrotic PMF as a separate entities

Limitations:

• How to interpret the historical data?

• Overlap between ET and pre‐PMF?

• MDS with fibrosis versus PMF?


• Elevated platelet count, must exclude myriad of other etiologies for

thrombocytosis

• Splenomegaly seen in fewer than 20%

• Morbidity: Thrombotic and/or bleeding problems, many none and shouldn’t be

treated

• Erythromelalgia, aquagenic pruritus, gout

• Transformation to MF and Acute leukemia

• Common disorder in young females (15‐25) not in males

• Generally no cytogenetic abnormalities

• Diagnosis easy if disease‐defining mutations present (50 JAK2 V617F ,~25% CALR

mutations, 5% c‐mpl (thrombopoietin receptor) positive

PV&ET Therapy

Low risk - no therapy?Phlebotomy for Hct >45

Intermediate and high risk:Hydrea ? Increased risk of AL, well-tolerated

Pegasys High likelihood of complete remission,

depression etc.

?JAK2 inhibitors

Primary Myelofibrosis (PMF)

Must exclude other causes of bone marrow fibrosis

• “Spent phase” of PV or ET

• CML

• Hairy cell leukemia

• Lymphoma

• Metastatic cancer

• Primary pulmonary hypertension

• Lupus


“Teardrop” Cells/ Dacrocytes

JAK2, MPL and CALR in MPN

Kampfl et al, NEJM, 2013


How to approach “Triple Negative” ET or MF?

• About 10% of ET and 5-10% of PMF are “triple negative”

• For ET:• May have MPL mutation outside of exon 10• May be not a true ET?

• For PMF:• Look for other mutations by gene panel sequencing• Could it be MDS with fibrosis?

Epigenetic mutations in PV (MPNs)

L Wang et al, Leukemia 2014; Vannucchi et al, Haematologica 2011


Diagnostic Criteria (WHO 2016)ET

• Major Criteria1. Sustained platelet count > 450 K/mcl

for atleast 2 months2. Bone marrow: primarily

megakaryocytic proliferation, with very rare reticulin fibrosis (grade 1)

3. No evidence of other myeloid neoplasms

4. Presence of JAK2, CALR or cMPL

• Minor Criterion1. Presence of clonal marker or no

evidence of reactive thrombocytosis

• Requires all major or first 3 major +the minor


Overt‐PMF

• Major Criteria1. Bone marrow: Megakaryocytic atypia

with reticulin fibrosis grade 2 or 3; 2. Exclude other myeloid neoplasm3. Presence of JAK2, CALR, cMPL or other

clonal marker, OR absence of reactivefibrosis

• Minor Criterion1. Anemia (not due to other conditions)2. Leukocytosis > 11 K/mcl3. Leukoerythroblastosis4. Elevated LDH5. Splenomegaly

• Requires all major and 1 minor

ET Subtype: Prefibrotic MF

• Elevated peripheral blood platelet count

• Hypercellular marrow with increased megakaryocytes with atypicalclustering

• No fibrosis, no splenomegaly

• Rapid progression to myelofibrosis

Peripheral blood Bonemarrow

Photomicrographs courtesy Dr. Mohamed Salama

ET vs Prefibrotic PMF vs Overt PMF – what is different?

Barbui et al, JCO 2011; Mudireddy et al, ASH 2016


Acknowledgments

Thanks to:

Patients and their families

Nurses & Research coordinators

Funding

NIH‐MPD Consortium

Leukemia & Lymphoma Foundation



Hematology Review

Advances in the Treatment of Lymphoma and CLL

Martha Glenn, MD


Martha Glenn, MD

Feb 24, 2018

Advances in the Treatment of Lymphoma and CLL

Highlights

• CAR T cell therapy for DLBCL

• CLL combinations

• Advanced HL BV for 1st line

Objectives

• CAR T cell therapy for DLBCL

– Understand use of CAR T cell in treatment of relapsed/refractory DLBCL, including limitations and outcomes

• Advanced HL BV for 1st line

– Evaluate results of PhIII Echelon trial

• CLL combinations

– Review results of Ph III MURANO trial for RR CLL

– Compare results of early PhI/II trials of non‐chemotherapy approaches for 1st line and RR CLL


DLBCL

DLBCL

Localized disease

RCHOP x 3 + XRT

Advanced disease

RCHOP x 6 +/‐ XRT

Outcomes

J Clin Oncol 2014 32:1066‐1073.

Rel/Ref DLBCLSalvage

chemotherapy

Response

AutoBMT Observe

No response

3rd line salvage

Response

AutoBMT Observe

No response

Palliation

Palliative Care

3 yr PFS = 39% 3 yr PFS = 14%

CORAL studyJCO 2012 28:4184‐4190BMT 2016 51(1):51‐7 1 yr PFS = 42% 1 yr PFS = 16%


Rel/Ref DLBCLSalvage

chemotherapy

Response

AutoBMT Observe

No response

3rd line salvage

Response

AutoBMT Observe

No response

Palliation

Palliative Care

3 yr PFS = 39% 3 yr PFS = 14%

CORAL studyJCO 2012 28:4184‐4190BMT 2016 51(1):51‐7 1 yr PFS = 42% 1 yr PFS = 16%

Refractory DLBCL

• “Outcomes in refractory DLBCL: results from theinternational SCHOLAR‐1 Study”

– Blood 2017; 130(16): 1800‐1808

• Outcome from start of salvage treatment forrefractory disease

• Data sources

– 2 PhIII studies for RR DLBCL

• CORAL and LY.12

– 2 observational cohorts

• MDA for relapsed DLBCL

• Iowa/Mayo lymphoma database

Refractory DLBCL


Selection Bias in RR DLBCL trials

Sarah C. Rutherford, and John P. Leonard Blood 2017;130:1778-1779


Refractory DLBCL: Scholar‐1 Study

• Benchmarking validity for prospective trials

– Median age = 55 yr

– Male = 64%

– ECOG 1‐2 = 73%

– Stage III/IV = 72%

– 28% primary refractory

– 49% refractory to salvage

– 22% early relapse after auto BMT

Refractory DLBCL: Scholar‐1 Study

Outcome

ORR 26%

CR 7%

PR 18%

Med OS 6.3 mos

2 yr OS 20%

CR then auto Med OS >6 yrs


Refractory DLBCL: OS

http://www.headaround.com/car‐t‐cell‐immunotherapy‐diagram/

antiCD19 CAR T cell products

Names DevelopersCompany

Co‐stim signalVector

Trial Names FDA approval

KTE‐C19Axicabtagene ciloleucel(axi cel)YescartaNEJM 2017 377:2531‐44

NCIKite now Gilead

CD28Retroviral

“ZUMA1” Ref DLBCL and tL

CTL019TisagenleucleucelKymriahNEJM 2017 377:2545‐54

UnivPennNovartis

4‐1BBLentiviral

“Juliet” B ALL (< 26 yo)

JCAR017Lisocabtagene maraleucel(liso cel)Blood 2017 abst 581

FHCRC/MSKCCJUNO now Celgene

4‐1BBLentiviral

“TranscendNHL”


antiCD19 CAR T studies

ORR CR CR3mo

KTE‐C19Axi‐cel“ZUMA‐1”

N=111; 101 tx’d(91%)

82% 54% ~52%

CTL019Tisa‐cel“Juliet”

N=141;85 tx’d(60%)

59% 43% 37%

JCAR017Liso‐cel“Transcend NHL”

N=69 75% 56% 40%

Axi cel

Axi cel


Tisa cel

Tisa cel

JCAR


• CRS– Fever, hypotension, tachycardia, hypoxia

• Neurotoxicity– Mild cognitive dysfunction to encephalopathy– Early signs: difficulty with word finding, calculation, handwriting

• Cytopenias– Neutropenia, anemia, thrombocytopenia– May be prolonged in 20‐30%

• Neutropenic Fever

Toxicity

ToxicityApprox RateGr3/4

Onset

CRS 35‐95%5‐17%

D2‐3~5 days

Neurotoxicity 20‐64%13‐34%

D5‐7~10+ days

Cytopenias ANC 41‐93%Hct 38‐66%Plts 29‐58%

Neutropenic Fever 36%

Tocilizumab given in 10‐45%Steroids in 0‐27%CRS/NT seen most in Axi‐cel

• Axi cell $373,000• CTL019 $475,000• Estim $1,000,000 per pt treated

“Health systems and Financial Implications of Offering CAR T Therapies” Silver ASH2017 • Mark up 110% (for in‐pt infusion; no toxicitymanagement)– Total charge $524,300

• Medicare payment = $86,836

• Mark up 400%– Total charge $1,606,000

• Medicare payment = $303,176

Cost


Refractory DLBCL: OS

Very rough estimate CART tx

Historical benchmark

• CR at 3 months seems to predict for durableresponses

– Roughly 40% reach this point

• Setting realistic expectations

– Selection bias

• Slower disease growth

• Excellent health despite RR DLBCL– ECOG 0‐1

– Expensive

– Considerable toxicity

CAR T Tx for Ref DLBCL: Summary

Adv’d HL

• ABVD x 6 cycles– 5 yr PFS = 53%; 5 yr OS = 66%

• EscBEACOPP x 6– 5yr PFS 89; 5 yr OS 95%

• Response adapted approach– ABVD PET2 neg, ABVD or AVD x 4

• 3 yr PFS 84%; 3 yr OS 97%

– ABVD PET2 POS, escBEACOPP x4• 3 yr PFS 67%; OS 88%


Brentuximab Vedotin Mechanism of Axn

Brentuximab vedotin (SGN-35) ADC

ADC binds to CD30

MMAE disruptsMicrotubule network

ADC-CD30 complex traffics to lysosome

MMAE is released

Apoptosis

G2/M cellcycle arrest

anti-CD30 monoclonal antibodyprotease-cleavable linkermonomethyl auristatin E (MMAE), potent antitubulin agent

Brentuximab Vedotin Mechanism of Axn

Brentuximab vedotin (SGN-35) ADC

ADC binds to CD30

MMAE disruptsMicrotubule network

ADC-CD30 complex traffics to lysosome

MMAE is released

Apoptosis

G2/M cellcycle arrest

anti-CD30 monoclonal antibodyprotease-cleavable linkermonomethyl auristatin E (MMAE), potent antitubulin agent

Single agent efficacy in RR HL post AutoBMT:CR 34%ORR 75%

Adv’d HL: ECHELON‐1

• “Brentuximab Vedotin with Chemotherapy forStage III or IV Hodgkin’s Lymphoma”

– Connors et al NEJM 2018: 378:331‐44

RANDOMIZATION

AAVD x 6

ABVD x 61334 pts

Primary Endpoint:2 yr PFS



RANDOMIZATION

AAVD x 6

ABVD x 61334 pts

Med follow 24.6 mo

AAVD ABVD

ORR 86% 83%

CR 73% 71%

2 yr PFSP=0.04

82% 77%

2 yr OSP=0.20

96.6% 94.2%

RATHL:3 yr PFS = 82%3 yr OS = 95%


RANDOMIZATION

AAVD x 6

ABVD x 61334 pts

Med follow 24.6 mo

AAVD ABVD

ORR 86% 83%

CR 73% 71%

2 yr PFSP=0.04

82% 77%

2 yr OSP=0.20

96.6% 94.2%

RATHL:3 yr PFS = 82%3 yr OS = 95%CONCLUDE:

1. AAVD no less short term toxicity2. Need long term OS data3. BV is expensive

ECHELON


Chronic lymphocytic leukemia

• MURANO trial RR CLL VR vs BR

• Venetoclax + Ibrutinib RR CLL

• Venetoclax + Ibrutinib + ObinutuzumabUpfront

• Venetoclax + Obinutuzumab Upfront

• “VR is superior to BR in RR CLL—results frominterim analysis of PhIII MURANO study”

– Seymour et al ASH2017 LBA‐2

RANDOMIZATION

BR x 6

VR x 6 389 ptsRR CLL V 2 yr

max

Primary Endpoint:Investigator Response

Assessement

Med follow 24 mo

RR CLL: MURANO

RR CLL: MURANO

ORR CR

VR 93% 26%

BR 68% 8%

OS benefit:HR 0.48 (CI 0.25‐0.90)

(P<0.0001)


RR CLL: Venetoclax/Ibrutinib

• “Initial Results of IBR + VEN in RR CLL(CLARITY): High rates of OR, CR and MRDeradications following 6 months of therapy”

– Hillmen et al ASH 2017

TX stopped if MRD neg x as long as took to get MRD

negIBR + VENIBR

X 2 mo

Primary Endpoint:BM MRD p 12 mo

MRD assess6, 12,24 mo

0 2 8


• “Initial Results of IBR + VEN in RR CLL(CLARITY): High rates of OR, CR and MRDeradications following 6 months of therapy”

– Hillmen et al ASH 2017

IBR + VENIBR

X 2 mo



0 2 8

25 pts 50 pts TX stopped if MRD neg x as long as took to get MRD

neg


IBR + VENIBR

X 2 mo



0 2 8

25 pts 50 pts TX stopped if MRD neg x as long as took to get MRD

neg

• ORR = 100%

• CR = 60%

• MRD neg = 28%


1st line: Venetoclax + Obinutuzumab

• “Safety, Efficacy and MRD Negativity ofVenetoclax + Obinutuzumab in Untreated CLLpts—Results from Ph1B study”

– Flinn et al ASH 2017

– OBIN + VEN x 6 monthly cycles; VEN x 6 more months

12

VEN

OBIN

Cycles

0 2 6

If <CR, VEN x 1 more yr

Response assessment

32 pts

1st line: Venetoclax + Obinutuzumab

• ORR = 100%

• CR = 56%

• MRD neg BM = 74%

• 1 yr PFS = 100%

12

VEN

OBIN

Cycles

0 2 6

If <CR, VEN x 1 more yr

Response assessment

32 pts

1st line: Venetoclax/Ibrutinib/Obinutuzuamb

• “Initial Results of Ph2 Treatment Naïve cohortstudy of OBIN, IBR, VEN in CLL”

– Rogers et al ASH 2017

14

IBR

VEN

OBIN

Cycles

0 2 8



• “Initial Results of Ph2 Treatment Naïve cohortstudy of OBIN, IBR, VEN in CLL”

– Rogers et al ASH 2017

14

IBR

VEN

OBIN

Cycles

0 2 8

Response assessment23 pts

25 pts

14

IBR

VEN

OBIN

Cycles

0 2 8


25 pts

• ORR = 100%

• CR = 50%

• MRD neg = 58%


14

IBR

VEN

OBIN

Cycles

0 2 8


25 pts

• ORR = 100% (100%)

• CR = 50% (56%)

• MRD neg = 58% (74%)



CLL‐‐summary

• RR CLL

– Venetoclax + Rituximab improves RR, PFS and OS over BR after previous CIT

• Venetoclax approval is for 17pDEL RR CLL currently

– Venetoclax + Ibrutinib with response (MRD) adapted discontinuation is promising

• 1st line

– Venetoclax + Obinutuzumab is promising

• Unclear that adding IBR adds increased efficacy

Current clinical trials at HCI• FL/iNHL

– Ph1/2 intratumoral injection of G100 (TLR4 agonist) +/‐ pembrolizumab– IMMU‐114 (humanized anti‐HLA DR Ab) Ph1

• MCL– Ibrutinib maintenance after frontline tx– IMMU‐114– Ibrutinib + selinexor (Selective inhibitor of Nuclear export)

• DLBCL– IMMU‐114– Ibrutinib + selinexor– SGN CD19B (anti‐CD19 ADC with DNA‐crosslinking drug payload SGD‐

1882))– Nivolumab + IDO inhibitor Ph I– BET (transcriptional activator) inhibitor Ph I/II (in MYC de‐regulated)

lymphoma)

• Information/Referrals – New pt coordinator: Laura Peay 801‐585‐6906– http://healthcare.utah.edu/huntsmancancerinstitute/clinical‐

trials/find‐clinical‐trials‐at‐hci/


Documents

Huntsman Cancer Institute goal of this course is to provide a comprehensive review and update on the ... Department of Internal Medicine, and Huntsman Cancer Institute, University