Prophylaxis of Graft-Versus-Host Disease (GVHD) with Pentostatin, Tacrolimus, and “Mini”-Methotrexate (MTX): A Phase I/II Controlled, Randomized Study in Unrelated Donor (UD) Transplantation.

Acute (a)GVHD is a major cause of morbidity and mortality after UD or mismatched related (MRD) donor stem cell transplantation (HSCT). The nucleoside analog pentostatin (pentos) is a potent inhibitor of the enzyme adenosine deaminase that induces lymphocyte depletion, with low risk of myelosuppression. We have investigated the addition of pentos to tacrolimus (tacro) and MTX as GVHD prophylaxis. Methods: This was an adaptive randomized, dose finding study that took into account toxicity and efficacy in a Bayesian adaptive design. Probability of assignment to the control group was fixed at 20%. Probability of assignment to the 4 dose groups was based on the probability that an arm’s success rate was greater than the control’s. Probabilities were recalculated after each observed patient outcome. Recipients of UD and MRD were eligible; all analysis is done by intention to treat. Success was patient being alive, engrafted, in complete remission (CR), without GVHD at study completion(100 days post HSCT). Grade III-IV aGVHD defined failure at any time, while gd. I-II did not constitute failure if absent on day 100. The study was designed to have a false positive rate of 0.05 and a power of 0.7 to detect a dose that had a 60% success rate for low-risk patients (HLA matched, in CR) and 45% for high-risk pts (mismatched, not in CR). High-resolution typing was prospectively available for 95% of donor-recipient pairs (HLA-A, B, C, DRB1 and DQB1 loci). Treatment plan: tacro from day-2; MTX 5 mg/m2 on days +1, +3, +6; day+11 was given only to controls. Pentos was given on days +8, +15, +22 and +30, in 4 ‘arms’: 0.5, 1, 1.5 and 2 mg/m2. Results: 147 pts, median age 49 yrs (18–72) were enrolled from 2001 to 2007. Diagnosis were AML/MDS (n=105), ALL(n=17), CML (n=18) and NHL (n=7); 48% of the pts were not in CR. Conditioning regimens (with ATG in 92% of the cases) were busulfan based (n=104), melphalan based(n=26), BEAM(n= 2), and CyTBI (n=15); 75% were ablative and 25%, reduced intensity. Stem cell source: bone marrow(n=120) and peripheral blood(n=27). Donors: UD(n=140) and MRD (n=7). Proportion of pts with donor-recipient HLA mismatches (HLA A, B, C, DRB1, DQB1) was 27%, 60%, 38%, 21% and 30%, respectively for the 5 study arms; median age was similar. 90% of the intended pentos doses were delivered. Time to engraftment was unafected. Incidence of toxicities (control vs study arms): renal(gd I-III) 34% vs 36%; TTP/HUS 6% vs 6%; early relapse 9% vs 5%; engraftment failure 3% vs 5.5%; delayed engraftment (>21 days): 6% vs 5%. Extensive cGVHD rate (control vs 1.5 mg/m2) was 52% vs 38%. Relapse rates are comparable. Conclusions: aGVHD rate may be reduced with pentostatin 1.5 mg/m2. A multicenter controlled study is planned in order to confirm these findings. | Pentostatin dose | control group n=37 | 0.5 mg/m² n=10 | 1 mg/m² n=29 | 1.5 mg/m² n=61 | 2 mg/m² n=10 | |:------------------------------------------- | ------------------ | -------------- | ------------ | -------------- | ------------ | | gd II-IV aGVHD | 57% | 44% | 40% | 33% | 50% | | gd III-IV aGVHD | 20% | 33% | 18% | 10% | 10% | | Skin only aGVHD | 45% | 25% | 50% | 63% | 67% | | Hepatic aGVHD | 17% | 50% | 14% | 2% | | | gd III-IV aGVHD n pts with <10/10 HLA match | 1 in 9 | 2 in 5 | 5 in 11 | 0 in 11 | 0 in 3 | | CMV reactivation | 63% | 30% | 48% | 49% | 50% | | Fungal infection | 14% | 10% | 30% | 16% | 20% | | Not evaluable (n) | 2 | 1 | 1 | 5 | |