Weill Cornell Preceptorship on B-Cell Melignancies: Mantle-Cell Lymphoma

Controversies in Mantle-Cell Lymphoma (MCL) - Peter Martin

1. What is indolent MCL?
2. Best induction therapy for MCL
3. Benefit from consolidation in MCL
4. Benefit from maintenance in MCL

Indolent MCL presents with splenomegaly, lymphocytosis and NO lymphadenopathy. It is similar to chronic lymphocytic leukemia (CLL). This subgroup of patients can be observed without therapy.

Best induction therapy for MCL.

In many areas of the world HyperCVAD/HD Mtx-Ara-C (HiperCVAD, for short) is the favored induction protocol for MCL based on the results by the MD Anderson. But HyperCVAD carries a 5-10% treatment related mortality, and a very high risk of infection and febrile neutropenia. Dr. Martin is definitely NOT a proponent of HyperCVAD for these reasons. In the S1106 trial patients with MCL were randomized to HyperCVAD or Bendamustine + Rituximab followed by auto stem-cell transplant (autoBMT). The study had to be interrupted due to poor stem cell collection in the HyperCVAD arm, but both had identical outcomes. 

R-CHOP was compared to alternating R-CHOP with DHAP, both followed by autoBMT. The R-CHOP arm achieved 39% CR rate compared to 55% in the alternating arm. Editorial: Alternating R-CHOP with DHAP is the standard induction therapy in MCL patients prior to autoBMT. Another alternative is the NORDIC R-DHAP followed by autoBMT with CR in the 89%-93%, range (Christian, Blood, 2008).  AutoBMT consolidation may not be required in low MIPI, low Ki67, CR by PET-CT and MRD negative, p53wt.

What about the best induction regimen in older, non-autoBMT candidates MCL patients? 

We have to keep in mind that only about 20% of MCL patients are candidates for transplant. We now know that R-CHOP induced MCL patients live longer than R-FC patients. But there are a number of options available for this group of patients, including R-BAC, R-BVD (Carlo Visco, JCO, 2013). The best one appears to be the VR-CAP (NEJM, 2015). There is the intriguing report of lenalidomide + rituximab in MCL with an impressive 85% ORR, and very high PFS at 2-yrs. But these patients had a very low disease burden and many could have been observed. Dr. Martin has not used this regimen, but he is tempted to use it. He would NOT use it in high-tumor burden MCL or patients with blastoid MCL, or in patients with Ki67 greater than 30%.

Maintenance therapy in MCL. 

Both maintenance rituximab (x24 months) and bortezomib have shown increased PFS, but failed to show increase in OS in MCL patients. But maintenance rituximab until progression improved OS in MCL (Kluin Nelemans, NEJM, 2012). Both agentes have also been studied post autoBMT without increasing OS (they do increase PFS). Editorial: R-CHOP followed by rituximab maintenance is the standard. Other options are also acceptable.

Second-line ibrutinib affords a 70% ORR with a 13 month PFS (Wang, NEJM, 2013). Editorial: Ibrutinib should be the standard second-line therapy in MCL.

Ibrutinib

Fairly consistent side-effect profile. Some practical issues: Lymphocytosis caused by compartmental shift from the lymph nodes. May be associated with intracranial bleed and can be treated with dexamethasone. Diarrhea, early, mild, short-lived. May be avoided if ibrutinib taken at night (after last meal). Rash, can be treated with steroids. Severe bleeding is rare. Atrial fibrillation occurs in up to 5%, risk increases with exposure. TLS is not an issue with ibutinib. Secondary malignancies are not more frequent than expected.