Leukemia research
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We treated 60 relapsed/refractory mixed-phenotype acute leukemia patients (MPAL-1) with increasing the aclarubicin dose in CAG regimen (HD-CAG, cytarabine (10 mg/m(2)/12 h, days 1-14), aclarubicin (5-7 mg/m(2)/day, days 1-14), granulocyte colony-stimulating factor (200 μg/m(2)/day, days 1-14). This was compared to 64 relapsed/refractory MPAL patients (MPAL-2) treated with DOAP regimen (daunorubicin, vincristine/vindesine, cytarabine and prednisone), 113 relapsed/refractory acute myeloid leukemia (AML) patients and 78 acute lymphocytic leukemia (ALL) patients treated with HD-CAG regimen. After one course, complete remission (CR) and overall response [OR, CR+partial remission (PR)] rates for MPAL-1 exceeded MPAL-2 (CR, 61.02% vs. 28.13%, P=0.000; OR, 72.88% vs. 34.38%, P=0.000), but these data were similar to AML and ALL (P>0.05). ⋯ The overall survival at 3 years in MPAL-1, MPAL-2, AML and ALL groups were 14.2%±6.8%, 14.1%±6.4%, 17.3%±5.0% and 15.0%±5.3% (P>0.05). Side effects were similar between HD-CAG and DOAP (P>0.05). HD-CAG regimen is efficacious for relapsed/refractory MPAL, especially for T+My patients.
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Dormant leukemia cells, which might escape the cytotoxic effect of conditioning before hematopoietic stem cell transplantation (HSCT), could be induced to enter the cell cycle by granulocyte colony-stimulating factor (G-CSF) and become more susceptible to the cell-cycle-specific agent cytarabine arabinoside (Ara-C). Based on this effect, we have utilized G-CSF-combined high-dose Ara-C in myeloablative conditioning for allogeneic bone marrow or peripheral blood stem cell transplantation from HLA-identical family donors since 1988. ⋯ In multivariate analysis, disease status at HSCT was associated with survival and relapse. These data demonstrate that G-CSF-combined myeloablative conditioning could be safely and effectively used for patients with myeloid malignancies.
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Randomized Controlled Trial
Discontinuation of hypomethylating agent therapy in patients with myelodysplastic syndromes or acute myelogenous leukemia in complete remission or partial response: retrospective analysis of survival after long-term follow-up.
Hypomethylating agents (HMA), such as 5-azacitidine or decitabine, are currently used to treat patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) until treatment failure. However, the outcomes for patients who discontinue therapy after achieving partial response (PR) or complete remission (CR) but before treatment failure have not been reported. We present a series of 16 patients with higher-risk MDS (n=5; 31%) or AML (n=11; 69%) who achieved PR (n=1) or CR (n=15) and stopped HMA therapy while in response in the context of clinical trials. ⋯ Patients who received 12 cycles of therapy or more had significantly better OS (median: 20 months [95% CI: 12-27]) than those who received fewer than 12 cycles (median: 4 months [95% CI: 1-8]) (p=0.043). Poor-risk cytogenetics were also associated with lower 1-year OS (33% versus 69%; p=0.046). According to these results and considering the poor prognosis after HMA failure, HMA interruption should be avoided once a sustained response has been achieved.
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CALR mutations are detected in about 50% of persons of predominately European descent with essential thrombocythemia (ET) or primary myelofibrosis (PMF) with wild-type alleles of JAK2 and MPL. We studied 1088 Chinese with diverse myeloproliferative neoplasms including ET (N=234) and PMF (N=50) without JAK2(V617F) or MPL exon 10 mutations. CALR mutation was detected in 53% (95% CI, 46-60%) of subjects with ET and 56% (95% CI, 41-70%) of subjects with PMF. 152 CALR mutations were identified clustering into 15 types including deletions (N=8), insertions (N=3) and complex indels (N=4). ⋯ Amongst persons with CALR mutations, those with PMF had different clinical features from those with ET. These data may be useful for diagnosing ET and PMF in Chinese who are about 40% of all persons with ET and PMF and for monitoring therapy-response. They also highlight similarities and differences in CALR mutations between Chinese and persons of predominately European descent with these diseases.
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Comparative Study
Mutational profiling of therapy-related myelodysplastic syndromes and acute myeloid leukemia by next generation sequencing, a comparison with de novo diseases.
In this study we used a next generation sequencing-based approach to profile gene mutations in therapy-related myelodysplastic syndromes (t-MDS) and acute myeloid leukemia (t-AML); and compared these findings with de novo MDS/AML. Consecutive bone marrow samples of 498 patients, including 70 therapy-related (28 MDS and 42 AML) and 428 de novo (147 MDS and 281 AML) were analyzed using a modified-TruSeq Amplicon Cancer Panel (Illumina) covering mutation hotspots of 53 genes. Overall, mutation(s) were detected in 58.6% of t-MDS/AML and 56.8% of de novo MDS/AML. ⋯ In summary, t-MDS/AML shows a mutation profile different from their de novo counterparts. TP53 mutations are highly and similarly prevalent in t-MDS and t-AML but mutations in genes other than TP53 were more frequent in t-AML than t-MDS. The molecular genetic profiling further expands our understanding in this group of clinically aggressive yet heterogeneous myeloid neoplasms.