In Mantle Cell Lymphoma, Velcade After Stem Cell Transplant Delays Disease Progression

Giving the targeted drug Velcade (bortezomib) after chemotherapy and stem cell transplant in patients with mantle cell lymphoma (MCL) delays progression of the disease, a study has found.

Previous research showed that patients with this blood cancer who underwent induction, or initial, chemotherapy followed by high-dose chemotherapy and then a stem cell transplant experienced no disease progression for a median of five years. Recently, scientists conducted a phase 2 study to determine whether supplementing those treatments with Velcade would improve results and found that patients who took the additional treatment went a median of 8.5 years before experiencing disease progression.

However, patients experienced significant side effects when Velcade was added, most commonly blood count drops, fatigue and neuropathy, which can feel like tingling, numbness or weakness in the extremities.

Results of the randomized, multicenter trial were published in the American Journal of Hematology on March 13.

MCL is an aggressive, rare form of non-Hodgkin lymphoma, a cancer that starts in the white blood cells within the body’s immune system. MCL often affects the gastrointestinal tract and/or bone marrow.

Velcade is part of a class of drugs known as proteasome inhibitors. Proteasomes are like garbage disposals that get rid of protein waste within cells. Velcade interferes with their cleaning process so that waste builds up inside MCL cells and disables or kills them.

Two Dosing Strategies

Researchers embarked on the recent study to seek a way to make treatment more effective, noting that “all current approaches are associated with late disease recurrences, even beyond 10 years.” They tested Velcade because it has demonstrated effectiveness in patients whose MCL has relapsed or recurred.

The current standard of care to protect patients with MCL from disease progression after chemotherapy and stem cell transplant is Rituxan (rituximab), a targeted drug that inhibits the activity of the cancer-driving protein CD20.

In the study, 102 patients were divided into two groups after receiving chemotherapy and transplant using their own stem cells. One group received Velcade for three months (called consolidation treatment) and the other for 18 months (called maintenance treatment).

Patients were adults, most male and with low-risk, stage 4 disease. Eligible patients had disease of any stage that fit a specific genetic profile, had responded partially or completely to chemotherapy and stem cell transplant as of 90 days after treatment, and had received up to one cycle of chemotherapy and/or Rituxan before that. After they began treatment with Velcade, the patients were repeatedly checked for disease progression via CT scan for a maximum of 10 years.

Improved Outcomes

At an eight-year follow-up, the median time without disease progression in the consolidation group was 8.2 years, with 54.1% of the patients free of progression. Median survival, measured from the start of study treatment, was 8.9 years, with 58% of participants alive at eight years.

In the maintenance group, at a median follow-up of 8.5 years, the median length of time without disease progression had not yet been reached and 64% of the patients were free from progression. Median survival had also not yet been reached; nearly 83% of participants in this group were alive at eight years.

Compared to the earlier trial, time until progression and the length of survival after transplant were both significantly extended, the authors reported.

The researchers also analyzed outcomes in subgroups of the patients.

They found that the percentage of patients who experienced disease progression varied depending upon the aggressiveness of their disease. At an eight-year follow-up, 52% of those with low-risk disease, 37.5% of those with intermediate-risk disease and 28.2% of those with high-risk disease were progression-free.

Among those with no discernable disease after induction chemotherapy, 80% were free of progression and 86% were alive eight years after starting treatment with Velcade, compared with rates of 43% and 64%, respectively, in those who had measurable disease remaining as they started the transplant process.

Significant expression of the protein Ki-67 by cancer was associated with shorter survival.

Side Effects and Conclusions

Of 50 patients in the consolidation group, 21 experienced severe hematologic side effects, and of 52 patients in the maintenance group, 16 had these effects. In the consolidation group, moderate and serious non-hematologic side effects occurred at rates of 40% and 42%; in the maintenance group, 46% had moderate non-hematologic side effects and 38.5% had serious ones. Fourteen patients in the consolidation group and seven in the maintenance group dropped out of the study due to side effects.

“Toxicity (of Velcade) seems to be more severe in the post-transplant setting when patients are still recovering from the effects of high-dose chemotherapy than reported in the relapsed setting as a single agent,” the researchers reported.

Based on their finding that patients who were disease-free after induction chemotherapy had better long-term outcomes, the researchers suggested that more aggressive chemotherapy regimens be explored with the aim of eliminating MCL in a larger proportion of patients prior to transplant.

They also questioned whether stem cell transplant and the high-dose chemotherapy that precedes it are even necessary in patients with MCL who are cancer-free after induction chemotherapy, and pointed out that a phase 3 trial is currently addressing that concern.

The researchers concluded that “the observation of apparent benefit” of post-transplant Velcade “should be tempered by the fact that the toxicities in this setting were significant.”

They added that future studies of whether high-dose chemotherapy and transplant are really needed in certain patients, as well as the rapid development of novel targeted drugs and immunotherapies, are likely to positively contribute to care for patients with MCL.