New chemotherapy-free approaches for the treatment of lymphoid malignancies

At the recent 15^th International Conference on Malignant Lymphoma (15-ICML), the Lymphoma Hub Satellite Symposium (Chaired by Prof. Gilles Salles and Prof. Anas Younes) highlighted recent advances in chemotherapy-free options in the field of lymphoma treatment.

There were four presentations discussing the pros and cons of chemotherapy-free regimens in diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and chronic lymphocytic leukemia (CLL). Each presentation is summarized below with links to relevant lymphoma hub articles included.

Diffuse large B-cell lymphoma (DLBCL)

Professor  Ulrich Jäger, the first speaker, summarised the status of DLBCL treatments, with chemotherapy still firmly the mainstay of first-line therapy, despite studies investigating additions to the primary R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone). An example is the Smart Start trial recently presented at the 2019 American Society of Clinical Oncology (ASCO) annual meeting and the 15^th International Conference on Malignant Lymphoma 2019 (15-ICML) meeting.

The data suggest that the use of rituximab, lenalidomide, and ibrutinib (RLI) as an induction treatment (prior to any chemotherapy) of non-germinal center (non-GCB) DLBCL results in high overall response rates (ORR) of 86% (after two rounds of RLI) and 100% when followed by chemotherapy treatment. Links to the summary of the  Smart Start trial data (click here) and to the interview with Dr. Westin (click here) are provided. Prof. Jäger highlighted that maintenance therapy is currently the only area where chemotherapy-free treatment options have demonstrated a benefit, referring to the REMARC trial. In REMARC, elderly patients with DLBCL showed significant improvement in progression-free survival (PFS) when lenalidomide maintenance was given for 24 months following a complete or partial response to R-CHOP. In terms of chemotherapy-free treatment for relapsed/refractory (R/R) DLBCL, several options have been used, including ibrutinib, ibrutinib+nivolumab, lenalidomide, lenalidomide+obinutuzumab, an EZH2 inhibitor, blinatumomab, pembrolizumab, obinutuzumab+venetoclax, tafasitamab+lenalidomide, and CAR-T cells. A summary table of ‘true chemo-free’ therapies for R/R DLBCL as shown by Prof. Jäger can be seen in the slides above.

Prof.  Jäger pointed out the variability of responses to these R/R chemotherapy-free therapies and the need to consider patient genetic profiles to determine appropriate options. He concluded by presenting two case studies of patients who were treated with truly personalized chemotherapy-free drugs, chosen to match their tumor mutation. A patient with MYD88 mutated DLBCL achieved a lasting response to ibrutinib therapy, and another with MUM1 positive DLBCL remains in third CR after treatment with lenalidomide. Prof. Jäger suggested that functional drug screening may be the way forward for the chemotherapy-free treatment of patients with DLBCL.

Follicular lymphoma (FL)

Professor Nathan Fowler presented the current state of play with FL chemotherapy-free treatments. He demonstrated that long-term survival rates have more than doubled in the last 50 years with improvements in chemotherapy regimens and the addition of rituximab. He also highlighted the influx of newer treatments in recent years (such as antibodies, PI3K inhibitors, and immunomodulatory treatments) of which, however, little is known of the long-term outcomes.

Prof. Fowler went on to discuss the distinctive tumor microenvironment and related immune dysfunction associated with FL which contribute to the promotion of tumor cell survival and proliferation. Therapeutics such as rituximab and lenalidomide can be used to exploit these altered mechanisms. Although many patients benefit from chemotherapy it is associated with toxicity, such as infections, fatigue, nausea, cytopenias, and even secondary malignancies. As many patients are not cured, Prof. Fowler emphasized the need for alternative chemotherapy-free treatment regimens. He went on to discuss PI3K inhibitors, stating that they (copanlisib [our interview with Prof Kim can be viewed here], duvelisib [our review of the DYNAMO trial can be found here], idelalisib [link to interview with Dr Sellner here, and our review of the work here], umbralisib and INCB050465) are similar in terms of ORR (40-60%) and a median PFS at around 11 months. However, they differ slightly in their side effect profile. All PI3K inhibitors appear to induce neutropenia, diarrhea, nausea, fatigue, and coughing at varying degrees. In addition, copanlisib seems to cause hypertension and was related to deaths from respiratory failure and circulatory relapse, while idelalisib, umbralisib, and INCB050465 may also cause transaminitis in some patients.

He then discussed the R2 combination treatment (lenalidomide and rituximab) presenting the RELEVANCE and AUGMENT trial data. The RELEVANCE trial assessed R2 as a front-line treatment and demonstrated a similar efficacy as chemotherapy, but with different side effects (cutaneous reactions and rashes with R2, more febrile neutropenia with chemotherapy). The AUGMENT trial (we summarised the publication here) assessed R2 as a treatment in cases of R/R FL and found it to convey better ORR and PFS  rates also in high-risk patients when compared to rituximab alone, yet had higher toxicity. In answer to questions, Prof. Fowler said he would treat most patients with R2, unless there were signs of transformation. In terms of post-treatment transformation, he had seen very few R2 treated patients with transformation at 5 years follow up. Prof. Fowler brought his presentation to a close with some preliminary data on tazemetostat (an EZH2 inhibitor; please see Dr. Salles interview on tazemetostat for R/R FL here) and CTL109, a CAR T-cell product.

Mantle cell lymphoma (MCL)

The third presentation of the symposium was by Professor  Simon Rule, who began by reviewing how MCL patients were treated historically: R-CHOP or rituximab+bendamustin (R-Benda) was used both in front-line and the R/R setting. Young and fit patients received autologous stem cell transplantation (ASCT) before undergoing allogeneic stem cell transplantation (allo-SCT) at first relapse. He highlighted the need to rethink treatment for MCL with the advent of ibrutinib, which is particularly efficacious in patients who have received only one prior therapy.

Durable responses lasting more than 2 years can be achieved in 50% of patients with ibrutinib as a monotherapy. Despite advocating for ibrutinib to be used as a second-line treatment in all patients, he did mention that in the high-risk group of younger, fit patients with a p53 mutation, ibrutinib should merely be used as a bridging therapy prior to allo-SCT due to their high risk of relapse. As part of a combination therapy (for example, RLI), high ORR and complete response (CR) have been demonstrated in patients with relapsed MCL (regardless of p53 type), and further, the AIM trial demonstrated similar benefits of ibrutinib in combination with venetoclax for newly diagnosed MCL patients.

Prof. Rule went on to discuss novel therapies being used for front-line treatment of MCL. He mentioned the Lyma-101 trial (the results of which were presented at the 24th European Hematology Association Congress, summarised on lymphoma hub here) which assessed obinutuzumab and dexamethasone, high dose cytarabine and cisplatin (O-DHAP; four-cycle induction phase) followed by consolidation therapy with ASCT and obinutuzumab maintenance for three years. Lyma-101 found acceptable toxicity, and good OS and PFS, though longer-term follow up is still ongoing. Prof. Rule also mentioned Window I/II, a trial with ibrutinib and rituximab induction followed by an intensive but short chemo-immunotherapy course, and studies assessing the combination of lenalidomide and rituximab, or obinutuzumab, venetoclax and ibrutinib (the OASIS trial) in older patients.

In his concluding remarks, Prof. Rule stressed the significance of ibrutinib treatment for most patients with relapsed MCL and recommended it as a standard of care. When questioned, Prof. Rule highlighted his preferred maintenance regimens: in younger patients, rituximab maintenance should be given after chemo or allo-SCT, in older patients, rituximab maintenance should only be considered after R-CHOP, but not after R-Benda due to a lack of benefit.

Chronic lymphocytic leukemia (CLL)

Professor  Michael Hallek was the last presenter of the symposium, providing his thoughts on chemotherapy-free regimens for CLL. He opened with the reminder that CLL treatment is already a pioneering chemotherapy-free regimen. Prof. Hallek went on to highlight the numerous novel therapies targeting specific pathways in CLL (Bruton’s tyrosine kinase, PI3-Kinase, and Lyn) drawing specific attention to BCL-2 inhibition by venetoclax which, in combination with obinutuzumab, conveys an ORR of 100% and a 90% CR in untreated CLL.

Prof. Hallek was keen to highlight conflicting trial data in the front line setting. For example, the German CLL Study Group (GCLLSG) trials in the 1990s found the best front-line treatment to be rituximab and bendamustine, or fludarabine, cyclophosphamide and rituximab (FCR), yet a more recent trial (ECOG-ACRIN, summary of the data presented at the 60th Annual Meeting of the American Society of Hematology (ASH) can be found here) found ibrutinib and rituximab to be more efficacious than rituximab and bendamustine. The Alliance North American Intergroup Study (AO41202) did not find ibrutinib and rituximab to be better than rituximab and bendamustine. Prof. Hallek went on to present recent results from the CLL14 trials by the GCLLSG. In this study older or unfit patients benefited more from a chemotherapy-free treatment with obinutuzumab and venetoclax in terms of PFS than from chlorambucil and obinutuzumab (a summary of two abstracts presented at the 24th European Hematology Society (EHA) meeting and the 15-ICML are summarised here). In his concluding remarks, Prof. Hallek presented his recommendations regarding front-line CLL treatments:

1. Patients with del(17p) or p53 mutations should receive ibrutinib with rituximab or venetoclax combined with obinutuzumab or idelalisib
2. Fit patients with or without IGVH mutation should be treated with FCR or ibrutinib, while bendamustine combined with rituximab should be used for patients over 65
3. Unfit patients with or without an IVGH mutation should receive venetoclax with obinutuzumab or chlorambucil combined with obinutuzumab or ibrutinib

He went on to advocate caution when using triplet combinations due to the higher risk of side effects.