Y. Volchek

Allo-SCT for AML and MDS with treosulfan compared with BU-based regimens: Reduced toxicity vs reduced intensity

Allo-SCT with reduced-intensity conditioning (RIC) results in lower non-relapse mortality (NRM), but higher relapse rate than myeloablative conditioning (MAC) in AML/myelodysplastic syndromes (MDS). Novel regimens with intensive anti-leukemic activity, but with limited toxicity will be of benefit. In all, 85 patients with AML/MDS, not eligible for MAC, were given fludarabine-treosulfan conditioning (FT). Outcomes were compared with those in patients given fludarabine-BU RIC (FB2, n=106) or reduced-toxicity (RTC) conditioning (FB4, fludarabine and myeloablative BU dose, n=85). The 5-year NRM was 29%, 20% and 18% after FT, FB2 and FB4, respectively (P=NS). Multivariate analysis (MVA) identified comorbidity score (HCT-CI) >2 and advanced disease as adverse factors with no independent impact of regimen. The 5-year relapse rate was 36%, 47% and 40%, respectively (P=0.17). MVA identified advanced disease as the major adverse factor, while FT had significantly lower relapse rate (hazard ratio 0.6, P=0.03). The 5-year survival (OS) was 37% with advanced disease. HCT-CI >2 and age ⩾50 were found as adverse factors. The 5-year OS was 46%, 44% and 50% after FT, FB2 and FB4 in early-intermediate-stage disease (P=NS) and 33%, 9% and 28% in advanced disease, respectively (P=0.02). FT is an RTC regimen with intensive anti-leukemia effect in MAC non-eligible patients.

Secondary malignancies after allogeneic stem-cell transplantation in the era of reduced-intensity conditioning; the incidence is not reduced

Secondary malignancies are well established complication in long-term survivors after allogeneic stem-cell transplantation (SCT) with myeloablative conditioning (MAC). Fludarabine-based reduced-intensity (RIC) and reduced-toxicity conditioning (RTC) regimens are increasingly used in the last decade; however, due to limited long-term follow-up, there is no data on secondary malignancies in this setting. The records of 931 consecutive patients given allogeneic SCT with MAC (n=257), RIC (n=449) or RTC (n=225), in a single institution over a 13-year period, were reviewed. Twenty-seven patients had secondary malignancy, diagnosed a median of 43 months (7 months–11.5 years) after SCT. The 10-year cumulative incidence was 5.6% (95% confidence interval (CI), 3.6–8.7), twice the expected rate in matched normal population. The incidence was 1.7, 7.4 and 5.7% after MAC, RIC and RTC, respectively (P=0.02). Multivariate analysis identified fludarabine-based conditioning (hazard ratio (HR) 3.5, P=0.05), moderate–severe chronic graft-versus-host disease (HR 2.8, P=0.01) and diagnosis of chronic myeloproliferative or non-malignant disease (HR 0.2, P=0.04) as risk-factors for secondary malignancy. The related 10-year mortality rate was 2.4% (95% CI, 1.0–5.4). In conclusion, the risk of secondary malignancies is not reduced and is even possibly increased in the era of fludarabine-based RIC/RTC. Patients and physicians should be aware of this association and life-long cancer screening is required for all transplant survivors.

Treatment with interferon alpha prior to discontinuation of imatinib in patients with chronic myeloid leukemia.

Imatinib (IM) is the current first line treatment for chronic myeloid leukemia (CML). However, the disease will progress in the majority of patients pausing IM. IFN-α may intensify the response and increase the percentage of patients maintaining remission after IM cessation. Eleven patients with stable (≥ 2 years) complete cytogenetic responses (CCyR) on IM therapy were recruited to the study. They were administered Peg-IFN-α for 9 months before and for 3 months following IM discontinuation. During the 12 months of Peg-IFN-α therapy the remission status improved in five (45%) of the patients. Six (55%) of the patients experienced cytogenetic relapses at a median period of 8 months (range 2-33) after IM withdrawal. All six patients regained CCyR following IM restart. With a median follow up of 47 months (range 35-50), five (45%) out of the 11 studied patients maintain cytogenetic response off IM therapy. The role of Peg-IFN-α in patients pausing IM is to be further evaluated.

Detection of BCR-ABL1 mutations in chronic myeloid leukaemia by massive parallel sequencing.

The ability to sequence nucleic acids at an unprecedented pace and decreased costs using massive parallel sequencing (MPS) strongly affects biomedical research. Here we applied MPS for the detection of rare, clinically relevant mutations in a chronic myeloid leukaemia (CML) patient. Tyrosine kinase inhibitors revolutionized CML therapy but in some patients the disease progresses due to resistance‐conferring mutations. MPS was applied herein to monitor such mutations in BCR‐ABL1 transcripts at different time points. The large volume of sequencing data increases sensitivity compared to direct sequencing and allows detection of marginally represented and previously uncharacterized mutations. We detected changes in the frequency of mutated clones including the emergence and disappearance of the resistance‐associated ABL1 T315I mutation. We also observed correlation in appearance of adjacent mutations, and exploited this observation to demonstrate the existence of mutated clones at the time of diagnosis. A tool is provided for detection of low frequency single nucleotide variants/mutations from deep coverage MPS data, applicable to clinical translation of advanced sequencing technologies.