Stockholm was awash with some of the biggest names in hematology one June weekend as the city played host to the annual meeting of the European Hematology Association (EHA). The theme for 2018 was “Immunotherapy: Frontiers in Hematology,” and there was certainly plenty to indicate how the boundaries of science and therapy were being pushed outward.
A defining feature in the treatment of relapsed/refractory (R/R) non-Hodgkin’s lymphoma (NHL) has been the lack of a standard of care, particularly in the third line and beyond, in which there has been a dearth of concrete recommendations and clinicians have had to rely on their individual experience and best judgment. However, this conundrum could be resolved based on the progress that has been made.
New Hope for Diffuse Large B-Cell Lymphoma
Diffuse large B-cell lymphoma (DLBCL), an aggressive subset of NHL, is an area that has seen little progress since the addition of rituximab to the treatment algorithm in 1997, a point referenced by multiple speakers. Although many DLBCL patients are cured by traditional rituximab + chemotherapy regimens, many experience disease relapse. Those who relapse and are unable to undergo an autologous stem-cell transplant face a dismal prognosis; median overall survival is less than six months.
Last year saw the addition of anti-CD19 chimeric antigen receptor (CAR) T cells to the treatment algorithm for DLBCL patients receiving therapy in the third line and beyond. Oncologists were cautiously optimistic that CAR T cells could produce durable, potentially curative responses. Although there was considerable excitement for this new treatment option, it has so far been available only in the United States; it is still under regulatory consideration by the EMA. At the EHA congress, two of the main players—Novartis and Celgene/Juno—updated the efficacy data from their ongoing pivotal trials, data that further support the new and evolving role of CAR T cells in the treatment of NHL.
- JULIET (N = 111): In the latest updated Phase II data, many patients treated with Novartis’s tisagenlecleucel continue to respond to treatment. Investigators reported 14 months of follow-up data, noting that the majority of patients who achieved a complete response (CR) remained in remission. In addition, a number of patients who initially achieved a partial response (PR) eventually converted to a CR. The 12-month response rates for tisagenlecleucel now stand at 40% in CR, with an overall response rate (ORR) of 52%.1 The OS at 12 months was 49%, and the median duration of response was not reached.
Most notably, patients in this trial did not proceed to stem-cell transplant (SCT) following CAR T-cell infusion, underlining the investigators’ intent that tisagenlecleucel be a stand-alone treatment.
- TRANSCEND NHL 001 (CORE N = 73): For liso-cel (JCAR-017), the pivotal Phase II portion of the trial is now fully enrolled and updated data were presented for patients after six months of treatment. Results were presented for both the FULL and CORE patient groups, although, notably, the six-month response in the CORE patient group was reported at 47% ORR and 41% CR.2 Compared with the response rates at three months (59% ORR; 45% CR), this response rate represents a fairly considerable decline, although patients in the TRANSCEND trial did not receive bridging chemotherapy (allowed in JULIET) and were allowed to proceed to SCT.
Based on the many back-to-back CAR T-cell presentations, this treatment is clearly a hot topic. However, despite the excitement and eagerness of clinicians to offer these ground-breaking therapies to their desperate patients, a number of questions were highlighted over the course of the conference. The first question raised centered on the durability of the response and the lack of long-term longitudinal data. Although the results coming from the presented trials were encouraging, the technology is still in its infancy. Whether CAR T-cell therapy is truly a stand-alone treatment or will require consolidation with SCT is still unknown.
The second set of questions relate to access. How will CAR T-cell treatment be made available in the EU? What sort of infrastructure and training will be needed? And how can we tackle the cost of these therapies without bankrupting national health systems or affecting patient access?
The first Topics-in-Focus session titled “Making CAR-T Happen in Europe” attempted to tackle some of these questions.3 Though not all questions could be answered concretely, the presenters did their best to provide actionable ideas, including a suggested framework for accreditation, such as Joint Accreditation Committee ISCT-Europe & EBMT (JACIE) approval and staff and patient education. Notably, Prof. S. Mielke, who presented at the session, emphasized the importance of industry involvement and collaboration, insisting that CAR T cells would not be possible without them.
A future without the first-line use of chemotherapy and cytotoxic drugs has long been a dream of oncologists and is often brought up in the context of the indolent lymphomas—follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL). There is growing interest in the development of chemotherapy-free treatment options that can spare patients the harsh treatment toxicities and preserve patients’ quality of life but without sacrificing treatment efficacy. The clinical studies that most reflect on the feasibility of this approach were the Phase III MURANO and RELEVANCE studies, although they also presented conflicting and contrasting points of view.
Originally presented at the American Society of Hematology (ASH) conference in 2017, the MURANO study assessed the combination of rituximab and venetoclax for the treatment of R/R CLL. The trial has become something of a landmark study by demonstrating that a chemotherapy-free regimen can be effective in indolent NHL. The readout of the trial results in December 2017 indicated that the combination significantly increased patients’ median progression-free survival (PFS) compared with that of patients treated with the standard combination of bendamustine and rituximab.4 At EHA, the study investigators also reported that 83% of patients who experienced a minimal residual disease-negative CR at the end of treatment with the combination remained in CR after a median 13.8 months of follow-up.5 Additionally, prior to the congress’s kick-off, AbbVie announced that it had received FDA approval for venetoclax in combination with rituximab for the treatment of R/R CLL based on the results of the MURANO study (AbbVie, press release, June 8, 2018).
In contrast, the RELEVANCE study, which assessed the combination of lenalidomide and rituximab (R2) in 255 patients with untreated FL, reported negative results. At the recent interim analysis, the two study arms showed no significant difference in median PFS between the lenalidomide combination and rituximab + chemotherapy.6 In addition, the three-year PFS for the R2 treatment arm was reported at 77%, compared with 78% for the rituximab + chemotherapy arm, and the three-year OS showed no difference as well—94% for both treatment arms. Longer follow-up will be needed to see if there are any clinically significant differences between the treatment arms.
Not surprisingly, the standards of care in NHL are rapidly shifting. The four-day conference oversaw the presentation of new evidence to support use of novel therapies often described as ground-breaking. However, many of the new technologies, such as CAR T cells, are still in their infancy. It will be interesting to see what the future brings for NHL as these technologies mature and new generations of these agents are ushered in.
Decision Resources Group can help you stay informed on the development and uptake of CAR T-cell therapy with our Chimeric Antigen Receptor (CAR) T-Cell Therapy—Special Topics (US) report and our in-depth pipeline and market coverage Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia Disease Landscape & Forecast report.
- Borchmann P, et al. An Updated Analysis of JULIET, a Global Pivotal Phase 2 Trial of Tisagenlecleucel in Adult Patients with Relapsed or Refractory (R/R) Diffuse Large B-cell Lymphoma (DLBCL). Presented at EHA, Saturday, June 18, 2018; abstract S799.
- Abramson J, et al. Updated Safety & Long-Term Clinical Outcomes in TRANSCEND NHL 001, Pivotal Trial of Lisocabtagene Maraleucel (JCAR017) in R/R Aggressive NHL. Presented at EHA, Saturday, June 18, 2018; abstract S800.
- Van de Loosdrecht AA, Kersten MJ. Kick-off Session: Making CAR-T Happen in Europe. EHA Topics-in-Focus Session. Friday, June 17, 2018.
- Seymour JF, et al. Venetoclax plus Rituximab Is Superior to Bendamustine plus Rituximab in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia—Results from Preplanned Interim Analysis of the Randomized Phase 3 Murano Study. Presented at ASH 59th Annual Meeting & Exposition, Tuesday, December 12, 2017; abstract 109076.
- Hillmen P, et al. High, Durable Minimal Residual Disease (MRD) Negativity with Venetoclax + Rituximab in Relapsed/Refractory CLL: MRD Kinetics and Response in Cytogenetic Risk Groups in PTs from Phase 3 MURANO Study. Presented at EHA, Saturday, June 18, 2018; abstract S805.
- Morschhauser F, et al. RELEVANCE: Phase III Efficacy and Safety Study of Lenalidomide plus Rituximab (R2) versus Rituximab plus Chemotherapy, Followed by Rituximab, in Previously Untreated Follicular Lymphoma. Presented at EHA, Friday June 17, 2018; abstract