Choosing the appropriate salvage therapy for B-cell non-Hodgkin lymphoma

KEYWORDS:

• Treatment options
• B-cell malignancies
• non-Hodgkin lymphoma
• relapsed disease

1. Introduction

Salvage therapy for relapsed or refractory B-cell, non-Hodgkin lymphomas (NHL) depends on a number of factors including tumor histology, prior therapy, duration of prior response, patient age, comorbid illnesses, and goals of therapy, among others. In this review, we briefly discuss the factors that could influence the choice for appropriate salvage therapy in B-cell NHL.

2. Treatment for relapsed indolent non-Hodgkin lymphoma (NHL)

Treatment recommendations for indolent NHL primarily derives from data obtained from larger studies on follicular lymphoma (FL) which is the second most frequent NHL histology. A recent large French observational study appropriately captures the variability in the treatment approaches for patients with relapsed follicular lymphoma, with no one particular therapy standing out as the most commonly utilized therapeutic regimen. Most patients are likely to be treated with chemoimmunotherapy (CIT) with a substantial percentage continuing on maintenance rituxima- [1].

Besides being utilized for initial treatment of FL, bendamustine and rituximab (BR) combination has extensively been explored as second-line therapy. Two phase-II trials of BR in a total of 130 patients with relapsed or refractory NHL (49% FL) reported 90% overall response (OR) rates with 50% complete response (CR) and a median progression free survival (PFS) of almost 2 years. The most common severe (grade 3/4) toxicity includes myelosuppression with leukopenia and thrombocytopenia [2,3]. In a randomized phase-III study, addition of obinutuzumab to bendamustine in rituximab-refractory patients resulted in superior PFS as compared to bendamustine monotherapy, without significant increase in toxicity [4]. Similarly, based on a phase-III randomized controlled trial, rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) followed by maintenance rituximab for 2 years was associated with OR rate of 85%, CR rate of 30%, and median PFS of 33 months. However, common severe side effects include granulocytopenia, alopecia, nausea, vomiting, and infusion-related reactions which make it a less desirable option as compared to BR [5].

While these regimens are also effective for patients with relapsed mantle cell lymphoma (MCL), its dependency on the B-cell receptor (BCR) signaling pathway allows for effective targeting with selective Bruton’s Tyrosine Kinase (BTK) inhibitors including ibrutinib and acalabrutinib, which are now approved for these patients. Prior to the advent of BTK inhibitors, lenalidomide had established its efficacy in patients with relapsed MCL by demonstrating an improved PFS as compared to treatment of investigators choice (8.7 vs. 5.2 months, p = 0.004) [6]. However, promising results with ibrutinib led to its rapid approval and a pooled analysis of three open label ibrutinib studies in MCL demonstrated OR rate of 60–70% with a median PFS of around 2 years [7]. The combination of ibrutinib and venetoclax in patients with relapsed disease has also demonstrated promising results with OR rate of 71% with a median duration of response of greater than 15 months [8]. Importantly, outcomes are dependent on performance status, MCL international prognostic index (MIPI) score, bulky disease, lines of prior therapy, and blastoid histology [7]. Unfortunately, patients relapsing after BTK inhibitors tend to present with more aggressive disease and have dismal outcomes [9]. While options are limited for these patients, single agent lenalidomide is active in this setting with OR rate of ~30% and median duration of response of 20 week [10].

Phosphatidylinositol 3kinase (PI3K) inhibitors are also effective BCR inhibitors with both idelalisib and copanlisib now approved for patients with relapsed FL. Promising responses have been observed in patients with relapsed FL and also in patients with MCL, specifically with copanlisib. Idelalisib is an oral inhibitor of PI3K-delta and demonstrated an OR rate of 57%, median time to response of 1.9 months, and median PFS of 11 months in patients with rituximab- and alkylator-refractory disease. Most common serious toxicities included neutropenia, elevated liver enzymes, diarrhea, and pneumonia [11]. Copanlisib, on the other hand is an intravenous inhibitor of PI3K-alpha and delta and has shown promising results with OR rate of 59%, median time to response 53 days, and PFS of 11.2 months in patients with refractory disease. Most common serious toxicities including hypertension, hyperglycemia, and neutropenia [12]. However, despite these promising results the use of these agents have been complicated by problematic adverse events including transaminitis, diarrhea, colitis, and infections [13,14]. Similarly, mammalian target of rapamycin (mTOR) and proteasome inhibitors like temsirolimus and bortezomib, respectively, have also been shown to be safe and effective in patients with mantle cell lymphoma either as monotherapy or when combined with CIT.

The advent of immunomodulatory agents like lenalidomide has also resulted in significant improvements in outcomes for patients with indolent lymphoid malignancies including FL. The combination of lenalidomide and rituximab (R [2]) as induction therapy, maintenance therapy, and those with early disease relapse within 2 years of initial diagnosis, has also demonstrated impressive results. The MAGNIFY trial also demonstrated acceptable safety profile, an OR rate of 67% with a CR rate of 36%, and promising activity across all subgroups including patients with MCL with the use of R [2] induction and maintenance [15].

Another important therapeutic modality to consider for the management of patients with relapsed follicular lymphoma is hematopoietic stem cell transplant (HCT). In a comparative analysis of outcomes of patients undergoing autologous HCT as reported by the Center for International Blood and Marrow Transplant Research (CIBMTR), compared to patients receiving standard of care nontransplant regimens from the National LymphoCare Study (NLCS) in the setting of early treatment failure; defined as failure to achieve at least partial response after frontline CIT or lymphoma progression within 2 years of frontline CIT; demonstrated an improvement in OS for patients undergoing transplant within 1 year of treatment failure [16]. This suggests a role of early consolidative HCT as a viable therapeutic option for suitable patients. Similarly, allogeneic (allo) HCT can be considered in appropriate patients who are refractory to conventional therapy as a potentially curative option [17].

3. Treatment for relapsed aggressive non-Hodgkin lymphoma (NHL)

Diffuse large B cell lymphoma (DLBCL) is considered to have more aggressive disease biology and patients with relapsed disease are generally treated with salvage chemotherapy followed by consolidation with high-dose chemotherapy and autologous stem cell transplant for those with chemosensitive disease.

For transplant eligible patients, intensive chemotherapy with agents that have not been employed before and that also allows for adequate stem cell collection is generally preferred. Commonly used regimens include GDP (gemcitabine, dexamethasone, cisplatin), DHAP (dexamethasone, high-dose cytarabine, cisplatin), ICE (ifosfamide, carboplatin, etoposide), and ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin). These regimens can be used with or without rituximab and have reported OR rates of 45–65% and are associated with variable degree of toxicities including myelosuppression, renal failure, and gastrointestinal side effects. R-GDP seems to be better tolerated than R-ICE and R-DHAP for relapsed DLBCL and may have better outcomes in both patients with germinal and nongerminal center B-cell DLBCL, with R-DHAP demonstrating better outcomes than R-ICE in patients with germinal center subtype [18,19]. Similarly, there is no data available to support either regimen for patients with double hit DLBCL, and these patients generally tend to have dismal outcomes.

Multiple novel therapies are being evaluated for the management of patients with DLBCL, including brentuximab vedotin that has shown an OR rate of 44% including 17% CR and a median duration of response of 16.6 months. No statistical correlation between response and CD30 expression was noted and most common serious toxicity included infusion-related reactions [20]. Similarly, polatuzumab vedotin is anti-CD79b monoclonal antibody conjugated to a microtubule toxin monomethylaurostatin E (MMAE). A phase-I study in relapsed/refractory NHL revealed promising results with the most common grade ≥ 3 toxicities including hematologic and neuropathy (9%), and an ORR of 55% with median PFS of 5.7 months [21]. Multiple other antibody drug conjugates are also being employed with promising early results including DCDS0780A, an anti-CD79b monoclonal antibody conjugated to MMAE, ADCT-402 (loncastuximab tesirine) an antibody drug conjugate targeting CD19 and conjugated to a pyrrolobenzodiazepine (PBD) dimer toxin and STRO-001 is an anti-CD74 monoclonal antibody conjugated to a noncleavable dibenzocyclooctyne (DBCO) linker, among others.

Auto-HCT is considered the standard of care for patients with relapsed/refractory DLBCL with chemosensitive disease. However, patients with primary progressive disease, myc gene rearrangement, and intermediate-high/high National Comprehensive Cancer Network-International Prognostic Index (NCCN-IPI) score, double hit lymphoma, and those progressing within a year of initial CIT, can be considered for alternative therapies including chimeric antigen receptor (CAR)-T-cells [22].

CAR-T cells are ex vivo, vector modified, autologous T-cells directed toward the patients’ lymphoma cells. These cells can be adapted to target any relevant tumor antigen and subsequently reinfused into the patient. Early results with Axicabtagene ciloleucel (a CD19 targeting CAR-T cell) demonstrated a promising OR rate of 82% with a CR rate of 54% and 18-month overall survival (OS) of 52% in patients with refractory, high-risk disease resulting in its FDA approval [23]. Similarly, tisagenlecleucel was also approved for patients with relapsed, refractory DLBCL after at least two prior treatments. This was based on the results of the pivotal phase-II JULIET trial that demonstrated an ORR of 53.1% with CR of 39.5% [24]. While extremely promising this treatment modality is associated with serious adverse events related to cytokine release syndrome and neurological toxicities that mandates treatment in a specialized and well-trained facility with the availability of appropriate supportive care. Multiple other CAR-T cell constructs are in development with various modifications to mitigate these adverse events and enhance efficacy and represent a promising tool for long-term disease control in patients with relapsed disease. Patients relapsing after CAR-T cell therapy, autoHCT, and those with chemorefractory disease can also be considered for alloHCT which may provide a curative option for a select group of patients.

4. Expert opinion

Patients with relapsed indolent NHL have a number of safe and effective options. These therapies, however, should be employed only at the time of progressive, symptomatic disease and the majority of patients can be safely followed with watchful waiting until that time. Once the decision has been made to initiate salvage therapy, consideration should be made toward patient’s disease characteristics and performance status. Every effort should be made to treat the patient on a clinical trial that employs novel therapeutics based on clinical, biological, and genetic, patient, and disease factors. Patients who are considered candidates for chemotherapy should ideally be treated with CIT combination either rituximab with CHOP or bendamustine or autoHCT. Conversely, patients with relapsed, aggressive NHL should be treated with salvage therapy with immediate consideration for CAR-T cell or HCT in suitable candidates. Cost effectiveness of the various treatments that are currently employed for the treatment of relapsed and refractory lymphoid malignancies should also be considered, keeping in mind that treatment failure represents the most significant human and financial cost [25].

Despite the substantial improvement in our understanding of the disease process, and the multitude of therapeutic options that are currently available for our patients, cure remains an elusive goal. An area of significant need is the development of therapeutic strategies that are rationally developed based on our understanding of the disease biology while limiting adverse events and duration of treatment. Moreover, novel methods need to be further studied to assess minimal residual disease as a surrogate marker for survival. In addition, incorporation of quality-of-life measures should be an important endpoint in clinical trials of novel therapies, especially if the intent is to continue therapy indefinitely until disease progression or death. These efforts and the substantial progress we have made in the recent years are expected to continue to improve patient outcomes and ultimately allow us to achieve cures in a subset of our patients.

Declaration of interest

F Awan has received research funding from Pharmacyclics and has served as an advisor for Gilead Sciences, AbbVie, Pharmacyclics, and Janssen Pharmaceuticals. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was not funded.