Novel and Expanded Oncology Drug Approvals of 2016-PART 2: New Options in the Management of Hematologic Malignancies

February 15, 2017

This article reviews newly approved drugs for hematologic malignancies: their indications, mechanisms of action, accompanying pivotal trial data, pertinent toxicities, use in special populations, and appropriate clinical context.

The recent past has brought pharmacotherapeutic advances that benefit patients with hematologic malignancies. In 2016, two novel hematology drugs were approved and four previously approved hematology drugs were granted expanded use for the treatment of appropriate patient populations by the US Food and Drug Administration. These new approvals and indications represent significant steps forward in patient management: they include the first-in-class B-cell lymphoma 2 inhibitor, venetoclax, the newest targeted therapy available for the treatment of hematologic malignancies; and nivolumab, the first immune checkpoint inhibitor to be approved for treatment of a hematologic malignancy. Other advances include defibrotide as the first drug approved for the treatment of veno-occlusive disease with evidence of multiorgan dysfunction, and the expansion of indications for the two anti-CD20 monoclonal antibodies ofatumumab and obinutuzumab, as well as the anti-CD38 monoclonal antibody daratumumab. This article reviews each of these drugs and their indications, mechanisms of action, accompanying pivotal trial data, pertinent toxicities, use in special populations, and appropriate clinical context.


Given that hematologic malignancies are a varied and complex array of tumors of the blood, bone marrow, and lymphatic system, the available pharmacotherapy can be correspondingly diverse. In 2016, the US Food and Drug Administration (FDA) approved two novel hematology drugs and expanded indications for four previously approved hematology drugs into new cancer patient populations (Table 1). Patients with chronic lymphocytic leukemia (CLL) benefited most directly from the latest approvals and indications: both the first-in-class B-cell lymphoma 2 (BCL-2) inhibitor, venetoclax, and the anti-CD20 monoclonal antibody ofatumumab were granted approval and new indications, respectively. Obinutuzumab, another previously approved anti-CD20 monoclonal antibody, gained an additional indication to treat follicular lymphoma. Daratumumab, an anti-CD38 monoclonal antibody now approved for use in combination with other agents for the treatment of multiple myeloma, appears to be a significant advance. The approval of the programmed death 1 (PD-1) inhibitor nivolumab for patients with classical Hodgkin lymphoma represents the first immune checkpoint inhibitor available for the treatment of a hematologic malignancy. Indeed, the development of immune checkpoint inhibitors is now recognized as an important milestone in cancer care; these agents have transformed the treatment of many solid cancers as well. The second novel hematologic agent approved in 2016 was defibrotide, an oligonucleotide mixture with profibrinolytic properties, for the treatment of patients with a potentially fatal complication from hematopoietic stem cell transplantation (HSCT).

All hematology approvals in 2016 made use of the FDA’s expedited approval programs (Table 2). Defibrotide and venetoclax, like nivolumab and daratumumab, were reviewed and approved as orphan drugs (therapies for conditions affecting < 200,000 people in the United States, or agents used for diseases/disorders in which treatment is not expected to recover the costs of developing and marketing a treatment drug). Also, venetoclax, nivolumab, and daratumumab were granted the Breakthrough Therapy designation, indicating their potential to provide substantial improvement over existing therapies. Further, all agents discussed were granted Priority Review designation.

In our review, we discuss the newly approved drugs available for use in the hematology population and the new indications of already approved agents, with a focus on the drug indication, mechanism of action, pivotal trial data, pertinent toxicities, use in special populations, and appropriate clinical context.

New Drug Approvals

Venetoclax, new approval for CLL with 17p deletion

Venetoclax is an oral small molecule and the first approved inhibitor of the BCL-2 protein. It was approved for use in CLL patients with 17p deletion (as detected by an FDA-approved companion test, the Vysis CLL FISH Probe Kit) who have been treated with at least one prior therapy. Deletion 17p is the most important independent negative prognostic indication for CLL and is associated with poor treatment response and short progression-free survival (PFS) and overall survival (OS) durations.[1]

BCL-2 is a key negative regulator of the intrinsic apoptotic pathway that coordinates a pro-survival signal, ultimately contributing to the ability of cancer cells to evade cell death.[2] Its direct role in a process that is essential to tumor survival has made BCL-2 an enticing therapeutic target for several decades.[3] However, targeting the protein-protein interaction between BCL-2 protein family members has proven to be highly challenging.[4] Clinical development of the first BCL-2 inhibitor, navitoclax, was halted due to dose-limiting thrombocytopenia. The thrombocytopenia was determined to be secondary to inhibition by navitoclax of the antiapoptotic protein Bcl-xL, which is essential for controlling the fate and function of platelets. Venetoclax represents a chemical modification of the structure of navitoclax, in that it targets the BCL-2 overexpression characteristic of CLL while sparing Bcl-xL in circulating platelets.[5] The direct binding of venetoclax to the BCL-2 protein gives the drug a more favorable toxicity profile.

The designation of venetoclax as a Breakthrough Therapy with accelerated approval was based in part on results from an open-label, single-arm, phase II trial evaluating venetoclax in patients with CLL and a 17p deletion who had been treated with at least one prior therapy. Because of the risk of tumor lysis syndrome (TLS), venetoclax was administered according to a weekly ramp-up schedule, with TLS prophylaxis and monitoring recommended. Patients were evaluated for efficacy by objective response rate (ORR), as assessed by an independent review committee. A total of 107 patients were enrolled. After a median follow-up of 12.1 months, the ORR was 79.4%, with a median time to first response of 0.8 months (range, 0.1 to 8.1 months), and a median duration of response that had not been reached. Ten percent of patients were confirmed to have complete response (CR) with incomplete recovery of blood counts or nodular partial response (PR).[1]

The most common grade 3/4 adverse events (AEs) were neutropenia (40%), infection (20%), anemia (18%), and thrombocytopenia (15%). Twelve percent of patients in the pivotal trial needed dose reductions due to toxicity, and 8% of patients discontinued treatment because of AEs that were not related to progression.[1] Patients should be assessed for risk of TLS and should receive appropriate prophylaxis. Patients with reduced renal function (creatinine clearance < 80 mL/min) are at increased risk of TLS and may require more intensive prophylaxis and monitoring.

Deletion 17p in the context of CLL is associated with poor outcomes, with short treatment-free intervals and median survival, as well as resistance to chemotherapy; therefore, the demonstrated activity of venetoclax in this population represents a significant and promising advance.[6,7] Currently, venetoclax is one of several recommended options for the treatment of relapsed/refractory CLL with or without deletion 17p/TP53 mutation.[8] At this time it is difficult to directly compare the efficacy of venetoclax with the standard of care in the relapsed/refractory setting, such as ibrutinib monotherapy and combination therapy with idelalisib plus rituximab. However, the results of the phase II RESONATE-17 study showed that ibrutinib monotherapy yielded an ORR of 82.6% in patients with CLL and 17p deletion,[9] which is similar to the ORR reported in the venetoclax pivotal trial. It is likely that patient-specific factors, including the number and type of prior therapies and molecular abnormalities, will aid in the selection of therapy choice in this setting. Future studies will be important to identify optimal combinations of venetoclax or sequencing of this drug with other agents for the treatment of CLL with 17p deletion.

Defibrotide, new approval for posttransplant veno-occlusive disease

Defibrotide sodium, an oligonucleotide mixture, was approved by the FDA for the treatment of adult and pediatric patients with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following HSCT. VOD/SOS is a potentially fatal complication of HSCT, with an estimated incidence rate of 13.7% and mortality rate of over 80%.[10] This is the first drug approved by the FDA for the treatment of VOD with evidence of multiorgan dysfunction; previous standard-of-care treatment consisted of supportive therapy.

The exact mechanism of action of defibrotide sodium is not fully understood. In vitro, defibrotide demonstrates protection of endothelial cells through its antithrombotic, profibrinolytic, anti-ischemic, and antiadhesive properties.[11,12]

The approval of defibrotide was based on survival at day +100 across three studies. One was a prospective, historical control study ( identifier: NCT00358501) enrolling 102 pediatric (43.1%) and adult (56.9%) patients. Patients treated with defibrotide were compared with 32 matched historical controls, identified by blinded independent reviewers. The observed rates of survival at day +100 post-HSCT were 38.2% (95% CI, 29%–48%) in the defibrotide arm compared with 25% (95% CI, 12%–43%) in the historical control arm, for an estimated difference of 23% (95% CI, 5.2%–40.8%; P = .0109).[13]

A phase II dose-finding study of defibrotide (study 99-118) randomized 151 pediatric and adult patients (representing 32% and 68% of the total study population, respectively) to treatment at a dosage of 25 mg/kg/day or 40 mg/kg/day, in divided doses every 6 hours. Of the 72 evaluable patients randomized to defibrotide at 25 mg/kg/day, the day +100 survival rate was 44%; this dosage was selected to advance into phase III testing.[14] In the expanded access trial (study 2006-05), 351 patients demonstrated a day +100 post-HSCT survival rate of 45% (95% CI, 40%–51%). In summary, defibrotide demonstrated day +100 survival rates ranging from 38% to 45% in 528 patients across three studies as compared with historical day +100 survival rates of 21% to 31% for patients with hepatic VOD with multiorgan dysfunction who received supportive care or other interventions.[15]

Defibrotide includes labeled warnings and precautions for hemorrhage and hypersensitivity reactions, and the drug is contraindicated for patients receiving concurrent systemic anticoagulant or fibrinolytic therapy.[16] The safety of defibrotide was determined in 176 adult and pediatric patients treated with the drug at the approved dose on the prospective trials. The most common AEs of any grade occurred at rates similar to those in the historical control group.[13,16] The most common grade 4–5 adverse reactions were hypotension (7%) and pulmonary alveolar hemorrhage (7%).[16]

Defibrotide was not found to be removed by hemodialysis, and there was no accumulation of defibrotide sodium following repeated dosing in patients with end-stage renal disease (requiring or not requiring hemodialysis) or with severe renal disease not requiring dialysis.[13,14] However, defibrotide exposure (as determined by the area under the concentration-time curve) in patients with severe renal impairment or end-stage renal disease was 50% to 60% higher than that observed in matched healthy subjects, and peak concentration was 35% to 37% higher following single- and multiple-dose administration of defibrotide sodium.[16]

Since defibrotide is the only approved drug therapy for use in adult and pediatric patients with hepatic VOD/SOS with renal or pulmonary dysfunction following HSCT, options for treatment of this condition are limited. While safety data from a randomized comparison trial are lacking, the available efficacy data on defibrotide have demonstrated significantly improved survival at day +100 in patients treated with this agent, compared with historical outcomes.

New Indications for Already Approved Drugs

In addition to newly approved drugs, there are also several previously approved agents that were granted additional FDA indications in 2016. These include ofatumumab, which was granted two new indications for the treatment of CLL; obinutuzumab; nivolumab; and daratumumab. These expanded approvals are reviewed below.

Ofatumumab, two new indications in CLL

Ofatumumab, a cytolytic monoclonal antibody directed against CD20, was granted two new indications for CLL by the FDA in 2016. The first was for extended treatment of patients who have achieved a CR or PR after at least two lines of therapy for recurrent or progressive CLL. The second was for use in combination with fludarabine and cyclophosphamide for patients with relapsed CLL. Ofatumumab has two previous indications in CLL: one is for use in combination with chlorambucil, as therapy for patients with previously untreated CLL who are not candidates for fludarabine-based therapy; and the other is for patients with CLL that is refractory to fludarabine and alemtuzumab.

CD20 is expressed on both normal B lymphocytes and on cells of patients with B-cell CLL. Other CD20-targeted agents such as rituximab and obinutuzumab have also demonstrated clinical benefit across a variety of malignancies, including CLL.[17,18] Ofatumumab binds to both the small and large extracellular loops of the CD20 molecule, two epitopes that are distinct from the binding sites of rituximab and obinutuzumab.[19] The high binding affinity of ofatumumab to the CD20 antigen on the surface of B lymphocytes results in B-cell killing through complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity.[20]

PROLONG, the pivotal trial that led to approval of ofatumumab as extended treatment for CLL, was an open-label, multicenter, randomized, phase III study of patients with CLL who experienced a CR or PR after second- or third-line treatment.[21] A total of 474 patients were randomized to receive ofatumumab or undergo observation. Most patients were in partial remission (81%), had two prior treatments (70%), and had received chemoimmunotherapy (80%) as prior therapy. The primary endpoint of investigator-assessed PFS in the intention-to-treat population was 29.4 months (95% CI, 26.2–34.2) in the ofatumumab arm and 15.2 months (95% CI, 11.8–18.8) in the observation arm (hazard ratio [HR], 0.50; 95% CI, 0.38–0.66; P < .0001). Notably, because patients were in remission, the presence of cytogenetic abnormalities like 17p deletion could not be accurately assessed. Additionally, while treatment extension with ofatumumab increased the PFS duration, there was no OS benefit (HR, 0.85; 95% CI, 0.52–1.37; P = .4877). Overall, maintenance therapy with ofatumumab after second- or third-line treatment for patients with CLL who have achieved a CR or PR demonstrated a significant PFS advantage compared with observation.

COMPLEMENT 2 was the pivotal trial that led to the approval of ofatumumab in patients with relapsed CLL. This open-label, multicenter, randomized, phase III study evaluated ofatumumab in combination with fludarabine/cyclophosphamide (O+FC) for up to 6 cycles vs fludarabine/cyclophosphamide (FC) for up to 6 cycles in patients with relapsed CLL.[22] A total of 365 patients were randomized, most of whom had received 1 or 2 prior treatments; 21% had received prior rituximab. PFS was increased by 10 months in the O+FC arm (28.9 months vs 18.8 months) compared with the FC arm (HR, 0.67; 95% CI, 0.51–0.88; P = .0032). Patients were well-balanced with respect to cytogenetic abnormalities; in total, 6% had 17p deletion and 22% had 11q deletion. With the exception of the 17p deletion arm, the data within each cytogenetic subgroup favored the O+FC arm, reaching statistical significance for the combined 6p deletion, trisomy 12, or 13q deletion arm. Patients in the O+FC arm also experienced an increased ORR (84% vs 68% with FC; P = .0003) and CR rate (27% vs 7% with FC).[22]

Since ofatumumab is a CD20-directed cytolytic antibody, its label carries black box warnings about the risk of hepatitis B virus reactivation and progressive multifocal leukoencephalopathy. Other labeled warnings and precautions are for infusion reactions, TLS, and cytopenias. In CLL populations treated with ofatumumab under the new extended-treatment and relapsed-disease indications, infusion reactions and neutropenia were among the most common AEs (occurring in ≥ 10% of patients). Additionally, upper respiratory tract infections were common in the extended-treatment population (occurring in 19% of patients).[21]

With these two new indications, ofatumumab is now approved as therapy for CLL in several settings. The extended-therapy indication is a first of its kind in the treatment of CLL. While the results of PROLONG clearly show the significant PFS advantage of ofatumumab compared with observation, some clinicians may prefer to simply observe patients, given the increased rates of neutropenia and infection-and lack of an OS benefit-associated with ofatumumab.

The approval of O+FC provides an additional option for patients with relapsed CLL. A variety of factors determine the choice of therapy, including the duration of initial response; age; renal function or other comorbidities; and the presence of chromosomal aberrations such as 11q, 17p, and 13q deletions. The combination of fludarabine, cyclophosphamide, and rituximab (FCR) is the preferred treatment option for younger patients (< 70 years) with standard-risk CLL, and would appear to be the option most similar to O+FC in terms of the composition of therapy. The only difference between the components of the two regimens is the choice of anti-CD20 agent: rituximab vs ofatumumab.

Previously, in a large, international, randomized, multicenter trial, Robak et al demonstrated that, after a median follow-up of 25 months, the median PFS duration for patients with relapsed CLL treated with FCR was 30.6 months, compared with 20.6 months for patients treated with FC.[23] The results, reported after a median follow-up of 34 months, were similar to those from the COMPLEMENT 2 trial, in which the median PFS duration was 28.9 months for O+FC compared with 18.8 months for FC. Further, 21% of patients in COMPLEMENT 2 had received prior treatment with rituximab. While providing some interesting clinical information, these results cannot be used to definitively compare FCR vs O+FC. Moving forward, additional clinical trials will be needed to further clarify the place of O+FC in the treatment of relapsed CLL. For the time being, the new indication for O+FC in CLL provides an additional option in fludarabine-based chemoimmunotherapy.

Obinutuzumab, approved for follicular lymphoma that is relapsed or refractory to rituximab

Obinutuzumab, a type II monoclonal antibody targeting the CD20 antigen, was approved by the FDA for use in combination with bendamustine followed by obinutuzumab monotherapy for the treatment of patients with follicular lymphoma who relapsed after, or are refractory to, a rituximab-containing regimen.[24] Follicular lymphoma is the most common indolent subtype of non-Hodgkin lymphoma.[25] Patients with follicular lymphoma have begun to experience significantly improved treatment outcomes; this is due in large part to the development of rituximab, the use of which has become near universal in the treatment of B-cell non-Hodgkin lymphomas. However, follicular lymphoma remains incurable, and when treatment with rituximab-containing regimens fails, patients are left with few therapeutic options and a poor prognosis.[26-28]

Obinutuzumab exerts its therapeutic effect by mediation of B-cell lysis. Obinutuzumab and rituximab bind with similar affinity to overlapping epitopes on CD20. However, compared with rituximab, in preclinical trials obinutuzumab has demonstrated increased antibody-dependent cellular cytotoxicity, phagocytic activity, induction of cell death, and less complement-dependent cytotoxicity.[29]

GADOLIN was a pivotal randomized, open-label, multicenter, phase III trial in 396 patients with non-Hodgkin lymphoma (including 321 [81%] with follicular lymphoma grades 1 to 3A at initial diagnosis) relapsed or refractory to rituximab. Patients were randomized to receive treatment with obinutuzumab at a dose of 1,000 mg (on days 1, 8, and 15 during cycle 1; and on day 1 of cycles 2 to 6) plus bendamustine for 6 cycles followed by up to 2 years of continued obinutuzumab monotherapy (at 1,000 mg every 2 months) or to receive 6 cycles of monotherapy with bendamustine. The primary endpoint was PFS, assessed by an independent review committee.

After a median follow-up of 20.3 months, median PFS was not reached in the combination arm; and after a median follow-up of 21.9 months, median PFS was 14.9 months in the bendamustine monotherapy arm (HR, 0.55; 95% CI, 0.40–0.74; P = .0001). Combination treatment with obinutuzumab plus bendamustine yielded improved outcomes for several secondary endpoints, including median duration of response (not established vs 13.2 months with bendamustine alone), median event-free survival (26.8 months vs 13.7 months, respectively), and median disease-free survival in patients with a CR (not established vs 13.2 months, respectively); no significant difference in OS was detected at the time of analysis.[29] The results of this trial indicate that the combination of obinutuzumab plus bendamustine followed by obinutuzumab maintenance extends PFS vs bendamustine monotherapy in patients with follicular lymphoma that has relapsed or is refractory to treatment with rituximab.

In the induction phase of the GADOLIN trial, during which patients were treated with either the combination of obinutuzumab plus bendamustine or bendamustine alone, the rates of AEs were similar between the two groups. The most common AEs of any grade were infusion-related reactions, neutropenia, and cough; and the most common grade 3/4 AEs were neutropenia and infusion reactions.

During the maintenance phase of the trial-when patients in the combination-therapy group remained on active treatment and received obinutuzumab monotherapy, the most common AEs were cough (in 15% of patients), upper respiratory tract infection (12%), neutropenia (10%), and infusion-related reactions (8%), all of which were grade 1 or 2. During the induction phase, 7.7% of patients in the combination arm discontinued treatment due to AEs, compared with 15.7% in the bendamustine monotherapy arm. During the maintenance phase, 5.6% of patients discontinued obinutuzumab. Dose reductions were not permitted for obinutuzumab.[29] Because obinutuzumab is a CD20-directed cytolytic antibody, the product labeling, like that of ofatumumab, carries black box warnings against the risk of hepatitis B virus reactivation and progressive multifocal leukoencephalopathy. In addition, there are labeled warnings/precautions regarding infusion-related reactions, TLS, neutropenia, thrombocytopenia, and immunization. Prior to infusion of obinutuzumab, patients should receive premedication with antihistamines, acetaminophen, and/or corticosteroids as prophylaxis against infusion reactions; and with the antihyperuricemics allopurinol or rasburicase to reduce the risk of TLS. In addition, patients should not receive live virus vaccines prior to or during treatment with obinutuzumab.

Given the widespread use of rituximab in the first-line treatment of follicular lymphoma, effective treatment for rituximab-refractory patients is an unmet need. Preclinical models of Burkitt lymphoma and precursor B-cell acute lymphoblastic leukemia showing the superiority of obinutuzumab to rituximab in enhancing cell death and antibody-dependent cytotoxicity generated excitement about obinutuzumab as a potential option in the refractory setting. Previously, obinutuzumab had failed to demonstrate PFS or OS benefit when compared with rituximab in patients with follicular lymphoma[30]; however, the GADOLIN trial showed that obinutuzumab plus bendamustine followed by obinutuzumab maintenance provided a PFS benefit over bendamustine alone in patients with rituximab-refractory follicular lymphoma. Based on this result, the National Comprehensive Cancer Network considers obinutuzumab maintenance to be an option for second-line consolidation or extended dosing in rituximab-refractory patients with grade 1/2 follicular lymphoma.

Questions remain regarding the use of obinutuzumab plus bendamustine followed by obinutuzumab maintenance. For example, it is unknown whether the prolonged PFS in the combination arm of the GADOLIN trial resulted from the activity of the obinutuzumab/bendamustine regimen itself or the extended duration of therapy. Further, longer follow-up periods are needed to determine its impact on OS and to assess long-term toxicities. Due to the lack of effective treatment options in the setting of rituximab-relapsed/refractory follicular lymphoma, the clear gain in PFS with use of the obinutuzumab/bendamustine combination makes it worthy of consideration.

Nivolumab, expanded approval to use in classical Hodgkin lymphoma

The anti–PD-1 immunoglobulin (Ig)G4 monoclonal antibody nivolumab was previously approved for the treatment of melanoma, non–small-cell lung cancer, and renal cell carcinoma. In May 2016, the FDA granted accelerated approval of nivolumab for the treatment of patients with classical Hodgkin lymphoma who experience disease relapse or progression after autologous HSCT and posttransplantation therapy with brentuximab vedotin.[31-33]

The PD-1 ligands, PD-L1 and PD-L2, are encoded by CD274 and PDCD1LG2, respectively. Both of these genes are located on chromosome 9p24.1, an area frequently amplified in the malignant Reed-Sternberg cells characteristic of classical Hodgkin lymphoma.[34] PD-1 pathway activation by PD-L1 and PD-L2 engagement suppresses cytotoxic T cells, limiting T-cell–mediated immune responses, and allowing the Reed-Sternberg cells to evade immune surveillance.[34,35] One mechanism for enhancing the immune response to the otherwise obscured cells is to use nivolumab to block the PD-1 pathway.[34]

The approval of nivolumab in this setting was based on the combined analysis of the phase I CheckMate 039 trial and the ongoing single-arm, multicenter, phase II CheckMate 205 trial. CheckMate 039 was a dose-escalation study of adult patients with hematologic malignancies. Disease-specific expansion cohorts received nivolumab at a dosage of 3 mg/kg every 2 weeks. The classical Hodgkin lymphoma cohort included 23 heavily pretreated patients with relapsed or refractory classical Hodgkin lymphoma. The primary objective was assessment of safety and toxicity, while secondary endpoints included efficacy and biomarker assessments. The ORR was 87%, with 17% achieving a CR, 70% achieving a PR, and 13% with stable disease. The rate of PFS at 24 weeks was 86%.[33] CheckMate 205 was subsequently initiated and is ongoing, with interim results reported for 80 patients. The primary endpoint was ORR after 6 months, as assessed by an independent review committee. After a median follow-up of 8.9 months, 66.3% of the patients had an objective response, including 9% with a CR, 58% with a PR, and 23% with stable disease. The median duration of response was 9.1 months, with further analysis and results still ongoing. The 6-month PFS rate was 76.9%, and the OS rate was 98.7%.[36]

The safety analysis was based on a combination of results from these trials. Immune-mediated AEs occurring in 1% to 5% of patients included rash, pneumonitis, hepatitis, hyperthyroidism, and colitis. Grade 3/4 AEs occurred in 21% of patients; the most common were pneumonia, pleural effusion, pneumonitis, pyrexia, infusion-related reactions, and rash (reported in 1% to 3% of patients).[33,36] In CheckMate 205, 60% of patients required a delay of 1 treatment cycle, 33% required more than one delay, and 5% discontinued therapy due to toxicity.[36] AEs were similar to those reported in previous studies of nivolumab in other cancer types, although infectious complications (pneumonia and upper respiratory tract infections) were more common in the patients with classical Hodgkin lymphoma than in select nonlymphoma cohorts. Hyperacute graft-vs-host disease was an uncommon but serious risk in this posttransplant population.

Nivolumab was approved for patients with classical Hodgkin lymphoma after autologous HSCT and posttransplantation treatment with brentuximab vedotin; approval was based on high response rates and a long duration of response, as well as an acceptable safety profile. To optimize the use of nivolumab in this patient population, trials are being planned that will evaluate the combination of brentuximab vedotin and nivolumab, and the sequencing of nivolumab-based therapy. Other nivolumab combinations in development for posttransplant therapy in patients with classical Hodgkin lymphoma are based on the underlying mechanisms of immunomodulation; they include pairings with lenalidomide, rituximab, obinutuzumab, and ibrutinib.[37]

Daratumumab, approved in combination with other agents for the treatment of patients with relapsed/refractory multiple myeloma

In late November 2016, daratumumab, an anti-CD38 monoclonal antibody, was approved for use in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy.[38] This expands the indication beyond that for which daratumumab was initially approved in 2015, namely use as monotherapy for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy. Multiple myeloma is a malignancy characterized by the clonal proliferation of plasma cells and was estimated to result in 12,650 deaths in 2016.[39,40] Over the past decade, great progress has been made in the management of multiple myeloma, with reduction of death rates tied to the approval of several new classes of drugs: immunomodulatory agents, proteasome inhibitors, monoclonal antibodies, and histone deacetylase inhibitors.[41]

CD38 is a mediator of signal transduction in lymphoid and myeloid cells. With its high relative expression on myeloma cells compared with normal myeloid and lymphoid cells, it is an attractive therapeutic target for the treatment of multiple myeloma.[42] Daratumumab is a human IgGκ monoclonal antibody targeting CD38, capable of target-cell killing of CD38-expressing tumor cells via diverse cytotoxic mechanisms.[43]

Support for the new indication came from the results of two pivotal trials, one for each of the new combination regimens. Eligible patients for either trial had received at least one therapy previously from which they experienced at least a PR, and they needed to have documented progressive disease. The primary endpoint for both trials was PFS in accordance with International Myeloma Working Group criteria.

The pivotal CASTOR trial was a multicenter, open-label, active-controlled, phase III trial in which 498 patients were randomized (1:1) to receive either daratumumab in combination with bortezomib and dexamethasone or bortezomib and dexamethasone alone. The results of a prespecified interim analysis led to an early unbinding of the trial in favor of the daratumumab, bortezomib, and dexamethasone arm, with a median PFS not reached in the daratumumab arm compared with 7.2 months in the control arm (HR, 0.39; 95% CI, 0.28–0.53; P < .001), a 61% reduction in the risk of disease progression or death. Other outcome variables including time to disease progression, the overall response rate, the proportion of patients who achieved a very good PR or better, the duration of response, and the time to response also favored the daratumumab arm. The superiority of the daratumumab combination was confirmed in all subgroups.[44]

The pivotal POLLUX trial was a multicenter, open-label, active-controlled, phase III study that randomized 569 patients in a 1:1 ratio to receive lenalidomide and dexamethasone with or without daratumumab. As in the CASTOR trial, the prespecified stopping boundary was crossed. The estimated median PFS had not been reached in the daratumumab arm and was 18.4 months in the control arm (HR, 0.37; 95% CI, 0.27–0.52; P < .0001), a 63% reduction in the risk of disease progression or death. Again, similar to results reported from CASTOR, the PFS benefit was observed in all prespecified subgroups.[45] Patients randomized to combination therapy with daratumumab experienced a CR rate of 43%, representing a significant advance in clinical benefit over other combination regimens for the treatment of relapsed multiple myeloma.[46]

In CASTOR, higher rates of grade 3/4 AEs were observed in the daratumumab group (76.1% vs 62.4%), with infusion-related reactions and higher rates of thrombocytopenia (45.3% grade 3/4) and neutropenia (12.8% grade 3/4) observed in the daratumumab group. In POLLUX, the most common grade 3/4 AEs were neutropenia (51.9% with daratumumab vs 37.0% without it), thrombocytopenia (12.7% vs 13.5%, respectively), and anemia (12.4% vs 19.6%, respectively). However, in neither trial did the AEs lead to higher rates of treatment discontinuation in the daratumumab arm.[44,45] The FDA warnings/precautions in daratumumab product labeling reflect the monitoring and management of infusion reactions, neutropenia, and thrombocytopenia related to daratumumab. Additionally, daratumumab is known to interfere with cross-matching and red blood cell antibody screening. Patients need to be typed and screened prior to starting treatment, and blood banks should be informed about daratumumab use.[47]

The introduction of daratumumab into combination regimens for the treatment of relapsed multiple myeloma represents a significant advance. The striking degree of benefit conferred by the combination of daratumumab, lenalidomide, and dexamethasone likely makes it the treatment of choice at first relapse in most patients not previously refractory to lenalidomide.[48] Given the rapid growth of active treatment options for multiple myeloma, clinicians are in the challenging position of determining the optimal drug sequence after relapse. Future trials directly comparing the triplet regimens will be necessary to determine optimal use in this chronically relapsing, but increasingly treatable, malignancy.[46]


While the number of newly approved drugs and expanded indications for patients with hematologic malignancies decreased in 2016 compared with recent years, significant treatment advances were made. The six agents that were granted first or additional approvals in 2016-a targeted drug, monoclonal antibodies, an immune checkpoint inhibitor, and an oligonucleotide-reflect the diversity of drug classes and drug mechanisms of action shown to be safe and effective for use in patients with hematologic malignancies. As advances in our understanding of the pathophysiology of various malignancies continue to inform and refine our pharmacotherapeutic approaches, agents are now being approved to treat increasingly specific subgroups of patients; consequently, there is a growing potential to develop treatments that provide substantial improvement over existing therapies. In turn, the ability to achieve clinically meaningful treatment outcomes in niche cancer populations enables drug developers to address unmet medical needs by using the expedited approval programs of the FDA. It is encouraging to see that the new approvals in hematology in 2016 provide patients with good additional therapeutic options-particularly those in higher-risk subgroups and with advanced disease.

Financial Disclosure:Dr. Walko has received honoraria from Bristol- Myers Squibb and Merck & Co, Inc. The other authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.


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