by ecancer reporter Clare Sansom

Mantle cell lymphoma is a rare, aggressive type of non-Hodgkin’s lymphoma that mainly affects men over 50.

It has a relatively poor prognosis, with an overall 5-year survival rate of about 50% for advanced disease.

Patients who are young and fit enough may be offered intensive chemotherapy followed by a stem cell transplant, and this treatment offers the best outcomes.

A combination chemotherapy regimen such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) is the standard treatment for patients who are not considered for stem cell transplantation, and patients initially respond well although progression-free survival is fairly limited.

The small-molecule proteasome inhibitor bortezomib is approved in many countries for treating mantle cell lymphoma and multiple myeloma that has relapsed after initial chemotherapy.

Results have now been reported from a Phase III clinical trial, LYM-3002, that was set up to test this drug as a replacement for vincristine in combination chemotherapy for previously untreated mantle cell lymphoma.

A multi-national team of investigators recruited 487 adults with newly diagnosed stage II-IV who were ineligible or not considered for stem cell transplantation into the trial between May 2008 and December 2011.

After stratification into low, medium and high risk categories, participating patients were randomised in a 1:1 ratio to receive an initial six 21-day cycle of either R-CHOP or an alternate regimen (VR-CAP) in which vincristine had been replaced by 1.3 mg/m2 of bortezomib four times per cycle.

Patients who responded at cycle 6 were eligible to receive another two cycles of the same treatment.

The primary end point was progression-free survival; secondary end points included response rates, time to progression, overall survival and toxicity.

Patients were assessed every 6-8 weeks during and after the study using CT scans; the expression of the prognostic marker Ki-67 was measured by immunohistochemistry and adverse events were recorded and graded according to the National Cancer Institute common terminology criteria.

There were no significant differences in demography or disease status between patients in the two study arms at randomisation.

After a median follow-up period of 40 months, a total of 298 patients in both study arms had progressive disease or had died.

The median progression-free survival was 14.4 months in the R-CHOP arm (standard treatment with vincristine) and 24.7 months in the VR-CAP arm (with bortezomib).

This represented a relative improvement of 59%, with a hazard ratio of 0.63 in favour of the VR-CAP group and a p-value of less than 0.001.

The findings were even more clear-cut using patient assessment by investigators, with reported progression free survival of 30.7 months in the VR-CAP arm compared to 16.1 months for R-CHOP (hazard ratio 0.51; p<0.001).

Similar results were observed with patients in all risk categories and both with and without significant expression of the marker Ki-67.

The complete response rate was also significantly higher in the VR-CAP arm, at 53% compared to 42% in the R-CHOP arm.

Overall survival after four years was 64% (95% confidence interval 56-71%) with VR-CAP and 54% (95% CI 45-623%) with R-CHOP.

Other efficacy-based secondary end point data was also significantly in favour of the VR-CAP arm, and therefore in favour of including bortezomib in combination chemotherapy.

However, toxicity was higher in the VR-CAP arm, with significantly more drug-related grade 3 or higher adverse events occurring in these patients.

The most common adverse events in both arms were haematological, with the largest difference observed in rates of thrombocytopenia.

Thrombocytopenia of grade 3 or higher occurred in 57% of patients receiving VR-CAP but only 6% of those receiving R-CAP.

Similarly, 23% of patients receiving VR-CAP but only 3% of those receiving R-CAP received platelet transfusions during the study period.

Neutropenia and infections including pneumonia also occurred more often in the VR-CAP arm

Taken together, the results of this Phase III trial show clearly that the VR-CAP regimen, which includes bortezomib, was more effective in controlling previously untreated mantle cell leukaemia than a standard one without this drug but at the cost of increased haematological toxicity, primarily thrombocytopenia.

Reference

Robak, T., Huang, H., Jin, J. and 17 others, for the LYM-3002 investigators (2015). Bortezomib-Based Therapy for Newly Diagnosed Mantle-Cell Lymphoma. New Engl. J. Med. 372, 944-53.