Update from ASH 2011: New treatments for mantle cell lymphoma are on the horizon

By Peter Martin, MD

Update: this study is closed to enrollment. 

Arguably the most exciting news to come from the American Society of Hematology (ASH) meeting this year was the presentation by Dr. Michael Wang of preliminary results from the phase 2 trial of PCI-32765 for patients with previously treated mantle cell lymphoma (MCL). PCI-32765 is an oral (pill form) inhibitor of an enzyme called Bruton’s Tyrosine Kinase (BTK). BTK plays an important role in communicating pro-survival signals from the cell microenvironment to the nucleus of the cell. Inhibition of BTK by PCI-32765 demonstrated promise in patients with MCL in a national phase 1 that was open at Weill Cornell Medical College. This phase 2 study, also open at Weill Cornell, demonstrated a response rate of approximately 60-70% with little toxicity (mostly mild gastrointestinal side-effects). It is too early to determine how long these effects will last or whether there are any side effects that will become apparent with longer treatment. Click here for more information about this trial.

Dr. Beata Holkova presented the results of a National Cancer Institute (NCI) phase 2 study that was open at several institutions across the country, including Weill Cornell. The trial evaluated the combination of bortezomib (FDA-approved for treatment of patients with previously treated MCL) plus the histone deacetylase inhibitor vorinostat. The combination demonstrated synergistic activity in preclinical studies and showed promised in earlier trials in patients with multiple myeloma. Preliminary results from this NCI trial were encouraging, particularly in the group of patients with MCL that had never been treated with bortezomib. The trial is ongoing. Click here for more information about this study.

Update from ASH 2011: Rituximab improves survival in patients with mantle cell lymphoma

By Peter Martin, MD

Until recently, the role of rituximab in treatment of mantle cell lymphoma (MCL) was unclear. Prior randomized trials demonstrated improved response rates to chemotherapy when combined with rituximab, but unlike other lymphomas, it had failed to demonstrate an improvement in survival. Two abstracts presented at the recent American Society of Hematology (ASH) meeting provided encouraging evidence regarding this most-important outcome.

Dr. Simon Rule presented the results of the recent UK National Cancer Research Institute trial comparing fludarabine/cyclophosphamide (FC) to FC plus rituximab (FCR) in patients of all ages with newly diagnosed MCL. The trial enrolled 370 patients with mostly intermediate and high-risk MCL and followed them for an average of 39 months. The addition of rituximab to FC improved response rate, complete response rate, time to progression, and overall survival. Combined with recent evidence from data registry studies and the data that has accumulated from prior trials, it is clear that standard of care first-line treatment of MCL should include rituximab.

Updated results from a European Mantle Cell Lymphoma Network trial (also presented at the meeting in Lugano last summer and discussed by Dr. Rebecca Elstrom in this blog) confirmed that rituximab maintenance administered to patients over 60 years of age after R-CHOP chemotherapy provided a significant survival benefit. Although longer follow-up and confirmatory trials are needed, rituximab maintenance may be considered standard of care for older patients not receiving more aggressive induction/consolidation regimens. The upcoming Intergroup trial for patients over 60 years of age will feature randomization between rituximab maintenance and maintenance with lenalidomide plus rituximab.

ASH Conference: Radioimmunotherapy as Part of First Line Therapy for Low Grade Lymphoma

By Rebecca Elstrom, MD

Update: this study is closed to enrollment. 

Radioimmunotherapy (RIT), or radiation targeted to lymphoma cells through conjugation to a monoclonal antibody, has long been known to be effective therapy in patients with relapsed indolent non-Hodgkin’s lymphomas.  Its use as first line therapy has been limited, however. This weekend at the American Society of Hematology (ASH) meeting, several studies exploring the use of RIT in initial therapy of low grade lymphomas, either alone or following chemotherapy, were reported.

Two studies explored the use of 90Y-ibritumomab tiuxetan (Zevalin) alone;  one presented by Dr. Pica of Genova on behalf of an Italian cooperative group exploring a single dose, and one presented by Dr. Illidge from the University of Manchester with fractionated dosing (multiple doses of the RIT, in this case 2). Both studies showed high response rates with this brief and simple strategy, and durations of remission comparable to front line chemotherapy with no excessive toxicity.

Two other studies explored the use of RIT as consolidation following initial chemotherapy. The first, presented by Dr. Press of the University of Washington, was a large multicenter study comparing Rituximab plus CHOP chemotherapy (R-CHOP) to CHOP followed by 131I-tositumomab (Bexxar). There was no difference between the two groups in response rate or duration of response. A caveat to this study is the fact that, at the time it was designed, there was concern that giving the anti-CD20 antibody rituximab prior to RIT would inhibit radiation dose delivery, as 131I-tositumomab also requires binding to CD20 in order to deliver the radiation dose to lymphoma cells. This concern does have support in laboratory studies, but it has become clear in the years since this study was designed that anti-CD20 antibody therapy with rituximab is a critical contributor to response and survival in follicular lymphoma. The second study of chemotherapy followed by RIT was presented by Dr. Fowler of MD Anderson Cancer Center. This group evaluated an induction chemotherapy regimen containing rituximab, fludarabine, mitoxantrone and dexamethasone (R-FND) followed by 90Y-ibritumomab tiuxetan. This study showed high response rates and long time to progression, but toxicity of the regimen was of some concern, possibly due to the fact that fludarabine has significant bone marrow suppressive effects, which is also the main side effect of RIT.

Overall, these presentations confirmed the impressive activity of RIT in low grade lymphoma, and extended the experience using RIT as part of first line therapy, demonstrating feasibility, safety and efficacy of this simple and very well tolerated therapeutic approach.

At Weill Cornell Medical College we are exploring radioimmunotherapy as first treatment of follicular lymphoma using a combined strategy of non-radiation tagged antibody to CD20 in combination with radio-labeled antibody against an alternative protein, CD22. This study is designed to maximize the benefit of anti-CD20 directed therapy in addition to radiation dose delivery by targeting the radio-labeled antibody to an alternative target. Click here to read more about this study.

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