Fludarabine + Busulfan: Improving Treatment-Related Mortality without Compromising Conditioning Intensity in High-Risk Multiple Myeloma

A myeloablative conditioning regimen consisting of fludarabine and busulfan was safe and effective in patients with high-risk multiple myeloma undergoing allogeneic hematopoietic cell transplantation (Allo-HCT) and decreased treatment-related mortality – and was comparable with conventional conditioning regimens – according to a report published in Biology of Blood and Marrow Transplantation. The fludarabine and busulfan regimen was also associated with no instances of early toxic death or graft failure.

“Despite the ongoing advent of more effective immunomodulators and proteasome inhibitors, multiple myeloma remains incurable and no effective therapy is available for advanced, aggressive disease,” the authors, led by Attaphol Pawarode, MD, from the Blood and Marrow Transplantation Program at the University of Michigan in Ann Arbor, wrote.

Although Allo-HCT has a curative potential for these patients, their clinical outcomes remain poor due to high treatment-related mortality, mostly related to “regimen-related toxicities and graft-versus-host disease (GVHD) with use of myeloablative conditionings, high relapse rate with use of reduced-intensity or nonmyeloablative regimens, and possibly other unknown multiple myeloma–specific issues,” the authors noted.

In an effort to improve treatment-related mortality without compromising conditioning intensity, Dr. Pawarode and investigators conducted a prospective study to examine the feasibility and efficacy of a myeloablative but reduced-toxicity conditioning regimen, which consisted of fludarabine and busulfan (FluBu4; fludarabine 40 mg/m2 per day and busulfan 3.2 mg/kg per day administered intravenously four times daily). Compared to other conventional conditioning regimens, the FluBu4 regimen was less intense; these regimens typically consist of intravenous melphalan and cyclophosphamide, the authors added.

A total of 22 patients with high-risk or advanced refractory multiple myeloma were included in the study; 14 of these patients (64%) had prior autologous HCT. The median HCT-specific comorbidity index (HCT-CI) score was three (range, 0-6), and 46 percent of patients had some impairment in their ability to function (determined by a Karnofsky performance score of less than 80%).

Among the study participants, 10 had unrelated donors, three of which were 7/8 human leukocyte antigen (HLA)–loci matched. Twenty patients (91%) received GVHD prophylaxis with tacrolimus and methotrexate.

Most patients had active multiple myeloma at transplant, with a partial response occurring in 12 of 22 patients (46%) and stable disease in one of 22 patients (4.5%).

All 22 patients tolerated the FluBu4 conditioning well, without early toxic deaths or graft failure. The most common regimen-related toxicities included mild to moderate mucositis (82%; n=18) and mild transient liver function abnormalities (41%; n=9). No grade 4 toxicities were recorded, though grade 3 mucositis occurred in 32 percent of patients (n=7).

When Dr. Pawarode and colleagues looked at GVHD incidence among these patients, they found that, at day 180, the cumulative incidence of severe grade 3 or 4 acute GVHD was 23 percent (95% CI 10-47) and 68 percent (95% CI 46-88) for chronic GVHD.

For treatment-related mortality, the cumulative incidence rates were:

  • 9% (95% CI 2-33) at day 100
  • 19% (95% CI 7-44) at one year
  • 29% (95% CI 13-55) at three years

Two cases of treatment-related mortality were due to idiopathic pneumonia syndrome, and one was due to cirrhosis; all of these patients had HCT-CI scores of greater than three, indicating pre-transplant organ dysfunction.

“The overall outcomes were not improved because of ongoing high relapse and chronic graft-versus-host disease rates,” the authors reported, with poor progression-free and overall survival over a median follow-up of 58.7 months (range = 39-82 months; TABLE).

Overall, the use of the myeloablative FluBu4 conditioning with allo-HCT in high-risk multiple myeloma patients resulted in treatment-related mortality rates comparable to those with other fludarabine-based myeloablative regimens. For instance, the authors noted, previous studies have shown treatment-related mortality of 19 percent at 100 days and 40 percent at 1 year with a fludarabine + melphalan regimen, and 13 percent at one year with a fludarabine +melphalan regimen with or without ATG.

However, the relapse rate was high, including in those who developed moderate-to-severe chronic GVHD. “This suggested a less robust graft-versus-myeloma effect against high-risk multiple myeloma, thus resulting in poor progression-free and overall survival,” Dr. Pawarode and colleagues stated. “Nonetheless, the FluBu4 regimen may be used as a lower treatment-related mortality platform [in these patients].

Despite these promising results, there are limitations to note: First, the current study was non-comparative in nature, so definitive conclusions about the superiority or non-inferiority of FluBu4 regimen over other regimens could not be made. The study also included only 22 patients enrolled from one cancer center, so the regimen will need to be investigated in a larger population of myeloma patients.

Additional strategies (e.g., combining a targeted agent with a GVHD-modulating property, especially a proteasome inhibitor, or maintenance therapy) are needed for this high-risk patient population, the authors concluded.


Reference

Pawarode A, Mineishi S, Reddy P, et al. Reducing treatment-related mortality did not improve outcomes of allogeneic myeloablative hematopoietic cell transplantation for high-risk multiple myeloma: a University of Michigan prospective series. Biol Blood Marrow Transplant. 2015 July 23. [Epub ahead of print]

TABLE. One- and Three-Year Outcomes after Allo-HCT with FluBu4 Conditioning
Cumulative incidence of relapse
1 year 37% (95% CI 20-61)
3 years 50% (95% CI 29-75)
Overall survival
1 year 58% (95% CI 40-83)
3 years 29% (95% CI 15-57)
Progression-free survival
1 year 40% (95% CI 23-67)
3 years 15% (95% CI 5-42)

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