AALL1331: Blinatumomab in First Relapse of Childhood B-Lineage ...€¦ · COG protocols are research plans designed to investigate particular study questions, that recommendations

C211 COG Track ‐ AALL1331: Blinatumomab in First Relaspe of B‐Lineage ALL 1

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Debra Schissel RN, CPON, CCRP Sue Zupanec MN, NPCOG Track at APHON 2016

AALL1331: Blinatumomab in First Relapse of Childhood

B-Lineage Lymphoblastic Leukemia

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COG Disclosure

The information in this presentation is intended for educational purposes only and is solely for the use of the individual nurse learner. This information is not intended as the sole source of guidance in providing Children’s Oncology Group (COG) protocol-directed nursing care, and current COG protocols should always be consulted prior to making patient care decisions for any patient enrolled on a COG protocol. Learners should also be aware that COG protocols are research plans designed to investigate particular study questions, that recommendations for treatment and dosing are made within the context of specific research aims, and that these recommendations are intended only for use within a structured research setting. Although every attempt has been made to assure that the informational content contained herein is as accurate and complete as possible as of the date of presentation, no warranty or representation, express or implied, is made as to the accuracy, reliability, completeness, relevance, or timeliness of this content. This information may not be copied or redistributed in any form, or used for any purpose other than nursing education.

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Disclosure

Debra Schissel and Sue Zupanec have no industry relationships to disclose

Off label use of blinatumomab will be discussed


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Definitions

Event Free Survival Survival free from unfavorable events (including induction failure, relapse, death from any cause, or SMN)

Overall Survival Survival regardless of disease status (includes all patients that are alive, even those who are relapsed)

Disease Free Survival Survival free from the disease under study (alive patients in remission)

Progression Free Survival Length of time during and after treatment that patient lives with the disease, but it does not get worse

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Objectives

Review background for Relapsed B-ALL♦ Currently reported EFS♦ Best published therapy: UKALLR3 (backbone)

Discuss blinatumomab – BiTE♦ Mechanism of action♦ Toxicity profile ♦ Unique delivery and practical considerations♦ Outcomes/lessons learned from early phase trials

Review current COG phase III trial AALL1331

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Relapsed ALL Risk Stratification

Time of Relapse

Early < 18 mos since initial diagnosis

Intermediate > 18 mos but < 36 mos since initial diagnosis

Late >36 mos since initial diagnosis

Site of Relapse

Isolated bone marrow

Isolated extramedullary

Combined bone marrow and extramedullary


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Survival in Relapsed ALL: Timing and Site

Data from Nguyen et al. (2008)

• COG patients with B- or T-ALL from 1988-2002• 1961/9585 (20.5%) experienced a relapse

12%

18%

44%

24%

12%

40%

60%

39%44%

68%

78%

59%

0%

20%

40%

60%

80%

Early Intermediate Late Overall

Isolated Marrow Combined Isolated CNS

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Survival Rates: Relapsed ALLEarly Isolated Bone Marrow: 12%

Intermediate Combined BM and CNS: 40%

Late Isolated CNS: 78%

Wide Range of EFS for Relapsed ALL

Complex Risk Stratification

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Survival Rates: Risk Factors

Evidence of refractory or resistant disease: Intervention!

At time of relapse •Site •Location

Disease response to re-induction

•Post re-induction response (BLK/Cycle1)•Measured by MRD

Disease persistence •MRD Pre-SCT

Post-SCT factors •Positive MRD•Lack of clinical aGVHD


Risk Assessment: Relapsed B-ALL

Site Isolated bone marrow Unfavorable

Isolated extramedullary Favorable

Combined bone marrow & extramedullary

Unfavorable (maybe slightly more favorable compared to isolated bone marrow)

Timing of Relapse Early Unfavorable

Intermediate Unfavorable

Late Favorable

Post Re-InductionResponse

MRD negative Favorable

M2/M3 or MRD positive Unfavorable

Pre-SCT MRD MRD negative Favorable

MRD positive Unfavorable

Post-SCT MRD detectable Unfavorable

No aGVHD Unfavorable

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MRD Predicts Survival in Relapsed ALL Disease response post initial Re-induction BLK♦ N = 60 BFM HR relapsed patients

MRD response remains a strong predictor of outcome!♦ 73% if MRD-♦ 19% if MRD+

Paganin, M. et al. (2008)

© 2

008

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MRD Prior to SCT SCT remains standard of care for subsets of patients with

relapsed ALL♦ HR/IR patients♦ MRD positive post re-induction

Relapse post SCT is a significant cause of treatment failure BFM Relapsed Patients with SCT indication♦ MRD level prior to SCT predicts EFS

• MRD < 0.001 EFS 61%• MRD > 0.001 EFS 27%

Bader et al. 2009

Resistant Disease!


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MRD pre SCT and Predicted Survival

Bader et al. 2009

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009

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More Predictors of Survival: Post SCT

ASCT0431: Predictors of Poor EFS post-SCT ♦ Detection of MRD+ disease♦ No aGVHD

Pulsipher, Blood (ASH Abstract), 2012

GVHD Status EFS PredictionNone •19%

Grade II-IV •35%

MRD+ post-SCT •14-fold increased relapse risk

Need for new/novel interventions post-SCT


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Treatment Options for Relapsed B-ALL

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Case Examples

Presentation: WBC 4 x 109/L/CNS negative Neutral cytogenetics /EOI M1 and MRD-Prior treatment: AALL0932 AR Arm CRelapse timing: 37 mos post diagnosis (late)Site: Isolated bone marrow diseaseRisk Classification at Relapse: LR

Jacob 7-yrs-old

Presentation: WBC 115 x 109/L CNS negative t(1:19)/EOI M1 and MRD-

Prior treatment: AALL1131 HR Arm BRelapse timing: 28 mos post diagnosis (early)Site: Isolated bone marrow diseaseRisk Classification at Relapse: HR

Georgie11-yrs-old

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UKALLR3: Backbone for AALL1331 Randomization occurs during induction♦ Idarubicin vs. mitoxantrone♦ 216 participants randomized

Primary outcome goal♦ PFS

Parker, C. et al. (2010)

Randomization stopped early due to significant differences in PFS and OS between groups


19Parker, C. et al. (2010)

UKALLR3: Results

© 2

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Survival Mitox Arm IDA Arm3-yr PFS •64.6% •35.9%

3-yr OS •69% •45.2%

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Challenges in Relapsed ALLOutcomes for patients remain unsatisfactory♦ Suboptimal remission rates (MRD response)♦ Poor OS rates

Treatment for relapsed ALL♦ Involves traditional cytotoxic chemotherapy ♦ SCT

• Unclear benefit of intensive chemotherapy versus SCT• Both strategies result in poor outcomes and undesired long term sequelae

Nguyen et al. 2008

New Agents Needed!!

https://visualsonline.cancer.gov/details.cfm?imageid=2191

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Targeted TherapiesAALL1331

https://en.wikipedia.org/wiki/Blinatumomab#/media/File:BiTE_antibody_en.svg


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New Targeted Agents for Relapsed ALL

Potential Benefits of a Targeted New Agent♦ Improve EFS and OS without further intensification of

standard chemotherapy♦ Reduce detectable MRD prior to SCT to improve outcomes

Picking a promising agent♦ A targeted approach!!!♦ CD19


CD3

CD19

TCR

BlinatumomabMechanism of Action(BiTE = Bi-specific T-Cell Engager)

Does not require MHC Class I and/or peptide antigen

Acts independently of specificity of TCR

Allows T cells recognition of TAA

Blina-tumomab

Tumor Cell

Any T Cell

Slide courtesy of Dr. Lia Gore

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Blinatumomab: BiTE

CD19 is an excellent target!!!♦ CD19 not expressed on pluripotent stem cells

Expressed on B Lymphocytes, from early precursor cells through mature B cells♦ Expressed on the majority of B precursor ALL cells

Aimee Ermel, 2012


25Over 16 years to get to current Phase III study!

History of BiTE

• Three phase I trials (NHL, CLL)• Phase II MRD+ ALL trial (First pivotal study in EU – 2010)• Compassionate use in Pediatric ALL• Phase III trial as COG AALL1331

Clinical Studies

• Started as short-term IV infusion• Changed to continuous IV infusionAdministration

• 1990’s preclinical development• 2001 clinical development• 2003 switched to continuous IV infusion• 2008 clinical concept published • 2010 start of 1st pivotal study

Key Milestones

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Relapsed/Refractory B-ALL: Adult Trials

Author Adult Patients Phase Outcomes

Topp(2014)

• n = 36•Ages 18-77 yrs •Refractory or relapsed B-ALL

• II • CR/CRh♦25/36 (69%)

•Responders♦22/25 (88%) ♦MRD negative

Topp(2015)

• n = 189•Refractory or relapsed B All

•II •Evaluated post 2nd cycle•CR/CRh♦81/189 (43%) ♦MRD evaluable responders 73/81♦60/73 (82%) MRD negative

Topp et al. (2014), Topp et al. (2015)

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Early Peds Experience with BiTE

Author Number of Patients

Phase Reported Outcomes

Handgretinger (2011)

• 3 All post HSCT • 3 patient cohort• Compassionate

• All 3 achieved MRD CR at day 28

Shlegel(2014)

• 9 - All patientsprior HSCT

• Cohort study• Compassionate

• 5/9 achieved MRD CR at day 28

VonStackelberg(2016)

• N=49 at phase I

• n=44 treated at phase II dose

• Phase I/II• Primary

endpoint CR within 2 cycles

• 70 evaluable – (27/70) achieved CR

• Those in CR (14/27) 53% MRD negative

Ability to achieve MRD negative Remission


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FDA Approval

Sept. 1, 2016

FDA approval of Blinatumomab for use in Pediatric Patients with Philadelphia Chromosome-Negative Relapsed or Refractory B-cell Precursor Acute Lymphoblastic Leukemia♦ Accelerated approval

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Lessons Learned From Early BiTE Trials

Evidence of clinical activity

Very short half-life: 2 hours♦ Required continuous exposure

for clinical benefit

Results in T-cell Activation:♦ T-cell proliferation♦ Lysis of tumor cells♦ Cytokine release

Development of AALL1331 ♦ Blinatumomab with UKALLR3 backbone

Aimee Ermel, 2012

Pluripotent Stem Cell

Lymphoid Progenitor

Myeloid Progenitor

B-lymphocyte

T-lymphocyte

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COG AALL1331Protocol Details


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AALL1331: Primary Aim

Will addition of blinatumomab to UKALLR3 backbone improve DFS for pediatric patients in first relapse of B-ALL?

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AALL1331 Schema

Induction – same for all patients♦ Risk classification occurs at end of BLK 1

• LR, IR/HR or treatment failure♦ Treatment failure at end of BLK 1 or 2

• Off protocol• May have BLINA salvage therapy x 2 cycle• Relapse at end of BLK 2 or pre SCT → OFF THERAPY

Therapy arms – IR/HR

ARM A No BLINA SCT

ARM B BLINA X 2 cycles SCT

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AALL1331 Schema

Induction – same for all patients♦ Risk classification occurs at end of BLK 1

• LR, IR/HR or treatment failure♦ Treatment failure at end of BLK 1 or 2

• Off protocol• May have BLINA salvage therapy x 2 cycles• Relapse at end of BLK 2 or pre SCT → OFF THERAPY

Therapy arms - LR

ARM C No BLINA, BLK 2 & 3, Continuation 1 &2 Maintenance

ARM D BLINA, Continuation1, BLINA, Continuation 2 Maintenance


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AALL1331 Schema – Blinatumomab-S

Salvage Arm♦ For patients who

• Are classified as treatment failure after BLK 1 or 2 treatment• Have NOT previously received BLINA on study• Do not have CNS disease

♦ Non-randomly assigned♦ Remain on study if CR obtained♦ Different dosing than BLK cycles (dose escalation)

BLINA-S BLINA 1, +/- BLINA 2 SCT

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Risk Classification AALL1331

Low Risk •Late -(> 36 mos) marrow, end-BLK 1, MRD <0.1%-(> 18 mos) IEM, end-BLK 1, MRD <0.1%

Intermediate Risk •Late -(> 36 mos) marrow, end-BLK 1, MRD >0.1%-(> 18 mos) IEM, end-BLK 1, MRD >0.1%

High Risk •Early -(< 36 mos) marrow-(< 18 mos) IEM

Treatment Failure(at end of BLK 1)

•Failure to achieve-M2 or better marrow-CNS1

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Hematopoietic Stem Cell Transplant

Decisions around transplant at discretion of transplant center♦ Donor selection♦ Transplant conditioning

Rapid taper of immunosuppression for patients with HR predictors of relapse post SCT♦ Early MRD detection post SCT♦ No aGVHD


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AALL1331: Exploratory Aims

To estimate for TF for patients not previously receiving blinatumomab, the CR and rate of MRD <0.01% prior to SCT, and the proportion able to proceed to SCT in CR after treatment with blinatumomab

To assess the feasibility and safety of rapid taper of immune suppression for the subset of SCT patients with MRD ≥0.01% pre-and/or post-SCT with no aGVHD

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AALL1331: Eligibility

Inclusion •>1 and < 31 yrs at time of relapse•First relapse of B-ALL +/- extramedullary disease

Exclusion •Ph+ ALL, T-ALL or TLL•Mature B-ALL or B-LL•Preexisting CNS pathology •Uncontrolled seizure disorder•Known concomitant genetic syndrome (e.g. DS)

See protocol for more specific inclusion and exclusion criteria

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Block 1 Timing

Complete BLK 1

Post-BLK 1 Evaluation♦ Risk assignment based on end-BLK 1 criteria

• End-BLK 1 cannot be done prior to Day 29 (+/- 1 day)

♦ Post-BLK1 treatment begins after end-BLK 1 • Patients should have full or partial recovery• Requires callback and receipt of treatment assignment• Must begin treatment according to time frames listed in the protocol


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Case Study - Georgie

Due for day 29 end-Induction evaluation♦ ANC 150/μL and platelets 31,000/μL

Can this evaluation be delayed?

The evaluation may be delayed no later than Day 36 (+/- 1 day) •If ANC < 500/μL and platelets < 50,000/μL on Day 29

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Case Studies: Risk Allocation

Jacob Georgie

Relapse Late Isolated BM Early Isolated BM

Post BLK 1 Response

M1 (<5% blasts)MRD 0.02% (<0.1%) = MRD negative

M2 (17% blasts)MRD positive

Eligible Arm LR randomization HR/IR randomization

SCT No Yes

Randomized ARM D ARM B

Blinatumomab

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When must the second block start?

HR/IR must begin within 14 days after risk assignment for patient to continue on protocol

Jacob Georgie

Protocol Arm LR Arm D HR/IR Arm B

2nd Course •LR pts- proceed to BLK 2• Chemo must start within 5

days of callback

•Blinatumomab

Count RecoveryRequired?

•No•LR arm proceeds to BLK 2 for Day 1 VCR and DEX

•Recommend await count recovery for Day 8 IV MTX

•Recommended but NOT required to have

- ANC ≥ 500/μL- Platelets ≥ 50,000/μL


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Blinatumomab: ♦ Continuous IV infusion over 28 days (Days 1-28)

♦ IV bag changes every 96 hours

Premedication: DEX♦ Day 1: 6-12 hours prior to initiation of infusion♦ Day 1: 30 minutes prior to infusion

Intrathecal therapyDay 8: IT MTX CNS1 and 2*, ITT CNS3Day 15: IT MTX CNS2*, ITT CNS3Day 22: IT MTX CNS2*, ITT CNS3, *CNS2 weekly ITs until 2 clear CSF samples

Blinatumomab Course

Blinatumomab infusion should not be interrupted for LPs!

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Case Study: Georgie – Adverse Event

20 hours into infusion Georgie spikes a fever (39.7⁰C )♦ She feels achy, has chills and is fatigued♦ O2 sats < 90 while she is sleeping- requires O2 support ♦ SOB with ambulation ♦ Crackles in right lower lobe with auscultation

What are concerns in caring for Georgie?♦ Hypoxia♦ Fever/Sepsis♦ Pulmonary edema♦ Capillary leak syndrome♦ Cytokine release syndrome

Aimee Ermel, 2012

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Cytokine Release Syndrome

Most common toxicity associated with BiTE

Constellation of inflammatory symptoms♦ Results from cytokine elevations

♦ Associated with T-cell proliferation

CRS ranges from mild to severe to life threatening♦ Mild: flu-like symptoms, fever, myalgia

♦ Severe: vascular leak, hypotension, pulmonary edema, coagulopathy

♦ Life threatening: can lead to multi-system organ failure

Cytokine elevations can be measured ♦ Degree of elevation does not always correlate with clinical severity

Barrett, D. et al. (2014)

Image from Blausen.com staff. "Blausen gallery 2014". Wikiversity Journal of Medicine. DOI:10.15347/wjm/2014.010. ISSN 20018762. -


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CRS: How Common?

Pediatric reported CRS based on high tumor burden♦ Blintatumomab as single agent at time of relapse

Gore et al. (2014, ASH)♦ n = 39 pediatric patients♦ CRS 8% (3/39) of patients

• Two with Grade 3 events

Topp et al. (2015, Lancet Oncology)♦ n =189 adult patients with relapsed or refractory B-ALL♦ Received Dex in prephase to reduce tumor burden♦ 2% of patients had Grade 3 CRS

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Klinger et al. (2012)© 2012

Cytokine Concentrations

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Management of CRS

Reported with first cycle of BiTE♦ Typically within first 12-72 hours

Most Significantly elevated cytokines:♦ IL10, IL6, IFNy

Is it possible to target the cytokines themselves?

Anti IL6 (tocilizumab) – resolution of CRS ♦ Reversal and clinical improvement seen within 24 hours♦ FDA approved for JIA in children as young as 2 years

Maude, 2014; Barrett, 2014

https://upload.wikimedia.org/wikipedia/commons/3/38/IL10_Crystal_Structure.rsh.png


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New CRS Toxicity Grading System

Porter, D. ASH, December 14, 2014 © 2014

Grade Clinical Picture Management

1 Mild: Flu-like symptoms, fever, myalgia •Antipyretics•Supportive care

2 Moderate: beginning S/S of organ dysfunction (e.g. grade 2 creatinine, grade 3 LFTs)

•Hospitalization•IV therapies

3 Severe: ↑ing S/S of organ dysfunction (e.g. grade 3 creatinine, grade 4 LFTs),hypotension, coagulopathy, hypoxia

•O2/IVFs/pressors•FFP/Cryo•Anti IL-6-Tocilizumab

4 Life threatening: Significant hypotension/ Hypoxia

•Multiple pressors•Ventilator support •Anti IL-6-Tocilizumab

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Tocilizumab: When and How?

Grade 1 and 2♦ Supportive interventions

Grade 3 and 4♦ Patient likely in PICU♦ Consideration for administration of Tocilizumab

• Dosing per institutional guidelines


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Case Study: Georgie

To PICU for grade 3 CRS♦ Receives Tocilizumab

What happened?♦ By hour 72, CRS has resolved to grade 1

What to do about blinatumomab?♦ Can resume at a lower dose for the remainder of this cycle

♦ Follow protocol dose modifications for next cycle

• Georgie should be in hospital for dose escalation


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Jacob’s nursing assessment at hour 24♦ Easily wakes, seems confused ♦ Struggles to perform finger-to-nose assessment ♦ He experiences a brief generalized seizure

(Grade 2 toxicity ) What to do?♦ Stop infusion♦ Administer DEX per protocol/Seizure medications♦ Investigate other causes

Can blinatumomab resume?♦ Refer to dose modification table (may

restart of resolves with 14 days)

Can dose be escalated?♦ Not allowed following neurotoxic event

Case Study: Jacob

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Unique Neurotoxicity with BiTE

All CNS reported toxicities with BiTE have been reversible!

Temporary CNS dysfunction may include♦ Encephalopathy♦ Trembling/Apraxia♦ Reversible seizures♦ Somnolence/Agitation♦ Dizziness/Confusion/Disorientation ♦ Speech/Coordination disorders/Loss of movement

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Daily Neurotoxicity Assessments

Adults♦ Daily handwriting sample predicts future nervous system toxicity

before clinical toxicity develops♦ Earlier introduction of DEX

Children♦ Daily finger-nose-finger or writing sample test is recommended

as age-appropriate for patient

If change noted in finger-nose-finger or handwriting test, it is recommended to start DEX


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Adverse Events: Criteria to Resume

If eligible to resume♦ The 28-days of infusion must be completed

♦ Subsequent cycles• After 7days of dose reduction – if no further AE may dose escalate

♦ No dose escalations following > Grade 2 neurotoxicity

Permanent discontinuation/Off protocol♦ AEs requiring interruption of infusion that do not resolve to

< Grade 1 toxicity within 14 days

♦ Second AE requiring interruption of infusion

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Practical Considerations

Double lumen central venous access♦ Dedicated line for blinatumomab

Hospitalization: close observation♦ Limited nursing assignment for first 72 hours

• Highest risk period for CRS

♦ Vital signs q 4hours♦ Daily Neuro checks: Finger-nose-finger, writing sample, sticker charts

Hospitalization is STRONGLY recommended for:- First 3 days of blinatumomab cycle AND- First 2 days s of subsequent blinatumomab cycles

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Blinatumomab/Equipment for Administration Infusion♦ Requires 0.2 micometer filter, and DEHP-free tubing♦ Rate of infusion: 5 mL/hr♦ BiTE stable 96 hours at room temperature

• IV bag change q 96 hours• IV bags can be made up to 8 days in advance

Infusion pumps must meet study requirements♦ CADD VIP and VIP Solis, Prizm or Legacy ♦ Must have visual/auditory alarms and be lockable♦ No cassettes (they have DEHP)♦ Spare pumps available (2 per patient) and 9-volt batteries as back-up

Home care pumps have lower infusion rate calibrations. Consider using it while patient in hospital to provide hands-on training.


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Other Tips!

Bags •Have child in clinic at least 1-hr prior to needed bag change

•Expect overfill•Have prepared back-ups

Pumps/Battery •Store where readily available if needed after-hours

Tubing/Caps •Do changes with 2 nurses to ↓ interruption time

CVL Flushing •Avoid flushing dedicated BiTEline to ↓ chance of bolus dose (less concerning on AALL1331 compared to early trials)

•Unavoidable in clearing occlusions/ or at end of 28-day infusion

Interruptions •Interruption > 1 hr must be recorded•Interruption > 4 hours requires readmission to hospital and use of new bag to resume infusion

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Jacob Case Study: Infusion Issues

Day 21 of blinatumomab♦ Jacob has a episode of bacteremia which requires antibiotic therapy

IV over an hour 4 times a day

How do you work this therapy around the continuous blinatumomab infusion?

Record all infusion interruptions Must be as minimal as possible

Re-start infusion as soon as possible


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Georgie Case Study: Pump/Infusion Issues

What to do????

Must follow institutional guidelines for unblocking CVL♦ Blinatumomab will likely be interrupted for >4 hours to unblock CVL♦ Patient to be admitted to hospital to resume infusion

• New bag of blinatumomab should be hung when infusion resumes

Georgie is at home and the mother calls to report the pump has malfunctioned and is no longer infusing the blinatumomab. They live 60 minutes from the hospital. When they arrive, the nurse is unable to flush or obtain blood return from the blinatumomab lumen.

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Research Studies

Immunogenicity/PK peripheral samples are required:♦ Pre Cycle 1: Immuno Hour 0 prior to start of blinatumomab♦ Day 2 Cycle 1: PK ♦ Day 14 Cycle 1: PK♦ Post Cycle 2: Immuno♦ Pre-maintenance: Immuno prior to start of Cycle 1 maintenance

In cases where blinatumomab treatment will not continue to Cycle 2, collect sample at the end of Cycle 1 • See section 13.0 for optional research studies

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Honoring our Patients

“Far and away the best prize that life offers is the chance to work hard at work worth doing”

- Theodore Roosevelt


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AALL1331: Discussion

[email protected]

[email protected]

We want to hear from you!

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Abbreviations

TERM ABBREVIATIONDi(2-ethylhexyl) phthalate DEHP

Absolute neutrophil count ANCAcute graft versus host disease aGVHDAcute lymphoblastic leukemia ALLAdverse events AEAmerican Society of Hematology ASHAverage risk ARBerlin Frankfurt Munster BFMBi-specific T-cell Engager BITE®Blinatumomab BLINABlock BLKBone marrow BM

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AbbreviationsTERM ABBREVIATION

Centigrade CCentral nervous system CNSCentral venous line CVLCerebrospinal fluid CSFChemotherapy ChemoChildren's Oncology Group COGChronic lymphocytic leukemia CLLClinical Remission WITHOUT Complete Hematologic Recovery CRhCryoprecipitate CryoCytokine Release Syndrome CRSDexamethasone DEX


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AbbreviationsTERM ABBREVIATION

Di(2-ethylhexyl) phthalate DEHPDisease free survival DFSDown syndrome DSEvent free survival EFSEvery qExample e.g.Fresh frozen plasma FFPGraft versus host disease GVHDHigh risk HRInterleukin ILIntermediate risk IRIntrathecal Triple ITT

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Abbreviations

TERM ABBREVIATIONIntravenous IVIsolated extramedullary disease IEMLiver function tests LFTEvent free survival EFSEvery qExample e.g.Fresh frozen plasma FFPGraft versus host disease GVHDHigh risk HRInterleukin ILIntermediate risk IRIntrathecal Triple ITT

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Abbreviations

TERM ABBREVIATIONIntravenous IVIsolated extramedullary disease IEMLiver function tests LFTLow risk LRLumbar puncture LPMajor Histocompatability Complex MHcMatched related donor MRDMethotrexate MTXMilliliter(s) mL(s) or ml(s)Mitoxantrone MITOXMonths mosNon-Hodgkin lymphoma NHL


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Abbreviations

TERM ABBREVIATIONOverall survival OSOxygen O2Pediatric intensive care unit PICUPharmacokinetics PKProgression free survival PFSSaturation satsSecond malignant neoplasm SMNShortness of breath SOBSigns and symptoms S/SStem cell transplant SCTT-cell receptor TCR

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Abbreviations

TERM ABBREVIATIONTranslocation tTreatment failure TFTumor-associated surface antigen TAAVersus vs.Vincristine VCRWhite blood count WBC

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References

Bader, P. Kreyenberg, H., Henze, GH, et al. Prognostic value of minimal residual disease quantification before allogeneic stem-cell transplantation in relapsed childhood acute lymphoblastic leukemia: the ALL-REZ BFM Study Group, Journal of Clinical Oncology, (2009), 27:377-384.

Gore, L., Locatelli, F., Zugmaier, G. Initial results from a phase 2 study of blinatumomab in pediatric patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia, Blood, (2014), 124, 3703.

Handgretinger, R., Zugmaier, G., Henze, G., et al. Complete remission after blinatumomab-induced donor T-cell activation in three pediatric patients with post=transplant relapsed acute lymphoblastic leukemia, Leukemia (2011), 25, 181-184.


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References

Klinger, M., Brandl, C., Zugmaier, G. et al. Immunopharmacologic response of patients with B-lineage acute lymphoblastic leukemia to continuous infusion of T-cell engaging CD19/CD3 specific BiTE antibody blinatumomab, Blood (2012), 119, 6226-6233.

Nagorsen, D., Kufer, P., Baeurle, PA, Bargou, R., Blinatumomab: a historical perspective, Pharmacology Therapeutics, (2012), 136(3), 334-342.

Nguyen, K., Devidas, M., Cheng, SC et al. Factors influencing survival after relapse from acute lymphoblastic leukemia: a Children’s Oncology Group study, Leukemia (2008), 22, 2142-2150.

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References

Paganin, M., Zecca, M., Fabbri, G. et al. Minimal residual disease is an important predictive factor of outcome in children with relapsed high risk acute lymphoblastic leukemia, Leukemia (2008), 22, 193-200.

Parker, C., Waters, R., Leighton, C. et al. Effect of Mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukemia (ALLR3): an open-label randomized trial, Lancet (2009), 376, 2009-2017.

Pulishpher, MA, Langholz, B, Wall, DA, et al. The relationship of acute GVHD and pre-and post transplant flow-MRD to the incidence and timing of relapse in children undergoing allogeneic transplantation for high risk ALL: defining a target population and window for immunologic intervention to prevent relapse (2012) ASH annual meeting abstracts, 120, 470.

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References

Schegel, P., Lang, P., Zugmaier, G., et al. Pediatric post transplant relapsed/refractory B-precursor acute lymphoblastic leukemia shows durable response by therapy with T-cell engaging bispecific antibody blinatumomab, Haematologica (2014), 99(7), 1212-1219.

Teachy, DT, Rheingold, SR, Maude, SL, et al. Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy, Blood (2013), 121: 5154-5157.


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References

Topp, MS, Gokbuget, ., Zugmaier, G., et al. Phase II trial of the anit-CD19 bispecific T cell-engager blinatumomab shows hematologic and molecular remission in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia, Journal of Clinical Oncology, (2014), 32, 4134-4140.

Topp, MS, Gokbuget, N., Stein, AS, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukemia: a multi-center, single arm, phase 2 study, Lancet (2015), April 16 (4).

Documents

AALL1331: Blinatumomab in First Relapse of Childhood B-Lineage ...€¦ · COG protocols are research plans designed to investigate particular study questions, that recommendations