Reduced‐intensity therapy for relapsed Philadelphia chromosome‐positive leukemia

This is the authors' abstract. We don't add key points for this paper.

To the Editor: Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) accounts for 3−5% of children with ALL. The outcomes of Ph+ ALL have significantly improved with the introduction of tyrosine kinase inhibitors. Slayton et al.1 reported excellent outcomes for 60 children with a 5-year event-free survival rate of 60% and overall survival rate of 86%. However, relapsed patients require more intensive treatment, including hematopoietic cell transplantation (HCT). It is unclear whether relapsed Ph+ ALL can be salvaged with lower-intensity treatment. We report the case of a child with relapsed Ph+ ALL who was successfully treated with dasatinib-combined reduced-intensity chemotherapy, excluding anthracyclines, cyclophosphamide, and etoposide, followed by HCT with reduced intensity conditioning (RIC). A 6-year-old Japanese male presented with persistent fever. A blood examination revealed anemia (hemoglobin, 5.5 g/dL), thrombocytopenia (platelets, 52 × 103/L), and hyperleukocytosis (white blood cells, 14.8 × 104/L with 78% blast cells). A bone marrow analysis revealed increased lymphoblasts (75.4%) with positive staining for CD10, CD13, CD19, CD33, CD79α, and HLA-DR. A chromosome analysis showed 46, XY, t(9;22)(q34;q11). Reverse transcriptase-polymerase chain reaction (PCR) confirmed the presence of a minor BCR::ABL1 transcript. Cytology revealed central nervous system involvement, with increased cell counts (5 cells/μL) in the cerebrospinal fluid. The patient had a sustained complete molecular response while receiving whole-brain irradiation (18 Gy) with imatinib (340 mg/m2)-combined chemotherapy according to the Associazione Italiana Ematologia Oncologia Pediatrica ALL 2000 study high risk group protocol.2 Six months after the end of the treatment, a routine bone marrow evaluation identified relapse with 13% lymphoblasts and 16% BCR::ABL1-positive cells by fluorescence in situ hybridization. No blasts were found in the cerebrospinal fluid. The patient received dasatinib (60 mg/m2) combined reduced-intensity chemotherapy, which omitted anthracyclines, cyclophosphamide, and etoposide from the previous protocol. PCR-measurable residual disease (MRD) and BCR::ABL1 transcripts after induction chemotherapy reached levels of <5 × 10−4 and 54 copies/μg RNA, respectively. HCT from 8/8 human leukocyte antigen-matched unrelated donors after the RIC regimen [fludarabine 30 mg/m2/day on days −8 to −4, melphalan 70 mg/m2/day on days −3 to −2, and total body irradiation (TBI) 3 Gy on day −4] was performed in the MRD-negative state. Grade I acute graft-versus-host disease (GVHD) was controlled by prophylaxis with tacrolimus and short-term methotrexate without steroid administration. The neutrophil and platelet counts recovered to 0.5 × 103/L and 20 × 103/L on days 21 and 27, respectively. The patient has achieved a complete molecular response with dasatinib maintenance therapy for 2 years without any complications for 26 months after HCT (Table 1). Anthracyclines, alkylating agents, and epipodophyllotoxins are well known to cause late sequelae, including secondary malignancies, cardiac dysfunction, and gonadal dysfunction. All organs can be affected by late sequelae after HCT using a myeloablative conditioning regimen. To date, there are no large-scale data on the efficacy of reduced intensity therapy for relapsed Ph+ ALL. A French multi-institutional study reported that 13 of 27 children with relapsed Ph+ ALL, who were initially treated with imatinib-based chemotherapy, were switched to dasatinib-based non-intensive chemotherapy consisting of two cytotoxic drugs. Complete remission and MRD negativity were achieved in 11 and 9 of the 13 patients, respectively. Four of the seven patients who achieved a 2nd complete remission followed by HCT were 4-year relapse-free survivors.3 All seven patients received a myeloablative conditioning regimen. Pediatric patients with high-risk ALL who received TBI (12 Gy) plus etoposide prior to HCT had a significantly better survival and a lower relapse risk rather than the patients who received myeloablative chemotherapy.4 However, patients receiving TBI (12 Gy) are at high risk of transplant-related mortality, GVHD, gonadal dysfunction, secondary malignancies, and cardiac dysfunction. RIC was selected for our patient and successfully managed without relapse or severe toxicities. Bachanova et al.5 reported that adult patients with Ph+ ALL without MRD positivity who received RIC followed by HCT had significantly better overall survival than patients with myeloablative conditioning (55 vs. 33%). However, the efficacy has not been widely evaluated in patients with relapsed Ph+ ALL. Our case suggests that RIC is also an attractive strategy for children and adults with Ph+ ALL who achieve an MRD-negative status. In our case, HCT was successfully managed without GVHD or transplant-related mortality. Furthermore, late sequelae were avoided. The efficacy of this approach should be confirmed in a larger population. S. N. wrote the initial manuscript. A. Y. and H. M. critically reviewed and revised the manuscript. M. N., M. K., S. K., Y. K., and S. O. treated the patient and contributed to the acquisition of clinical data. All authors read and approved the final manuscript. The authors declare no conflicts of interest in association with the present study.