Mantle cell lymphoma (MCL) is a rare non-Hodgkin lymphoma (NHL) that arises from the transformation of the B lymphocytes in the mantle zone of lymph nodes. The hallmark feature of MCL is a reciprocal translocation involving chromosomes 11 and 14—t(11;14)—that results in overexpression of the oncogene cyclin D1. MCL is an aggressive disease which predominantly affects men over the age of 60 years and represents 4% of newly diagnosed NHL in the United States and 7% to 9% in Europe. Patients commonly present with stage III/IV disease and extensive lymphadenopathy, splenomegaly, and bone marrow involvement. MCL carries a poor prognosis, with the median overall survival (OS) of patients with the most common MCL variant being approximately 4.5 years. An intensive approach is often recommended for younger patients requiring treatment, including induction therapy with high-dose cytarabine-based regimen in combination with a monoclonal antibody. Autologous stem cell transplantation (ASCT) is then used as consolidation therapy. In older patients with other comorbidities, rituximab is often added in addition to conventional chemotherapy. Since MCL is an incurable disease, the goal of therapy is to prolong time to progression, palliate symptoms, and improve OS. When the cancer inevitably does progress, it can be due to either a return of the disease (relapse) or from a partial response to treatment (refractory disease).
There is currently no consensus on an approach to treatment of relapsed or refractory MCL after ASCT failure. As an illustration of this lack of guidance, the US National Comprehensive Cancer Network currently provides no recommendations for treatment of relapsed or refractory disease following ASCT other than recommending rituximab as a maintenance therapy. As such, there is clearly a need for a review of available evidence in the literature on this topic.
Following a literature search using the Cochrane Library and PubMed, we could not identify any published comprehensive systematic or scoping review on this specific topic, only a few reviews on related topics. Schulz et al authored a systematic review on the use of rituximab and chemotherapy in NHL and found benefit in this regimen over chemotherapy alone with respect to OS in patients with follicular and MCL. However, this review looked at patients with indolent lymphoma rather than refractory or relapsed MCL. Atilla et al published a narrative review highlighting initial treatment approaches and a select number of trials on newer agents used in relapsed and refractory lymphoma in December of 2016. This review was limited by the lack of a methods section, which limits reproducibility; however, it did confirm several treatment options for patients which include bortezomib, idelalisib, lenalidomide, temsirolimus, and ibrutinib. More recently, a systematic review by Parrott et al that examined treatment options for relapsed or refractory MCL focusing on patients unsuitable for intensive treatment. The authors concluded that there is a paucity of evidence with respect to treatment for patients with relapsed or refractory MCL. The trials available were notably heterogeneous in nature and as such Parrott et al were unable to pool data for meta-analysis. It was noted, however, that direction of effect for progression-free survival (PFS) and OS was the direction of the experimental treatment in all trials included. Given the lack of guidelines around treatment of MCL patients post-ASCT failure, we chose to undertake a scoping review to examine the evidence around treatment as a means of evaluating possible treatment options in this population.
The primary research objectives of this scoping review included:
- 1. Identify treatment options available for MCL patients who have documented disease progression following prior ASCT.
- 2. Evaluate both quality and available evidence from published literature and discuss the implications to clinical practice.
- 3. Identify any gaps in the literature and provide recommendations for future research in this area.
3.1 Study design
A scoping review was conducted to provide a narrative description of the available evidence for treatment options for relapsed or refractory MCL post-ASCT. By mapping the existing literature, the evidence for supporting treatment options in the post-ASCT population can be concisely displayed and gaps can be identified to inform future research. The characteristics of any trials identified, including study design and baseline patient characteristics, were also assessed. This review follows the scoping review framework previously proposed by Arksey and O’Malley.
3.2 Search strategy
A comprehensive literature search was conducted using the following databases: PubMed, EMBASE, and the Cochrane Library. The search included English language articles published before October 3, 2017. ClinicalTrials.gov (http://www.clinicaltrials.gov/) was searched for grey literature related to the topic. To align with the research objective, search terms were divided into 2 concepts which are outlined in Table 1. Medical Subject Headings (MeSH) and keywords in PubMed were established and related to the other databases. The first concept included terms used for “mantle cell lymphoma” while the second concept combined terms used to describe “stem cell transplantation.” The reference lists of all included studies were screened to identify any additional studies that may have been missed. References were imported into RefWorks (ProQuest, Ann Arbor, USA) and exact duplicates were manually removed before exportation to an Excel spreadsheet (Microsoft, Seattle, USA).
3.3 Data collection and extraction
Inclusion and exclusion criteria (Table 2) were developed a priori and applied to the literature search to guide the screening process. Two independent reviewers (E.C.C. and T.M.) screened both the title and abstract to identify eligible studies. Following this, full-text review of all potentially eligible studies was conducted. Any discrepancies were resolved through discussion between the reviewers. One author (E.C.C.) charted the data and extracted information regarding the author, year of publication, location, patient characteristics, intervention, and primary and secondary outcomes reported.
The initial search identified (Table 3 and Fig. 1) 3045 articles following removal of duplicates. Forty full-text articles were analyzed with 12 trials being included in the final review (Table 4 ). The treatment options identified included: allogeneic transplantation, novel oral agents, and conventional chemotherapy. All trials included were relatively small in size, ranging from 16 to 280 participants, the majorities of whom were men in their sixties.
Three trials supported the use of 25 mg oral lenalidomide daily every 28 days from days 1 to 21 until disease progression or intolerance developed.[14,15,16] A phase II randomized controlled trial (RCT) conducted by Trněný et al examined PFS of lenalidomide versus investigator's choice, and found that lenalidomide demonstrated a statistically significant increase in PFS to 8.7 months compared with an average of 5.2 months in the control group. Goy et al conducted a subgroup analysis including only patients with prior ASCT and the results were similar to the overall study population. Overall, PFS in patient groups treated with lenalidomide ranged from 4 to 8.7 months. However, 2 of the 3 trials included lacked a comparator group, while only 1 (Trněný et al) compared lenalidomide to a control drug of the investigator's choice.
Temsirolimus administered 175 mg weekly for 3 weeks followed by 75 mg weekly intravenously was found to significantly improve the PFS and objective response rate (ORR) in MCL patients post-ASCT (median PFS of 4.8 months vs. 1.9 months). The authors of this study also compared the adverse effects profile of the 75 mg continuation dose and a 25 mg continuation dose, and ultimately recommended a 75 mg dose as similar rates of adverse effects were observed.
A phase I study of idelalisib was carried out by Kahl et al This dose-escalation study included 40 MCL patients with doses ranging from 50 mg to 350 mg daily or twice daily for a total duration of 48 weeks. Median PFS was reported as 3.7 months.
Bortezomib in combination with rituximab and dexamethasone was identified as a potential therapy in relapsed or refractory MCL. Out of 5 patients studied who had a prior ASCT, 3 had a complete response, 1 had a partial response, and 1 did not respond to therapy. Toxicities of therapy included thrombocytopenia, peripheral neuropathy, and fatigue, with two patients discontinuing therapy due to grade III neuropathy.
A trial conducted by Morrison et al combined bortezomib with lenalidomide and found no additional benefit. Out of 53 patients, 15% showed a complete response and the 1-year PFS rate was 40%. The authors suggested that the low response rate may be attributed to the suboptimal lenalidomide and bortezomib dosing due to toxicity.
4.5 Allogeneic hematopoietic transplantation
Allogeneic hematopoietic transplantation (alloHSCT) as a therapeutic regimen was explored by Maris et al AlloHSCT demonstrated a high response rate, especially in those previously treated with less than 4 treatment regimens. However, the investigators also reported a high non-relapse associated mortality rate (24%)—potentially limiting the usefulness of alloHSCT as a therapy for relapsed or refractory MCL.
4.6 Conventional chemotherapy regimens
Conventional chemotherapy consisting of gemcitabine, dexamethasone with or without cisplatin was evaluated in terms of efficacy and safety. All ASCT patients who received this regimen with the addition of cisplatin showed improved response rate and duration of response, with median PFS reported as 8.5 months. The authors suggested that convention chemotherapy be considered before high-dose therapy or alloHSCT in younger patients who are able to tolerate the regimen.
Everolimus administered orally was given daily for 4 weeks to evaluate response rates and safety. Unfortunately, disease progression was a persistent problem as the median time to treatment discontinuation was 2 months. The cause of this poor response is thought to be attributed to the resistance of mTORC1 inhibition in these patients’ cancer.
A phase I trial of venetoclax in patients with relapsed or refractory NHL, including 7 patients (25%) with MCL and prior ASCT, was conducted by Davids et al The dose associated with a ORR in MCL of 75% was less than 800 mg. Compared to the other NHL subtypes, the MCL cohort had the highest response rate with a median PFS of 14 months. The authors cautioned that future studies, including ones with combination therapy, are required to evaluate the efficacy and safety of venetoclax in this patient population.
Dreyling et al published additional evidence to support the use of the oral agent ibrutinib. Ibrutinib 560 mg given orally once daily was compared with intravenous temsirolimus 175 mg on days 1, 8, and 15 of cycle 1 followed by 75 mg on days 1, 8, and 15 of subsequent 21-day cycles. Ibrutinib was found to provide a significant improvement in PFS and better tolerability in comparison to temsirolimus. In particular, the PFS time was reported as 14.6 months in the ibrutinib group compared with just 6.2 months in the temsirolimus group. These results support the use of ibrutinib over temsirolimus.
This scoping review provides new insight on the treatment options available for patients with relapsed or refractory MCL following ASCT. While most treatment options identified through this review are supported with a single trial, lenalidomide (n = 3) and bortezomib (n = 2) had additional studies supporting their use in relapsed/refractory MCL. All trials included patients with similar baseline demographic characteristics reflective of the MCL population. The majority of patients included in the trials were men in their mid-sixties. The median number of prior regimens were included in a number of trials examined, providing some interesting insight into the role of specific therapies in complex cases where patients had failed multiple previous drug regimens. For instance, Hess et al reported better outcomes using temsirolimus in a patient population that received heavily prior treatment. This suggests that in patients who have failed numerous prior regimens, temsirolimus may be of benefit. A patient's pretreatment status may therefore help to explain differences in reported outcomes such as PFS or ORR across multiple trials. The number of previous regimens also illustrates the distinct pattern of relapse seen with MCL. A lack of response may be attributed to resistance mechanisms in MCL or to patient factors such as age and sex. In the everolimus trial by Witzig et al, the median age of patients was 70 years old and patients received a median of 3 prior therapies. This study also reported that resistance to mammalian target of rapamycin (mTORC1) inhibition may have caused the lower ORR to everolimus. The authors suggested that the effectiveness of everolimus could be increased in combination therapy with sorafenib, a tyrosine kinase inhibitor. As a result, a phase I/II trial is currently being conducted to evaluate everolimus in combination therapy.
Overall, our results indicate that treatment with ibrutinib and venetoclax appear to achieve the highest response rates and median PFS lengths in patients with relapsed/refractory MCL post-ASCT. The evidence is stronger for ibrutinib where 72 patients with prior ASCT were included while the trial looking at venetoclax had just 7 patients with prior ASCT. This finding supports the European Society for Medical Oncology guidelines, which recommends ibrutinib as first-line therapy in relapsed/refractory disease post-ASCT. ESMO guidelines also recommend consideration of lenalidomide where contraindications exist for ibrutinib. However, study design and outcomes reported across the trials identified were highly variable, and as a result, it is difficult to draw any meaningful conclusions regarding how the efficacy of each treatment regimen compared with every other. High response rates were also seen with alloHSCT, with high mortality rates likely limiting the applicability of this approach.
These results are comparable with the review conducted by Parrott et al in the nontransplant eligible population of MCL. Though a definitive conclusion could not be reached in either review, some of the same treatments were examined, with numerically highest response rates and PFS durations being seen using ibrutinib (ORR 72%, PFS 14.6 months) and bortezomib plus chemotherapy regimen (ORR 82.6%, PFS 16.5 months). The authors concluded that RCTs are required in this area, as 84 of the 85 trials involving this population at the time of publication of the review were single-arm trials.
In conclusion, this scoping review identified a total of 12 trials in which investigators examined treatment options for MCL patients with relapsed or refractory disease. A total of 9 therapeutic options were explored and for the majority of these options (7/9) at least 1 trial supported the regimen. Several gaps and limitations in the current literature were identified. First, there were substantial differences in the study design and reported outcomes of the trials identified and few trials performed a subgroup analysis of post-ASCT patients, making it difficult to directly compare the results of these trials. Second, many of the trials identified were directly funded by the company that manufactured the drug under study, which in some cases had control over the data collection and analysis, putting the validity of some of the conclusions reached into question. Though ibrutinib and venetoclax seemed to demonstrate the best results in this patient population numerically, this review identified serious gaps in the literature regarding what is actually known about the efficacy of treatment regimens for relapsed/refractory MCL in post-ASCT patients. Since ASCT remains one of the most effective consolidation therapies available for MCL,[28,29] more evidence is needed on outcomes of treatment of relapsed/refractory disease post-ASCT. With recent therapeutic advancements and a greater understanding of MCL, it is evident that novel oral agents and combination therapy will continue to revolutionize the standards of care.
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