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©2018 MFMER | slide-1

ALL You Need to Know: Immunotherapy in Relapsed/Refractory Acute Lymphoblastic Leukemia

Kristen Peterson, PharmDPGY-1 Pharmacy ResidentFebruary 13, 2018


Learning Objectives• Describe the current standard of care for treatment

of acute lymphoblastic leukemia (ALL)• Review newly approved therapies for

relapsed/refractory (r/r) ALL• Discuss treatment considerations for selection of

newly approved therapies in r/r ALL


• Acute: Disease that progresses quickly• Lymphoblastic: Develops from immature

lymphocytes• Leukemia: Cancer that primarily affects bone

marrow and blood

Acute Lymphoblastic Leukemia


Acute Lymphoblastic Leukemia • Blood cancer characterized by clonal

proliferation of a malignant lymphoblast

• Represents <4% of all cancers• ~80% of childhood leukemia• ~20% of adult leukemia

• Cure rates• ~ 80% in children vs 30-40% in adults

American Cancer Society. Acute Lymphoblastic Leukemia. 2017


Lymphoid Cell Lineage

National Cancer Institute. General Information About ALL. 2017


Diagnostic Criteria • ≥ 20% lymphoblasts in bone marrow • Gene characterization

• Fluorescence in situ hybridization (FISH) testing• PCR Testing BCR-ABL1

• High Risk • Presence of MRD, elevated WBC, increased age• Unfavorable cytogenetics

• Hypodiploidy and complex karyotype• t(9;22), t(4;11), t(8;14)

American Cancer Society. Acute Lymphoblastic Leukemia. 2017NCCN. Acute Lymphoblastic Leukemia. Version 5.2017

MRD: Minimal residual diseaseWBC: White blood cell


Treatment Overview • Goal is curative! • Consists of different phases

• Induction • Intensification (Consolidation)• Maintenance Therapy

• CNS Prophylaxis• IT chemotherapy, HiDAC, HD-MTX

• Allogenic Stem Cell Transplant

NCCN Acute Lymphoblastic Leukemia Version 5.2017HiDAC: High‐dose cytarabineHD‐MTX: High‐dose methotrexate


Which of the following is considered a first line therapy for ALL?

• Clinical trial

• Hyper-CVAD/Methotrexate-cytarabine

• Tyrosine kinase inhibitors

• Daunorubicin, vincristine, prednisone, pegaspargase


Standard of Care Treatment

NCCN. Acute Lymphoblastic Leukemia. Version 5.2017

Clinical TrialDaunorubicin,

vincristine, prednisone,

pegaspargase

Hyper-CVAD/Methotrexate-

cytarabine

Targeted therapy utilized for cellular

markers


Targeted Therapy

ALL Ph(+) Ph (-)

CD20+ Chemo+Rituximab+TKI Chemo+Rituximab

CD20- Chemo+TKI Chemo

Ph: Philadelphia chromosomeTKI: Tyrosine kinase inhibitor NCCN Acute Lymphoblastic Leukemia Version 5.2017


Evolution of Targeted Therapy

Imatinib(BCR‐ABL) 2004

Bosutinib (BCR‐ABL) 2016

2000 2017

Dasatinib(BCR‐ABL) 2010

2010

Ponatinib(BCR‐ABL) 2017

Blinatumomab(CD19/CD3) 2014Rituximab

(CD20+) 2006

Tisagenlecleucel(CD19+ CAR‐T)2017

Thomas, DA et al. Cancer. 2006 Apr 1;106(7):1569‐80.Ravandi, F et al. Blood. 2010 Sep 23;116(12):2070‐7.

Castillo E et al. Blood 2010 116:2144

Inotuzumab ozogamicin(CD22+ ADC) 2017

Nilotinib(BCR‐ABL) 2010


Relapsed/Refractory ALL

• Relapsed • Reappearance of blasts after complete remission (CR)

• Refractory • Failure to achieve CR at the end of induction

• Very poor prognosis• Median overall survival (OS) of 4.5 to 6 months• 5-year OS rate of 3 to 10%

• Extramedullary involvement• Lymph, spleen, skin/gums, testicles, and CNS

NCCN. Acute Lymphoblastic Leukemia. Version 5.2017CR: Complete remissionOS: Overall survivalCNS: Central nervous system


Treatments for R/R ALL

Historical

• FLAG• Fludarabine, HiDAC, GCSF

• BFM • High-dose methotrexate

and cytarabine

• Clofarabine

• Nelarabine

• Liposomal vincristine

Novel

• Blinatumomab• Landmark Trial: TOWER

• Inotuzumab ozogamicin• Landmark Trial: INO-VATE

ALL

• CAR-T Cell Therapy (Tisagenlecleucel)

• Landmark Trial: ELIANA


Blinatumomab• First-in-class bispecific monoclonal antibody

targeted at CD19 and CD3• Indication

• Treatment of relapsed/refractory B-cell ALL in adults and children

Pt Wt C1 C2 C3-5 C6-9

<45kg5 mcg/m2/day

15 mcg/m2/day15 mcg/m2/day 15 mcg/m2/day 15 mcg/m2/day

>45kg9 mcg/day

28 mcg/day 28 mcg/day 28 mcg/day 28 mcg/day

Blincyto® [package insert]. Amgen Inc., Thousand Oaks, CA, 2017


Mechanism of Action

T Cell B Cell

BiTE


TOWER Trial: BlinatumomabStudy Design

Phase 3, multi-center, open-label, prospective RCT

Participants

405 patients ≥18 y.o. with heavily treated B-cell precursor ALL

Interventions

Patients randomly assigned 2:1 ratioEither blinatumomab or standard-of-care chemotherapy

Primary Outcome

Overall survival

Kantarjian H, Stein A, Gökbuget N, et al. N Engl J Med. 2017;376(9):836‐847.


Inclusion and Exclusion Criteria

Inclusion Exclusion

Ph-negative B-Cell precursor ALL Other active malignancies

>5% blasts in bone marrow Autoimmune/GVHD

ECOG of 2 or less SCT within 6 wks

ALL refractory to primary or salvage therapy Chemo/radio within 2 wks



Baseline Blinatumomab Chemotherapy

Age (years) 40.8 41.1

ECOG0: 961: 1342: 41

0: 521: 612: 20

Salvagetreatment

phase

Third: 45Fourth: 14

Fifth/later: 7

Third: 45Fourth: 5

Fifth/later: 5

Max central/local

blasts

10-50% 60≥50% 201

10-50% 23≥50% 104

Previous SCT Yes 94 (34.7) Yes 46 (34.3)

Baseline Characteristics



Primary Endpoint



Secondary Endpoint



Efficacy Data


34%

44%

31%

16%

25%

12%

0% 10% 20% 30% 40% 50%

CR w/ full hematologic recovery w/in 12weeks of initiation

CR w/ full, partial, or incomplete recoveryw/in 12 weeks of initiation

6 month event-free survival

Complete Remission

ChemotherapyGroup (N=134)Blinatumomab(N=271)


Adverse Effects


Adverse Event BlinatumomabGroup

Chemotherapy Group

Neurologic event 25 (9.4%) 9 (8.3%)

Cytokine ReleaseSyndrome 13 (4.9%) -


TOWER Trial: Conclusions• Blinatumomab resulted in significantly longer

overall survival than standard-of-care chemotherapy

• The independent safety monitoring committee recommended that the trial be stopped early because of benefit observed with blinatumomab



Inotuzumab ozogamicin• First-in-class antibody conjugate targets CD22

and delivers calicheamicin toxin

• Indication• Relapsed or refractory B-cell precursor ALL

• Dosing

Day 1 Day 8 Day 15Cycle 1 21 days 0.8 mg/m2 0.5 mg/m2 0.5 mg/m2

Besponsa® [package insert]. Pfizer, Inc., Philadelphia, PA, 2017


Mechanism of Action

B Cell


INOVATE-ALL TrialStudy Design

Randomized, controlled, open-label, phase III trial

Participants

218 patients ≥18 y.o. with heavily treated B-cell precursor ALL (either Ph+ or Ph-)

Interventions

Patients randomly assigned 1:1 ratio to: Inotuzumab ozogamicin OR standard-of-care chemotherapy

Primary Outcome

Complete remission and overall survival

Kantarjian H. et al., N Engl J Med. 2016 Aug 25;375(8):740‐53


INO-VATE ALL Results

Efficacy EndpointsInotuzumabozogamicin

(n=109)

Chemotherapy(n=109)

Complete Remission 39 (35.8%) 19 (17.4%)

CR with incomplete blood count recovery 49 (45.0%) 13 (11.9%)

Overall Survival 7.7 months 6.7 months

Duration of Remission 4.6 months 3.1 months

Progression-Free Survival 5 months 1.8 months

Kantarjian H. et al., N Engl J Med. 2016 Aug 25;375(8):740‐5CR: Complete remission


Adverse Events

Kantarjian H. et al., N Engl J Med. 2016 Aug 25;375(8):740‐5

Inotuzumab Group ChemotherapyGroup

Any grade Grade≥3 Any grade Grade≥3

Any Event 48% 46% 46% 43%

Febrile Neutropenia 12% 11% 18% 18%

Thrombocytopenia 37% - 59% -

Veno-occlusive disease (VOD) 11% 9% 1% 1%


Hepatotoxicity and VOD

• Fatal and life-threatening

• Risk Factors• Increased age• Ongoing or prior liver disease• Prior HSCT• HSCT conditioning regimens containing 2 alkylating

agents

• Risk is greater in patients who proceeded to HSCT• Higher non-relapse mortality rates at day 100

Besponsa® [package insert]. Pfizer, Inc., Philadelphia, PA, 2017HSCT: Hematopoietic stem cell transplant


INO-VATE ALL: Conclusion• Inotuzumab ozogamicin was associated with:

• Higher rates of complete remission • Higher percentage of patients with results below the

threshold for minimal residual disease• Longer progression-free and overall survival • Higher incidence of veno-occlusive disease


Tisagenlecleucel

• Utilizes patient’s own T cells with a chimeric antigen receptor to identify and eliminate CD19-expressing cells

• Indication• Treatment of patients up to 25 years of age with B-

cell precursor r/r ALL

• DosingPt Wt Weight-Based Dosing

<50kg 0.2 to 5.0 x 106 CAR-positive viable T cells/ kg body weight

>50kg 0.1 to 2.5 x 108 CAR-positive viable T cells/ kg body weight

Kymriah® [package insert]. Novartis Pharmaceuticals Corporation, East Hanover, NJ. 2017


ELIANA Trial: TisagenlecleucelStudy design

Open‐label, multicenter, single‐arm trial

Participants

63 pediatric and young adult patients

Intervention

Fludarabine 30 mg/m2 daily for 4 days and cyclophosphamide 500 mg/m2 daily for 2 days followed by a single dose of tisagenlecleucel

Primary outcome

Complete remission within 3 months after infusion, duration of CR, and proportion of patients with CR and MRD

CR: Complete remissionMRD: Minimal residual disease



Efficacy Data

Response Rates Tisagenlecleucel(n=63) P-Value

CR/CRi 52 (83%) 0.0001

CR 40 (63%) ---

CRi 12 (19%) ---

Duration of Remission Not Reached 0.0001

CR: Complete remissionCRi: Complete remission with incomplete blood count recovery



Selected Adverse Events

All Grade (%) Grades ≥3 (%)

Cytokine Release Syndrome 79% 49%

Neurological Toxicities 65% 18%

Unspecified Infections 41% 16%

Hypotension 31% 22%



Cytokine Release Syndrome

• Symptoms• High fever, low BP, difficulty breathing, coagulopathy

• Risk Factors• High tumor burden• Active infection• Inflammation

• Treatment• Tocilizumab• Supportive care• Corticosteroids


BP: Blood pressure


• Symptoms • Headaches, encephalopathy, delirium, tremor

• Timing• Concurrent, after resolution, or in the absence of

CRS

• Treatment• Supportive care

Kymriah® [package insert]. Novartis Pharmaceuticals Corporation, East Hanover, NJ. 2017CRS: Cytokine release syndrome

Neurological Toxicities


Which of the following represents the correctly matched adverse effect to the drug?

• Blinatumomab: Metabolic disorders• Inotuzumab ozogamicin: Veno-occulsive

disease• Tisagenlecleucel: Rhabdomyolysis• None of the above are true


Future Directions• KTE-C19 in Adult Subjects With

Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (r/r ALL)

• (ZUMA-3) -- NCT02614066 – Recruiting

• KTE-C19 in Pediatric and Adolescent Subjects With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia

• (ZUMA-4) -- NCT02625480 – Recruiting


Cost

Immunotherapy Agent Acquisition Cost

Blinatumomab $3,599.45 per 35mcg kit

Inotuzumab ozogamicin $18,700 per 0.9mg vial

Tisagenlecleucel $475,000

Axicabtagene ciloleucel $373,000


Patient Case• LM is 44 y.o. F• Diagnosed with Ph + ALL 3/2017, entered into a

clinical trial then relapsed, most recently treated with Hyper CVAD and relapsed again

• Goal is to get her into remission and take her to HSCT


Which agent would be the best choice for LM?

• Blinatumomab• Inotuzumab ozogamicin• Tisagenlecleucel (CAR T)• Tocilizumab


Conclusion• ALL is a malignant disorder of the blood

• Relapsed/refractory ALL has a characteristically poor prognosis

• Novel immunotherapies have improved outcomes in patients with r/r ALL


Questions & Discussion

Kristen Peterson, PharmDPGY-1 Pharmacy ResidentFebruary 13, [email protected]


Blinatumomab Pearls• Pre-medicate with dexamethasone• Do not flush the line• Hospitalization is recommended for first nine days

of first cycle, first two days of second cycle• If you have to hold blinatumomab infusion greater

than 4 hours, must re-dose dexamethasone• If interruption is no longer than 7 days, continue the

same cycle to a total of 28 days of infusion• If interruption due to an adverse event is longer

than 7 days, start a new cycleBlincyto® [package insert]. Amgen Inc., Thousand Oaks, CA, 2017


Inotuzumab ozogamicin Pearls • If peripheral blast count is ≥10,000/mm3

• Can give a combination of hydroxyurea, steroids, and/or vincristine

• Infusion reaction • Pre-medicate: corticosteroid, antipyretic,

antihistamine• Monitor for one hour after infusion ends

• Duration is usually 2 cycles• Consider a third cycle if no CR or CRi and MRD

negativity• If no CR or CRi by cycle 3 discontinue

• Not transplant eligible up to 6 cycles

Besponsa® [package insert]. Pfizer, Inc., Philadelphia, PA, 2017

CR: Complete remissionCRi: CR with incomplete blood count recoveryMRD: Minimal residual disease


Tisagenlecleucel Pearls

• Pre-medicate • Acetaminophen and an H1-antihistamine

• Confirm availability of tocilizumab prior to infusion

• Use universal precautions when handling


peterson 021318 all you need to know pgr - …...• diagnosed with ph + all 3/2017, entered into a...

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