Use of the potent tyrosine kinase inhibitor imatinib as the first-line treatment in chronic myeloid leukemia (CML) has decreased mortality from 20% to 2%. Approximately 30% of CML patients experience ...imatinib resistance, however, largely because of point mutations in the kinase domain of the BCR-ABL1 fusion gene. The aim of this study was to use next-generation sequencing (NGS) to identify mutations related to imatinib resistance. The study included 22 patients diagnosed with CML and experiencing no clinical response to imatinib. Total RNA was used for cDNA synthesis, with amplification of a fragment encompassing the BCR-ABL1 kinase domain using a nested-PCR approach. Sanger and NGS were applied to detect genetic alterations. HaplotypeCaller was used for variant calling, and STAR-Fusion software was applied for fusion breakpoint identification. After sequencing analysis, F311I, F317L, and E450K mutations were detected respectively in three different participants, and in another two patients, single nucleotide variants in BCR (rs9608100, rs140506, rs16802) and ABL1 (rs35011138) were detected. Eleven patients carried e14a2 transcripts, nine had e13a2 transcripts, and both transcripts were identified in one patient. One patient had co-expression of e14a2 and e14a8 transcripts. The results identify candidate single nucleotide variants and co-expressed BCR-ABL1 transcripts in cellular resistance to imatinib.
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•NGS was used to find BCR-ABL1 fusion mutations linked to imatinib resistance in CML.•NGS detected several common single nucleotide variants linked to resistance.•NGS facilitated detection of co-expressed BCR-ABL1 transcripts in CML.
Philadelphia chromosome-positive Acute Myeloid Leukemia (AML) is a de novo acute leukemia in which patients show no evidence of Chronic Myeloid Leukemia (CML) before or after their treatment. This ...kind of leukemia has an aggressive clinical course, with poor response to traditional chemotherapy or monotherapy with Tyrosine Kinase Inhibitors (TKI), and a high risk of early relapse after induction therapy. We report a rare case of de novo ALM with t(9;22). A 26-year-old male patient was referred to our hospital for an examination of anemia, thrombocytopenia (hemoglobin 5.7 g/dL and platelets 110 000/L) and elevated White Blood Cell (WBC) count (11 600 μ/L, 24% segmented, 63% lymphocytes, 11% monocytes). Bone marrow smear was compatible with AML. Cytogenetic study revealed t(9;22)(q34;q11). Our patient was treated with chemotherapy for AML and a second-generation TKI and remains in complete remission pending a bone marrow transplant.
Obesity has been associated with a low-grade proinflammatory state, and it has been related to the development of cancer in general, including hematologic cancer.
The present work aimed to identify ...the association of the diagnosis of obesity according to the body mass index (BMI) with prognostic factors of adult patients with Acute Lymphoblastic Leukemia (ALL).
This observational, retrospective study included hospitalized patients diagnosed with ALL of the B-cell lineages. BMI was estimated based on the weight and height registered on clinical records at the admission of the patients. The relapse risk and bone marrow relapse were determined, and the survival rate was measured. The statistical analysis included the Kaplan-Meier method using the log-Rank test.
This study included 128 clinical records of patients. Weight had no significant association with relapse risk. The frequency of bone marrow relapse was 43.8%. Obesity did not impact overall survival (p = 0.640) or disease-free survival (p = 0.527). The presence of obesity does not behave as a relapse risk variable (p = 0.873). BMI with a 30 kg/m2 cut-off point did not influence relapse risk (OR 1.078).
Obesity is not an independent risk factor for the prognosis of adult patients with Acute Lymphoblastic Leukemia B-lineage.
Background: Despite the advances in treating adult Acute Lymphoblastic Leukemia (ALL), relapses are among the most significant challenges to improving the prognosis. One of the tools that can predict ...bone marrow relapse, according to its positivity, is Measurable Residual Disease (MRD). Unfortunately, due to the high cost, access to innovative therapies is limited, so chemotherapy remains the most common treatment option. The combination of Bortezomib with Hyper-CVAD has already shown efficacy in patients with Multiple Myeloma. However, in patients with ALL, it is not yet proven. Material and Methods: A prospective cohort was carried out in patients with ALL who presented an +MRD or relapse and received treatment based on the combination of Bortezomib and Hyper-CVAD in two reference centers in Mexico City. Results: 20 cases with positive MRD were analyzed; 60% (n=12) became negative after the combination, 30% (n=6) persisted with a positive result, and 10% (n=2) passed away. Of the 43 individuals with bone marrow relapse, 43.5% (n=10) achieved a second complete remission (2CR), 34.8% (n=6) were refractory, and 21.7% (n=5) passed away. To integrate a second complete remission, 20% (n=2) achieved it in < 4 cycles, while 50% (n=5) required four cycles of treatment (2 cycles A and two cycles B), and 30% (n=3) required six cycles. Conclusion: The combination of Bortezomib with the increased Hyper-CVAD scheme showed better results in making MRD negative, suggesting that this combination can be incorporated into first-line strategies. Keywords: Bortezomib; Chemotherapy; Acute Lymphoblastic Leukemia; Relapse; Measurable Residual Disease.
Introduction: Even in the tyrosine kinase inhibitors (TKIs) era, there's still a subgroup of patients with chronic myeloid leukemia (CML) with poor response to treatment and therefore worse ...prognosis. The most frequent cause of resistance to treatment is the mutation in ABL fusion protein reported in 15-25% of the failures to TKIs. Nevertheless, there are other several factors not clearly described yet in published data, including myeloid mutations assessed by Next-Generation Sequence (NGS) beyond BCR-ABL kinase domain mutations. Methods: We performed a multicenter, open, prospective trial to identify the frequency and clinical implications of myeloid mutations. We included all patients with relapsed/refractory CML to any TKI defined as failure to achieve cytogenetic response at 3 months or decrease <10% of BCR/ABL at 6 months or progression of CML after any response achieved by TKI. Patients with intolerance or non-adherence to treatment were excluded. For adherence validation, the MMAS-8 test was applied. We calculated a sample of 29 patients. Recruitment began in February 2021 and the sample was completed in August 2022. DNA was extracted from a bone marrow blood in EDTA with the automatized equipment, Maxwell 16 DNA purification Kits. The evaluation of DNA was performed by massive parallel sequencing of 40 genes frequently mutated in myeloid malignancies identifying ABL mutations and simultaneous mutations in other genes. Results: Twenty-nine patients were evaluated in 16 centers from February 2021 to August 2022; seventeen were men. Six patients were diagnosed from 2002 to 2009, seventeen from 2010 to2019 and 6 after 2020. At time of diagnosis, the mean age was 45 years ± 14.8, two were in accelerated phase (AP-CML) and the rest were diagnosed in chronic phase (CP-CML). Sokal score was achievable in 24 cases being low, intermediate and high in 6, 15 and 3 cases respectively. In karyotype, two patients showed minor chromosomal aberrations and another one had complex karyotype. The study was performed at 68.1 months from diagnosis; 9 cases had relapse and the rest didn't achieve molecular responses. All the treatment failures were identified by PCR-BCR/ABL by the exception of two cases that presented blast phase (BP-CML). At recruitment, 23 cases were in CP-CML (2 in its second), 4 cases in AP-CML and 2 in BP-CML. The patients had a mean of 4 previous lines of treatment. The NGS panel showed the next results: Sixteen mutations were found in eleven patients (37.9%). As expected the most frequently mutated gene was ABL in four cases. The mutations involved were G252H, T315I, E255V, Y253H. Nevertheless, there were more patients with mutations in genes other than ABL with seven cases. Three mutations were repeated in two occasions: DNMT3A, ASXL-1 y TP53. The other mutations detected were RUNX1, ATM, PFH6, SF3B1, y WT1. Patients with mutations detected had higher Sokal score compared to non-mutated ones, 0.96 vs 1.05 points, without statistical significance. The only variable that showed statistical value for the presence or absence of mutations was the platelet count at diagnosis (281,200 vs 478,523) Conclusion: This study shows us that there are more mutations associated with therapeutic failure in patients with CML in addition to those in the ABL domain. Knowing these mutations can support the diagnosis, prognosis, establish target therapies and even guide the decision of a bone marrow transplant. Studies with larger populations are required to corroborate the data presented here to generate correlations the clinical and prognostic relevance of myeloid mutations, both at the time of treatment failure and perhaps at diagnosis.
RESUMEN Antecedentes: La obesidad se ha asociado con estado proinflamatorio de bajo grado que se ha relacionado con el desarrollo del cáncer en general incluyendo el hematológico. Objetivos: El ...presente trabajo tiene el objetivo de identificar la asociación del diagnóstico de obesidad acorde al índice de masa corporal (IMC) con indicadores pronóstico de pacientes adultos con Leucemia Linfoblástica Aguda (LAL). Pacientes y Método: Se trata de un estudio observacional, retrospectivo que incluyó pacientes hospitalizados con diagnóstico de LAL de linaje de células B. Se estimó el IMC con base al peso y talla registrado al ingreso de los pacientes. Se determinó el riesgo de recaídas, recaídas a médula ósea y supervivencia. Se utilizó el método de Kaplan-Meier mediante el test log-Rank en el análisis estadístico. Resultados: Se incluyeron 128 pacientes. El peso y el IMC no mostraron una asociación significativa con el riesgo de recaídas. La frecuencia de recaída a médula ósea fue del 43,8%. La obesidad no impactó con la supervivencia global (p = 0,640) ni en la supervivencia libre de enfermedad (p = 0,527). La presencia de obesidad no se comportó como una variable de riesgo de recaída (p = 0,873). El IMC con punto de corte de 30 kg/m2 no se comportó como un factor de riesgo de recaída (OR 1.078). Conclusión: La obesidad no es un factor de riesgo independiente para el pronóstico de los pacientes adultos portadores de Leucemia Linfoblástica Aguda de linaje B.
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