Changing Landscape in the Treatment of Relapsed/Refractory Hodgkin Lymphoma

Hodgkin lymphoma (HL) is highly curable with combination chemotherapy like ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine). However, relapse/refractory HL (R/R HL) is still a problem in about 10-30% of cases. Even though an overall survival (OS) benefit has not been demonstrated, high dose chemotherapy followed by autologous stem cell transplant (HD-ASCT) is the standard of care in R/R HL. Two-phase III randomized studies have shown improvement in progression-free survival (PFS) in chemo-sensitive patients with R/R HL using HD-ASCT.¹

etoposide, cytosine arabinoside [Ara-C], and melphalan

New Agents in HL

Many first-line salvage combination chemotherapy regimens have shown variable response rates (70-80%) in R/R HL but at the cost of hematological toxicities. The regimens most commonly used are mini BEAM (BCNU, ), dexa-BEAM (dexamethasone-BEAM), ICE (ifosfamide, carboplatin, and etoposide), DHAP (dexamethasone, Ara-C, and cisplatin), GVD (gemcitabine, vinorelbine and liposomal doxorubicin), GDP (gemcitabine, dexamethasone ,and cisplatin: outpatient regimen), and many others. These regimens have not been compared head-to-head with each other, and some of them affect stem cell mobilization. Patients who relapse after HD-ASCT (about 50%) have extremely poor survival. For patients with HL who have relapsed post HD-ASCT, allogeneic bone marrow transplant could be a goal if they are fit and eligible.In August of 2011, the FDA approved brentuximab vedotin (BV) for two indications in Hodgkin lymphoma: post HD-ASCT and for those who have relapsed after two multiagent chemotherapy and HD-ASCT. BV is now being tested in the frontline setting in a phase III open label clinical trial in combination with AVD (doxorubicin, vinblastine, and dacarbazine) versus ABVD (NCT01712490).

Bendamustine is an alkylating agent that is approved for chronic lymphocytic leukemia and indolent lymphomas. It has shown single agent activity in HL (CR: 33%).² It is now being evaluated in combination with BV (table).

Immune checkpoint inhibitors (PD-1 and PD-L1 inhibitors) are being evaluated in various solid tumors. Earlier this month, nivolumab (human monoclonal antibody against PD-1, Opdivo, Bristol-Myers Squibb) was approved for advanced melanoma. Pembrolizumab (humanized monoclonal antibody against PD-1, Keytruda, Merck) was approved in September 2014 for advanced melanoma. Interestingly, classical HL, which is characterized by Reed-Sternberg cells dispersed into an inflammatory milieu, overexpresses PD-1, making it a good target. Both pembrolizumab and nivolumab are being investigated in HL with interesting results (table).

The future seems bright. Ongoing clinical trials will give us a better idea about these agents and various combinations. These findings also raise questions concerning sequencing, maintenance, and replacing the existing myelotoxic multiagent chemotherapies in R/R HL. I am hoping these agents will climb up to the frontline setting and are comparable or better than age old ABVD.

Table: Clinical Trials Exploring New Agents in HL

Agent

Study Design

No of Patients

ORR

Outcome Measures

Toxicities

Bendamustine²

(120mg/m2, D1,2 q 28 days)

Phase II

36

(34 evaluable, 75% post ASCT, median 4 previous treatments)

ORR: 53% (ITT)

(CR: 33%

PR: 19%)

Median Response Duration: 5 months (in responding patients)

Thrombocytopenia (20%)

Anemia (14%) and Infection (14%)

Nivolumab³ (3mg/kg q 2 wks)-Intrim analysis

I-dose escalation f/b expansion cohort

23

(78% post ASCT, 78% post BV)

ORR: 87%

(CR: 17%

PR: 70%

SD: 13%)

PFS: 86% at 24 weeks.

Any grade: 78%, Grade 3 (22%).

Other: Rash (22%), TCP (17%), fatigue, pyrexia, nausea, diarrhea, pruritus (13%)

Pembrolizumab⁵ (10mg/kg q 2 weeks)-interim analysis

Phase Ib

15

(all failed BV, 67% previous ASCT)

ORR: 53% (CR: 20%, PR: 33% and PD: 27%)

Not reached at 12 weeks

Grade 3-5: One patient (pain and joint swelling-not related to drug). Grade 1-2: Respiratory events (20%), 1 discontinued secondary to pneumonitis. Thyroid disorders (20%). 3 discontinuation secondary to PD

Brentuximab Vedotin⁴ (BV, 1.8mg/kg infusion q 3 weeks up to 16 treatments)

Phase II open label multicenter

102

(Median prior therapies 3.5 (1-13), prior ASCT: 100%).

ORR: 75% (CR: 34%, CR+PR+SD = 96%)

Median duration of response: 6.7 months (20.5 months in patients with CR)

Grade >3: Peripheral sensory neuropathy (8%), neutropenia (20%), anemia (6%), and thrombocytopenia (8%).

Bendamustine⁶ (90mg/m² day 1 and 2) with BV (1.8mg/kg)

Phase I followed by phase II

45

(Relapse or refractory after front line therapy)

ORR (for evaluable patients n = 34): 94% (32/34), CR: 82% (28/32)

Those who had CR, median duration of response not reached

Infusion related side effects (dyspnea, flushing and chills) 36% but after addition of steroids and antihistamine as premeds, it dropped to 15%.

(0 SAE, 1 discontinuation and 2 grade 3 toxicities)

ORR = Objective Response Rate; CR = Complete Response; PR = Partial Response; SD = Stable Disease; PD = Progressive Disease; SAE = Serious Adverse Events; q = Every

1. Kuruvilla J, Keating A, Crump M. How I treat relapsed and refractory Hodgkin lymphoma. Blood, 117(16), 4208-4217 (2011).
2. Moskowitz AJ, Hamlin PA, Jr., Perales MA et al. Phase II study of bendamustine in relapsed and refractory Hodgkin lymphoma. J Clin Oncol, 31(4), 456-460 (2013).
3. Ansell SM, Lesokhin AM, Borrello I et al. PD-1 Blockade with Nivolumab in Relapsed or Refractory Hodgkin's Lymphoma. N Engl J Med, (2014).
4. Younes A, Gopal AK, Smith SE et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma. J Clin Oncol, 30(18), 2183-2189 (2012).
5. Moskowitz et al. American Society of Hematology meeting 2014. Abstract 290
6. LaCasce et al. American Society of Hematology meeting 2014. Abstract 294.