Preliminary Results of Phase II Trial of Clofarabine with Parenteral Busulfan Followed by Allogeneic Related or Unrelated Donor Transplantation for the Treatment of Hematologic Malignancies and Diseases.

BACKGROUND: Allogeneic transplantation, a treatment previously reserved only for healthy younger patients, can be modified by reducing the intensity and toxicity of the chemotherapy regimens, to allow older patients to receive this treatment safely. Such reduced intensity transplant (RIT) regimens are now in common use in patients through age 70, but relapse of the underlying disease (such as leukemia or lymphoma) remains a frequent cause of post-transplant mortality. To address this issue, we proposed and tested a “mid-intensity” conditioning regimen using the nucleoside analogue clofarabine (CLO) with busulfan (BU). We hypothesized that this combination would be well tolerated and offer greater anti-leukemic efficacy than existing RIT regimens. METHODS: To date, thirteen patients have been enrolled on this single institution, phase II, IRB-approved trial. The diagnoses at the time of transplant were AML(n=6), ALL (n=1), MDS (n=1) and MDS transforming to AML (n=5). 9 of 13 patients had prior therapies, 1 with 3 lines, 4 with 2 lines, and 4 with 1line. The conditioning regimen consisted of CLO 40mg/m 2 /day iv daily d-8 through d-4, BU 3.2 mg/kg/day iv daily d-3 and -2, followed by a day of rest. Donor cells were infused on day 0. Donors were matched at HLA A, B, C, DR and DQ using DNA sequence-based typing or mid-resolution DNA-based typing. Mismatch at 1 allele was permitted and occurred for 1 donor. GVHD prophylaxis consisted of oral Tacrolimus and MTX 5mg/m 2 iv d+1, +3 and +6. BU and CLO pharmacokinetic samples were collected on all patients for subsequent analysis. RESULTS: Study endpoints included toxicity, incidence and severity of acute graft vs. host disease (AGVHD), and response to therapy. Grade 4 hematologic toxicity was observed in all patients. All patients had hematologic nadirs lasting 9–15 days. GCSF was used in 11 of 13 subjects. The median time to recovery of ANC (defined as 3 days >500/ul) was 13 days. Donor engraftment (defined as >80% donor chimerism at d30) occurred in all patients based on FISH and/or chromosomal analysis (STR-short tandem repeats). There were no cases of hepatic, cardiac, or renal toxicity attributed to the conditioning regimen by d60. Hand/foot syndrome occurred in two patients; one of these was the only incidence of grade 3 toxicity considered to be definitely related to clofarabine. One subject suffered respiratory failure (grade 3) of unknown etiology that resolved completely and was deemed to be possibly related to the treatment. Grade 4 toxicities attributed to the conditioning regimen were not seen in this study. There were no transplant related mortalities. Milder acute toxicities considered definitely or probably related to the regimen included: fluid retention/edema , n=3 (23%) (2 grade 1 and 1 grade 2); nausea/vomiting n=6(46%) (5 − grade 1 and 1 − grade 2); skin rash , n=3(23%) (all grade 1); erythroderma , n=1(8%) (grade 1); elevated transaminases , n= 4(31%) (3 − grade 1 and 1 − grade 2); elevated ALP (alkaline phosphatase) , n=1(8%) (grade 1); elevated total bilirubin n=1(8%) (grade 1); diarrhea, n=1(8%) (grade 1). Acute GVHD (AGVHD) occurred in 10 of 12 (83%) evauable patients within the first 100 days. Of these, 90% were grade 1–2 and 10% grade 3–4. No patients died as a result of AGVHD. The disease responses are as follows: 9 (75%) patients who were refractory, in relapse, or with active disease (n= 4, 1, 4) prior to initiation of CLO/BU, achieved a complete remission by d30. 3 (25%) patients were in remission at initiation of clofarabine, and all were in continued complete remission at d30. One patient was not evaluable for disease response at d30 due to illness. Relapse occurred in 4 (33%) patients at d62, d60, d120, and d335. Of these patients, 2 were refractory, 1 was in relapse and 1 was in CR at baseline. Currently, 8 (67%) patients remain in remission with a median follow up of 208 days. CONCLUSIONS: CLO/BU is a mid-intensity allogeneic transplant conditioning regimen with promising antileukemic efficacy that seems to be well tolerated without significant cardiac, renal or pulmonary toxicities. Furthermore, CLO/BU resulted in full allogeneic engraftment by day 30 in all patients. The study continues to accrue patients and will be updated at the meeting.