Researchers document negative effects of fludarabine-melphalan on OS, non-relapse mortality in these patients

In patients with non-Hodgkin lymphoma undergoing allogeneic hematopoietic cell transplant (HCT), treatment with a more intense reduced-intensity conditioning and nonmyeloablative conditioning (RIC-NMAC) regimen—such as fludarabine-melphalan (Flu-Mel140), the most commonly used of these regimens—may negatively affect overall survival (OS) and be associated with higher non-relapse mortality, according to results published in JAMA Oncology.

In addition, researchers found that lower intensity RIC-NMAC regimens of fludarabine-intravenous busulfan (Flu-Bu) and fludarabine-cyclophosphamide (Flu-Cy) with or without 2 Gy total body irradiation (2GyTBI) brought about comparable results in OS.

“[RIC-NMAC] regimens have significantly expanded the access to [HCT] in the treatment of hematologic malignant neoplasms. Although RIC-NMAC regiments generally are associated with lower nonrelapse mortality compared with myeloablative conditioning regimens, disease relapse remains the most common cause of treatment failure among patients with [NHL] undergoing allogeneic HCT with such lower-intensity platforms,” wrote authors led by Nilanjan Ghosh, of the Levine Cancer institute, Atrium Health, Charlotte, NC.

“The various RIC-NMAC regimens commonly used in practice differ in their immunosuppressive and cytoreductive effects, but to our knowledge, no prospective randomized trials are available to define an optimal regimen among patients with NHL,” they added.

Using data from the Center for International Blood and Marrow Transplant Research registry, Ghosh and colleagues assessed 1,823 adult patients (mean age: 54.8 years; 65% male) with non-Hodgkin lymphoma who underwent allogeneic HCT to determine whether RIC-NMAC regimens of higher intensity were associated with increases in non-relapse mortality and lower OS compared with lower intensity regimens.

Patients were randomized to treatment with one of four RIC-NMAC regimens:

  • Flu-Bu (≈6.4 mg/kg; n=458).
  • Flu-Mel140 (140 mg/m2; n=885).
  • Flu-Cy (n=391).
  • Flu-Cy with 2Gy TBI (Flu-Cy-2GyTBI; n=89).

Patients treated with Flu-Bu and Glu-Cy-2GyTBI tended to be older than 60 years compared with those in the Flu-Mel140 and Flu-Cy cohorts, and those in the Flu-Bu cohort were more likely to have a Karnofsky performance score of less than 90, HCT comorbidity index of at least 3, and be of Caucasian race. Finally, patients in the Flu-Bu and Flu-Mel140 cohorts were more likely to have aggressive lymphomas—diffuse large B-cell lymphoma and T-cell NHL.

“We hypothesized that within the RIC-NMAC spectrum, patients with NHL receiving a higher-intensity regimen, such as Flu-Mel140, would have higher nonrelapse mortality and inferior OS compared with those receiving lower-intensity regimens, such as Flu-Bu, Flu-Cy, or [Flu-Cy-2GyTBI],” explained Ghosh and fellow researchers.

Indeed, what they found was that patients treated with Flu-Mel140 compared with Flu-Bu had a significantly higher mortality risk (HR: 1.34; 95% CI: 1.13-1.50; P ˂ 0.001) upon regression analysis adjusted for age, Karnofsky performance score, HCT comorbidity index, NHL subtype, remission status at HCT, and the use of antithymocyte globulin or alemtuzumab.

Ghosh and colleagues also observed that patients treated with Flu-Cy-2GyTBI had the highest 4-year adjusted OS the group (67%), followed by those in the Flu-Cy cohort (63%), the Flu-Bu cohort (58%), and the Flu-Mel140 cohort (49%). No significant differences in OS were seen between Flu-Bu, Flu-Cy-2GyTBI, and the Flu-Cy patients.

Further, the risk of chronic graft versus host disease (GVHD) was higher in the Flu-Mel140 cohort compared with the Flu-Cy cohort (HR: 1.38; 95% CI: 1.15-1.65; P ˂ 0.001), but the risk of grade 3 to 4 GVHD did not differ significantly between groups.

The most common causes of death in all patients were recurrent or progressive lymphoma, GVHD, and infectious complications. Treatment with Flu-Mel140 was associated with a higher nonrelapse mortality compared with the Flu-Bu regimen (HR: 1.78; 95% CI: 1.37-2.31; P ˂ 0.001). The 4-year adjusted cumulative incidence of nonrelapse mortality was 26% in the Flu-Mel140 cohort, followed by 17% in both the Flu-Cy-2GyTBI and Flu-Cy groups, and 16% in the Flu-Bu cohort (P ˂ 0.001).

Patients in the Flu-Cy cohort had the highest adjusted cumulative incidence of relapse or progression at 4 years (50%), followed by those in the Flu-Bu cohort (47%), the Flu-Mel140 cohort (37%), and the Flu-Cy-2GyTBI cohort (33%) (P ˂ 0.001). Upon regression analysis adjusted for remission status at HCT, NHL subtype, donor type, and treatment with antithymocyte globulin or alemtuzumab, however, differences between the Flu-Mel140 and Flu-Bu cohorts were not significantly different (HR: 0.79; 95% CI: 0.66-0.94; Q=0.07).

Four-year adjusted progression-free survival (PFS) was highest with Flu-Cy-2GyTBI treatment (51%), followed by Flu-Mel140 (39%), Flu-Bu (38%), and Flu-Cy (35%). Compared with Flu-Bu, however, PFS was not significantly improved with Flu-Mel140 (HR: 1.03; 95% CI: 0.89-1.19), Flu-CY-2GyTBI (HR: 0.70; 95% CI: 0.51-0.98), or Flu-Cy (HR: 1.07; 95% CI: 0.89-1.29) upon adjustment for Karnofsky performance scores, remission status at HCT, NHL subtypes, and treatment with antithymocyte globulin or alemtuzumab.

Day 30 neutrophil recovery was significantly lower in the Flu-Mel140 cohort, compared with the other three cohorts (P ˂ 0.001), as was day 100 cumulative platelet recovery (P ˂ 0.001).

Limitations of this study included the variety of NHL subtypes included, variations in the busulfan and melphalan dosing intensities, the use of registry data, and the exclusion of haploidentical HCT recipients.

In an accompanying editorial, Tobias Berg, MD, of McMaster University, Hamilton, Ontario, Canada, and colleagues, commented on the significance of these results:

“When these main findings are considered in the context of any imbalances in baseline characteristics that appeared to favor the Flu-Mel140 group compared with the Flu-Bu group, it is most reasonable to adopt Flu-Bu instead of Flu-Mel140 as the preferred standard of care for patients with lymphoma, which could lead to a change in practice for many centers. To change this conclusion would require conflicting results form an RCT.”

They added: “Many now regard chimeric antigen receptor T-cell (CART-C) therapy as the preferred option compared with allogeneic HCT for many patients with B-cell lymphomas. The role of allogeneic HCT will thus require new levels of evaluation either as a subsequent option for patients with persisting lymphoma after CART-C therapy or as an alternative to CART-C therapy. It should be expected that observational data from registries will provide the initial lens assessing these roles.”

  1. Treatment with a higher-intensity fludarabine-melphalan regimen in patients with non-Hodgkin lymphoma undergoing allogeneic transplant was associated with higher nonrelapse mortality and inferior overall survival.
  2. Use of three lower-intensity regimens—fludarabine-intravenous busulfan, fludarabine-cyclophosphamide with and without 2 Gy total body irradiation—had more positive and comparable effects on overall survival.

E.C. Meszaros, Contributing Writer, BreakingMED™

Ghosh has received grants and personal fees from Celgene Corp, Janssen/Pharmacyclics, Seattle Genetics and TG Therapeutics; grants from Genentech and Forty Seen Inc., personal fee from AbbVie, AstraZeneca, BMS, and Gilead/Kite outside the submitted work; participated in speakers bureaus for AbbVie, AstraZeneca, BMS, Celgene Corp. Gilead, Janssen/Pharmacyclics, and Seattle Genetics; and consulted for Celgene Corp., Gilead, Janssen/Pharmacyclics, Seattle Genetics, and TG Therapeutics.

Berg has served as a consultant for Riemser Pharma, received honoraria from Roche, and travel funding from AbbVie, Alexion, Astellas, Celgene Corporation, and Incyte.


Cat ID: 467

Topic ID: 78,467,730,467,192