Feasibility of Post-Transplant Velcade in Mantle Cell Lymphoma Encourages Further Study

Treatment with Velcade (bortezomib) following induction chemotherapy and stem cell transplantation seemed safe and effective for untreated patients with mantle cell lymphoma, encouraging further evaluation for more active, less toxic targeted agents.
BY Beth Fand Incollingo
PUBLISHED December 10, 2018
Treatment with either consolidation therapy (to kill any cancer cells that may be left in the body) or maintenance therapy (to help keep cancer from coming back) with Velcade (bortezomib) following induction chemotherapy and stem cell transplantation appeared to be safe and effective for patients with untreated mantle cell lymphoma, according to data from the phase 2 CALGB 50403 trial.

However, of note, Velcade’s use in consolidation therapy was associated with more withdrawals from the trial due to toxicity.

Velcade – which was approved in 2014 for use before stem cell transplant for patients with untreated mantle cell lymphoma – comes with some serious side effects and may not be the best targeted drug to use post-transplant in these patients. But the study results showed that giving targeted drugs after transplant in this population can increase the time from treatment until disease progression, said lead study author Lawrence Kaplan, M.D., director of the adult lymphoma program at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, during the 2018 American Society of Hematology (ASH) Annual Meeting. As a result, he said, the findings should encourage researchers to study more active, less toxic targeted drugs for use in this setting.

At the meeting, Kaplan reported on eight years of follow-up from the CALGB 50403 trial, and compared this data with outcomes from the CALGB 59909 trial, which differed from CALGB 50403 only by the absence of post-transplant Velcade.

Why Post-Transplant Velcade?

The CALGB 50403 study was undertaken because there was evidence that aggressive treatment improves progression-free and overall survival in patients with mantle cell lymphoma – a rare, aggressive form of non-Hodgkin lymphoma that starts in the lymph nodes. However, more needed to be done to prevent relapse after transplant. In the CALGB 59909 trial, Kaplan noted, the targeted drug Rituxan (rituximab) plus an intensive chemotherapy cocktail were used before transplant, with Rituxan alone given after transplant. Progression-free survival was five years in that study, with some relapses occurring. The hypothesis for the CALGB 50403 study was that using the same regimen and then adding Velcade afterwards would prolong disease-free outcomes and reduce the rate of late recurrences.

As in the 59909 study, the CALGB 50403 trial gave patients a regimen known as R-Maxi-CHOP as their first treatment. This included Rituxan on day one, the chemotherapy methotrexate on day two, the chemotherapies cyclophosphamide, doxorubicin and vincristine on day three, and the steroid prednisone on days three through seven.

After that, in both studies, patients whose bone marrow contained fewer than 15 percent mantle cells started an additional regimen, taking the chemotherapies etoposide and cytarabine on days one through four and Rituxan on days six and 13. Then, their own stem cells were collected and they underwent transplant in conjunction with a regimen of cyclophosphamide, etoposide and another chemotherapy, carmustine. Finally, after transplant, they were given Rituxan.

Ninety days later, the patients in CALGB 50403 were tested for the presence of cancer cells and the stage of those cells. Patients were randomized to receive different doses and cycles of Velcade – consolidation (four three-week cycles; 50 patients) and maintenance therapy (alternate months of cycles for 18 months; 52 patients).

The study aimed for patients to go six years or more without experiencing disease progression. The study also tested the tolerability of Velcade and whether the drug improved overall survival.

Improved Survival

In the consolidation group, the complete response rate — meaning the percentage of patients who had no signs of cancer — improved from 48 percent prior to Velcade treatment to 78 percent following therapy. In the maintenance group, the percentage went from 60 percent to 78 percent. Overall, the addition of Velcade improved complete response rates in the total population from 54 percent to 79 percent.

After a median follow-up of 8.4 years, the researchers saw no further progression-free survival benefit in the consolidation group; however, the agent continued to derive benefit in the maintenance therapy arm, with an eight-year progression-free survival rate of 77 percent compared with 58 percent in the consolidation arm.

Velcade yielded a median progression-free survival of 8.5 years compared with just five years in patients treated in the CALGB 59909 study.

In addition, the researchers of the CALGB 50403 trial evaluated minimal residual disease (MRD) — which shows whether there are any discernable cancer cells in the body after treatment — to predict relapse. Of those tested for MRD after induction therapy, 17 had no discernable cancer and 25 had detectable cells.

Those with no detectable cancer had dramatically better outcomes. At eight years, 80.2 percent of those who were MRD-negative did not experience disease progression, compared with just 43.2 percent of MRD-positive patients. In terms of overall survival, at 10 years, approximately 85 percent of the MRD-negative patients were alive compared with 50 percent of patients who were MRD-positive.

Overall, 13 percent and 28 percent of patients from the maintenance and consolidation therapy arms, respectively, withdrew from the study due to side effects. The most common side effects included neutropenia, thrombocytopenia, sensory neuropathy and fatigue.

In addition, six patients in the maintenance group withdrew from the study due to disease progression, versus none in the consolidation group.

Next steps

“Post-transplant therapy with (Velcade) is feasible but is associated with significant toxicity – more of it in the consolidation group than in the maintenance group,” Kaplan said. “The apparent benefit post-transplant should encourage study of more active, less toxic targeted agents either post-transplant or to improve MRD negativity (after induction chemotherapy).”

He added that a clinical trial (EA4151; NCT03267433) is now testing whether patients who are MRD-negative after induction therapy need to undergo stem cell transplant at all.
 
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