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Dasatinib-induced restoration of donor chimerism in BCR-ABL1-positive ALL after failure of imatinib therapy and allo-SCT

Bone Marrow Transplantation volume 43, pages 579–581 (2009)Cite this article

The BCR-ABL1 kinase that drives the pathogenesis of CML can also be detected in 5–10% of children and 20–30% of adults with ALL (Ph+ALL). In the latter, BCR-ABL1 portends a very poor prognosis.1 The tyrosine kinase inhibitor imatinib mesylate inactivates the kinase activity of BCR-ABL1 and is considered standard front-line therapy for CML.2 The addition of imatinib to conventional chemotherapy has improved the response rates in patients with Ph+ALL. The multikinase inhibitor dasatinib has shown improved activity in Ph+ALL compared with that of imatinib.

A 17-year-old man presented in April 2003 with abdominal pain. Initial laboratory evaluation revealed WBC count 138 × 109/l, Hb 9.5 g per 100 ml and platelet count 61 × 109/l. A BM biopsy showed infiltration by blastic cells CD19+, CD10+, CD34+ and TdT+, consistent with B-cell precursor ALL. Cytogenetic studies revealed 100% Ph+ metaphases. The presence of an e1a2 transcript (p190BCR−ABL1 protein) was shown by reverse transcriptase-PCR. Both his mediastinum and cerebrospinal fluid were free of disease. Induction therapy with the DFCI-ALL Consortium Protocol 01–91 scheme (doxorubicin, VCR, high-dose MTX, L-asparaginase and prednisone)3 for high-risk ALL was started along with CNS prophylaxis. A day 28 BM aspirate showed 20% blasts. He was deemed to be primary resistant and intensification therapy was started as per the DFCI scheme (doxorubicin, VCR, L-asparaginase, 6-MP and prednisone) with the addition of imatinib mesylate 600 mg daily. Intrathecal therapy was administered twice weekly. Four weeks after intensification was started, the patient achieved a complete cytogenetic response (CCyR). A decision was made to proceed immediately with allo-SCT from his HLA-identical brother. In July 2003, he received a conditioning regimen that involved TBI (2400 cGy) and CY. He engrafted on day 11 and his post transplant course was complicated by increased liver function tests without evidence of GVHD. A short course of MTX and CYA until day 100 post transplant was given as GVHD prophylaxis. In March 2004, the patient presented with fever, WBC 69 × 109/l, Hb 15.7 g per 100 ml and platelet count 204 × 109/l. The cerebrospinal fluid was infiltrated with leukemic cells and the Ph was detected again in the BM, along with loss of chromosome Y. Therapy with hyperCVAD and imatinib 800 mg daily was commenced. At day 14 of therapy, 5 × 107 CD3+ T cells from his HLA-identical brother were infused. A cerebrospinal fluid analysis was unremarkable and a BM biopsy showed a diploid karyotype without evidence of Ph chromosome. Microsatellite polymorphism analysis revealed the presence of 100% donor cells. The second cycle of hyperCVAD was complicated by seizures and a subdural hematoma that required drainage. Intrathecal therapy was withheld during this cycle. CCyR was confirmed in BM and he continued chemotherapy. In July 2004, the patient received his fourth hyperCVAD cycle, after which he developed respiratory insufficiency and leukoencephalopathy with recurrent seizures that kept him hospitalized for 6 weeks. A decision was made to withhold further chemotherapy. He remained in CCyR and the imatinib dose was reduced to 400 mg daily because of elevated liver function tests.

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  1. Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

    A Quintás-Cardama & J Cortes

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Quintás-Cardama, A., Cortes, J. Dasatinib-induced restoration of donor chimerism in BCR-ABL1-positive ALL after failure of imatinib therapy and allo-SCT. Bone Marrow Transplant 43, 579–581 (2009). https://doi.org/10.1038/bmt.2008.354

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