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 1

Current results in selected targeted therapies in HL

Drug/Phase	Main Target	Clinical Trial Number	Failed ASCT (%)	Clinical Results	Reference
Receptor Targeted Therapies
SGN-30 (I)	CD 30+ HRS cells	NCT00051597	83 a	No significant response
SGN-30 (II)		NCT00337194	68
MDX-060 (1/2)	CD 30+ HRS cells	NCT00284804	87 a	No significant response
BV
BV/(I)	CD 30+ HRS cells	NCT00947856	73 a	PIVOTAL Trial: ORR 75%, CR 34%, median
BV/(I)		NCT01100502	68 a	PFS 5.6 mo, median DOR 20.5 mo
BV/(II)		NCT01060904	100	—
HCD122 (II)	CD40+ HRS cells; Th2/Treg signaling	NCT00670592	NR	ORR 16% (all PR)
Galiximab (II)	CD80+ HRS cells	NCT00516217	83	ORR of 6.9%, TTP 1.6 mo
Microenvironment Targeting
Lenalidomide (II)	Immunomodulation, antiangiogenesis	NCT00540007	76	ORR 19% (N = 32)
Lenalidomide (II)		NCT00478959	67	ORR 13% (N = 15)
AFM 13 (I)	CD 16/30+ HRS cells	NCT01221571	NR	7% PR/50% SD
Rituximab single agent (I pilot)	CD20+ peritumoral B lymphocytes CD20+ HRS cells	—	82	ORR 22%, median DOR 8.7 mo
Rituximab + gemcitabine (II)		—	55	ORR 48%, median FFS 2.7 mo
Rituximab + ABVD frontline (I)		NCT00504504	0	EFS 83% and OS 96%
Rituximab + ABVD frontline (II)		NCT00369681	0	EFS 83% and OS 98%
PLX3397 (II)	CSF1R inhibitor	NCT01217229	NR	ORR 5%
Adoptive Immunotherapy
EBV+ specific cytotoxic T cells	EBV+ HRS cells	NCT00058617 a	40	83% of 28 patients with EBV+ HL had a clinical response, including 4 CRs sustained >9 mo
Downstream Signaling Pathway
Panobinostat (I)	Histone modification	NCT00742027	100	ORR 27% including 4% CR, median PFS was 6.1 mo
Vorinostat (I)	Histone modification, STAT signaling (pSTAT6)	NCT00132028	44	ORR 4%
Mocetinostat (I)	Histone modification, STAT signaling	NCT00358982	84	ORR 21%
Everolimus (I)	PI3K signaling, mTOR, TNFR signaling	NCT01022996	84	ORR 47% 8 PR, 1 CR median TTP 7.2 mo, 4 responders remained progression free at 12 mo
SB1518	JAK/STAT pathway	NCT01263899	NR	No significant clinical activity

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