Treatment of patients (PTS) with chronic myeloid leukemia (CML) and imatinib failure after developing BCR-ABL kinase mutations with allogeneic stem cell transplantation (ASCT)

Abstract

ASCT is curative for many pts with CML, and may be effective after imatinib failure. Resistance to imatinib is most often associated with point mutations in the Bcr-Abl kinase domain. The outcome of pts with Bcr-Abl kinase mutations after ASCT is not known. We assessed the outcome of ASCT in 9 pts with CML (chronic phase [CP] = 3, accelerated phase [AP] = 3, blast phase [BP] n = 3) harboring 8 different protein kinase mutations. P-loop mutations were detected in 4 (44%) pts; T315I mutation was detected in 2 pts (one AP and one CP). Seven male and 2 female pts, median age of 44 years (range, 26-63 years), received their ASCT between June 2003 and July 2005. At the time of ASCT, one pt was in major molecular remission (MMR) (BP, Q252H), one was in major cytogenetic response (CP, T315I), and 2 were in complete hematologic response (2 BP, Y253H and E281A). Preparative regimen was busulfan + cyclophosphamide in 7 and fludarabine + cyclophosphamide in 2 pts. Donor was fully matched related in 4 (44%) and unrelated in 5 (56%) pts. Source of stem cells was peripheral blood and bone marrow in 7 and 2 pts, respectively. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and mini methotrexate. All patients engrafted; there was no treatment-related mortality. Chimerism studies at day 30 and 100 post ASCT were available in 7 pts and were 100% of donor type. Eight pts achieved a complete molecular remission (CMR); one pt with a T315I mutation achieved a MMR. Two (22%) pts (Q252H [BP] and T315I [AP]) relapsed after a median of 7 months; one of them (T315I) died of disease progression. All the remaining 7 pts were in CMR for a median of 13 months (range, 3-20+ months). We conclude that ASCT remains an important salvage option for pts who develop resistance to imatinib through Bcr-Abl mutations. Early introduction of such strategy may result in better outcome. ASCT is curative for many pts with CML, and may be effective after imatinib failure. Resistance to imatinib is most often associated with point mutations in the Bcr-Abl kinase domain. The outcome of pts with Bcr-Abl kinase mutations after ASCT is not known. We assessed the outcome of ASCT in 9 pts with CML (chronic phase [CP] = 3, accelerated phase [AP] = 3, blast phase [BP] n = 3) harboring 8 different protein kinase mutations. P-loop mutations were detected in 4 (44%) pts; T315I mutation was detected in 2 pts (one AP and one CP). Seven male and 2 female pts, median age of 44 years (range, 26-63 years), received their ASCT between June 2003 and July 2005. At the time of ASCT, one pt was in major molecular remission (MMR) (BP, Q252H), one was in major cytogenetic response (CP, T315I), and 2 were in complete hematologic response (2 BP, Y253H and E281A). Preparative regimen was busulfan + cyclophosphamide in 7 and fludarabine + cyclophosphamide in 2 pts. Donor was fully matched related in 4 (44%) and unrelated in 5 (56%) pts. Source of stem cells was peripheral blood and bone marrow in 7 and 2 pts, respectively. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and mini methotrexate. All patients engrafted; there was no treatment-related mortality. Chimerism studies at day 30 and 100 post ASCT were available in 7 pts and were 100% of donor type. Eight pts achieved a complete molecular remission (CMR); one pt with a T315I mutation achieved a MMR. Two (22%) pts (Q252H [BP] and T315I [AP]) relapsed after a median of 7 months; one of them (T315I) died of disease progression. All the remaining 7 pts were in CMR for a median of 13 months (range, 3-20+ months). We conclude that ASCT remains an important salvage option for pts who develop resistance to imatinib through Bcr-Abl mutations. Early introduction of such strategy may result in better outcome.