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
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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.
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.
• 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
Total BM blasts below MRD
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
Total BM blasts below MRD
49/109 34/49
45.0 69.4
13/109 3/13
11.9 23.1
33.0 46.3
<0.001 0.004
Kantarjian HM, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med 2016;375:740-53.
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)
Kantarjian HM, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med 2016;375:740-53.
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)
Kantarjian HM, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med 2016;375:740-53.
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, 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
Kantarjian H, Stein A, Gokbuget N, et al. Blinatumomab verus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med 2017;376:836-47.
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
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