Leukemia. Roland B. Walter, MD PhD MS. Fred Hutchinson Cancer Research Center University of Washington

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1 Leukemia Roland B. Walter, MD PhD MS Fred Hutchinson Cancer Research Center University of Washington

2 Discussed Abstracts Confirmatory open-label, single-arm, multicenter phase 2 study of the BiTE antibody blinatumomab in patients with relapsed/refractory B-precursor acute lymphoblastic leukemia (Max S. Topp; abstract 7005) Randomized comparison of ibrutinib versus ofatumomab in relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma: results from the phase 3 RESONATE trial (John C. Byrd; abstract 7008) Results of a prospective, randomized, open label phase 3 study of ruxolitinib in polycythemia vera patients resistant to or intolerant of hydroxyurea: the RESPONSE trial (Srodan Verstovsek; abstract 7026)

3 Learning Objective After reading and reviewing this material, the participant should be able to: Assess the benefits and toxicity profiles of three novel targeted agents (blinatumomab, ibrutinib, and ruxolitinib) for the treatment of adult patients with hematologic malignancies Describe their role in future treatment algorithms

4 Adult ALL Effective Therapies Needed A Incidence Rates (per 100,000) < Age (Years) High rates of initial response B Most patients will relapse < Median survival after relapse with salvage chemotherapy: months 5-Year Relative Survival (%) Age (Years) Males Females SEER 2014

5 Emerging Therapies for Adult ALL Pediatric-inspired chemotherapy regimens Novel conventional agents: clofarabine, liposomal vincristine, nelarabine Targeted therapeutics Tyrosine kinase inhibitors (for Ph + ALL) Naked antibodies (e.g. CD20) Antibody-drug/toxin conjugates (e.g. CD22) CAR T-cells (e.g. CD19) Bispecific antibodies (e.g. CD19/CD3)

6 Blinatumomab Mode of Action Bispecific T-cell engaging (BiTE) antibody that redirects CD3 + T-cells to lyse CD19 + ALL cells CD3 Ab CD3 CD3 + T-cell Cytotoxic Granules BiTE Ab Lytic Synapse Nuclear Condensation Membrane Blebbing CD19 Perforins Granzymes CD19 Ab CD19 + ALL Target Cell Adapted from: Blood Rev 2014;28:

7 Blinatumomab in Adult ALL 20 patients with persistent/recurrent MRD after chemotherapy: 80% MRD response; 61% RFS at 33 months (Blood 2012;120:5185) 36 patients with relapsed/refractory ALL: 69% CR/CRh rate (88% MRD neg ) after 2 cycles; 9 mo median OS (Bone Marrow Transplant 2013;48:S40) Several clinical challenges Requirement for continuous IV drug administration Cytokine-release syndrome Reversible neurologic toxicities

8 Screening and Enrollment Follow-up (up to 24 months) ASCO 2014: Confirmatory Study Multicenter phase 2 study in 189 adults aged 39 (18-79) years with Ph - B-cell ALL Primary refractory disease, early 1 st relapse, early relapse after allogeneic HCT, any disease >1 st salvage At least 10% bone marrow blasts (i.e. measurable disease) No history of clinically relevant CNS pathology Blinatumomab 28 μg/day* civ infusion 4 weeks on, 2 weeks off Up to 2 cycles Induction Blinatumomab 28 μg/day civ infusion 4 weeks on, 2 weeks off Up to 3 cycles Consolidation Study Endpoints Primary CR/CRh during the first two cycles Secondary CR, CRh Relapse-free survival Overall survival HSCT realization Incidence of adverse events HSCT Offered to Patients in CR/CRh Exploratory Minimal residual disease response by PCR during the first two cycles *Only cycle 1, days 1 to 7: 9 μg/day

9 Main Study Findings CR/CRh within 2 therapy cycles: 43% (CR: 33%; CRh: 10%) MRD response: 82% Allogeneic HCT after CR/CRh: 40% Median OS/RFS: 6.1 months/5.9 months Landmark analysis: OS 9.9 months for responders (vs. 2.7 months) Grade 3/4 toxicities in 67% of patients (neurologic: 13%) Deaths in 15% (none while in response) Drug may be more efficacious with lower tumor burden All responders N CR/CRh Rate % 95% CI (36 50) Bone marrow blasts 10% to <25% 25% to <50% 50% to <75% 75% (48 84) (59 90) (15 54) (20 38) CR/CRh Rate, %

10 Summary and Next Steps Study confirms single-agent activity of blinatumomab in adults with relapsed/refractory Ph - B-ALL Bridge to transplant for many patients Drug likely more effective in lower burden disease Registration trial in R/R patients ongoing (NCT ) Role in upfront/combination therapy? Phase 3 trial ongoing (NCT ) Could drug eliminate need for HCT in some patients? Role in maintenance or post-hct therapy? Avoidance of conventional chemotherapeutics if combined with other targeted agents?

11 CLL/SLL A Incidence Rates (per 100,000) < Age (Years) Highly variable natural history Poor outcomes in defined patient subsets (e.g. 17p13.1 deletion) Recent years: evolution from monotherapy with alkylating agent to chemoimmunotherapy (e.g. FCR) Improved outcomes, but typically not curative Challenge: treatment-related toxicities B 5-Year Relative Survival (%) < Age (Years) Males Females SEER 2014

12 B-Cell Receptor as Therapeutic Target J Clin Oncol 2014; Epub 7/21/14 BCR signaling plays key role in CLL/SLL pathogenesis Several components targetable by small molecule inhibitors Approved: Idelalisib, Ibrutinib Investigational: many

13 Ibrutinib in CLL/SLL Orally available, irreversible inhibitor of Bruton s tyrosine kinase (BTK) Breakthrough therapy, accelerated FDA approval February 2014 Phase Ib/II: ORR 71%, PR with lymphocytosis 15-20%, 2-year PFS 75% (NEJM 2013;369:32) Mild toxicities: diarrhea, fatigue, upper respiratory tract infection

14 ASCO 2014: Confirmatory Study Randomized phase 3 study in 391 patients with relapsed/refractory CLL/SLL 1 prior therapies Considered inappropriate for purine analogs Comparator = Ofatumomab: ORR 58% in CLL resistant to fludarabine and alemtuzumab (FDA approved since 2009) R A N D O M I Z E 1:1 Oral ibrutinib 420 mg once daily until PD or unacceptable toxicity n=195 IV ofatumumab initial dose of 300 mg followed by 2000 mg 11 doses over 24 weeks n=196 Study Endpoints Primary Progression-free survival Secondary Overall survival Overall response rate Safety, toxicity Crossover to ibrutinib 420 mg once daily after IRC-confirmed PD (n=57)

15 Main Study Findings At median follow-up of 9.4 months Median PFS: not reached vs. 8.1 months At 12 months, OS 90% vs. 81% Benefit across subgroups NEJM 2014;371:213

16 Main Study Findings ORR = PR and PL+L: NEJM 2014;371:213 Ibrutinib toxicities: diarrhea, fatigue, pyrexia, nausea Also: atrial fibrillation, petechiae/ecchymoses No difference in Richter s transformation

17 Summary and Next Steps Study changes treatment paradigm for CLL/SLL Upfront and combination studies with ibrutinib ongoing Seqence? Combine? Avoid chemotherapy? Long-term toxicities and economics? Impact on allogeneic transplantation? Ibrutinib relapse: associated with mutations in BTK and PLCγ2 (NEJM 2014;370:2286)

18 Polycythemia vera Natural history: thrombosis/bleeding > myelofibrosis > leukemic transformation Therapy aimed at lowering thrombosis risk Low risk: phlebotomy + low-dose aspirin High risk: phlebotomy/aspirin + cytoreduction Challenge: few good options if first line fails Current second line therapies have leukemogenic potential Role of JAK/STAT pathway offers novel therapeutic opportunities

19 Ruxolitinib Small molecule inhibitor of JAK1/JAK2 Approved for intermediate/high-risk myelofibrosis Improves spleen size, constitutional symptoms, QoL Likely improves survival Main adverse events: anemia, thrombocytopenia Explored in hydroxyurea-refractory/intolerant PV (Cancer 2014;120: ) Hematocrit control without phlebotomy in 97% Reduction in spleen size 44% at week 24 Improvement in constitutional symptoms

20 Randomized (1:1) ASCO 2014: Confirmatory Study Randomized phase 3 study in 222 PV patients: Hydroxyurea resistance or intolerance Phlebotomy requirement Splenomegaly Comparator = BAT : hydroxyurea, interferon, anagrelide, pipobroman, IMIDs, observation; could be changed during trial Ruxolitinib 10 mg BID n = 110 Extended treatment phase Week 208 Study Endpoints Primary Hct control AND spleen response at week 32 Pre-randomization (day 28 to day 1) Hct 40%-45% BAT Crossover to ruxolitinib Week 208 Secondary Maintenance of response at week 48 Remission rate at week 32 n = 112 Week 32 (primary endpoint) Week 48 Week 80 NOT SURVIVAL

21 Main Study Findings 77% of ruxolitinib patients met at least 1 component of primary endpoint Primary Endpoint Individual Components of Primary Endpoint P <.0001 OR, (95% CI, ) 91% of patients maintained response at week 48

22 Main Study Findings Higher rate of complete hematologic remission with ruxolitinib at week 32 P =.0034 OR, 3.19 (95% CI, ) n = 26 n = 10 89% of patients maintained response at week 48

23 Main Study Findings Higher rate of symptom improvement with ruxolitinib at week 32 n = MPN-SAF Total Symptom Score Cytokine Symptom Cluster Hyperviscosity Symptom Cluster Splenomegaly Symptom Cluster Tiredness Itching Muscle ache Night sweats Sweating while awake Headache Concentration problems Dizziness Skin redness Vision problems Ringing in ears Numbness/tingling in hands/feet Fullness/early satiety Abdominal discomfort

24 Summary and Open Questions Ruxolitinib may be therapeutic option for subset of patients with poorly controlled, symptomatic PV Can it change natural history of disease? Value for front-line therapy? Value before transplantation (e.g. via reduction in spleen size)?

25 Take-Home Points Novel targeted therapeutics provide exciting strategies for hematologic malignancies Harnessing of immune effector cells Interference with critical signaling pathways of cancer cells Results demonstrate non-crossreactivity with standard chemotherapeutics More to come in next few years!!!