ASCO 2017 | Diagnosis and treatment options for Mantle Cell Lymphoma – Educational session 

An Educational Session took place during the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting discussing the diagnosis and treatment options available for patients with Mantle Cell Lymphoma (MCL).

The session was chaired by Brad S. Kahl, MD, from the Washington University School of Medicine in St. Louis, MO USA.

The first talk during this session was given by Jonathon Brett Cohen, MD, MS, from Emory University, Atlanta, GA, USA, and discussed how to differentiate between more and less aggressive MCLs.

Cohen began by providing some background information. MCL is fairly rare, accounting for less than 10% of cases of NHL. The majority of cases are positive for cyclin D by immunohistochemistry and positive for markers such as CD5 and CD20, but is negative for CD23. MCL is also characterized by the t(11;14) translocation. This immunophenotype makes it easy to identify if suspected but can often be mistaken for a different NHL subtype. Disease is often stage IV, has bone marrow involvement, and displays peripheral blood lymphocytosis; commonly splenomegaly and/or involvement of the GI tract is observed. Based on data from the National Cancer Database, between 2004 and 2011 there has not been a significant improvement overall in survival of MCL; a large proportion of patients die from MCL or other causes within 5 years of diagnosis. MCL is a challenging disease to diagnose and treat.

The talk then outlined the current “traditional” approach to treatment. Firstly, diagnosis is confirmed and a staging/prognostic work-up is carried out. If the patient is eligible for ASCT as consolidation in CR1, then they undergo more intensive induction therapy followed by ASCT. Is ineligible for ASCT, then they receive less intensive induction, which sometimes consists of combination chemotherapy or modern therapy with less aggressive agents for frail patients. In both instances, maintenance is considered. Moreover, there is a patient subset which undergo observation (10–30% depending on series).

Patients with indolent MCL can potentially be observed, something we have known for the last 8 years based on work by Martin et al.; in subsequent studies including an analysis of the National Cancer Database (Cohen et al. Cancer. 2016), there is no significant difference in worsening of survival in patients who undergo observation and those who receive immediate therapy. A cut-off of 90 days from diagnosis was used to define patients who received immediate treatment and those who were deferred. Cohen et al. did find significantly improved OS in deferred patients compared to patients treated immediately. It was cautioned that patients are “not necessarily hurt by receiving treatment”, but we are accurately identifying low-risk patients who are likely to have long survival even if deferred at diagnosis.

A number of predictors for deferred therapy have been consistently reported in a range of publications, and include:

• Lack of B-symptoms/minimal symptoms at diagnosis (good candidates for observation)
• Normal LDH levels
• Leukemic, non-nodal subtype of MCL (i.e. CLL-like)
• Good ECOG PS
• Ki67 <30%
• Lack of aggressive disease (e.g. blastoid variant)

Moreover, in numerous studies, MCL International Prognostic Index (MIPI) has not been associated with deferred treatment. Cohen the presented a summary of findings with deferred therapy:

Patients in each series have been safely observed for many years. Median OS does not significantly differ between patients who deferred and those treated immediately. However, these studies are all retrospective and no randomized studies are available. It is possible that survival could be improved even further in lower-risk patients with immediate therapy, however this is unknown, and for now it seems that deferring therapy does not harm patients. Cohen also stated that we have been very successful at identifying low-risk patients and deferring them even without newer technologies such as NGS.    

Jonathon Cohen moved on to discuss SOX11, a candidate marker for identifying patients with indolent MCL. However, results have been mixed. The majority of recent studies, but not all, indicate that patients negative for SOX11 are more associated with indolent disease. Findings by Fernandez et al. found that patients who were SOX11 negative (n=15) had significantly improved outcome compared to SOX11 positive patients (n=97). It was emphasized that most patients with MCL are SOX11 positive and so this should not be used alone to identify low- vs. high-risk patients. However, patients with indolent presentation (non-nodal disease, splenomegaly, leukocytosis, and lower Ki67) and are SOX11 negative could potentially be observed.

Methods to identify high-risk MCL patients were then discussed, which include high MIPI score (most common), Ki67 proliferation index, and cytogenetics.

MIPI was first described nearly 10 years ago (Hoster et al. Blood. 2008) and includes WBC count, ECOG PS, age, and LDH level at time of diagnosis. High-risk patients continue to have poorer outcomes than those with intermediate- and low-risk disease and therefore present a group of patients not benefiting from the current therapeutic strategies that we have. MIPI has been explored in the context of Minimal Residual Disease (MRD). Potts et al. reported that in elderly patients, 67% where negative for MRD but 40% of these had a high-risk MIPI, suggesting MRD negativity can be achieved in patients with high-risk MIPI. However, it has also been found that patients with high-risk MIPI are more likely to experience earlier molecular relapse (Kolstad et al. BBMT. 2017).

Ki67 proliferation index is measurable by immunohistochemistry, making it feasible in the majority of pathology labs. However, it can vary between patients as well as pathologists. A cut-off of 30% is the most commonly implemented to identify high- vs. low-risk. Hoster et al. reported in JCO in 2016 that patients with a Ki67 of ≥30% had a median OS of only 3.4 years vs. not reached in patients with a Ki67 of <30%. Cohen said that he sometimes finds Ki67 challenging, for example, what do you do with a patient who has a Ki67 of 35%? Is it that much significantly different from 30%? But, it is certain that patients with a very high Ki67 have worse outcomes than those with lower proliferation indices.

Recently, MIPI has been combined to form the MIPI-C and appears to be more accurate at discriminating between low- and high-risk patients, while using factors that are easily obtainable in clinical practice (Hoster et al. JCO. 2016):

Cytogenetics have been around for a long time and have been commonly used in other blood cancers such as AML, CLL, and MM. Complex Karyotype (CK), defined as more than three abnormalities, is associated with poorer outcomes in MCL patients. Consistent predictors of CK have been found; and CK has been associated with OS.

Other markers for high-risk patients include specific chromosomal abnormalities such as del(17p), as well as absolute lymphocyte to monocyte ratio of less than 2. The problem that Cohen emphasizes is that it is quite simple to identify patients with high-risk disease, however the intensive therapeutic strategies currently available (such as cytarabine containing regimens, ASCT, etc.) are inadequate. A retrospective analysis by Greenwell et al. found that treatment intensification does not significantly improve median OS in patients with CK:

• With intensive induction = 4.5 years; with non-intensive induction = 3.8 years
• With transplant in CR1 = 5.1 years; no transplant = 4.0 years

Some newer methods to risk-stratify patients include mutational analysis/genomic assessments and proliferation signature. Multiple recurrent genomic aberrations (ATM, cyclin D1, TP53 genes) have been identified in many MCL series and potentially could associate with clinical outcomes however, this is currently not well understood.

Multiple studies indicate that TP53 mutations are important and associate with poor outcome. Beyond this, assessing individual abnormalities is challenging and costly, and is of questionable use outside of the research setting as currently there is no standard treatment approach for these patients. Continually, new genes are being identified that associate with prognosis and multi-gene panels are required in order to better integrate the prognostic importance of each individual aberration. Rosenwald et al. reported a multi-gene proliferation signature in 2003 which identified and associated with OS. However, it relied upon fresh tissue samples, making its use in routine practice challenging. The British Columbia group defined the MCL35 assay (Scott et al. JCO. 2017), which identifies high, standard, and low-risk patients using FFPE tissue meaning samples can be taken, fixed, and sent to alternative locations to undergo the assay. High Ki67 and MIPI patients do appear to cluster in the high-risk patients defined by the MCL35 assay, however some lower-risk patients defined by the assay also have high Ki67 and MIPI scores. So, it remains to be seen what the impact of the MCL35 assay will have. It was found that high-risk patients as defined by the MCL35 assay did have the worst OS, followed by standard- then low-risk patients. Cohen noted that it was impressive that of 110 biopsies from patients who received R-CHOP with or without ASCT, the assay could be performed on 108. However, to be eligible patients must have excisional biopsies if lymph nodes with >60% tumor content available, and normally the luxury of such a large lymph node/sample is not always present. However, what do you do with this information and how can therapy be altered? Hopefully, some of the more targeted agents in development can be used based on these kinds of assays resulting in personalized treatment for MCL. But, studies are still urgently required to identify improved treatment strategies for patients with high-risk disease and/or genetic abnormalities.

Jasmine M. Zain, MD, from the City of Hope Comprehensive Cancer Center, Duarte, CA, USA, and was titled “ Understanding Who Should Receive a Hematopoietic Cell Transplant for Mantle Cell Lymphoma.”

Patients who require treatment are assessed on their ability to tolerate Stem Cell Transplant (SCT) as the majority of treatment and management guidelines for MCL include ASCT as part of first-line therapy. Stratification of disease (disease characteristic, clinical subtype, MIPI score, biologic factors, and genetic factors) and the patient (physiologic age, comorbidity index, ability to tolerate intensive chemotherapy and ASCT, minimum cardiovascular function, pulmonary reserve, and renal function) should take place to ensure the patients is physiologically for high-dose treatment, ASCT, and the potential side effects and complications that can arise with conditioning therapy.

Eligibility for transplant also relies on where the stem cells for transplant will come from. ASCT uses cells from the patient’s own bone marrow, which therefore must be healthy enough for stem cell mobilization. Allogeneic (allo) SCT requires an appropriate donor such as a sibling, a matched unrelated donor, cord blood, or a haplo-identical donor. 

Up-front treatment including ASCT

Dr Zain gave an overview of treatment for “fit” patients. She did not use the word “young”, as more commonly physiological age rather than chronological age is being used during assessment. In most trials, the age limit has now increased to 65–70 years. Other factors that define fit patients include adequate cardiac, pulmonary, and renal function, as well as a lack of comorbidities. The established recommendations for treatment include up-front use of rituximab in combination with intensive chemotherapy, use of high dose Ara-C in the regimen, high dose therapy and ASCT in responding patients, and maintenance.

In the very first attempts at treating MCL, approaches similar to CHOP resulted in poor results, and the majority of patients relapsed within 2–3 years. The addition of rituximab was shown pretty early on to improve outcomes in MCL patients (Lefrere et al. Leukemia. 2012; Delarue et al. Blood. 2012):

• CR after CHOP = 7%; CR after R-CHOP = 12%
• ORR after CHOP = 50%; ORR after R-CHOP = 93%
• ORR after DHAP = 84%; ORR after R-DHAP = 95%

In addition, rituximab added to FCR or CHOP has been reported to improve responses without significantly worsening time to treatment failure or OS. Based on these findings, numerous aggressive regimens, unsuitable for frail or elderly patients, have been developed with the aim of improving outcomes in patients with stage II–IV MCL who are thought to be eligible for transplant. ASCT is only carried out in patients who respond to chemotherapy.

The overall findings of these trials were that rituximab improved initial response rates, the R-hyper-CVAD x8 regimen was too toxic for patients, and the Dreyling et al. 2005 randomized trial demonstrated the efficacy of ASCT up-front for MCL patients and established the use of ASCT consolidation in patients who had received R-CHOP or R-CHOP-like induction regimens

An early retrospective analysis by Milpied et al. indicated that treatment strategies based on Total Body Irradiation (TBI) have a benefit in MCL, achieving a 4-year PFS of 71%, however this approach has been reported to be toxic and is associated with an increased incidence of secondary malignancies. Therefore, treatment approaches have moved away from this.

Y-ibritumomab-tiuxetan and I-tositumumab present as promising ways of targeting radiation directly at malignant cells and as monotherapies have both shown anti-lymphoma activity in treatment naïve and relapsed patients. In addition, both in combination with high-dose chemotherapy as conditioning for ASCT have been shown not to increase toxicity. Due to the sub-optimal responses to upfront chemoimmunotherapy achieved in the Nordic MCL-2 trial, the MCL-3 trial used Y-ibritumomab-tiuxetan to try and overcome resistance to chemotherapy. ORR was 97%, 4-year OS was 78%, and 4-year PFS was 71% (similar to what was achieved in MCL-2). However, in a phase II pilot trial by the GELTAMO (Arranz et al. 2013), consolidation with Y-ibritumomab-tiuxetan after hyper-CVAD resulted in the deaths of 20% of patients from secondary malignancies.

Predictors of response after ASCT

The first-line treatment strategies outlined above confer challenges and significant toxicity. Moreover, due to treatment resistance and complications, only 10–30% of patients actually undergo ASCT. Evaluation of the larger studies available has identified factors which predict outcomes after ASCT: MIPI/MIPI-b, MRD status, and response per PET scan before transplant. Indeed, the MCL-2 trial found that of patients with low-intermediate and high-risk MIPI-b scores, 70% and 23% were alive at 10 years. The MCL-3 trial found that patients who were PET positive and MRD positive predicted poorer outcomes. In an analysis of 27 post-ASCT patients who underwent evaluation for MRD, median PFS was 92 months vs. 21 months in MRD-negative and MRD-positive patients, respectively (Potts et al. 2006). Furthermore, a large European MCL Network study found that MRD-negativity predicted higher response rates at 2-years: 94% vs. 71% in MRD-negative and MRD-positive patients, respectively. ASCT was found to improve MRD-negativity rates from 55% to 72%, and sustained MRD-negative disease was an indicator of improved 2-year outcome (100%) compare to MRD-positive disease (65%). Thus, patients who are MRD-positive or display other poor prognostic characteristics potentially benefit from other therapeutic strategies.

ASCT for relapsed MCL patients

ASCT achieves a median PFS of only 1–2 years in patients with relapsed MCL. In numerous reports, it has been found that responses to ASCT are improved in CR1 compared to transplants performed later in the disease course, even in patients who were sensitive to chemotherapy. Encouragingly, it has been found that ASCT followed by subsequent radioimmunotherapy improves outcomes (in particular OS and PFS) in relapsed patients.

Allogeneic SCT for MCL

Unfortunately, the majority of patients will experience relapse; despite the improvements we have seen in treatment. In patients who experience relapse after ASCT, the median OS is only 19 months. Allo-SCT has been reported to achieve long-term remissions and potential cures in these patients, but at the risk of GvHD, infections, and organ dysfunction.

Dr Zain summarized the different series of allo-SCT performed in MCL:

Jasmine Zain concluded her portion of the session by stating that currently allo-SCT is only recommended to be carried out in patients in first complete remission in clinical trials only and not in routine practice.

The last talk was on the topic of whether maintenance therapy has a role for MCL, and was given by the session chair Brad S. Kahl, MD.

 Based on the efficacy and durability of rituximab maintenance in patients with FL, it was sensible to investigate if these results could also be achieved in MCL patients. An improved OS have been found with maintenance rituximab in MCL; however, numerous questions still remain such as the optimal dose and schedule of rituximab as well as the impact of different induction regimens on rituximab’s efficacy.

Early studies of rituximab maintenance in MCL

The first trial investigating rituximab maintenance was a conducted by the Swiss Group for Clinical Cancer Research (SAKK) and was published by Ghielmini et al. in 2005. After induction treatment with 375mg/m² weekly x 4, responding patients or those with SD at week 12 from the treatment initiation were randomized to either no further treatment or prolonged rituximab administration (375mg/m²) every 8 weeks for four times. The authors concluded that after the standard schedule, adding four single doses of rituximab every 8 weeks did not appear to significantly improve response rate, DoR, or EFS.

One year later, the German Low Grade Lymphoma Study Group (GLSG) published findings of their study investigating rituximab maintenance after R-chemotherapy (Forstpointner et al. Blood. 2006). Patients with R/R FL and MCL were randomly assigned to either four courses of FCM alone or R-FCM. Patients who responded were then further randomized to rituximab maintenance. DoR was significantly prolonged by rituximab maintenance after R-FCM in both FL (P = 0.035) and MCL (P = 0.049) patients.

The Wisconsin Oncology Network investigated rituximab maintenance (four weekly doses every 6 months for 2 years) after R-hyperCVAD in the frontline setting in a single-arm, phase II trial of 22 patients (Kahl et al. Ann Oncol. 2006). No methotrexate or Ara-C was administered. ORR was 77% and the CR rate was 64%. After a median follow-up of 37 months in surviving patients, the median PFS was 37 months and the median OS was not reached. After longer follow-up, 30% of patients were progression free after 5 years, indicating the long-term benefit of rituximab maintenance (Kenkre et al. Leuk Lymphoma. 2011).

In 2011, the Wisconsin Oncology Network published (Chang et al. Br J Haematol. 2011) findings from their study assessing the addition of bortezomib (VcR-CVAD) and extending maintenance rituximab to beyond 2 years in newly diagnosed MCL patients. CR/CRu was achieved in 77% of patients, and after a median follow-up of 42 months, 3-year PFS was 63% and 3-year OS was 86%. No relapses were reported beyond 5 years, although 5 years of rituximab maintenance did associate with more infections and only one-fifth of patients completed the full 5 years of planned treatment.

The Eastern Cooperative Oncology Group (ECOG) confirmed this in their phase II E1405 trial of VcR-CVAD with maintenance rituximab for newly diagnosed patients with MCL (Chang et al. Blood. 2014). VcR-CVAD chemotherapy was administered every 21 days for 6 cycles, followed by rituximab maintenance for 2 years. Transplant-eligible patients could also undergo ASCT consolidation rather than rituximab. ORR was 95% and a CR rate of 68% was achieved. Median follow-up was 4.5 years, 3-year PFS was 72%, and 3-year OS was 88%. No significant difference was found between consolidation with rituximab or ASCT in terms of PFS or OS. No unexpected toxicities were reported.

Maintenance rituximab in older MCL patients

The European MCL Consortium conducted a phase III trial assessing the efficacy of maintenance rituximab after induction chemotherapy (R-CHOP or R-FC) in elderly patients (60 years or older) not eligible for ASCT (Kluin-Nelemans et al. N Engl J Med. 2012). Median age of enrolled patients was 70 years. CR rates were similar with R-FC (40%) and R-CHOP (34%; P = 0.10), but PD was more common in patients treated with R-FC (14% vs. 5% with R-CHOP). OS was also substantially shorter R-FC compared to R-CHOP (4-year survival rate 47% vs. 62%; P = 0.005) and a higher proportion of patients died while in first remission in the R-FC group (10% vs. 4%). In 274/316 patients randomly assigned to maintenance therapy, rituximab reduced risk of PD or death by 45% (in remission after 4 years, 58% vs. 29% with IFNα; HR for PD or death, 0.55; 95% CI, 0.36–0.87; P = 0.01). In patients who responded to R-CHOP, rituximab maintenance resulted in a significantly improved OS (4-year survival rate, 87% vs. 63% with IFNα; P = 0.005). The study concluded that R-CHOP induction followed by rituximab maintenance is effective for older MCL patients.

Bendamustine-rituximab (BR) has been demonstrated to be a superior induction regimen versus R-CHOP in two small randomized clinical trials (Rummel et al. 2013; Flinn et al. 2014) and so has gained much traction especially in North America and Europe. The efficacy of 2 years of rituximab maintenance following 6 cycles of BR was investigated recently in the front-line StiL NHL7–2008 study in patients with indolent lymphoma, with a MCL subgroup.  Median PFS was longer in patients randomized to rituximab maintenance (72.3 months) compared to those randomized to observation (54.7 months; HR, 0.71; P = 0.223). This statistical insignificance has raised questions as to whether maintenance rituximab after BR induction is necessary.

Maintenance rituximab in younger MCL patients

A retrospective study conducted at the Fred Hutchinson Cancer Research Center was the first to suggest that rituximab maintenance may confer benefit to younger patients who had received highly intensive induction therapy (Graf et al. Ann Oncol. 2015). MCL patients who had undergone ASCT were evaluated for their outcomes according to whether they received maintenance rituximab (n = 50) or not (n = 107). After a median follow-up of approximately 5 years, rituximab maintenance resulted in improved PFS (HR, 0.44; CI,0.24–0.80; P = 0.007) and OS (HR, 0.46; CI, 0.23–0.93; P = 0.03). Grade 4 neutropenia was increased in patients who received rituximab maintenance (34% vs. 18%; P = 0.04), but no change was reported on the rate of mortality unrelated to relapse. Dr Kahl did point out that the results of this retrospective analysis were not definitive due to differences between the two populations. High-dose Ara-C was more likely to have been administered during induction to patients in the rituximab maintenance group, and they were more likely to be in CR at time of ASCT.

Confirmation of these results came in the form of a randomized, open-label, phase III study (LyMa; NCT00921414) assessing the efficacy of first-line maintenance rituximab in patients aged between 18 and 65 years; the final results were presented during the ASH 2016 Annual Meeting (abstract 145). Patients received four cycles of R-DHAP induction followed by ASCT using R-BEAM conditioning. Patients were then randomized to observation (n=120) or rituximab maintenance (single dose every 2 months for 3 years; n=120). Maintenance with rituximab resulted in significantly longer EFS (78.9%) compared to observation (61.4%) at 4-years (HR, 0.46; P = 0.0016) as well as 4-year OS (88.7% vs. 81.4%, respectively; HR, 0.5; P = 0.045). Between the two arms, no difference was seen in the rate of severe infections. This data strongly supports rituximab maintenance for younger patients with MCL after ASCT.

Other maintenance strategies currently being investigated

Brad Kahl ended the session by summarizing currently on-going trials that are yet to be analyzed investigating alternative maintenance strategies.

References:

1. Kahl B.S. Current Approaches to Mantle Cell Lymphoma: Diagnosis, Prognosis, and Therapies. 2017 American Society of Clinical Oncology (ASCO) Annual Meeting; 2017 June 2–6; Chicago, IL, USA.
2. Cohen J.B. Differentiating Between Aggressive and Less Aggressive Mantle Cell Lymphoma. 2017 American Society of Clinical Oncology (ASCO) Annual Meeting; 2017 June 2–6; Chicago, IL, USA.
3. Zain J.M. Understanding Who Should Receive a Hematopoietic Cell Transplant for Mantle Cell Lymphoma. 2017 American Society of Clinical Oncology (ASCO) Annual Meeting; 2017 June 2–6; Chicago, IL, USA.
4. Kahl B.S. Is There a Role for Maintenance Therapy for Mantle Cell Lymphoma? 2017 American Society of Clinical Oncology (ASCO) Annual Meeting; 2017 June 2–6; Chicago, IL, USA.