Fludarabine Combined with Myeloablative Busulfan (FluBu4) Results in Reliable Engraftment and Low Transplant-Related Mortality in Pediatric Patients

For many years the standard conditioning regimen for children with myeloid malignancies and certain non-malignant diseases, such as sickle cell disease, was myeloablative busulfan combined with high dose cyclophosphamide. Regimen-related toxicity remains a concern, with sinusoidal obstructive syndrome (SOS) occurring in up to 28% of patients (Ozkaynak et al, BMT 1991). The substitution of fludarabine for cyclophosphamide led to less toxicity and better outcomes in adult patients (Andersson et al, BBMT 2008), but there is little data for fludarabine/myeloablative busulfan (FluBu4) in children.

We report the outcomes for 23 consecutive pediatric patients (median 7 years old, range 0-17) who underwent allogeneic BMT following FluBu4 conditioning between December 2006 and May 2014. The indications for transplant were acute leukemia (N=12), MDS/MPD (N=7), CML (N=1), and non-malignant disorders (N=3). There were 17 unrelated donors and 6 sibling donors. Stem cell sources were marrow (N=15) or cord blood (N=8). All cord blood transplants were matched at 4-6/6 HLA-loci. Marrow grafts were allele matched at 8/8 HLA-loci in 13/15 patients; 2 were 7/8 matched. The conditioning regimen consisted of once daily fludarabine 40 mg/m² (1.3 mg/kg for patients <10kg) and pharmacokinetically-adjusted busulfan targeting a CSS of 600-900 mcg/L daily on days -5 to -2. Thirteen patients at higher risk for graft failure (HLA-mismatched grafts, cord blood or non-malignant disease) received either anti-thymocyte globulin (N=8) or low dose (2-4 Gy) radiation (N=5). All patients received a calcineurin inhibitor for GVHD prophylaxis along with short-course methotrexate (N=15) or MMF (N=8) per institutional guidelines. Notable non-GVHD toxicities developed in two patients (9%). There was one case of self-limited moderate SOS. One patient experienced fatal primary graft failure that occurred after receiving an HLA-mismatched cord blood graft for PNH; all other patients (96%) engrafted neutrophils (median 14 days, range 12-26). There were no cases of idiopathic pneumonia syndrome. Acute GVHD grade II-IV developed in 4 patients (17%) at a median onset of 26 days (range 9-139 days). Two patients developed BK virus-associated hemorrhagic cystitis while on high-dose steroids for acute GVHD. The cumulative incidence of relapse at 2 years for patients transplanted for malignancy was 31%; relapse occurred at a median of 45 days post-transplant (range 22-201 days). Non-relapse mortality and overall survival at 2 years are 14% and 63%, respectively (Figure 1). In summary, in children receiving BMT from both sibling and alternative donors, a FluBu4 backbone ± ATG or low dose radiation was an exceptionally well-tolerated conditioning regimen that resulted in prompt and reliable engraftment. Relapse rates and overall survival were similar to those seen with other myeloablative regimens.