Page 1379 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 75 Hodgkin Lymphoma 1225

toxicity to a minimum. Early attempts with myeloablative condition- by the US FDA for the treatment of patients with relapsed or refrac-
ing regimens in this patient population were associated with unaccept- tory HL following ASCT.
able rates of treatment-related mortality. As such, reduced-intensity, More recently, a potential role for BV as maintenance therapy
nonmyeloablative conditioning before aSCT, has been adopted as a following ASCT has also been suggested: Initial data from the inter-
more appropriate alternative. national randomized AETHERA trial, presented in abstract form at
In 2012 results of the largest prospective phase II study to date the 2014 American Society of Hematology (ASH) Annual Meeting,
(HDR-ALLO study) were published by the EBMT and the Grupo show significantly improved PFS following the administration of BV
Espanol de Linfomas/Trasplante de Medula Osea (GEL/TAMO). In every 3 weeks for up to 12 months after ASCT versus placebo in
this study the role of reduced-intensity aSCT was investigated in 92 patients with high-risk relapsed or refractory HL.
patients with relapsed or refractory HL. Fourteen patients died as a On the back of its success in the relapsed/refractory setting, BV
result of refractory, and subsequently progressive, disease, with 78 is now being evaluated in the frontline setting in combination with
proceeding to reduced-intensity aSCT. The PFS of these patients was standard chemotherapy and results so far are promising, particularly
16
48% at 1 year and 24% at 4 years, with an OS of 71% at 1 year and in the advanced disease setting (see New Directions in the Treat-
43% at 4 years. A nonrelapse mortality (NRM) rate of 8% at 100 ment of Advanced Hodgkin Lymphoma: Novel Therapies section,
days and 15% at 1 year was observed. Interestingly, chronic graft- earlier).
versus-host disease (GVHD) was associated with lower rates of relapse
and improved PFS.
For those who relapse after aSCT, donor-lymphocyte infusion NOVEL AGENTS
(DLI) has been attempted as a salvage strategy to enhance the graft-
versus-lymphoma effect with the aim of preventing relapse. In the The approval of BV as standard of care for patients with relapsed HL
HDR-ALLO study described earlier, DLI was administered to half following autologous transplantation has improved the survival in
of the patients who relapsed following aSCT. This was associated with this challenging patient population. The success of BV has paved the
an overall response rate (ORR) of 40% and a median time to progres- way for the development of a number of other novel therapeutics for
sion of 7 months. Evidence for the use of DLI in this setting, however, the treatment of relapsed or refractory HL, including immune
remains limited. checkpoint inhibitors, epigenetic therapeutics, and other small mol-
These data suggest that aSCT has the potential to achieve relatively ecules, with promising clinical activity being demonstrated so far
long-term remissions in selected, heavily pretreated, patients with HL (Fig. 75.6).
who relapse following ASCT and that with a reduced-intensity
approach NRM is substantially reduced. In this sense its use may be
extended to greater number of patients than previously assumed. The PD-1/PDL-1 Checkpoint Inhibitors
prognosis of these individuals, however, remains extremely poor. A
key concern with this approach is the relatively high risk of relapse, PD-1 (programmed cell death protein 1) is a cell surface receptor that
which continues to be the main cause of failure and represents the is expressed on T regulatory and activated T cells (CD4 and CD8),
major on-going therapeutic hurdle. activated B cells and NK cells. PD-1 binds PDL-1 and PDL-2, two
Robust evidence to support a clear role for these potential strate- ligands that are expressed by antigen-presenting cells and several
gies in the treatment of those with multiply relapsed HL is lacking cancer cells, including RS cells in HL (see Fig. 75.5). The PD-1/
and the absence of randomized studies has prevented a standard of PDL-1/2 interaction inhibits kinases that are normally involved in
care from being identified. Patients with relapsed or refractory disease T-cell activation. In this way the PD-1 pathway serves as a checkpoint
following ASCT have unaddressed clinical needs and, as such, enroll- to restrict T-cell−mediated immune responses, enabling tumor cells
ment into well-designed clinical trials evaluating novel agents should to evade immune detection. Inhibitors of PD-1, which block PD-1/
be encouraged for all these individuals where possible. One such PDL-1/2 engagement, may enhance T-cell immunity and prevent
agent that has shown striking success over recent years and which, at immune evasion by tumor cells, leading to effective cancer cell death.
present, remains the only drug approved by the US Food and Drug Remarkable single-agent activity in patients with relapsed HL has
Administration (FDA) for this indication is BV. been demonstrated with nivolumab, a specific monoclonal antibody
directed against PD-1. Preliminary data from an ongoing trial evalu-
ating the safety and efficacy of this agent in heavily pretreated patients
Brentuximab Vedotin with HL were recently published. Of 23 enrolled patients, 78% had
failed prior ASCT and 78% had failed prior treatment with BV.
The cell surface antigen CD30 is highly expressed on Hodgkin and Overall response rate following nivolumab therapy was 87% (95%
Reed-Sternberg (HRS) cells. The efficacy of agents targeting CD30 CI, 66−97), with 17% achieving a CR and 70% achieving a PR. PFS
has been extensively investigated for patients with relapsed and survival at 24 weeks was 86% (95% CI, 62−95). Drug-related adverse
refractory HL. Brentuximab vedotin (SGN-35) is an antibody-drug events were reported in 78% of patients and none of these were
conjugate (ADC) comprising an anti-CD30 monoclonal antibody greater than grade 3 toxicity (22%). 26
conjugated to antitubulin monomethyl auristatin E (MMAE). The PD-1 blockade with another monoclonal antibody, pembroli-
impressive activity demonstrated by BV in the preclinical setting zumab, is also under clinical development for patients with relapsed
has been matched by its marked efficacy in phase I and II clinical HL after BV failure and preliminary results from a phase Ib study,
trials. which were recently presented at the 2014 ASH Annual Meeting, are
An initial phase I dose-escalation study in patients with relapsed encouraging.
or refractory CD30-positive hematologic cancers showed that BV is The striking therapeutic activity and tolerability of PD-1 inhibi-
associated with a favorable safety profile and established 1.8 mg/kg tors suggests real potential for their inclusion in the future standard
every 3 weeks as the MTD. Significant efficacy was also observed in of care treatment of patients with relapsed or refractory HL, either
this study: tumor regression was demonstrated in 86% of patients, as single-agent therapy or in combination with other agents. Long-
with a median durable response of 9.7 months. 24 term data, however, are awaited.
In a pivotal phase II trial of 102 patients with CD30-positive
relapsed or refractory HL who had failed ASCT the safety and efficacy
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of BV was evaluated further. ORR was 75%, with 34% of patients Histone Deacetylase Inhibitors
achieving a complete response. The median duration of response was
20.5 months. Peripheral neuropathy, nausea, fatigue, neutropenia, Histone deacetylase (HDAC) inhibitors are a class of agents that
and diarrhea were the most common treatment-related toxicities. As bring about tumor response in two distinct ways: by directly inhibit-
a result of this study, in 2011 BV was the first drug to be approved ing tumor cell proliferation as a result of inducing cell cycle arrest