Key points

• 
  

  Objectives

  
  
• 1.
  

  Review recent advances in HL biology

  
  
• 2.
  

  Review development of novel targeted therapies in the context of HL biology

  
  
• 3.
  

  Review results of clinical trials with targeted therapies

Introduction

Classic Hodgkin lymphoma (HL) represents approximately 10% of all lymphomas diagnosed annually in the developing world. In 2013, approximately 9000 cases of HL were diagnosed in the United States. With a median age of 38 years, and at least 40% of patients younger than 35 years at the time of diagnosis, it is the most common lymphoma affecting young patients. Over the past 30 years, valuable lessons learned about the late effects of therapy, specifically cardiovascular and second cancer risk, have led to treatment modifications of radiation dose and field size as well as alkylator exposure, which have led to significant risk reduction of competing causes of death. As a result of these advances, more than 75% of patients are cured with contemporary frontline therapy.

For patients who relapse after attaining an initial complete remission (CR) or have primary refractory disease, the standard treatment approach is salvage chemotherapy followed by autologous stem cell transplant (ASCT), with an approximately 50% cure rate. Several studies show that achieving a CR before ASCT is one of the most important factors in determining a long-term outcome after ASCT. Other pretransplant prognostic factors include duration of initial remission, extent of disease at relapse, and constitutional symptoms. In an international collaborative effort from 5 countries, data on 756 patients with relapsed HL with a minimum of 1-year follow-up after the transplant were pooled. The overall median postprogression survival (PPS) for patients relapsing after ASCT was 1.3 years. Seventy-one percent of relapses occurred within 1 year after ASCT and were roughly equally distributed in the following periods: less than 3 months (22%), more than 3 and less than 6 months (22%), and more than 6 and less than 12 months (27%). The median PPS for these periods were 0.55, 1.6, 1.68, and 2.26 years for the time to relapse after ASCT, respectively ( P <.0001). Allogeneic stem cell transplantation (alloSCT) can induce durable remissions in some of these patients; however, its utility is limited by the challenges of finding an available stem cell donor, and achieving adequate disease control before transplantation. Therefore novel treatments to increase the CR rate pre SCT, or significantly prolong remission duration post SCT, have been sought.

The recent approval in 2011 of brentuximab vedotin, an antibody-drug conjugate (ADC) targeting CD30, has been the first major advance in the management of HL after several decades and offers considerable hope to patients with refractory disease or relapse after stem cell transplant. Better understanding of the biology of HL has led to the exploration of several other potential targets as therapeutic options. This review provides an overview of HL tumor biology in the context of the development of novel targeted therapies. The authors discuss 4 broad categories of targeted therapies either approved or under investigation: (1) therapies targeting Hodgkin Reed Sternberg (HRS) cell-surface receptors, (2) therapies targeting reactive immune cells in the tumor microenvironment, (3) adoptive immunotherapy, and (4) therapies targeting signaling and intracellular survival pathways ( Tables 1 and 2 ). Although some of the agents discussed later are highly active as single agents, many others demonstrate modest single-agent activity. Moving forward, the challenge will be how to develop rational combinations of these novel agents within the context of current paradigms of care to achieve enhanced efficacy with minimal toxicity.

Introduction

Classic Hodgkin lymphoma (HL) represents approximately 10% of all lymphomas diagnosed annually in the developing world. In 2013, approximately 9000 cases of HL were diagnosed in the United States. With a median age of 38 years, and at least 40% of patients younger than 35 years at the time of diagnosis, it is the most common lymphoma affecting young patients. Over the past 30 years, valuable lessons learned about the late effects of therapy, specifically cardiovascular and second cancer risk, have led to treatment modifications of radiation dose and field size as well as alkylator exposure, which have led to significant risk reduction of competing causes of death. As a result of these advances, more than 75% of patients are cured with contemporary frontline therapy.

For patients who relapse after attaining an initial complete remission (CR) or have primary refractory disease, the standard treatment approach is salvage chemotherapy followed by autologous stem cell transplant (ASCT), with an approximately 50% cure rate. Several studies show that achieving a CR before ASCT is one of the most important factors in determining a long-term outcome after ASCT. Other pretransplant prognostic factors include duration of initial remission, extent of disease at relapse, and constitutional symptoms. In an international collaborative effort from 5 countries, data on 756 patients with relapsed HL with a minimum of 1-year follow-up after the transplant were pooled. The overall median postprogression survival (PPS) for patients relapsing after ASCT was 1.3 years. Seventy-one percent of relapses occurred within 1 year after ASCT and were roughly equally distributed in the following periods: less than 3 months (22%), more than 3 and less than 6 months (22%), and more than 6 and less than 12 months (27%). The median PPS for these periods were 0.55, 1.6, 1.68, and 2.26 years for the time to relapse after ASCT, respectively ( P <.0001). Allogeneic stem cell transplantation (alloSCT) can induce durable remissions in some of these patients; however, its utility is limited by the challenges of finding an available stem cell donor, and achieving adequate disease control before transplantation. Therefore novel treatments to increase the CR rate pre SCT, or significantly prolong remission duration post SCT, have been sought.

The recent approval in 2011 of brentuximab vedotin, an antibody-drug conjugate (ADC) targeting CD30, has been the first major advance in the management of HL after several decades and offers considerable hope to patients with refractory disease or relapse after stem cell transplant. Better understanding of the biology of HL has led to the exploration of several other potential targets as therapeutic options. This review provides an overview of HL tumor biology in the context of the development of novel targeted therapies. The authors discuss 4 broad categories of targeted therapies either approved or under investigation: (1) therapies targeting Hodgkin Reed Sternberg (HRS) cell-surface receptors, (2) therapies targeting reactive immune cells in the tumor microenvironment, (3) adoptive immunotherapy, and (4) therapies targeting signaling and intracellular survival pathways ( Tables 1 and 2 ). Although some of the agents discussed later are highly active as single agents, many others demonstrate modest single-agent activity. Moving forward, the challenge will be how to develop rational combinations of these novel agents within the context of current paradigms of care to achieve enhanced efficacy with minimal toxicity.

Table 2

Selected ongoing clinical trials of novel agents

Drug	Main Target	Clinical Trial Number
Receptor Targeted Therapies
BV combinations
Frontline
Phase 3 frontline with AVD vs brentuximab/AVD	CD 30+ HRS cells	NCT01712490
ECAPP B vs ECADD B (frontline)		NCT01569204
Relapsed/Refractory
ABVD→ BV (relapsed)		NCT01578967
BV + bendamustine (relapsed)		NCT01874054
BV + ipilimumab (relapsed)		NCT01896999
BV vs ICE pre ASCT (relapsed)		NCT01393717
BV→ ICE (relapsed)		NCT01508312
BV + rituximab (relapsed)		NCT01900496
Maintenance
BV maintenance after ASCT (ATHERA) (maintenance)		NCT01620229
TNX-650	IL-13	NCT00441818
Microenvironment Targeting
Lenalidomide Combinations (relapsed)
AVD	Immunomodulation, antiangiogenesis	NCT01056679
Bendamustine		NCT01412307
Romidepsin		NCT01742793
Everolimus		NCT01075321
Rituximab Combinations
Frontline
Rituximab ABVD vs ABVD phase 2	CD20+ peritumoral B lymphocytes; CD20+ HRS cells	NCT00654732
Rituximab + BEACOPP (HD18)		NCT00515554
Relapsed
Rituximab + Bendamustine		NCT01900496
Ipilimumab (relapsed)	Immunomodulation of tumor microenvironment	NCT01896999
Nivolumab a (relapsed)	PD-1 expressing peritumoral lymphocytes	NCT01592370
CDX1127 (relapsed)	Anti-CD27 antibody	NCT01460134
Adoptive Immunotherapy
Autologous CAR.CD30 EBV specific-cytotoxic T-lymphocytes (relapsed)	EBV+ CD30+ HRS cells; CD30+ HRS cells	NCT01192464
Downstream Signaling Pathways
MLN4924 (relapsed)	NFκB via inhibition of Ned8	NCT00722488
Everolimus (relapsed)
Everolimus and panobinostat	PI3K signaling, mTOR, TNFR signaling	NCT00918333
Everolimus and lenalidomide		NCT01075321

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