Managing Newly Diagnosed MCL

From:  Clinical Oncology News

MARCH 7, 2016

How I Manage: Newly Diagnosed Mantle Cell Lymphoma

Timothy S. Fenske, MD

Associate Professor
Division of Hematology and Oncology
Department of Medicine
Medical College of Wisconsin
Milwaukee, Wisconsin

Approximately 4,200 people are diagnosed with mantle cell lymphoma (MCL) each year in the United States. This represents roughly 6% of newly diagnosed non-Hodgkin lymphoma (NHL) cases. Patients generally present with advanced-stage disease, often with extranodal involvement. Historically, MCL was associated with a very poor prognosis, with a median survival in the 2- to 3-year range. In recent years, however, a better understanding of MCL disease biology has emerged, and with this, new therapies and an improvement in prognosis have been realized for many patients. As an example, younger patients who undergo aggressive first-line therapy with autologous hematopoietic cell transplantation (auto-HCT) in first complete remission (CR) can reasonably expect their first remission to last 6 to 8 years.^1,2 For many MCL patients under 60 years of age, survival of 10 years or longer is an achievable goal.³ In addition, several novel agents known to be active in the relapsed setting are being moved into the front-line setting, which is expected to improve outcomes further.

Despite this progress, many challenges and questions remain in managing patients with newly diagnosed MCL. One of the major challenges relates to the clinical heterogeneity of MCL. On one end of the spectrum are patients with an indolent form of MCL who can be observed safely off therapy, sometimes for several years. On the other end of the spectrum are aggressive subtypes, such as the blastoid variant. In addition to variability of disease-related factors at the time of diagnosis, response to first-line therapy can vary considerably and have a significant effect on outcomes. For all of these reasons, selecting an appropriate treatment plan for an individual patient remains a challenge.

Can patients with MCL be observed without therapy?

Yes. A significant proportion of MCL patients can be safely observed, in many cases for a year or longer. For example, there is a subtype of MCL characterized by lymphocytosis and splenomegaly, without significant adenopathy. Patients with this subtype generally have an indolent course, and can be safely observed.⁴Martin et al reported on outcomes of 31 MCL patients who had initial therapy deferred. These patients had a median time to treatment of 1 year, with 3 patients not undergoing treatment for 5 or more years. Survival was not inferior in the cohort of patients undergoing initial observation.⁵

I have several patients in my practice for whom we elected to defer therapy. Some of these patients have gone 3 to 4 years without treatment, and one patient still has not been treated 7 years after diagnosis.

When considering observation as an option for a MCL patient, I like to see that the patient has a low disease burden (by exam and CT scan) and lacks significant cytopenias or symptomatic splenomegaly. I feel reassured if the patient has a low Mantle Cell Lymphoma International Prognostic Index (MIPI) score and/or a proliferation index under 30%, and lacks blastoid or pleomorphic histology. I also am comfortable monitoring non-nodal MCL patients who present with lymphocytosis and splenomegaly.

What is your preferred induction regimen for transplant-eligible patients?

Several highly active induction regimens are available for patients for whom the goal is to undergo auto-HCT in first CR. These regimens typically have an R-CHOP (rituximab [Rituxan, Genentech], cyclophosphamide, doxorubicin, vincristine, prednisone)-like component that alternates with a high-dose cytarabine component and include the Nordic MCL-2 regimen (augmented R-CHOP alternating with high-dose cytarabine, followed by high-dose therapy with auto-HCT),¹ R-CHOP alternating with R-DHAP (rituximab, dexamethasone, cytarabine, cisplatin) followed by auto-HCT,² and R-HyperCVAD (rituximab, cyclophosphamide, vincristine, doxorubicin, dexamethasone)/R-MTX-araC (rituximab, methotrexate, cytarabine) with our without auto-HCT.⁶ Other, less-intense induction regimens are available, such as R-CHOP and BR (bendamustine [Treanda, Cephalon]-rituximab); however, these regimens lack high-dose cytarabine, and they also lack long-term prospective data as induction regimens prior to auto-HCT. The Nordic MCL-2 regimen and the R-CHOP/R-DHAP regimen, with auto-HCT consolidation, have been evaluated in large prospective studies and have been shown to produce median progression-free survival (PFS) in the 7- to 8-year range.

My preferred induction regimen in this setting is the Nordic MCL-2 regimen. No other regimen has shown superior results in transplant-eligible patients. For patients with low or intermediate MIPI scores who undergo this treatment, 70% are alive at 10 years, with 23% of high MIPI patients alive at 10 years. Compared with R-HyperCVAD, Nordic MCL-2 confers considerably less toxicity and a lower risk for a suboptimal peripheral blood stem cell collection. In the 3 published studies of R-HyperCVAD in MCL, the treatment dropout rate was between 29% and 63%, illustrating the significant toxicity of this regimen in MCL patients.^6-8 In addition, SWOG 1106 was closed early due to an excessively high rate of insufficient peripheral blood stem cell collection.⁹ Compared with the R-CHOP/R-DHAP regimen, the Nordic regimen does not require cisplatin, which in my experience causes significant toxicity, such as nausea, renal insufficiency, electrolyte wasting, and ototoxicity in MCL patients. In addition, it is feasible to safely administer the entire Nordic regimen, along with the auto-HCT, on an outpatient basis for properly selected patients, which is important from a quality-of-life standpoint. Finally, the Nordic regimen has higher doses of cytarabine (three times more cytarabine compared with the R-CHOP/R-DHAP regimen). High doses of cytarabine have been associated with improved outcomes in MCL in some studies.² However, in some of these studies, the improved outcomes also may have been due to other factors, such as younger age, less aggressive pathology, and/or differences in supportive care. It is worth noting, however, that probably less than half of MCL patients will be good candidates for high-dose cytarabine. High-dose cytarabine is most appropriate for those under age 60 and is not recommended for those over age 70. For those over 65, reduced-dose cytarabine is recommended. A comparison of outcomes of several intensive front-line approaches to MCL is presented in Table 1.^1,2,6-14

Table 1. Outcomes of Intensive First-Line Therapy Including auto-HCT (Prospective Studies) Reference Design N Regimen TRM, % OS PFS auto-HCT–Based Regimens Dreyling European MCL Network (2005)10 Randomized, Phase III 122 CHOP + interferon maintenance vs CHOP + auto-HCT 0 vs 5 77 (3 y) vs 83 (3 y) Median PFS 1.4 y vs median PFS 3.3 y Damon CALGB (2009)11 Phase II 77 R-CHOP + MTX ? HiDAC/etoposide ? auto-HCT 3 64 (5 y) 56% (5 y) Van’t Veer (2009)12 Phase II 87 R-CHOP + HiDAC + auto-HCT 5 66 (4 y) 36% (4 y) Geisler Nordic MCL-2 (2012)1 Phase II 160 R-Maxi CHOP/R-HiDAC + auto-HCT 5 58 (10 y) Median PFS 7.4 y Hermine European MCL Network (2012)2 Randomized, Phase III 455 R-CHOP + auto-HCT vs R-CHOP/R-DHAP + auto-HCT 4 Median OS 6.8 y vs median OS NR Median PFS 3.8 y vs median PFS 7.3 y LeGouille Lysa (2014)13 Randomized, Phase III 299 R-DHAP + auto-HCT vs R-DHAP + auto-HCT + maintenance R 94 (2 y) vs 93 (2 y) 82% (2 y) vs 93% (2 y) Chang ECOG 1405 (2014)14 Phase II 22 VcR-CVAD + auto-HCT 0 100 (2 y) 76% (2 y) Chen SWOG 1106 (2015)9 Randomized, Phase III 53 R-hyperCVAD/R-MTX-cytarabine ? auto-HCT vs BR ? auto-HCT 86 (2 y) vs 91 (2 y) 87% (2 y) vs 87% (2 y) Non–auto-HCT–Based Regimens Romaguera MDACC (2010)6 Phase II, single center 97 R-hyperCVAD + R-MTX/cytarabine 8 56 (8 y) 43% (8 y) Merli (2012)7 Phase II, multicenter 60 R-hyperCVAD + R-MTX/cytarabine 6 73 (5 y) 61% (5 y) Bernstein SWOG 0213 (2013)8 Phase II, multicenter 49 R-hyperCVAD + R-MTX/cytarabine 2 63 (5 y) 49% (5 y) auto-HCT, autologous hematopoietic cell transplantation; BR, bendamustine, rituximab; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; MTX, methotrexate; OS, overall survival; PFS, progression-free survival; R-CHOP, rituximab-CHOP; R-DHAP,rituximab, dexamethasone, cytarabine, cisplatin; HiDAC, high-dose intermittent cytarabine; R-HiDAC, rituximab, HiDAC; R-hyperCVAD, rituximab, cyclophosphamide, vincristine, doxorubicin, dexamethasone; R, rituximab; TRM, transplant-related mortality;VcR-CVAD, bortezomib, R-HyperCVAD

Should all transplant-eligible patients receive auto-HCT?

Only one prospective, randomized trial has compared auto-HCT and a non–auto-HCT strategy. In that study, conducted by the European MCL Network, CHOP was used as the induction regimen. Patients who responded to CHOP were then randomized to auto-HCT or interferon-alfa (IFN-α). The patients randomized to auto-HCT had improved PFS (39 vs 17 months) but no difference in overall survival (OS).¹⁰ Retrospective studies have suggested that auto-HCT is more beneficial when it is applied early in the disease course; however, such studies are not able to address the question of whether auto-HCT can safely be omitted for certain patients.^15-17 In addition, there has not been a prospective randomized trial testing the benefit of auto-HCT using modern, more-intensive induction regimens containing rituximab and cytarabine. There also have been no trials evaluating whether auto-HCT provides benefit after recently developed regimens incorporating highly active agents, such as bendamustine, lenalidomide (Revlimid, Celgene), bortezomib (Velcade, Millennium), or ibrutinib (Imbruvica, Pharmacyclics). As a result of this uncertainty, the question of whether all transplant-eligible patients should undergo auto-HCT in first CR remains one of the most debated questions in the management of MCL.

I suspect that, for some patients, the incremental benefit of auto-HCT consolidation following a highly effective induction regimen may be marginal. However, at this time, we do not have reliable methods to identify those patients. In the future, it may be possible to use tools such as minimal residual disease (MRD) analysis and/or molecular profiling to identify the patients who benefit from auto-HCT consolidation. In the meantime, at our institution, we continue to offer auto-HCT consolidation to transplant-eligible patients in first CR, on a case-by-case basis. I present the patient with an intensive (transplant) option as well as a non-intensive (non-transplant) option, and discuss the risks and benefits in detail. The benefit of the intensive approach is that there are robust, long-term data showing a median duration of first remission in the 7- to 8-year range, with some patients still in remission 10 years after diagnosis. There is more toxicity; however, for most patients, significant toxicities have resolved by the time they are 1 to 2 months post-transplant. For patients over 65 to 70 years of age, or those with significant comorbidities, I am not convinced that the benefits of up-front auto-HCT exceed the risks. For such patients, I favor a non-intensive approach, unless they have particularly high-risk biological features, such as blastoid variant and/or complex cytogenetics.^18,19

What is your preferred induction regimen for transplant-ineligible patients?

There are several published regimens with excellent activity that are appropriate for patients who are not felt to be good candidates for aggressive therapy: R-CHOP followed by maintenance rituximab,²⁰ VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone),²¹ BR²² or R² (lenalidomide and rituximab).²³

My preferred regimen is BR, and I generally follow this with maintenance rituximab for 2 years. The BR regimen produces a median PFS of 35 months, without maintenance rituximab, which is superior to that produced by R-CHOP^20,21or VR-CAP.²¹ R-CHOP followed by maintenance rituximab produced a median remission duration of 4 to 5 years in responding patients. With the addition of maintenance rituximab to BR, it is reasonable to expect that the PFS would also be in the 4- to 5-year range, although this has not formally been proven. In addition, from a toxicity standpoint, BR is quite favorable, with minimal neuropathy, alopecia, and cardiotoxicity, and a lower rate of grade 3/4 cytopenias than R-CHOP or VR-CAP. BR followed by maintenance rituximab forms the backbone (control arm) regimen for the ongoing Intergroup/ECOG 1411 trial. In addition, BR is known to produce a high rate of MRD negativity.²⁴ The R² regimen looks very promising as well, with a 2-year PFS of 85%, although long-term follow up has not yet been reported.²³ A comparison of outcomes of several non-intensive front-line approaches in MCL is presented in Table 2.^{14,20-23,25,26}

Table 2. Outcomes of Non-Intensive First-Line Therapy (Prospective Studies) Reference Design N Regimen OS PFS Lenz (2005)25 Randomized, Phase III 112 CHOP vs R-CHOP 76% (2 y) vs 76% (2 y) Median PFS 14 mo vs median PFS 21 mo Kluin-Nelemans (2012)20 Randomized, Phase III 239 (R-CHOPsubset) R-CHOP + IFN vsR-CHOP + maintenance R Median OS 64 mo vs median OS NR Median PFS 23 mo vs median PFS NR Rummel (2013)22 Randomized, Phase III (subset) 94 (MCL subset) R-CHOP vs BR NR NR Median PFS 22 mo vs median PFS 35 mo Visco (2015)26 Phase II 57 R-BAC500 89% (2 y) 80% (2 y) Chang ECOG 1405 (2014)14 Phase II 44 VcR-CVAD + maintenance rituximab 93% (2 y) 79% (2 y) Robak (2015)21 Randomized, Phase III 487 R-CHOP vs VR-CAP Median OS 56 mo vs median OS NR Median PFS 14 mo vs median PFS 25 mo Ruan (2015)23 Phase II 38 Lenalidomide, rituximab 97% (2 y) 85% (2 y) BR, bendamustine, rituximab; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; IFN, interferon; NR, not reported; R-BAC, rituximab, bendamustine, cytarabine; R-CHOP, rituximab-CHOP; VR-CAP, bortezomib, rituximab, cyclophosphamide, doxorubicin, prednisone; VcR-CVAD, bortezomib, R-HyperCVAD

What is the role of maintenance therapy in transplant-eligible and transplant-ineligible patients with MCL?

Maintenance therapy is assuming an increasingly important role in MCL. In the non-transplant setting, following R-CHOP, maintenance rituximab produced a PFS as well as an OS benefit.²⁰ In the ECOG 1405 study, 75 MCL patients were treated with a regimen consisting of 6 cycles of VcR-CVAD (rituximab, bortezomib, modified hyperfractionated cyclophosphamide, doxorubicin, and vincristine). Transplant-eligible patients then had the option of consolidation with auto-HCT versus 2 years of maintenance rituximab; 44 patients received maintenance rituximab. These patients had a PFS of 79% and OS of 93% at 2 years.¹⁴ In the ongoing Intergroup/ECOG 1411 trial, all 4 arms receive maintenance therapy with either rituximab or rituximab and lenalidomide.

For transplant-eligible patients, there also are some emerging data supporting maintenance rituximab following auto-HCT. A recent study in younger MCL patients evaluated the benefit of maintenance rituximab after intensive rituximab and cytarabine-based induction and auto-HCT consolidation. In this study, a superior PFS was seen at 3 years for the rituximab maintenance group versus the observation group (88% vs. 73%, respectively). An OS difference has not yet been seen between the 2 groups at 3 years.13 There are retrospective data showing that maintenance rituximab was associated with improved OS 5 years after auto-HCT. This benefit in survival remained even after multivariate adjustment for confounding factors.27

An alternative approach, which may be more cost-effective and less toxic, is to monitor patients following auto-HCT using MRD, as was done in the Nordic MCL-2 study.1 There is now a commercially available assay to detect MRD in MCL. This assay (clonoSEQ, Adaptive Biotechnologies) is a deep sequencing–based assay designed to detect minimal levels of circulating lymphoma cells in the peripheral blood, with a sensitivity to detect approximately 1 lymphoma cell in 1,000,000. When patients became positive by MRD, a 4-week course of rituximab was given preemptively, which produced an MRD-negative response in the majority of patients (81%), with the majority of these responders remaining free from clinical relapse for 2 to 3 years.

My personal practice is to offer 2 years of maintenance rituximab following rituximab-based induction therapy in non-transplant patients. For patients who have undergone auto-HCT, in general I prefer to monitor using MRD and treat preemptively with rituximab if needed. This spares some patients long-term rituximab after auto-HCT; this may result in better immune reconstitution and less hypogammaglobulinemia, which can be a significant issue for some patients. For patients at particularly high risk for relapse after auto-HCT (such as those with the blastoid variant), I favor planned maintenance rituximab after auto-HCT.

Future Prospects

There are a number of exciting recent developments in the treatment of MCL, including novel induction regimens, as well as several new and novel agents shown to have activity in the relapsed/refractory setting. It is likely that some of these new agents will show benefit as part of front-line therapy. A complete discussion of these lines of research is beyond the scope of this article, but they include already-approved agents such as ibrutinib, lenalidomide, and bortezomib. Novel agents targeting the proteasome, signaling pathways/enzymes such as the BTK pathway and PI-3 kinase, and immune checkpoint proteins also are being evaluated in the treatment of MCL, and these eventually may find a role in first-line therapy or maintenance therapy for patients in first CR.

Ongoing Frontline Therapy Clinical Trials in Mantle Cell Lymphoma Trial Sponsor Trial Name ClinicalTrials.gov Identifier Eastern Cooperative Oncology Group (ECOG) 1411 Rituximab, Bendamustine, +/- Bortezomib Followed by Rituximab +/- Lenalidomide in Treating Older Patients With Previously Untreated Mantle Cell Lymphoma NCT01415752 National Institutes of Health/ National Cancer Institute Randomized Phase II Study of Dose-Adjusted EPOCH-Rituximab-Bortezomib (EPOCH-R-B) Induction Followed by Bortezomib Maintenance Versus Observation in Untreated Mantle Cell Lymphoma With Microarray Profiling and Proteomics NCT00114738 Northwestern University A Phase II Clinical Trial Evaluating Ibrutinib Maintenance Following Intensive Induction for Patients With Previously Untreated Mantle Cell Lymphoma NCT02242097 Emory University A Phase I/II Study of MLN9708 as Post-Transplant Maintenance for Patients With Mantle Cell Lymphoma Undergoing Autologous Stem Cell Transplant in First Remission NCT02632396 Memorial Sloan Kettering Cancer Center Sequential Chemotherapy and Lenalidomide Followed by Rituximab and Lenalidomide Maintenance for Untreated Mantle Cell Lymphoma NCT02633137

Another area of intensive research in MCL is identifying patients with high-risk disease using clinical factors such as the MIPI score, pathologic factors such as proliferation rate or histologic variants (eg, blastoid variant), or MRD analysis after induction therapy, and using that information to customize therapy. It is hoped that in the near future, an increasingly evidence-based approach to therapy for MCL can be employed, such that patients with higher-risk disease can receive an intensified therapy proven to improve outcomes for that subgroup of patients.

Prayers requested: LINDA Strong

Linda and, her husband, Gordon live in Paducah, KY. Linda has, MCL, the same type of Non-Hodgkins Lymphoma as my wife Mary Jo had before her successful transplant in 2013.

Linda has started the process to have a stem cell  transplant at the Ingram Cancer Center at Vanderbilt 
University Hospital in Nashville, TN. 

Please pray for Linda and Gordon as they begin this process, and a successful transplant in the near 
future. 

Saint Peregrine, patron saint of cancer patients,pray for her!

Visit Linda's Facebook page LINDA Strong!

It's May 6th...Day+365

It's May 6th, Day+365 since Mary Jo's stem cell transplant at Vanderbilt University Hospital last year. 

Here I am with a syringe infusing those refreshed, life giving stem cells into Mary Jo's catheter with nurse practicioner, Liz. 


 
We were so blessed to have so many wonderful doctors and nurses at Vanderbilt whose work worked so that God could do his work and make Mary Jo well. We are grateful for each and everyone. We were also blessed to have so many people praying for us while we were in Nashville uplifting us, especially on the terrible days. 

We pray for all of the people facing the challenges of stem cell and bone marrow transplants, especially, my friend, Wayne, and we pray for many more birthdays for Mary Jo, the love of my life. Glory and praise to God who makes all things possible!