Sequencing Treatments in Relapsed Hodgkin Lymphoma Leonard T. - - PowerPoint PPT Presentation

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Sequencing Treatments in Relapsed Hodgkin Lymphoma Leonard T. - - PowerPoint PPT Presentation

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Sequencing Treatments in Relapsed Hodgkin Lymphoma Leonard T. Heffner, Jr., M.D. July 27, 2017 1 Hodgkin Lymphoma Arises from B lymphocytes Accounts for 10% or all lymphomas <1% of all cancers in the U.S. Incidence: 8500

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Sequencing Treatments in Relapsed Hodgkin Lymphoma

Leonard T. Heffner, Jr., M.D. July 27, 2017

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2 Winship Cancer Institute | Emory University

Hodgkin Lymphoma

  • Arises from B lymphocytes
  • Accounts for 10% or all lymphomas
  • <1% of all cancers in the U.S.
  • Incidence: 8500 in U.S. in 2016
  • Mortality: 1120 in U.S. in 2016

Siegel RL, et al. CA Cancer J Clin. 2016;66(1):7-30.

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Teras LR, et al. CA Cancer J Clin. 2016;66(6):443-459.

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DeVita VT Jr. N Engl J Med. 2003;348(24):2375-2376.

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FFR, freedom from relapse

Canellos GP, et al. J Clin Oncol. 2014;32(3):163-168.

Changes in survival of all patients with all stages of Hodgkin disease (HD) treated by radiotherapy and/or combination chemotherapy at Stanford from 1960 to 2006

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2, 5 and 10 yr survival rates for Hodgkin Lymphoma by Sex and Race

Teras LR, et al. CA Cancer J Clin. 2016;66(6):443-459.

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Cumulative incidence of relapse in patients observed to be free from relapse >5 years after diagnosis of classical Hodgkin lymphoma in HD7 to HD12 German trials

Bröckelmann PJ, et al. J Clin Oncol. 2017;35(13):1444-1450.

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Options for Treatment of Relapsed/Refractory Hodgkin Lymphoma

1.Autologous stem cell transplant 2.Radiation Therapy 3.Chemotherapy: monotherapy or combination 4.Check-point inhibitors 5.Monoclonal antibodies 6.Immunomodulatory agents 7.Second Autologous stem cell transplant 8.Allogeneic stem cell transplant

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Moskowitz CH, et al. Blood. 2001;97(3):616-623.

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Risk Factors

  • 1. B symptoms before

ICE

  • 2. Extranodal disease

before ICE

  • 3. CR duration <1 yr.

Overall Survival Based on Number of Risk Factors Present at Transplant

Moskowitz CH, et al. Blood. 2001;97(3):616-623.

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75% 30%

Moskowitz CH. Hematology Am Soc Hematol Educ Program. 2016;2016(1):331-338.

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Autologous Stem cell Transplant (ASCT) for Relapsed/Refractory Hodgkin Lymphoma

Relapsed HL: At least 12 trials (retrospective, prospective and randomized) show high-dose ChRx (HDC) followed by ASCT can rescue 30-80% of patients. Refractory HL: At least 13 trials (all retrospective) show HDC followed by ASCT results in PFS = 40-45% and OS = 30-70% Cochrane Review: (2013) identified only 3 randomized controlled trials totaling 398 pts comparing ASCT to ChRx for relapsed/refractory HL (BNLI, HDR1 and HDR2)

Perales MA, et al. Biol Blood Marrow Transplant. 2015;21(6):971-983. Fedele R, et al. J Immunol Res. 2015;968212.

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Cochrane Review of Three Randomized Controlled Trials of HDC and ASCT for Rel/Ref HL

Rancea M, et al. Cochrane Database Syst Rev. 2013;(6):CD009411.

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Use of Second-line, non-Cross-resistant Chemotherapy to Achieve pre-ASCT PET Negativity

Moskowitz CH, et al. Blood. 2012;119(7):1665-1670.

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Moskowitz CH, et al. Blood. 2012;119(7):1665-1670.

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Peralses MA, et al. Biol Blood Marrow Transplant. 2015;21(6):971-983.

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N = 356 allo = 18 Relapse within 5 yrs: 100 Relapse > 5 yrs and < 10 yrs: 3 Relapse > 10 yrs and < 15 yrs: 2 Relapse > 15 yrs: 0

Overall Survival of Patients Undergoing Transplant at Emory (Unselected)

Unpublished data

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Alinari L, et al. Blood. 2016;127(3):287-295.

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Selected Studies of Combination Regimens for Rel/Ref cHL After ASCT

GVD=gemcitabine,vinorelbine,doxorubicin GemOx=gemcitabine,oxaliplatin GCD=Gemcitabine,carboplatin,dexamethasone GV=Gemcitabine,vinorelbine ESHAP=Etoposide,methylpred,cytarabine,cisplatin

Modified from: Alinari L, et al. Blood. 2016;127(3):287-295.

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No. Prior ASCT Response PFS (mos)

Lenalidomide 36 31 CR = 3 PR =16 6.0 Everolimus 19 16 CR = 5 PR = 42 7.2 Panobinostat 129 129 CR = 4 PR = 23 8.L Rituximab 22 18 CR = 4 PR = 18 7.8 2nd ASCT 21 21 *5yr PFS=32% vs 0% OS =41% vs 13%

Selected Studies of Novel Agents in Patients for Rel/Ref cHL After ASCT

*Relapse post first ASCT >12 mos vs <12mos

Modified from: Alinari L, et al. Blood. 2016;127(3):287-295.

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Brentuximab vedotin (SGN35)

  • Brentuximab vedotin is an anti-CD30 monoclonal antibody(SGN35) conjugated

to monomethyl auaristatin E (MMAE) via a valine-citrulline peptide linker

  • 2010: Phase I trial¹: 45 pts (42 with rel/ref HL)

MTD 1.8mg/m2 IV q3wks 17/45 (38%) ORR with 11 CR (9 HL, 2 ALCL)

  • 2012: Phase II trial²: 102 pts with rel/ref HL after auto SCT

ORR: 75% with 34% CR med PFS 5.6 mos and med OS 22.4 mos Toxicity: sensory neuropathy (42%), fatigue, neutropenia, nausea, diarrhea Rare(not this trial): PML (5 pts); pancreatitis

  • 1. Younes A, et al. N Engl J Med. 2010;363(19):1812-1821. 2. Younes A, et al. J Clin Oncol. 2012;30(18):2183-2189.
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Phase 2 Trial of BV after auto- SCT for Rel/Ref HL: OS and PFS

Younes A, et al. J Clin Oncol. 2012;30(18):2183-2189.

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AETHERA Trial: Phase 3 Trial of Post-ASCT Consolidation w ith BV vs Placebo PFS by Independent Review

Med PFS 42.9 vs 24.1 mos Moskowitz CH, et al. Lancet. 2015;385(9980):1853-1862.

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Aethera Trial: 3-year PFS

61% (median NYR) 43% (median 15.8 mos)

Moskowitz CH. Hematology Am Soc Hematol Educ Program. 2016;2016(1):331-338.

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AETHERA Trial: Overall Survival

Moskowitz CH, et al. Lancet. 2015;385(9980):1853-1862.

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Moskowitz CH. Hematology Am Soc Hematol Educ Program. 2016;2016(1):331-338.

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Phase I Study of Nivolumab in Relapsed/Refractory Hodgkin Lymphoma

Ansell SM, et al. N Engl J Med. 2015;372(4):311-319.

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Pembrolizumab in Rel/Ref Classical Hodgkin Lymphoma

Decrease in tumor burden from baseline K-M estimate of objective response duration

PFS = 72.4% at 6 mos.

Chen R, et al. J Clin Oncol. 2017;35(19):2125-2132.

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Pembrolizumab after failure of Brentuximab Vedotin in cHL

Armand P, et al. J Clin Oncol. 2016 Jun 27 [Epub ahead of print].

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Pembrolizumab in Rel/Ref Classical Hodgkin Lymphoma

Chen R, et al. J Clin Oncol. 2017;35(19):2125-2132.

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Adverse Effect Profile of PD-1/PD-L1 Inhibitors

  • Dermatologic: rash, pruritis
  • Metabolic: lipid changes, hyperglycemia, hypoalbuminemia, electrolyte

changes

  • Hematologic: anemia and lymphopenia
  • Gastrointestinal: nausea/vomiting; change in bowel habits, abnormal

LFTs

  • Respiratory: cough dyspnea
  • Constitutional: fatigue
  • Immune-related:
  • Pneumonitis
  • Dermatologic: TEN
  • Gastrointestinal: colitis, pancreatitis
  • Endocrine: hypophysitis, thyroiditis, adrenal insufficiency
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The Cancer Letter June 9, 2017

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Autologous T-cells Expressing CD30 Chimeric Antigen Receptors in Rel/Ref cHL n = 18 ORR 39 %

Wang CM, et al. Clin Cancer Res. 2017;23(5):1156-1166.

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Clinical Trials at Winship Cancer Institute for Relapsed/Refractory Hodgkin Lymphoma

  • E4412: -Phase I study of Ipilimumab/brentuximab/nivolumab

with expansion cohort

  • S15-00285: Phase I/II study of pembrolizumab + lenalidomide
  • MEDI4736-NHL-001: Phase I/II study of durvalumab (IgG

monoclonal antibody against PD-L1)

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Second ASCT for Relapsed cHL

  • Limited data (small numbers:3-10)
  • CIBMTR series: 40 patients—21 cHL

19 DLBCL, FL, immunoblastic

  • Chemosensitive disease 73% for entire gp.

1-yr PFS 1-yr OS Relapse <6 mos 11% 22% Relapse >12 mos 64% 78% Relapse >18 mos 53% 72% Conclusion: Recommended only in selected settings

Smith SM, et al. Biol Blood Marrow Transplant. 2008;14(8):904-912.

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There are NO prospective clinical trials comparing Allo-SCT to non-transplant treatment in cHL rel after ASCT

Perales MA, et al. Biol Blood Marrow Transplant. 2015;21(6):971-983.

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Kharfan-Dabaja MA, et al. Bone marrow Transplant. 2014;49(5):599-606.

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Retrospective Comparison of Chemo/XRT vs Allo-RIC for HL Failure after ASCT

Treatment No. Median Survival 4-yr OS P-value Allo-RIC 195 19 mos. 32% Chemo/XR T 49 45 mos. 48% 0.08

Martinez C, et al. Ann Oncol. 2013;24(9):2430-2434.

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Rel/Ref classical Hodgkin Lymphoma after Initial Therapy

Candidate for SCT?

No

  • 1. Clinical Trial
  • 2. MAb—brentuximab
  • 3. CPI– nivolumab

pembrolizumab

  • 4. CD30 CAR-T cell
  • 5. Conventional ChRx

Gemcitabine based Bendamustine

  • 6. Immunomodulatory therapy

HDAC inhibitor lenalidomide mTOR inhibitor Yes ASCT CR Rel/Ref Allo SCT

  • MAC
  • RIC

2nd ASCT