Larry W. Buie, Pharm.D., BCOP, FASHP Manager, …ncop.memberlodge.org/resources/Documents/RR ALL slides.pdf · Etoposide 150 mg/m2/d d3-5 Peg-asparaginase 2500 UI/m2 d7 Clofarabine

UPDATES IN RELAPSED/REFRACTORY B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)

Larry W. Buie, Pharm.D., BCOP, FASHP Manager, Adult Clinical Pharmacy Services PGY2 Adult Oncology Residency Program Director Memorial Sloan Kettering Cancer Center 5 August 2017

Faculty Disclosures • Advisory board member for Pfizer regarding

inotuzumab

• Advisory board member for Amgen regarding blinatumomab

– Other Advisory Board Participation

• Taiho Oncology, Inc

• Onconova Therapeutics, Inc

• ProStrakan, Inc

• Teva Pharmaceuticals, Inc

• Off-label and investigational use of medications will be discussed

Objectives

• Discuss the role of conventional chemotherapy and hematopoietic stem cell transplantation in the management of relapsed or refractory (r/r) B-cell ALL

• Review appropriate strategies and monitoring plans with tyrosine kinase inhibitors (TKIs) in r/r Philadelphia-Chromosome positive (Ph+) ALL

• Describe the role of immunotherapy in patients with r/r B-cell ALL, with emphasis on monoclonal antibodies, BiTE® therapy with blinatumomab and cellular therapy with CAR T- cells

ALL Overview

• Proliferation of immature lymphoid cells in bone marrow, peripheral blood or other organs

• 6590 new cases and 1430 deaths estimated in US in 2017

– 80% less than 20 years of age

– 20% adult leukemias

• Risk factors

– >70 years of age

– Exposure to chemotherapy or radiation

– Genetic disorders

• 5 year survival decreases substantially with age

NCCN. Acute Lymphoblastic Leukemia.Version 1. 2017. Available at http://www.nccn.org/professionals/physician_gls/pdf/all.pdf. Accessed 7/1/2017.

http://www.nccn.org/professionals/physician_gls/pdf/all.pdf

Diagnosis

Immunophenotyping

Early Precursor B-Cell ALL TdT, CD19/CD22/CD79a +, CD10-

Precursor B-Cell ALL Cytoplasmic immunoglobulins, CD10/CD19/CD22/CD79a +, CD20+ (50%)

Mature B-Cell ALL Surface immunoglobulins, clonal light chains, CD20 (80%), TdT -

Cytogenetics and Molecular Subtypes

Favorable Unfavorable

ETV6-RUNX1 t(12;21) Hyperdiploidy (>50 chromosomes)

Trisomy 4,10 17

Ph+ or Ph+ like t(4;11) MLL rearrangement

Hypodiploidy (<44 chromosomes) Complex karyotype (>5 abnormalities)

IKFZ1

Bone Marrow with ≥ 20% lymphoblasts

MLL=mixed lineage leukemia IKFZ1=Ikaros family zinc finger 1



Poor Prognostic Factors in Adult ALL

Prognostic Variable Negative Prognostic Association

Age >35 years

Initial WBC >30 X 109 cells/L

Cytogenetics Philadelphia chromosome + t(4;11) MLL rearrangement t(8;14) MYC Complex karyotype (>5 abnormalities) Hypodiploidy (30-39 chromosomes)

Risk stratification Standard High-Risk

Fielding AK et al. Blood 2007; 109:944-950



Management of Adult ALL Induction Goal: Reduce tumor burden

•Backbone: vincristine, anthracycline, steroids ± asparaginase •Linker, Hyper-CVAD, AYA protocols •±CD 20 targeted therapy •TKI if Ph+

CNS Prophylaxis Goal: Prevent CNS disease •Radiation •IT chemotherapy •High dose systemic therapy

Consolidation/ Intensification

Goal: Eliminate residual leukemia •High dose chemotherapy •6-MP/thioguanine •Asparaginase •TKI if Ph+ •HSCT if high risk

Maintenance Goal: Prevent disease relapse •POMP •TKI if Ph+ •Radiation to scrotal sac if testicular involvement

AYA=adolescent and young adult

6-MP=6-mercaptopurine

POMP=6-MP, vincristine, methotrexate and prednisone

NCCN. Acute Lymphoblastic Leukemia.Version 1. 2017. Available at http://www.nccn.org/professionals/physician_gls/pdf/all.pdf Accessed 7/1/2017.



Meet Patient KS

40 yo male with Ph- B-cell ALL diagnosed in 12/2012

• Pediatric inspired protocolCR1; relapse 5/2014

– BM Bx

• 40% blasts

• Abnormal B-cell population detected – CD10(bright), CD19 (bright),CD20 (subset, <20%),CD22+,

CD38/CD45 (dim), CD34 (absent)

• Plan is for a clofarabine containing regimen

• His brother is determined to be a donor option

Predictors for Outcomes in R/R ALL

• Duration of first remission

• Response to salvage

• Age

• Ability to undergo HSCT

• Molecular response

Gokbuget N, et al. Blood 2012;120:2032-2041 Frey NV, et al. Blood 2015;126:589-596

Minimal Residual Disease (MRD)

• MRD is the presence of leukemic cells below the threshold of detection by conventional morphologic methods

• May have a CR with MRD positivity • Flow cytometry

– Detects abnormal phenotypes

• PCR – Fusion genes – Clonal rearrangements in immunoglobulin heavy chain genes – T-cell receptor gene rearrangements

• MRD increases risk of relapse • MRD may emerge due to immune escape mechanisms • MRD persistence may be useful in predicting future course of treatment

PCR=polymerase chain reaction NCCN. Acute Lymphoblastic Leukemia.Version 1. 2017. Available at http://www.nccn.org/professionals/physician_gls/pdf/all.pdf. Accessed 7/1/2017.


Myth: The Second Remission

Trial

First CR Rate

Relapse Rate

Time to Relapse

Median Survival

1-year OS

5 year OS

ECOG 2993 (N=1508)

91% 44% 11 months 6 months 22% 7%

PETHEMA (N=589)

89% 50% 11 months 4.5 months

24% 10%

Oriol A et al. Haematologica 2010;95;589-596 Fielding AK et al. Blood 2007; 109:944-950

Bottom line: Survival is poor for patients with r/r B-Cell ALL without consolidative transplant

Role of HSCT in ALL

• Benefit of HSCT in CR1 has been seen in multiple clinical trials and meta-analyses for high risk patients

• No consensus for transplantation with standard risk ALL in CR1 • Ph+ patients have best results from allogeneic stem cell

transplantation in first CR with molecular remission • Minimal residual disease presence after CR has been shown to

predict relapse-free survival • Allogeneic HSCT is the best curative option for patients achieving

CR2 • Allogeneic HSCT is preferred over autologous HSCT

NCCN. Acute Lymphoblastic Leukemia.Version 1. 2017. Available at http://www.nccn.org/professionals/physician_gls/pdf/all.pdf Accessed 7/1/2017.



Criteria for Complete Response

• No circulating blasts or extramedullary disease

• Trilineage hematopoiesis with <5% blasts

• ANC >1000/microL

• Platelets >100,000/microL

• No recurrence at 4 weeks

• May have a CR with incomplete count recovery

NCCN. Acute Lymphoblastic Leukemia.Version 2. 2015. Available at http://www.nccn.org/professionals/physician_gls/pdf/all.pdf. Accessed 10/21/2015


Historical Salvage Experience • MD Anderson

– 288 patients treated between 1980 and 2007

– 53% had a CR after salvage chemotherapy

– Median duration of remission was 7 months

Response Rates by Therapy Received

Therapy Number of Patients Number of CRs (%)

VAD/Hyper-CVAD 61 17 (28)

Cytarabine Combinations 54 17 (32)

Allogeneic HSCT 22 9 (41)

Methotrexate/Asparaginase 52 3 (6)

Other combinations 29 4(14)

Single Agent 70 3 (4)

O’Brien S et al. Cancer 2008;113:3186-3191

Cytarabine Containing Regimens

N=88 Previously treated ALL Relapsed or refractory

disease after induction

chemotherapy

Hyper-CVAD X 8 alternating

courses Vincristine 2 mg IV d1,8,15

Dexamethasone 80 mg IV or PO d1-4,15-18

Weekly Asparaginase or monthly pegasparaginase with each cycle

IT prophylaxis

Maintenance X 12 months

Faderl S et al. Clinical Lymphoma, Myeloma & Leukemia 2011;11:54-59

Primary Endpoints: CR and induction mortality rates

Cytarabine Containing Regimens Results from Augmented Hyper-CVAD

CR CRp (incomplete PLT recovery) ORR

47% 13% 64%

Median remission duration 5 months

Median OS for CR 10.2 months

HSCT 32%

Safety Induction mortality Asparaginase Associated Anaphylactic reactions Coagulopathy

9% 4% 2%

Faderl S et al. Clinical Lymphoma, Myeloma & Leukemia 2011;11:54-59

Clofarabine Containing Regimens

N=55 Previously treated ALL Relapsed or refractory

disease after induction

chemotherapy

VANDEVOL N=37 Dexamethasone 10 mg/m2/q12h

d1-5 Mitoxantrone 8 mg/m2/d d3-4 Etoposide 150 mg/m2/d d3-5

Peg-asparaginase 2500 UI/m2 d7 Clofarabine 30 mg/m2/d d1-5

ENDEVOL N=18 Cyclophosphamide 300

mg/m2/d d1-3 Clofarabine 30 mg/m2/d d1-5

Primary Endpoints: CR rate

OR

Pigneux A, et al. Blood 2011;118:Abstract 2586 d=day

Clofarabine Containing Regimens

Results from Clofarabine Containing Regimens

VANDEVOL ENDEVOL

CR 41% 50%

Early death 14% 6%

HSCT rate 29% in both groups

Safety Grade 3-4 infection Neurological GI Liver Abnormality

59% 14% 14% 30%

56% None None 11%

Pigneux A, et al. Blood 2011;118:Abstract 2586

Vincristine Sulfate Liposome Injection (VSLI)

N=65 Ph- ALL

Second or greater relapse (chemo or HSCT)

At least one CR with 90 day leukemia free interval

Weekly VSLI 2.25 mg/m2 without dose capping on

D 1,8,15,22 of a 28 day cycle

Response Progression

Toxicity HSCT

O’Brien S, et al. J Clin Oncol 2013;31:676-683

Primary Endpoint: CR and CRi rates Secondary Endpoints: CR/CRi duration, OS, HSCT, ORR

CRi=complete remission with incomplete count recovery

Vincristine Sulfate Liposome Injection Results for Vincristine Sulfate Liposome Injection (VSLI)

CR CRi ORR

11% 9% 35%

Time to CR (median) 54 days

CR and CRi duration 23 weeks

OS OS rates

4.6 months 35% at 6 months, 8% at 12-18 months, 4% at 2 years

HSCT OS

19% 9.3 months

MRD negativity among responders 67%

Adverse Events Neuropathy grade 3 Constipation grade 3 30 day mortality

23% 3% 12%

O’Brien S, et al. J Clin Oncol 2013;31:676-683

Back to KS, ARS #1

• KS received the clofarabine containing regimen with no response. He went on to complete 2 cycles of VSLI. His repeat bone marrow shows CR2 with MRD negativity. What should be the next step?

1. Continue VSLI until disease progression

2. Offer HSCT

3. Place on maintenance therapy with POMP

4. Hold additional treatment until MRD positive

MONOCLONAL ANTIBODIES

Rituximab for CD20+ Disease: Phase III

N=209 Ph- B-lineage ALL NEWLY diagnosed

>20% CD20 expression on leukemic cells

N=105 Chemotherapy Plus Rituximab 375 mg/m2:

Induction D1, 7 Salvage (if needed) D1, 7

Consolidation Blocks 1,3 4,6 Late intensification D1,7 Maintenance 6 infusions

Total 16-18 doses of rituximab

Maury S, Chevret S, Thomas X, et al. N Engl J Med 2016;375:1044-53.

Primary Endpoint: EFS

Secondary Endpoints: hematologic remission, relapse during first remission, death during first remission, OS, safety

CD20 present on majority of B cells Present on 30-50% of B-cell precursor ALL Blasts

GRAALL-2005/R

N-104 Chemotherapy Alone

GRAALL-2005/R Results Variable Rituximab Group

(N=105) Control Group (N=104)

P-Value, HR

EFS, 2 years 65% 52% 0.04, 0.66

Relapse, 2 years 18% 32% 0.02, 0.52

Death during first remission

12% 12% 0.96, 0.98

OS, 2 years 71% 61% 0.10

CR, Induction 92% 90%

MRD-, induction 65% 61%

MRD-, consolidation 91% 82%

Transplant first CR 34% 20%

Older age, CNS involvement, High WBC associated with poorer EFS Fewer asparaginase allergic reactions in rituximab group, P=0.002

Rituximab should be considered during r/r ALL disease if CD20 expression>20%

Maury S, Chevret S, Thomas X, et al. N Engl J Med 2016;375:1044-53.

Inotuzumab Ozogamicin

• Humanized monoclonal antibody targeting CD22

• Antibody-drug (calicheamicin) conjugate

• Low levels of CD22 expression results in high intracellular calicheamicin levels

• Results in G2/M cell cycle arrest

Ohanian M, et al. Expert Opinion on Biological Therapy 2015;15 (4):601-611

Phase III INO-VATE: Inotuzumab versus Chemotherapy

N=218 B-lineage ALL :

-relapsed or refractory CD22-positive

Ph+ or Ph- -first or second salvage

N=109

Inotuzumab Ozogamicin 0.8 mg/m2 d1

0.5 mg/m2 d8, 15 Cycle 1=21 days

≥ Cycle2=28 days

Kantarjian HM, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med 2016;375:740-53.

Primary Endpoint: CR, OS Secondary Endpoints: Duration of remission, progression-free survival, rate of stem

cell tranplantation, MRD response, safety

Prospective, randomized, phase III trial

N=109

Chemotherapy: FLAG

Cytarabine + mitoxantrone High dose Cytarabine

Inotuzumab Ozogamicin End Point Inotuzumab Standard

Therapy Between Group

Difference P-value

No/total % No/total % %

Complete remission or complete remission with Incomplete hematologic recovery

Total BM blasts below MRD

88/109 69/88

80.7 78.4

32/109 9/32

29.4 28.1

51.4 50.3

<0.001 <0.001

Complete Remission


39/109 35/39

35.8 89.7

19/109 6/19

17.4 31.6

18.3 58.2

0.002 <0.001

Complete remission with Incomplete hematologic recovery


49/109 34/49

45.0 69.4

13/109 3/13

11.9 23.1

33.0 46.3

<0.001 0.004


Inotuzumab Ozogamicin: Secondary Endpoints

Inotuzumab Ozogamicin

Standard-Therapy Group HR (P=)

Duration of Remission

4.6 Months 3.1 Months 0.55 (P=0.003)

PFS 5.0 Months 1.8 Months 0.45 (P<0.001)

OS 7.7 Months 6.7 Months 0.77 (P=0.04)


Inotuzumab Ozogamicin: Safety

Serious Adverse Event

Inotuzumab Ozogamicin (N=139)

Standard-Therapy Group (N=120)

Any Grade Grade ≥3 Any Grade Grade ≥3

Any Event 67 (48) 64 (46) 55 (46) 52 (43)

Febrile Neutropenia

16 (12) 15 (11) 22 (18) 21 (18)

VOD 15 (11) 13 (9) 1 (1) 1 (1)

Sepsis 3 (2) 3 (2) 6 (5) 6 (5)

Pyrexia 4 (3) 2 (1) 3 (2) 1 (1)


NOVEL IMMUNOTHERAPY: BITE ANTIBODIES AND CAR T-CELLS

Tumor Immune Escape

• Metabolically hostile microenvironment • Thymic selection • T-cell anergy • Impaired tumor MHC antigen presentation • Increased expression of negative co-stimulatory ligands • Expansion of Tregs • Increased production of inhibitory enzymes and cytokines • Downregulation of NK cells

Dunn GP, et al. Annu Rev Immunol 2004;22:329-360

Tregs=regulatory T-cells

NK=natural killer

Harnessing the Immune System

• Stem cell transplant

• Vaccination

• Cytokine therapy

• Immune checkpoint inhibitors

• Adoptive transfer of tumor infiltrating cells

• Bi-specific T-cell engaging antibody (BiTE®) therapy

• Chimeric antigen receptor (CAR) T-cells

Dunn GP, Old JL et al. The three Es of Cancer Immunoediting. Annu Rev Immunol 2004;22:329-60

BiTE® Antibodies: Blinatumomab

• Produced by Chinese hamster ovary cells

– 2 single chain antibodies • Heavy and light chains of larger antibodies

• Joined by a linker

• Force the formation of an immunologic synapse between T-cells and tumor cells – Occurs by simultaneous binding of BiTE antibodies to CD3ε on T-cells

and a surface target antigen on cancer cells

– Independent of MHC presentation and T cell receptor specificity

Frankel SR, et al. Current Opinion in Chemical Biology 2013;17:385-392 .Permission granted. MHC=major histocompatibility complex

Blinatumomab Mechanism of Action

• Binds CD19 on target B-Cell and CD3 on T-Cell – Induces a cytolytic synapse – Granules containing granzymes and perforin fuse with T-

cell membrane and release – Granzymes penetrate target cells perforated by perforin – Apoptosis of target CD19 cell is activated by granzyme B – Activation markers on T-cell (CD69 and CD25) remain

expressed and T-cells are capable of serial lysis and expansion

Nagorsen D, et al. Experimental Cell Research 2011;317:1255-1260

Blinatumomab Pharmacokinetics

Pharmacokinetics Linear over dose range of 5 to 90 mcg/m2/day

Distribution Vd 4.52 L with continuous infusion

Metabolism Degraded to small peptides and amino acids via catabolic pathways

Elimination Half-life was 2.11 hr; negligible amounts excreted in the urine

Special populations Age, gender, body weight and body surface area do not influence PK of blinatumomab

Renal impairment No information for dialysis or severe renal impairment; mild to moderate impairment similar to normal renal function

Buie LW et al. Ann Pharmacother 2015;49:1057-1067

Blinatumomab Pharmacodynamics

Peripheral T-cell redistribution

Occurred after initiation of infusion or dose escalation; T-cell counts declined within 1-2 days and returned to baseline with 7 to 14 days

Peripheral B-cell Counts Decreased to less than 10 cells/microliter during the initial treatment; no recovery of peripheral B-cell counts during the treatment free period

Cytokines IL-6, IL-10 and IFN-γ were increased within the first 2 days and returned to normal within 48 hours; subsequent cycles resulted in lower cytokine elevations

Topp MS, et al. J Clin Oncol 2011;29:2493-2498

Activity/Safety Expanded in R/R B-ALL

N=189 Ph- B-lineage ALL refractory after

induction Relapsed within 12

months of first remission or HSCT

≥10% blasts ECOG ≤2

Life expectancy ≥12 weeks

>50% blasts or WBC ≥15000 cells/μL

Elevated LDH

Prephase dexamethasone

10-24 mg/m2/d for up to 5 days

Blinatumomab CI 9 mcg/day for 1 week

28 mcg/day for 3 weeks

Dexamethasone 20 mg premedication

Two weeks treatment free between cycles

Topp MS, Gokbuget N et al. Lancet Oncol 2015;16:57-66

Primary Endpoint: CR or CRh at 2 cycles

Secondary Endpoints: RFS, OS, HSCT, 100 day HSCT mortality, adverse events Exploratory Endpoint: MRD Response

CRh=complete remission with partial hematologic recovery


Response Rates

Category Patient Numbers %

Overall Response (CR/CRh)

81/189 43

Best Response CR CRh No response Not Evaluable

63/189 18/189 90/189 18/189

33 10 48 10

HSCT after CR or CRh Allo after CR Allo after CRh 100 day mortality

32/81 28/63 4/18

40 44 22 11

MRD Response 60/73 82

OS 6.1 months Topp MS, et al. Lancet Oncol 2015;16:57-66


Adverse Events

Event Number (%) Grade 3 to 4 (%)

Any Event 188 (99) 68

Febrile neutropenia 53 (28) 25

Neutropenia 33 (17) 16

Anemia 38 (20) 14

Pneumonia 18 (10) 9 ( 2 grade 5)

Thrombocytopenia 21 (11) 8

Hyperglycemia 24 (13) 8

Leucopenia 19 (10) 8

Transaminitis 24 (13) 7

Hypokalemia 45 (24) 7

Pyrexia 113 (60) 7

Sepsis 13 (7) 4 (4 grade 5)

Hypophosphatemia 13 (7) 5

Topp MS, et al. Lancet Oncol 2015;16:57-66


Neurologic Adverse Events

Event Number (%) Grade 3 to 4

Any Event 98 (52) 13

Tremor 33 (17) 1

Dizziness 26(14) 1

Confusion 14 (7) 2

Encephalopathy 10 (5) 4

Ataxia 9 (5) 2

Somnolence 9 (5) 1

Mental status change 7 (4) 1

Convulsion 4 (2) 1

Syncope 1 (<1) <1

Neurological toxicities, which may be severe, life-threatening, or fatal, occurred in patients receiving blinatumomab. Interrupt or

discontinue blinatumomab as recommended.

Topp MS, et al.. Lancet Oncol 2015;16:57-66

Cytokine Release Syndrome

• Cytokine release syndrome

– Increased IL-6, IL-10 and INF-γ

– Fever, headache, chills, flu-like symptoms, nausea

– Elevated LFTs

– Hypotension

– Severe Cases: capillary leak syndrome, DIC, HLH/MAS

– May be indistinguishable from infusion reactions

Cytokine Release Syndrome (CRS), which may be life-threatening or fatal, occurred in patients receiving blinatumomab. Interrupt or

discontinue blinatumomab as recommended.

Teachey DT, et al. Blood 2013;121:5154-57

HLH=hemophagocytic lymphohistiocytosis

MAS=macrophage-activation syndrome

Phase III Tower: Blinatumomab verus Chemotherapy

N=405 Ph- B-lineage ALL :

-Refractory to primary induction or salvage with

intensive chemo -Relapsed within 12 months

of first remission -Second or greater relapse

-Relapse after HSCT > 5% blasts ECOG ≤ 2

N=271

Blinatumomab: 6-week cycle 9 mcg/day ->

28 mcg/day x 4 weeks 2 weeks off

Stratification:

Age Salvage

Prior HSCT

Kantarjian H, Stein A, Gokbuget N, et al. Blinatumomab verus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med 2017;376:836-47.

Primary Endpoint: OS Secondary Endpoints:CR rates, duration of repsonse, MRD response, EFS, rate of

AlloSCT, adverse events

Prospective, randomized, phase III trial

N=134

Chemotherapy: FLAG ± Anthracycline High-dose AraC based High dose MTX based

Clofarabine based

Tower Results: Overall Survival


Tower Results: Remission Rates

MRD response: 76% blinatumomab 48% chemotherapy

Allogeneic Stem Cell Transplantation:

24% in each group


Tower: Adverse Events Adverse Events, N (%)

Event Blinatumomab (N=267) Chemotherapy (N=109)

Any adverse event 263 (98.5) 108 (99.1)

Event leading to premature discontinuation

33 (12.4) 9 (8.3)

Serious adverse event 165 (61.8) 49 (45.0)

Fatal serious adverse event

51 (19.1) 19 (17.4)

≥ grade 3 event Neutropenia Infection Elevated liver enzymes Neurologic events CRS Infusion reaction Lymphopenia

231 (86.5) 101 (37.8) 91 (34.1) 34 (12.7) 25 (9.4) 13 (4.9) 9 (3.4) 4 (1.5)

100 (91.7) 63 (57.8) 57 (52.3) 16 (14.7)

9 (8.3) 0

1 (0.9) 4 (3.7)


Treatment of CRS/Neurotoxicity

• Dexamethasone

– 24 mg IV or PO/day

– Tapered to off over a 4 day period

• Tocilizumab

– 8 mg/kg over 60 minutes

– Rarely necessary

MSK IRB 12-069. Accessed online 10/21/2015. Website Not Publically Available

Additional Blinatumomab Information Dose modification If an interruption is >7 days, begin new cycle

Grade 4 CRS or neurotoxicity Discontinue permanently

Grade 3 CRS Hold until resolved, restart at 9 mcg/day

Grade 3 Neurotoxicity Discontinue permanently if >1 seizure occurs Withhold until toxicity is not greater than grade 1 and at least 3 days, restart at 9 mcg/day Greater than 7 days to resolve, discontinue permanently

Hepatotoxicity Interrupt if transaminases >5X ULN or bilirubin >3X ULN

Drug Interactions No formal drug interaction studies Cytokines may suppress CYP metabolic enzymes Monitor patients receiving CYP substrates that have a narrow therapeutic index Highest risk is at drug initiation and when the dose is increased

Admixture and Administration

Must add IV solution stabilizer to the bag prior to blinatumomab Infusions must be calculated to run for 24 hours to 7 days as per the package insert May use CADD® pumps for outpatient or inpatient administration Efforts to minimize drug waste should be utilized Patients should never run out of drug waiting for a bag to be changed

Buie LW et al. Ann Pharmacother 2015;49:1057-1067 CADD=computerized ambulatory delivery device

Chimeric Antigen Receptor T-Cells (CAR-T)

• Autologous Transfer

– Apheresis

– Gene transfer • CAR design

– CD3ζ signaling element

– Costimulatory receptor

– Anti-CD19 single chain variable fragment

• Armored CAR T-cells – Multiple costimulatory receptors

• Suicide genes may be incorporated

– Expansion

– Reinfusion

Davila ML and Brentjens R. Hematol Oncol Clin N Am 2013;27:341-353 . Permission granted.

Dose, Tumor Burden, and Conditioning

• No significant correlation between T-cell expansion and clinical outcome

• Results are best in patients that have the lowest tumor burden

– T-cells may become exhausted in patients with excessive tumor bulk or antigen specific burden

• Conditioning with chemotherapy or radiation improves efficacy

– Optimal conditioning regimen remains unknown • Should include a tumor-responsive conditioning regimen

– Reduction in tumor bulk – Enhances antigen presentation for endogenous immune

response – Enhances persistence and function of CAR-Ts

Davila ML and Brentjens R. Hematol Oncol Clin N Am 2013;27:341-353

CAR-Ts in B-Cell ALL: Eliana

N=88 Pediatric and adults

CD19+ R/R B-cell ALL

≥5% lymphoblasts 59% prior alloSCT

Leukapheresis

Conditioning

T-Cell Infusion (N=68)

Primary Outcome:

Overall Remission Rates

(CR+Cri) Within 3 months

Buechner J, Grupp SA, Maude SL, et al. European Hematology Association 2017; Abstract S476.

Single-arm, open-label, multicenter, phase II study

Secondary Endpoints: Duration of Remission, OS, safety, cellular kinetics

CAR-Ts in B-Cell ALL: Eliana

• 83% achieved CR/CRi within 3 months

• All had MRD negative bone marrow – 13% proceeded to alloSCT within 6 months

• Relapse free survival 75% at 6 months

• Median duration of response not reached

• 6 month overall survival 89%, 75% at 12 months

• CRS 78% and no deaths – 38% received tocilizumab

• Other non-hematologic toxicities: hypotension, hypoxia, LFT abnormalities

Buechner J, Grupp SA, Maude SL, et al. European Hematology Association 2017; Abstract S476.

ODAC greenlights tisagenlecleucel (Novartis CTL019) for FDA approval later this year based on Eliana results

Safety of CAR-Ts in ALL

• Cytokine-release syndrome (CRS)

– Associated with peak cytokine elevations consistent with T-cell expansion and proliferation

– Can be mild to moderate or severe and life-threatening

– Systemic markers of inflammation were elevated in all patients

• C-reactive protein

• Ferritin

– Disease burden was associated with CRS • Treat with tocilizumab 8 mg/kg X 1 if necessary—AVOID STEROIDS!

• Encephalopathy with aphasia, confusion, delirium and hallucinations

• B-cell aplasia

Maude SL, Frey N, Shaw PA et al. N Engl J Med 2014;371:1507-17

Grading of CRS CRS revised grading system

Grade Toxicity

1 Symptoms are not life threatening and require symptomatic treatment only

2 Symptoms require and respond to moderate intervention Oxygen requirement < 40% or Hypotension responsive to fluids or low dose of one vasopressor or Grade 2 organ toxicity

3 Symptoms require and respond to aggressive intervention Oxygen requirement ≥ 40% or Hypotension requiring high-dose or multiple vasopressors or Grade 3 organ toxicity

4 Life-threatening symptoms Requirement for ventilator support or Grade 4 organ toxicity (excluding transaminitis)

5 Death

Lee DW, Gardner R, Porter DL, et al. Blood 2014;124:188-195.

Back to KS, ARS #2

• KS eventually received CAR-T cells. He experienced altered mental status, fevers, hypotension and tachycardia. He was transferred to the ICU. Should there be an intervention?

1. Yes, dexamethasone 24 mg per day for 3 days, followed by a 4 day taper

2. Yes, he should be offered pressor support until the episode resolves

3. Yes, he should be given a one time dose of tocilizumab

4. Yes, he should receive IV fluids until the episode resolves

Follow-Up on KS, ARS Question #3

• KS has a transplant following a third CR from CAR-T cells. However, he relapses again with 60% blasts. His flow reveals an abnormal B-cell population that is now CD19 negative and CD22 positive. KS strongly desires additional treatment. What is a reasonable option?

1. Blinatumomab

2. Second HSCT

3. Supportive Care

4. Inotuzumab

Philadelphia Chromosome Positive ALL

• Suppose KS was philadelphia chromosome positive (Ph+)…

– Induction received with an AYA protocol plus dasatinib

– What should the approach be at relapse?

R/R Philadelphia Chromosome + B-Cell ALL • Mutation testing for ABL gene

• Use a TKI not used during initial induction

• Clinical Trial or HSCT if donor available

Mutations TKI Choice

Y253H E255K/V F359V/C/I

Dasatinib

V299L T315A F317L/V/I/C

Nilotinib

E255K/V F317L/V/I/C F359V/C/I T315A Y253H

Bosutinib

T315I Ponatinib NCCN. Acute Lymphoblastic Leukemia.Version 2. 2015. Available at http://www.nccn.org/professionals/physician_gls/pdf/all.pdf. Accessed 10/21/2015 Soverini S , et al. Blood 2011;118:1208-1215


TKI + Intensive Chemotherapy Hyper-CVAD +

Imatinib, N=54

Dasatinib, N=72

Ponatinib, N=37

CR 93% 96% 100%

Cytogenetic CR

95% 83% 100%

CMR or MMR 83% 93% 100%

MRD negativity

88% 94% 97%

Median OS 31 months 47 months Not Reached

HSCT 30% 17% 24%

Daver N, et al. Haematologica 2015;100:653-661 Ravandi F, et al. Cancer 2015;000:000-000 Jabbour E, et al. Lancet 2015;000:000-000

MMR=major molecular response

N=45 R/R Ph+ ALL

Progressed on 2nd or later generation TKI

Intolerant to 2nd generation or later TKI

with documented intolerance/progressi

on on imatinib >5% BM blasts

Blinatumomab: 6-week cycle 9 mcg/day ->

28 mcg/day x 4 weeks 2 weeks off

Up to 5 cycles

CR/CRh after 2 cycles 36%

Martinelli G, Dombret H, Chevallier P, et al. ASH 2015. Abstract 679.

Secondary Endpoints: MRD, RFS, OS, AlloSCT rate

Prospective, Phase II

Blinatumomab in Ph+ ALL: ALCANTARA

ARS Question #4 • JV is a 50 yo Ph+ B-cell ALL patient who received initial

treatment with Hyper-CVAD + Dasatinib and achieved a MMR. Six months later he is noted to have a rising PCR for BCR-ABL transcripts while on maintenance dasatinib. What should happen next?

1. Perform ABL gene mutation testing

2. Change dasatinib to ponatinib given MMR rates with ponatinib

3. Discontinue TKI therapy and offer more traditional chemotherapy

4. Offer autologous stem cell transplantation

The Future… • Ongoing clinical trials

– Ph+

– Initial treatment in B-ALL

– Investigational agents

• Best sequence of agents to be determined

• The best bridge to transplant unknown

In Summary • Clinical trials should be offered for induction and relpase or

refractory disease

• HSCT should be offered in CR1 for high risk disease

• MRD status predicts disease response

• Conventional chemotherapies may give second CR rates as high as 50%, but not all patients will be candidates

• Monoclonal antibodies should be considered in patients with targetable antigens present on leukemic blasts

• Novel immune therapies may help patient overcome immune escape mechanisms

• The best sequence for therapy in r/r ALL is unknown

UPDATES IN RELAPSED/REFRACTORY B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)

Larry W. Buie, Pharm.D., BCOP, FASHP Manager, Adult Clinical Pharmacy Services PGY2 Adult Oncology Residency Program Director Memorial Sloan Kettering Cancer Center 5 August 2017