Relapsed/Refractory Hodgkin Lymphoma

Transcription

1 Relapsed/Refractory Hodgkin Lymphoma Anas Younes, MD Chief, Lymphoma Service Memorial Sloan-Kettering Cancer Center New York, New York, United States

2 Case Study 32-year-old woman was diagnosed with stage IV classical Hodgkin lymphoma (chl) a year ago. She was treated with ABVD and achieved a complete response. Today, she presents with fatigue and enlarged right cervical lymph node measuring 2 x 2 cm. Imaging studies showed PET avid lesions above and below the diaphragm with the largest nodal mass measuring 3 x 2 cm. Bone marrow biopsy was negative. Echocardiogram showed left ventricular ejection fraction of 60%. ABVD: Doxorubicin, bleomycin, vinblastine, dacarbazine

3 What would you recommend for this patient as initial therapy? 1. Brentuximab vedotin (BV) x 16 doses followed by ASCT 2. ICE x 2-3 cycles followed by ASCT 3. BEACOPP X 6 cycles 4. DHAP x 2-3 cycles followed by ASCT followed by maintenance brentuximab vedotin x 16 doses 5. GVD x 2-3 cycles followed by ASCT ASCT, autologous stem cell transplant; ICE, ifosfamide, carboplatin, etoposide; BEACOPP, bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone; DHAP, dexamethasone, cytarabine, cisplatin; GVD, gemcitabine, vinorelbine, doxorubicin

4 The patient received 3 cycles of ICE and achieved a complete response (CR). This was followed by stem cell collection, BEAM, and stem cell reinfusion (ASCT). One year later, she had enlarged nodes above and below the diaphragm, and a biopsy of a left inguinal node confirmed the presence of relapsed HL.

5 What would you recommend for this patient who relapsed 1 year after high-dose chemotherapy and ASCT? 1. Brentuximab vedotin x 16 doses followed by allogeneic stem cell transplant (allo-sct) 2. Brentuximab vedotin up to 16 doses, unless disease progression or prohibitive toxicity 3. Brentuximab vedotin x 4 then PET/CT. If CR continues for at least 8 doses and a maximum of 16 doses, follow with observation 4. Clinical trial

6 Treatment of Relapsed/Refractory (R/R) HL ABVD Relapse/refractory Platinum-based regimen Response Response No Response Gemcitabine-based regimen No response Cure ASCT No Response/relapse Third-line regimen (BV) Investigational agents

7 Results of Pretransplant Regimens in chl IGEV mini-beam ASHAP Complete response (CR) Partial Response (PR) MINE Dexa-BEAM ICE DHAP GVD GDP ESHAP % Response Rate

8 ASCT for Relapsed/Refractory HL ICE + ASCT GVD + ASCT GVD + ASCT GVD postasct Moskowitz CH, et al. Blood. 2001;97(3): Bartlett N, et al. Ann Oncol. 2007;18(6):

9 Date of Prep 09/10/13 EUCAN/ADC/ l Overall Survival (OS) by Time to Relapse After Transplant TTR N Median OS (y) >12 m m m m Horning S, et al. Ann Oncol. 2008:19 (suppl 4): Abstract 118. Arai S, et al. Leuk Lymphoma. 2013;54(11):

10 Phase I BV in Relapsed CD30+ HL and Anaplastic Large-Cell Lymphomas (ALCL) Treatment Response Investigator assessment Independent Review Facility (IRF) assessment 86% of patients achieved tumor reductions 83% of patients achieved tumor reductions Younes A, et al. N Engl J Med, 2010;363:

11 Phase I BV in Relapsed HL 21-year-old female HL diagnosed 2003 ABVD + XRT to mediastinum ICE BEAM ASCT HDAC-inhibitor SGN mg/kg x 8 cycles Best clinical response: CR CT 93% reduction, PET- PET negative Younes A, et al. N Engl J Med, 2010;363:

12 Date of Prep 09/10/13 EUCAN/ADC/ Phase II Pivotal Study of BV in Patients With R/R HL Post ASCT Eligibility Treatment (n = 102) Follow-up Relapsed or refractory CD30+ HL Age 12 years Measurable disease 1.5 cm ECOG PS of 0-1 Prior ASCT Brentuximab vedotin 1.8 mg/kg IV Q3wk Administered outpatient over 30 min Min 8 - max 16 cycles for stable disease (SD) or better Restage* at cycles 2, 4, 7, 10, weekly for 2 years 6 monthly years 3 5 Annually after 5 years Primary endpoint: ORR by IRF *Revised response criteria for malignant lymphoma (Cheson 2007) ECOG PS, European Cooperative Oncology Group Performance Status Younes A, et al. J Clin Oncol. 2012;30: Cheson BD, et al J Clin Oncol. 25:

13 Date of Prep 09/10/13 EUCAN/ADC/ h Phase II Pivotal Study of BV in Patients With R/R HL Post ASCT Demographics and clinical characteristics n = 102 Median age, years (range) 31 (15-77) Gender 48 M / 54 F ECOG PS 0 42 (41%) 1 60 (59%) Refractory to frontline therapy 72 (71%) Refractory to most recent treatment 43 (42%) Prior chemotherapy regimens* 3.5 (1 13) Prior radiation 67 (66%) Prior ASCT 1 91 (89%) 2 11 (11%) Time from ASCT to first post-transplant relapse* 6.7 months (0-131) * Median (range) Younes A, et al. J Clin Oncol. 2012;30:

14 Phase II Pivotal Study of BV in Relapsed HL Post ASCT 94% patients achieved tumour reduction Younes A, et al. J Clin Oncol. 2012;30:

15 BV: Pivotal Phase II Trial Progression-Free Survival (PFS) Results by Best Response Phase II pivotal study of brentuximab vedotin in 102 patients with relapsed/refractory HL post ASCT: PFS by best response Younes A, et al. J Clin Oncol. 2012;30:

16 Three-Year Follow-up Data and Characterization of Long-Term Remissions From an Ongoing Phase II Study of BV in Patients With Relapsed or Refractory HL Gopal A, et al. Blood. 2013;122: Abstract 4382.

17 Phase II Study of BV Tolerability Adverse Events (AEs) in 20% of Patients Adverse event All grades (%) Grade 3 (%) Grade 4 (%) Peripheral sensory neuropathy Fatigue Nausea Upper respiratory tract infection Diarrhea Pyrexia Neutropenia Vomiting Cough All patients completed treatment as of August 2010 Other grade 3/4 events in 5% of patients: Thrombocytopenia: 8% Anemia: 6% Chen R, et al. Blood. 2012;120: Abstract 3689.

18 Phase II Study of BV Treatment Related Adverse Event, 3-Year Follow-up Treatment-related grade 3 AEs Preferred term Grade 3 AEs Neutropenia 20% Peripheral sensory neuropathy 9% Thrombocytopenia 8% Anemia 6% Fatigue 2% Pyrexia 2% Diarrhea 1% The most common ( 15%) BV-related adverse events of any grade were peripheral sensory neuropathy, nausea, fatigue, neutropenia, and diarrhea. Adverse events of grade 3 or higher that occurred in 5% of patients were neutropenia, peripheral sensory neuropathy, thrombocytopenia, and anemia Gopal A, et al. Blood. 2013;122: Abstract 4382.

19 Brentuximab Vedotin Initial Treatment vs Retreatment HL Systemic ALCL N = 102 N = 15 N = 58 N = 8 Younes A, et al. Presented at: 2012 American Society of Clinical Oncology; June ; Chicago, Illinois.

20 Retreatment With BV in Patients With CD30-Positive Hematologic Malignancies Bartlett N, et al. J Hematol Oncol. 2014;7:24.

21 Brentuximab Vedotin Pre & Post Allogeneic Transplant

22 Retrospective Analysis: BV Reduced Intensity Allo-SCT Post Baseline characteristics (N = 19) N = 19 Median age, years (range) 31 (23-55) Prior chemotherapy regimens, median (range) 5 (3-8) Prior ASCT, n 18/19 Prior radiotherapy, n 10/19 Best response to BV, % CR: 42%; PR: 42%; SD: 11%; PD: 5% Number cycles of BV, median (range) 8 (2-16) Disease status at time of allo-sct CR: 37%; PR: 37%; SD: 11%; PD: 16% *Treated at City of Hope or Seattle Cancer Care Alliance/Fred Hutchinson Cancer Center PD, progressive disease Chen R, et al. Presented at: 12th International Conference on Malignant Lymphoma; June 19-22, 2012: Lugano, Switzerland. Abstract 140.

23 Retrospective Analysis: BV Reduced Intensity Allo-SCT Post Outcome N = 19 Engraftment Days to ANC 0.5 x 10 9 /L Days to platelets >20,000 % Chimerism Acute GVHD, % I II Chronic GVHD, % Limited Extensive Infectious disease, % EBV reactivation, % CMV reactivation Clinical zoster 14 (range: 0-21) 14 (range: 0-21) >99% (day ) ANC, absolute neutrophil count; GVHD, graft-versus-host disease; EBV, Epstein-Barr virus; CMV, cytomegalovirus Chen R, et al. Presented at: 12th International Conference on Malignant Lymphoma; June 19-22, 2012: Lugano, Switzerland. Abstract 140.

24 Retrospective Analysis: BV Reduced Intensity Allo-SCT Post Clinical outcome N = 19 Median follow-up, months year OS, % 79.3 (CI: 56.0, 91.1) 2-year PFS, % 59.3 (CI: 43.9, 71.7) 2-year PFS in CR patients, % 71.4 (CI: 40.3, 88.3) 2-year PFS in non-cr patients, % 54.6 (CI: 37.5, 68.9) Chen R, et al. Presented at: 12th International Conference on Malignant Lymphoma; June 19-22, 2012: Lugano, Switzerland. Abstract 140.

25 Treatment With BV After Allo-SCT *Includes ASCT, allo-sct, DLI, systemic chemotherapy, and external beam radiotherapy Conditioning therapy for SCT is not counted as a separate regimen. n = 25 Median age, years (range) 32 (20-56) Male sex, n (%) 13 (52) ECOG PS, 0 / 1, n 9 / 16 Median time from HL diagnosis to first dose of BV, months (range) 72 (19-159) Total number of prior regimens,* median (range) 9 (5-19) Prior ASCT, n (%) 19 (76) Prior allo-sct, n (%) 25 (100) Prior donor lymphocyte infusion, n (%) 6 (24) Gopal AK, et al. Blood. 2012;120(3):

26 % of Patients Free of PD or Death Treatment With BV After Allo-SCT N Events Median (weeks) CR PR SD/PD Time ( Weeks) N = 24 evaluable patients; one patient died before first response assessment Gopal AK, et al. Blood. 2012;120(3):

27 Treatment With BV After Allo-SCT A univariate analysis of factors potentially associated with response to brentuximab vedotin found no statistically significant comparisons BV post allo-sct patients N = 25 a Single-agent brentuximab post ASCT N = 102 Overall response (OR), % CR, % Disease control (CR + PR + SD), % Median PFS, weeks (range) 7.8 ( ) 5.6 (NA) 95% CI NA (5.0, 9.0) Median time to OR, weeks (range) 8.1 (5.3-32) 5.7 (5.1-56) Patients with CR, n (%) 9 (38) 35 (34) Median time to CR, weeks (range) 10.7 ( ) 12 (5.1-56) a N = 24 evaluable patients Patients who had previously received allo-sct were excluded from phase II study Activity of brentuximab vedotin in HL patients post allo-sct compared with HL patients in phase II study. Gopal AK, et al. Blood. 2012;120(3):

28 Conclusions The addition of BV prior to allogeneic transplantation does not appear to adversely affect engraftment, GVHD, or mortality BV may provide sufficient disease control for selected patients to proceed to allo SCT BV is active in HL patients who relapse after allo-sct Treatment with brentuximab vedotin was associated with manageable AEs similar to those in the pivotal trial

29 Proposed Algorithm for Treating Patients Post ASCT ASCT <CR/ Relapse CR Brentuximab Vedotin Observe (Role of adjuvant BV?) CR <CR Continue BV to 8-16 doses Relapse from CR Retreat with BV then allo-sct Consider Allo-SCT Continue BV until disease progression

30 The AETHERA Study 329 patients were randomized at 78 sites in North America and Europe X 16 Moskowitz CH. Clin Adv Hematol Oncol. 2015;13(2 Suppl 2):20-23.

31 Progression-Free Survival PFS per IRF PFS per Investigator BV (N = 165) Placebo (N = 164) BV (N = 165) Placebo (N = 164) Hazard ratio (95% CI) 0.57 ( , P =.001) Events Median PFS (months) year PFS rate 63% 51% Hazard ratio (95% CI) 0.50 ( ) Events Median PFS (months) year PFS rate 65% 45% * Regularly scheduled CT scans Includes information from both radiographic assessments and clinical lymphoma assessments Moskowitz CH. Clin Adv Hematol Oncol. 2015;13(2 Suppl 2):20-23.

32 Subgroup Analysis of PFS per IRF Moskowitz CH. Clin Adv Hematol Oncol. 2015;13(2 Suppl 2):20-23.

33 Emerging Novel Therapy for Relapsed HL

34 OX40 (CD134) T cell TCR PD1 4-1BB (CD137) OX40L (CD252) PD-L1 MHC I/II PD-L2 4-1BBL (CD137L) Stathis G, et al. Ann Onc. In press. HRS

35 Nivolumab in Relapsed HL Ansell SM, et al. N Engl J Med. 2015;372(4):

36 Change From Baseline, % Pembrolizumab (MK-3475) in Patients With Relapsed Classical Hodgkin Lymphoma Complete remission Partial remission Stable disease Progressive disease * Moskowitz C, et al. Blood. 2014;124: Abstract 290.

37 % Response Rate Single-Agent Activity of Novel Agents in Relapsed chl 2015 CR PR 25 0 Updated from: Betlevi CL and Younes A. Hematology Am Soc Hematol Educ Program. 2013;2013:

38 Hodgkin Lymphoma: Future Directions Strategy A Strategy B PD1/PDL1 an bodies Chemo therapy Brentuximab Vedo nn PI3Ki/ mtori Chemo therapy Brentuximab Vedo nn + PD1/PDL1 an body PI3Ki/ mtori HDACi HDACi