Prolonged Engraftment and/or Primary Graft Failure Following Allogenic Stem Cell Transplant in Patients Treated with Dasatinib.

Abstract The impact of pre-transplant dasatinib therapy on engraftment after allogenic stem cell transplant remains unknown. We report delayed engraftment in the first three consecutive chronic myeloid leukemia (CML) patients at our center who received allogenic stem cell transplant after treatment with dasatinib for imatinib mesylate resistant (CML). All the patients were enrolled on the BMS clinical trial CA180035 for accelerated or blast phase chronic myeloid leukemia resistant or intolerant to imatinib. All three patients received G-CSF 5mg/kg sc daily starting from day +1 × 3 days post transplant to achieve ANC >1000. Patient 1: 53 yr female developed lymphoid blast crisis on imatinib and was given one cycle of HyperCVAD, entered a complete molecular remission (RT-PCR/BCR-ABL fish negative) and then received 140 mg PO daily of dasatinib continuously for 100 days prior to transplant. Dasatinib was discontinued one week prior to transplant and the patient was conditioned with fractionated TBI/CY 60mg/kg × 2 and infused with 2.32× 106 CD34/kg BM from a 10/10 matched unrelated donor. Patient 2: 36 yr male with accelerated phase (CML) failed imatinib and developed myeloid blast crisis. After starting dasatinib 70mg PO BID patient remained in accelerated phase and was taken off study drug after 82 days approximately two months prior to transplant because of recurrent blast crisis requiring admission for standard anti-leukemic therapy. This patient was conditioned with BU/CY and infused with 16.2× 106 CD 34/kg PBSC from a 9/10 (C antigen mismatched) unrelated donor. Primary graft failure with recurrence of disease was documented on day 30 requiring additional investigational therapy. Patient 3: 61 yr female with accelerated phase (CML) was treated with dasatinib 70mg PO BID after progression on imatinib and was unable to continue on dasatinib after 20 weeks due to myleosuppression. Dasatinib was discontinued one month prior to transplant and no additional therapy was needed. She received single dose 550 cGy TBI/CY 60mg/kg × 2 followed by infusion of 6.9 106 CD34/kg PBSC from a HLA-matched sibling donor. Primary graft failure occurred and patient was re-infused with additional G-mobilized PBSC (5.5 × 106 CD34/kg) on day +30. Patient did not achieve neutrophil recovery until 5 days after second infusion of G-mobilized PBSC from the same donor. Although the number of patients is limited, 3/3 patients treated with dasatinib prior to allogenic transplant experienced either delayed engraftment or primary graft failure. Additional patients treated with dasatinib prior to allogenic transplant will need to be studied to confirm these observations and to provide more information on dose and duration of dasatinib therapy that may impact hematopoietic engraftment after myeloablative allogenic stem cell transplantation. Patient Characteristics Patients 1 2 3 Type of Transplant BM PB PB CD34/kg 2.32×10^6/kg 16.2×10^6/kg 6.9×10^6/kg Conditioning TBI/CY BU/CY TBI/CY Disease status at transplant CMR AP CML AP CML ANC 500 +21 +27 +30 ANC 1000 +25 +27 +38 PLTS 25 +21 Not Achieved Not Achieved PLTS 50 +25 Not Achieved Not Achieved Donor Chimerism 100% day +30 0% day +30 73% day+24/100% day+84