Allogeneic stem cell transplant induces long-term responses in follicular lymphoma

Nonmyeloablative allogeneic stem cell transplant results in complete responses that last for up to a decade among patients with relapsed follicular lymphoma, including individuals who receive transplants from matched unrelated donors, according to findings presented at the ASH Annual Meeting.

In addition, conditioning therapy with a yttrium-90 ibritumomab tiuxetan regimen, or a bendamustine, fludarabine and rituximab regimen in more recent years, substantially reduces myelosuppression and results in a more rapid neutrophil recovery than other conditioning regimens, according to Issa F. Khouri, MD, professor of medicine and internist in the department of stem cell transplantation and cellular therapy at the University of MD Anderson Cancer Center in Houston, and colleagues.

“We have previously reported the outcomes of nonmyeloablative allogeneic stem cell transplant in 47 patients with relapsed/chemosensitive follicular lymphoma who received a matched sibling donor after fludarabine, cyclophosphamide and rituximab conditioning,” the researchers wrote. “In subsequent trials, eligibility was expanded to include transplants from matched unrelated donors using a 90y-ibritumomab tiuxetan-based regimen or, more recently, bendamustine, fludarabine [and] rituximab conditioning.”

The analysis included 98 patients with follicular lymphoma enrolled in these three consecutive trials between 1999 and 2017. Median age was 53 years (range, 29 to 71 years); 24% of patients (n = 24) were older than 60 years.

The bendamustine, fludarabine and rituximab regimen was administered to 20 patients. The fludarabine, cyclophosphamide and rituximab regimen was administered in 47 patients.

Bendamustine 130 mg/m² IV was administered every day for 3 days, starting 5 days before transplant. The dose and schedule for fludarabine (30 mg/m² IV daily for 3 days) and rituximab (375 mg/m² IV administered 13 days before transplant and 1,000 mg/m² administered 6 days before transplant and days 1 and 8 after transplant) were comparable in both groups. Cyclophosphamide replaced bendamustine in the fludarabine, cyclophosphamide and rituximab arm.

Patients treated with the 90y-ibritumomab tiuxetan-based regimen (n = 31) received a diagnostic dose of 111in-ibritumomab 14 days before transplant and then a fixed dose of 0.4 mCi/kg 90y-ibritumomab tiuxetan 7 days before transplant. Chemotherapy with the bendamustine, fludarabine and rituximab regimen or the fludarabine, cyclophosphamide and rituximab regimen was then given at the same dose and on1 the same schedule as outlined above, starting 5 days before transplant.

The researchers used tacrolimus and methotrexate for graft-versus-host disease prophylaxis. Thymoglobulin 1 mg/kg was administered on the final 2 days prior to transplant in patients with a matched unrelated donor.

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The median number of previous therapies was 3 (range, 2 to 9). Slightly more than half of patients (52%; n = 51) were treated with rituximab chemotherapy induction at diagnosis. A Hematopoietic Cell Transplantation-specific Comorbidity Index score of 3 or greater was noted in 29% of patients (n = 28).

Most patients (72%; n = 71) relapsed within 2 years of induction therapy. Median duration of final remission before allogeneic stem cell transplant was less than 1 year in 61% of patients. At the time of transplant, chemotherapy-sensitive disease was present in 84% of patients (n = 82), with complete responses of 46% and partial responses of 38%. The researchers detected refractory disease in 16% of patients, PET-positive disease in 22% of patients and elevated serum lactate dehydrogenase (LDH) in 20% of patients.

Most patients (71%; n = 70) received an allogeneic stem cell transplant from a matched sibling donor; 29% of transplants (n = 28) came from matched unrelated donors. Fifteen percent of transplants (n = 15) involved female-to-male donors.

Almost every patient (94%) received a transplant from the peripheral blood. The median number of CD34-positive cells infused was 4.9 x 10⁶/kg.

Fewer than half of transplants (43%; n = 42) were mismatched according to ABO blood group. Cytomegalovirus infection was reactive in 80% of patients and/or donors.

Median follow-up period for all patients was 98 months (range, 3 to 208 months). OS and PFS at this point were 82% (95% CI, 73-89) and 74% (95% CI, 64-82), respectively, and treatment-related mortality at 1 year was 9%.

Recovery of absolute neutrophil count differed greatly between the conditioning regimens, according to the study results. Neutrophil counts recovered to greater than 0.5x10⁹/L at a median of 0 days (range, 0 to 16 days) in the bendamustine, fludarabine and rituximab groups compared with 10 days (range, 0 to 17 days) and 11 days (range, 5 to 17 days) for the fludarabine, cyclophosphamide and rituximab and 90y-ibritumomab tiuxetan-based regimens, respectively (P < .0001). This difference was “consistent for each transplant type,” according to Khouri and colleagues.

The cumulative rate of grade 2 to 4 and grade 3 to 4 acute GVHD was 22% and 9%, respectively, and the cumulative rate of chronic GVHD was 38%.

The researchers also analyzed the impact of patient demographics, disease characteristics and transplant features on outcomes. The following factors correlated with decreased OS: more than one relapse, previous treatment with more than two chemotherapies, a final remission duration before allogeneic stem cell transplant of less than 1 year, three or more comorbidities, elevated LDH, acute GVHD of grades 2 to 4 and chronic, extensive GVHD. On multivariable analysis, duration of last remission before transplant of less than 1 year (HR, 6.48; P = .024) and acute GVHD of grades 2 to 4 (HR, 8.61; P < .001) correlated with inferior OS. No significant predictive factors for PFS or risk for GVHD, both acute and chronic, were observed in multivariable analysis.

“Nonmyeloablative allogeneic transplant can induce complete responses lasting over a decade in most patients with relapsed follicular lymphoma,” the researchers wrote. “Our initial findings published in 2008 were thus confirmed in a larger number of patients, including those who received matched unrelated donor transplants. Bendamustine, fludarabine and rituximab conditioning has been associated with significantly lesser myelosuppression and a faster neutrophil recovery than other regimens used, validating our initial observation in earlier reports.” - by Julia Ernst, MS

Reference:

Khouri IF, et al. Abstract 4561. Presented at: ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego.

Disclosures: HemOnc Today was unable to confirm relevant financial disclosures for Khouri at the time of publication. Please see the abstract for all other authors’ relevant financial disclosures.