Recent advances in the management of Hodgkin lymphoma

Clinical activity of brentuximab vedotin in Hodgkin lymphoma

An initial phase I dose-escalation study investigated the safety and clinical activity of BV in 45 patients with relapsed CD30-positive lymphomas, 42 of them with HL⁸. A total of 15 patients (36%) with HL achieved an objective response to treatment with BV, nine (21%) of whom had a complete response. Overall, the drug was well tolerated and safe at the dose level of 1.8 mg/kg given every 3 weeks, which moved forward into clinical development.

A multinational phase II study was then designed to evaluate the efficacy of BV in patients with advanced HL who had failed autologous stem cell transplantation (auto-SCT). A total of 105 patients with HL were treated with 1.8 mg/kg of BV every 3 weeks for a maximum of 16 cycles and assessed primarily for objective response. An objective response was observed in 76 patients (75%), including 35 (34%) complete remissions (CRs). The median duration of response was 6.7 months for all responders and 20.5 months for those achieving CR. The drug was well tolerated and the most common adverse effects were peripheral neuropathy, fatigue, gastrointestinal symptoms, and neutropenia. There were no cases of febrile neutropenia or deaths attributed to BV.

Based on the results of this trial, BV received accelerated approval from the US Food and Drug Administration (FDA) on 19 August 2011 for the treatment of patients with HL after failure of auto-SCT or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not candidates for auto-SCT. Updated results from that trial after a median follow-up of 3 years confirmed that responses were durable, especially for the group achieving CR⁹.

Additional studies were designed to evaluate the role of BV in other settings. A large phase III trial demonstrated increased progression-free survival (PFS) when BV was used as consolidative treatment following auto-SCT¹⁰. A phase I dose-escalation trial studied the use of BV + ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) or BV + AVD (ABVD without bleomycin) in treatment-naïve patients with HL¹³. Fifty-one patients were treated and CR was achieved in 95% of BV + ABVD and 96% of BV + AVD patients. Aside from excessive pulmonary toxicity in the BV + ABVD group, treatment was generally well tolerated. A large multicenter phase III trial of BV + AVD versus ABVD (NCT01712490) for newly diagnosed advanced HL has recently completed accrual.

Toxicities associated with brentuximab vedotin

BV has been approved for use as a single agent at the dose of 1.8 mg/kg (up to 180 mg) administered intravenously every 3 weeks until a maximum of 16 cycles, disease progression, or unacceptable toxicity. At this dose level, BV is generally well tolerated. The most clinically relevant side effect of BV is peripheral neuropathy. Sensory neuropathy is more commonly seen (42%) than motor neuropathy (11%). Cases of BV-induced neuropathy may be severe (up to 31% at least grade 2) and constituted the leading cause of drug discontinuation in some of the clinical trials^12,13. Median time to onset of neuropathy was about 12 weeks and severity was cumulative. The majority of patients (80%) experienced some improvement of symptoms (of at least one grade) with drug discontinuation but complete resolution was observed in only half of the cases. It is important to mention that the incidence of febrile neutropenia was extremely low, making BV an attractive drug for combination with multi-agent chemotherapy regimens.

The combination of BV with bleomycin in a phase I trial investigating the use of BV in combination with standard therapy (ABVD) led to unacceptable pulmonary toxicity¹¹. On the basis of these findings, the label of BV was modified to include a contraindication to its use in conjunction with bleomycin. Consequently, the trials currently evaluating the use of BV in combination with chemotherapy have modified the regimens to exclude bleomycin.

Although BV is generally safe and well tolerated, two other uncommon but serious adverse events potentially associated with the use of BV are worth mentioning: progressive multifocal leukoencephalopathy (PML)^14,15 and pancreatitis¹⁶. Post-marketing reports linked BV to these serious and potentially life-threatening conditions. These resulted in the addition of a black-box warning for the risk of PML and raised awareness for the occurrence of acute pancreatitis in patients treated with BV.

Other antibody-based conjugates currently in development for Hodgkin lymphoma

The success of BV – the first ADC approved for the treatment of lymphomas – has spurred interest in developing new agents using the same platform. ADCT-301 is an ADC that combines a monoclonal antibody against CD25 to an antibiotic with anti-tumoral properties (pyrrolobenzodiazepine or PBD). This compound has demonstrated pre-clinical activity¹⁷ and is now accruing patients with HL for a phase I study (NCT02432235). Another compound targeting CD25 combines the specificity of a monoclonal antibody (daclizumab) to the anti-tumoral activity of radiotherapy (RT) by linkage to a beta-emitter particle (⁹⁰Y). ⁹⁰Y-daclizumab has now been tested in patients with advanced HL in a recently published phase II study with encouraging results¹⁸.

Clinical activity of nivolumab in Hodgkin lymphoma

Nivolumab is a monoclonal antibody that binds to the PD-1 receptor and prevents it from interacting with its ligands (PD-L1 and PD-L2). By disrupting the PD-1:PD-L1/2 axis, nivolumab seeks to overcome immune tolerance induced by cancer cells, thereby releasing the immune system for an effective anti-cancer response. Nivolumab has now been tested in several malignancies and received FDA approval for use in melanoma, non-small cell lung cancer, and renal cell carcinoma²³.

A phase I dose-escalation trial tested the safety and efficacy of nivolumab in patients with heavily pre-treated advanced HL. The original manuscript reported on the experience with the first 23 patients treated at the 3 mg/kg dose level after a median follow-up of 40 weeks²⁴. An objective response was observed in 20 (87%) patients, including four (17%) with a complete response. The additional three patients had stable disease, indicating that all 23 patients derived some degree of clinical benefit from the treatment. Nivolumab was well tolerated and the safety profile was consistent with previous experience documented for other tumor types. No serious adverse events or deaths attributed to the drug were observed.

Updated long-term results on these patients after a median follow-up of 86 weeks were presented at the most recent American Society of Hematology (ASH) annual meeting²⁵. Of the 20 initial responders, 10 demonstrated responses lasting over 41 weeks (range 41.7 to 90.7 weeks), including one who was retreated at progression after treatment was discontinued. Of the remaining 10 responders, four developed progressive disease, one discontinued due to adverse effects (without progression), and five discontinued nivolumab to undergo allogeneic SCT. These results provide early evidence that responses obtained with nivolumab in HL may be durable.

Based on these encouraging early results, nivolumab received breakthrough therapy designation for HL from the FDA. A registrational phase II trial utilizing nivolumab for the treatment of HL is currently underway (NCT02181738).

Pembrolizumab

Pembrolizumab is another monoclonal antibody that belongs to the class of PD-1 inhibitors. Similar to nivolumab, this agent works by targeting the PD-1 receptor and is approved by the FDA for the treatment of melanoma and non-small cell lung cancer²⁶.

The safety and clinical activity of pembrolizumab is being tested in a phase Ib multicenter clinical trial for patients with relapsed/refractory HL after failure of auto-SCT and BV. Patients who were deemed ineligible for or refused auto-SCT were also included. Patients were treated with 10 mg/kg of pembrolizumab every 2 weeks. An updated report on the first 31 patients was presented at the most recent ASH annual meeting²⁷. At a median follow-up of 9.7 months, an objective response was observed in 20 (65%) patients including five (16%) achieving CR. An additional seven (23%) patients had stable disease as best response, indicating that 87% of patients derived clinical benefit. Pembrolizumab was well tolerated and toxicity was consistent with previous experience in other cancers. Fourteen of the 20 responses were ongoing at the time of data cut-off. No serious adverse events or deaths were attributed to the treatment.

These results reinforced the notion that PD-1 inhibition is a safe strategy with a strong signal of clinical activity in heavily pre-treated HL patients. These and other studies are currently open and accruing patients with HL.

Adverse effect profile of programmed death 1 inhibitors

PD-1 inhibitors are usually well-tolerated drugs, even for patients who are heavily pre-treated with standard cytotoxic agents. The most common adverse effects of this class are dermatologic (rash and pruritus), metabolic (lipid changes, hyperglycemia, hypoalbuminemia, and electrolyte imbalances), hematologic (anemia and lymphopenia), gastrointestinal (changes in bowel habits and nausea/vomiting), and respiratory (cough and dyspnea)^26,28 in nature and also include fatigue, abnormal liver enzymes, and arthralgia.

A distinct class of adverse effects – collectively known as immune-related adverse effects (IrAEs) – deserves special mention, since they are uniquely associated with these immunotherapeutic agents²⁹. These are the result of the immune-stimulatory effects of these drugs and can affect different organs with pleomorphic presentations. Despite being uncommon, early recognition and management is crucial, as these events can progress rapidly to cause significant morbidity or even death. Potentially affected organs are the lungs (pneumonitis), the endocrine system (hypophysitis, thyroiditis, and adrenal insufficiency), the skin (toxic epidermal necrolysis), and the gastrointestinal tract (colitis and pancreatitis). These occurrences should trigger immediate evaluation and providers should have a low threshold to hold therapy (for mild cases) and treat with systemic steroids (for moderate to severe cases). Expert consultation with organ-specific specialties is highly advised, as these patients often need invasive testing (i.e. bronchoscopies and colonoscopies) to rule out alternative diagnoses (i.e. infection or tumor progression). Standardized guidelines on the management of these patients are not yet available and treatment must be individualized.

Caution is advised when utilizing checkpoint inhibitors in patients with a documented history of autoimmune disorders, especially if poorly controlled. The same applies for the use of checkpoint inhibitor therapy in patients who have failed allogeneic SCT and have active graft-versus-host disease (GVHD). Evidence is starting to surface supporting the safety of the use of these agents in patients with pre-existing autoimmune conditions³⁰ (as long as they are adequately controlled) or after allogeneic transplant (as long as GVHD is minimal)^31–34. These are mostly retrospective studies or small case series; therefore, therapy in these special situations must be individualized and include a thorough discussion of the risks, benefits, and uncertainties.