Similar Survival but Increased Toxicity with a Sequential Versus Concurrent FluBu4 Regimen

Combined in vitro treatment with fludarabine and busulfan has been shown to lead to synergistic cytotoxicity. Maximal synergy is achieved when fludarabine is administered immediately prior to busulfan. However, fludarabine and myeloablative busulfan (FluBu4) has been administered in both a concurrent and a sequential, non-overlapping fashion. Because timed sequential regimens are becoming increasingly popular, we sought to compare survival and relapse outcomes as well as toxicity between patients receiving allogeneic stem cell transplant (SCT) with a concurrent 5-day versus a sequential 9-day FluBu4 regimen.

We analyzed 102 consecutive patients who received FluBu4 prior to allogeneic SCT between 2003 and 2016. Thirty-seven (36%) patients received the 5-day regimen, which consisted of fludarabine 40 mg/m² and intravenous busulfan (target AUC 4800 mmol-min per dose) administered daily from Day -5 to Day -2. In 65 (64%) patients, the 9-day regimen was administered, utilizing equivalent doses of fludarabine on day -9 to day -6 and busulfan on day -5 to day -2. All patients received graft-versus-host disease (GVHD) prophylaxis with tacrolimus and methotrexate. Patients undergoing a matched unrelated donor transplant received anti-thymocyte globulin.

Baseline characteristics including gender, race, median time to transplant, median lines of prior treatment, disease risk index, hematopoietic cell transplantation-comorbidity index (HCT-CI), donor type, stem cell source, and mean CD34 count were similar between the two groups. Patients in the 9-day group were younger compared to the 5-day group (median age 45 versus 51 years, p=0.003). The majority of patients in both groups were diagnosed with acute myeloid leukemia, myelodysplastic syndrome, or acute lymphoblastic leukemia.

The median time to neutrophil and platelet engraftment was not different between the two groups. More patients receiving the 9-day regimen experienced Grade 4 mucositis (53 versus 6 patients, p<0.0001). Thus, 23 (35.4%) patients in the 9-day group versus 5 (13.5%) patients in the 5-day group required a day +11 methotrexate dose reduction or omission (p=0.02). This resulted in a higher cumulative incidence of both Grade 2-4 (27% versus 38%, p=0.01) and Grade 3-4 (11% versus 34%, p=0.006) acute GVHD (aGVHD) in the 9-day group compared to the 5-day group. In a multivariate analysis, receiving the 9-day regimen predicted for a greater risk of grade 3-4 aGVHD (p=0.025). Additonally, extensive chronic GVHD was found to be higher in the 9-day FluBu4 cohort (19% vs. 40% p=0.047).

Median one-year GVHD-free, relapse-free survival (GRFS) was significantly worse for patients receiving a 9-day FluBu4 regimen (68.4 versus 144 days, p=0.032). In a multivariate analysis adjusted for HCT-CI, a trend towards significance was observed with the 5-day regimen predicting for longer GRFS compared to the 9-day regimen (p=0.07). Notably, we observed no differences in overall survival, progression-free survival, or relapse rates between the 5- and 9-day regimen.

This is the first study to compare outcomes between a concurrent 5-day and sequential 9-day FluBu4 regimen. We demonstrate similar survival and relapse rates, suggesting that concurrent administration of fludarabine and busulfan may not be necessary for synergistic cytotoxicity. At the same time, we observed increased early toxicity, less MTX administration, and higher aGVHD rates in patients receiving sequential 9-day FluBu4. Contrary to what has been observed with timed sequential regimens, our data suggests that a prolonged administration schedule of conditioning chemotherapy leads to greater toxicity resulting in higher GVHD rates.