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Total body irradiation (TBI)-based conditioning regimens are generally recommended for allogeneic HSCT (allo-HSCT) in patients with acute lymphoblastic leukemia (ALL). Recent evidence suggests that modern chemotherapy-based regimens may be as effective. This multicenter retrospective study compared the clinical outcomes of myeloablative allo-HSCT with thiotepa, busulfan, and cyclophosphamide/fludarabine (TTB) to TBI-based conditioning. Between 2002 to 2018, 63 and 114 patients received TTB- and TBI-based conditioning regimens, respectively. The 5-year cumulative incidence of relapse was lower in the TBI cohort compared to the TTB cohort (30% [95% CI, 22-38] versus 47% [95% CI, 36-59]; P = 0.03). Multivariate analysis identified T-ALL, Ph-negative B-ALL, and measurable residual disease associated with a higher relapse risk. The 5-year cumulative incidence of non-relapsed mortality (NRM) was significantly lower with TTB (12% [95% CI, 5-20]) compared to TBI (25% [95% CI, 18-33]) (P = 0.001). Multivariate analysis found TBI conditioning, older age, and advanced stages of ALL at transplantation associated with a higher NRM. No statistical difference was seen in overall survival (49% [95% CI, 40-58] and 46% [95% CI, 35-60]) in the TBI and TTB groups, respectively; P = 0.9). The study suggests that TTB-based conditioning may be a promising option for ALL patients undergoing allo-HSCT, as it resulted in similar OS and lower NRM than TBI-based conditioning.
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Busulfano , Trasplante de Células Madre Hematopoyéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Tiotepa , Acondicionamiento Pretrasplante , Irradiación Corporal Total , Humanos , Irradiación Corporal Total/métodos , Acondicionamiento Pretrasplante/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Busulfano/uso terapéutico , Busulfano/administración & dosificación , Adulto , Tiotepa/administración & dosificación , Tiotepa/uso terapéutico , Femenino , Masculino , Trasplante de Células Madre Hematopoyéticas/métodos , Persona de Mediana Edad , Estudios Retrospectivos , Adolescente , Adulto Joven , Trasplante Homólogo/métodosRESUMEN
The introduction of all-trans retinoic acid (ATRA) combined with anthracyclines has significantly improved the outcomes for patients with acute promyelocytic leukemia (APL), and this strategy remains the standard of care in countries where arsenic trioxide is not affordable. However, data from national registries and real-world databases indicate that low- and middle-income countries (LMIC) still face disappointing results, mainly due to high induction mortality and suboptimal management of complications. The American Society of Hematology established the International Consortium on Acute Leukemias (ICAL) to address this challenge through international clinical networking. Here, we present the findings from the ICAPL study involving 806 patients with APL recruited in Brazil, Chile, Paraguay, Peru, and Uruguay. The induction mortality rate has decreased to 14.6% compared to the pre-ICAL rate of 32%. Multivariable logistic regression analysis revealed as factors associated with induction death: age ≥ 40 years, ECOG = 3, high-risk status based on the PETHEMA/GIMEMA classification, albumin level ≤ 3.5 g/dL, bcr3 PML/RARA isoform, the interval between presenting symptoms to diagnosis exceeding 48 hours, and the occurrence of central nervous system and pulmonary bleeding. With a median follow-up of 53 months, the estimated 4-year overall survival (OS) rate is 81%, the 4-year disease-free survival (DFS) rate is 80%, and the 4-year cumulative incidence of relapse (CIR) rate is 15%. These results parallel those observed in studies conducted in high-income countries, highlighting the long-term effectiveness of developing clinical networks to improve clinical care and infrastructure in LMIC.
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This study aimed to investigate the kinetics of immune recovery following umbilical cord blood transplantation (UCBT) in adults who received a myeloablative conditioning (MAC) regimen and antithymocyte globulin (ATG). While the immune recovery kinetics has been extensively studied in pediatric UCBT recipients, limited data exist for adults. We conducted a comprehensive analysis of 221 consecutive adult patients who underwent UCBT with MAC and ATG at a single institution. Our objective was to evaluate the influence of patient, disease, and transplant factors, along with acute graft-versus-host disease (aGVHD), on immune reconstitution and overall survival. Our findings confirm a delayed recovery of T cells, while B and NK cell reconstitution exhibited rapid progress, with NK cell counts reaching normal levels within 3 months post-transplantation and B cells within 6 months. Within CD3+ T cells, CD8+ T cells also experienced a delayed recovery (12 months), but to a lesser extent compared to CD4+ T cells (18 months). Delayed immune recovery of T-cell subsets was associated with the development of aGVHD grade II-IV, older age, CMV negativity, and a female donor. Patients with lymphoproliferative diseases showed slower NK cell recovery. Our study demonstrates that adult patients undergoing MAC with ATG and receiving a single unit UCBT for hematologic malignancies experienced rapid reconstitution of NK and B cells. However, T cell recovery, particularly CD4+ T cells, was significantly delayed. To enhance T cell recovery, it may be crucial to consider UCB units with higher cellularity and optimize ATG doses in conditioning.
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Suero Antilinfocítico , Trasplante de Células Madre de Sangre del Cordón Umbilical , Enfermedad Injerto contra Huésped , Neoplasias Hematológicas , Reconstitución Inmune , Acondicionamiento Pretrasplante , Humanos , Acondicionamiento Pretrasplante/métodos , Femenino , Neoplasias Hematológicas/terapia , Masculino , Adulto , Trasplante de Células Madre de Sangre del Cordón Umbilical/métodos , Suero Antilinfocítico/uso terapéutico , Persona de Mediana Edad , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Anciano , Adulto Joven , Adolescente , Células Asesinas Naturales/inmunología , Agonistas Mieloablativos/uso terapéuticoRESUMEN
The most important challenges in acute promyelocytic leukemia (APL) is preventing early death and reducing long-term events, such as second neoplasms (s-NPLs). We performed a retrospective analysis of 2670 unselected APL patients, treated with PETHEMA "chemotherapy based" and "chemotherapy free" protocols. Only de novo APL patients who achieved complete remission (CR) and completed the three consolidation cycles were enrolled into the analysis. Out of 2670 APL patients, there were 118 (4.4%) who developed s-NPLs with the median latency period (between first CR and diagnosis of s-NPL) of 48.0 months (range 2.8-231.1): 43.3 (range: 2.8-113.9) for s-MDS/AML and 61.7 (range: 7.1-231.1) for solid tumour. The 5-year CI of all s-NPLs was of 4.43% and 10 years of 7.92%. Among s-NPLs, there were 58 cases of s-MDS/AML, 3 cases of other hematological neoplasms, 57 solid tumours and 1 non-identified neoplasm. The most frequent solid tumour was colorectal, lung and breast cancer. Overall, the 2-year OS from diagnosis of s-NPLs was 40.6%, with a median OS of 11.1 months. Multivariate analysis identified age of 35 years (hazard ratio = 0.2584; p < 0.0001) as an independent prognostic factor for s-NPLs. There were no significant differences in CI of s-NPLs at 5 years between chemotherapy-based vs chemotherapy-free regimens (hazard ratio = 1.09; p = 0.932). Larger series with longer follow-up are required to confirm the potential impact of ATO+ATRA regimens to reduce the incidence of s-NPLs after front-line therapy for APL.
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Leucemia Promielocítica Aguda , Neoplasias Primarias Secundarias , Humanos , Adulto , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/tratamiento farmacológico , Leucemia Promielocítica Aguda/epidemiología , Tretinoina , Neoplasias Primarias Secundarias/tratamiento farmacológico , Incidencia , Estudios Retrospectivos , Resultado del Tratamiento , Factores de Riesgo , Respuesta Patológica Completa , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
The incidence of cardiac morbimortality in acute myeloid leukemia (AML) is not well known. We aim to estimate the cumulative incidence (CI) of cardiac events in AML patients and to identify risk factors for their occurrence. Among 571 newly diagnosed AML patients, 26 (4.6%) developed fatal cardiac events, and among 525 treated patients, 19 (3.6%) experienced fatal cardiac events (CI: 2% at 6 months; 6.7% at 9 years). Prior heart disease was associated with the development of fatal cardiac events (hazard ratio (HR) = 6.9). The CI of non-fatal cardiac events was 43.7% at 6 months and 56.9% at 9 years. Age ≥ 65 (HR = 2.2), relevant cardiac antecedents (HR = 1.4), and non-intensive chemotherapy (HR = 1.8) were associated with non-fatal cardiac events. The 9-year CI of grade 1-2 QTcF prolongation was 11.2%, grade 3 was 2.7%, and no patient had grade 4-5 events. The 9-year CI of grade 1-2 cardiac failure was 1.3%, grade 3-4 was 15%, and grade 5 was 2.1%; of grade 1-2, arrhythmia was 1.9%, grade 3-4 was 9.1%, and grade 5 was 1%. Among 285 intensive therapy patients, median overall survival decreased in those experiencing grade 3-4 cardiac events (p < 0.001). We observed a high incidence of cardiac toxicity associated with significant mortality in AML.
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Acute myeloid leukemia (AML) with retinoic acid receptor γ (RARG) rearrangement has clinical, morphologic, and immunophenotypic features similar to classic acute promyelocytic leukemia. However, AML with RARG rearrangement is insensitive to alltrans retinoic acid (ATRA) and arsenic trioxide (ATO) and carries a poor prognosis. We initiated a global cooperative study to define the clinicopathological features, genomic and transcriptomic landscape, and outcomes of AML with RARG rearrangements collected from 29 study groups/institutions worldwide. Thirty-four patients with AML with RARG rearrangements were identified. Bleeding or ecchymosis was present in 18 (54.5%) patients. Morphology diagnosed as M3 and M3v accounted for 73.5% and 26.5% of the cases, respectively. Immunophenotyping showed the following characteristics: positive for CD33, CD13, and MPO but negative for CD38, CD11b, CD34, and HLA-DR. Cytogenetics showed normal karyotype in 38% and t(11;12) in 26% of patients. The partner genes of RARG were diverse and included CPSF6, NUP98, HNRNPc, HNRNPm, PML, and NPM1. WT1- and NRAS/KRAS-mutations were common comutations. None of the 34 patients responded to ATRA and/or ATO. Death within 45 days from diagnosis occurred in 10 patients (â¼29%). At the last follow-up, 23 patients had died, and the estimated 2-year cumulative incidence of relapse, event-free survival, and overall survival were 68.7%, 26.7%, and 33.5%, respectively. Unsupervised hierarchical clustering using RNA sequencing data from 201 patients with AML showed that 81.8% of the RARG fusion samples clustered together, suggesting a new molecular subtype. RARG rearrangement is a novel entity of AML that confers a poor prognosis. This study is registered with the Chinese Clinical Trial Registry (ChiCTR2200055810).
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Leucemia Mieloide Aguda , Leucemia Promielocítica Aguda , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Promielocítica Aguda/genética , Tretinoina , Antígenos HLA-DR , Trióxido de ArsénicoRESUMEN
Bone marrow (BM) is the recommended stem cell source for hematopoietic stem cell transplantation (HSCT) from matched sibling donors (MSDs) in patients with severe aplastic anemia (SAA) for its superior survival and graft-versus-host disease (GVHD) outcomes compared to recipients of unmanipulated peripheral blood (PB) HSCT. Nevertheless, no studies comparing BM with ex vivo T cell-depleted (TCD) PB have been reported to date. The aim of the present study was to compare the transplantation outcomes of MSD HSCT recipients with SAA using PB (with partial ex vivo TCD targeted cell dose grafts) with those of MSD HSCT recipients with SAA using unmanipulated BM. We performed a matched-pair analysis of MSD-HSCT using TCD PB in a single institution with unmanipulated BM MSD-HSCT in the United States between 2013 and 2019 reported to the Center for International Blood and Marrow Transplant Research. We compared 23 recipients of TCD PB HSCT for SAA (cases) and 69 recipients of unmanipulated BM grafts (controls) matched for age, Karnofsky Performance Status, Hematopoietic Cell Transplantation-Specific Comorbidity Index, time from diagnosis to transplantation, and recipient cytomegalovirus serostatus. We found significantly faster neutrophil and platelet recovery in the TCD PB cohort (P < .001 and P = .03, respectively), as well as a lower incidence of grade II-IV acute GVHD (0% versus 17%; P = .05) and similar overall survival (96% versus 97% at 3 years; P = .8). Our study shows that TCD PB can be considered a safe source for MSD-HSCT in patients with SAA, with potential advantages in engraftment and GVHD that could challenge the standard with BM. These findings provide a basis for future research in a prospective controlled clinical trial.
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Anemia Aplásica , Enfermedad Injerto contra Huésped , Humanos , Anemia Aplásica/terapia , Médula Ósea , Estudios Prospectivos , Hermanos , Linfocitos TRESUMEN
Although a growing body of evidence demonstrates that altered mtDNA content (mtDNAc) has clinical implications in several types of solid tumours, its prognostic relevance in acute promyelocytic leukaemia (APL) patients remains largely unknown. Here, we show that patients with higher-than-normal mtDNAc had better outcomes regardless of tumour burden. These results were more evident in patients with low-risk of relapse. The multivariate Cox proportional hazard model demonstrated that high mtDNAc was independently associated with a decreased cumulative incidence of relapse. Altogether, our data highlights the possible role of mitochondrial metabolism in APL patients treated with ATRA.
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Leucemia Promielocítica Aguda , Humanos , Leucemia Promielocítica Aguda/tratamiento farmacológico , Leucemia Promielocítica Aguda/genética , Tretinoina/uso terapéutico , ADN Mitocondrial/genética , Relevancia Clínica , Recurrencia Local de Neoplasia/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resultado del TratamientoRESUMEN
FLT3−ITD results in a poor prognosis in terms of overall survival (OS) and relapse-free survival (RFS) in acute myeloid leukemia (AML). However, the prognostic usefulness of the allelic ratio (AR) to select post-remission therapy remains controversial. Our study focuses on the prognostic impact of FLT3−ITD and its ratio in a series of 2901 adult patients treated intensively in the pre-FLT3 inhibitor era and reported in the PETHEMA registry. A total of 579 of these patients (20%) harbored FLT3−ITD mutations. In multivariate analyses, patients with an FLT3−ITD allele ratio (AR) of >0.5 showed a lower complete remission (CR rate) and OS (HR 1.47, p = 0.009), while AR > 0.8 was associated with poorer RFS (HR 2.1; p < 0.001). Among NPM1/FLT3−ITD-mutated patients, median OS gradually decreased according to FLT3−ITD status and ratio (34.3 months FLT3−ITD-negative, 25.3 months up to 0.25, 14.5 months up to 0.5, and 10 months ≥ 0.5, p < 0.001). Post-remission allogeneic transplant (allo-HSCT) resulted in better OS and RFS as compared to auto-HSCT in NPM1/FLT3−ITD-mutated AML regardless of pre-established AR cutoff (≤0.5 vs. >0.5). Using the maximally selected log-rank statistics, we established an optimal cutoff of FLT3−ITD AR of 0.44 for OS, and 0.8 for RFS. We analyzed the OS and RFS according to FLT3−ITD status in all patients, and we found that the group of FLT3−ITD-positive patients with AR < 0.44 had similar 5-year OS after allo-HSCT or auto-HSCT (52% and 41%, respectively, p = 0.86), but worse RFS after auto-HSCT (p = 0.01). Among patients with FLT3−ITD AR > 0.44, allo-HSCT was superior to auto-HSCT in terms of OS and RFS. This study provides more evidence for a better characterization of patients with AML harboring FLT3−ITD mutations.
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Gemtuzumab ozogamicin (GO) is a conjugate of a monoclonal antibody and calicheamicin, which has been reapproved for the treatment of acute myeloid leukemia (AML). AML patients with the CD33 rs12459419 CC genotype might benefit from the addition of GO to intensive treatment in contrast to patients with CT/TT genotypes. Nevertheless, contradictory results have been reported. We sought to shed light on the prediction of GO response in AML patients with rs12459419 polymorphism who were treated with GO in the consolidation (n = 70) or reinduction (n = 20) phase. The frequency distribution of the rs12459419 polymorphism in the complete cohort of patients was 44.4% (n = 40), 50% (n = 45), and 5.6% (n = 5) for CC, CT, and TT genotypes, respectively. Regarding the patients treated with GO for consolidation, we performed a Kaplan-Meier analysis of overall survival and relapse-free survival according to the rs12459419 polymorphism (CC vs. CT/TT patients) and genetic risk using the European Leukemia Net (ELN) 2010 risk score. We also carried out a Cox regression analysis for the prediction of overall survival, with age and ELN 2010 as covariates. We found no statistical significance in the univariate or multivariate analysis. Additionally, we performed a global Kaplan-Meier analysis for the patients treated with GO for reinduction and did not find significant differences; however, our cohort was too small to draw any conclusion from this analysis. The use of GO in consolidation treatment is included in the approval of the compound; however, evidence regarding its efficacy in this setting is lacking. Rs12459419 polymorphism could help in the selection of patients who might benefit from GO. Regrettably, in our cohort, the rs12459419 polymorphism does not seem to be an adequate tool for the selection of patients who might benefit from the addition of GO in consolidation cycles.
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Aminoglicósidos , Leucemia Mieloide Aguda , Lectina 3 Similar a Ig de Unión al Ácido Siálico , Aminoglicósidos/uso terapéutico , Anticuerpos Monoclonales Humanizados/genética , Gemtuzumab/uso terapéutico , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Polimorfismo de Nucleótido Simple , Lectina 3 Similar a Ig de Unión al Ácido Siálico/genéticaRESUMEN
Infections by multidrug-resistant Enterobacteriaceae (MRE) are life-threatening to patients. The intestinal microbiome protects against MRE colonization, but antibiotics cause collateral damage to commensals and open the way to colonization and subsequent infection. Despite the significance of this problem, the specific commensals and mechanisms that restrict MRE colonization remain largely unknown. Here, by performing a multi-omic prospective study of hospitalized patients combined with mice experiments, we find that Lactobacillus is key, though not sufficient, to restrict MRE gut colonization. Lactobacillus rhamnosus and murinus increase the levels of Clostridiales bacteria, which induces a hostile environment for MRE growth through increased butyrate levels and reduced nutrient sources. This mechanism of colonization resistance, an interaction between Lactobacillus spp. and Clostridiales involving cooperation between microbiota members, is conserved in mice and patients. These results stress the importance of exploiting microbiome interactions for developing effective probiotics that prevent infections in hospitalized patients.
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Enterobacteriaceae , Lactobacillus , Animales , Antibacterianos/farmacología , Butiratos/farmacología , Clostridiales , Ratones , Estudios ProspectivosRESUMEN
This retrospective study investigated outcomes of 404 patients with relapsed/refractory (R/R) FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) acute myeloid leukemia (AML) enrolled in the PETHEMA registry, pre-approval of tyrosine kinase inhibitors. Most patients (63%) had received first-line intensive therapy with 3 + 7. Subsequently, patients received salvage with intensive therapy (n = 261), non-intensive therapy (n = 63) or supportive care only (n = 80). Active salvage therapy (i.e., intensive or non-intensive therapy) resulted in a complete remission (CR) or CR without hematological recovery (CRi) rate of 42%. More patients achieved a CR/CRi with intensive (48%) compared with non-intensive (19%) salvage therapy (p < 0.001). In the overall population, median overall survival (OS) was 5.5 months; 1- and 5-year OS rates were 25% and 7%. OS was significantly (p < 0.001) prolonged with intensive or non-intensive salvage therapy compared with supportive therapy, and in those achieving CR/CRi versus no responders. Of 280 evaluable patients, 61 (22%) had an allogeneic stem-cell transplant after they had achieved CR/CRi. In conclusion, in this large cohort study, salvage treatment approaches for patients with FLT3-ITD mutated R/R AML were heterogeneous. Median OS was poor with both non-intensive and intensive salvage therapy, with best long-term outcomes obtained in patients who achieved CR/CRi and subsequently underwent allogeneic stem-cell transplant.
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The hypomethylating agents, decitabine (DEC) and azacitidine (AZA), allowed more elderly acute myeloid leukemia (AML) patients to be treated. However, there are little direct comparative data on AZA and DEC. This multicenter retrospective study compared the outcomes of AZA and DEC in terms of response and overall survival (OS). Potential predictors associated with response and OS were also evaluated. A total of 626 AML patients were included (487 treated with AZA and 139 with DEC). Response rates were similar in both groups: CR was 18% with AZA vs. 23% with DEC (p = 0.20), CR/CRi was 20.5% vs. 25% (p = 0.27) and ORR was 32% vs. 39.5% (p = 0.12), respectively. Patients with leukocytes < 10 × 109/L, bone marrow blasts < 50% and ECOG ≥ 2 had higher ORR with DEC than with AZA. OS was similar in both groups: 10.4 months (95% CI: 9.2−11.7) vs. 8.8 months (95% CI: 6.7−11.0, p = 0.455), for AZA and DEC, respectively. Age (≥80 years), leukocytes (≥ 10 × 109/L), platelet count (<20 × 109/L) and eGFR (≥45 mL/min/1.73 m2) were associated with higher OS with AZA compared to DEC. In conclusion, we found no differences in response and OS rates in AML patients treated with AZA or DEC.
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BACKGROUND: Information regarding the impact on healthcare systems of secondary acute myeloid leukemia (sAML) is scarce. METHODS: A retrospective review of medical charts identified patients aged 60-75 years with sAML between 2010 and 2019. Patient information was collected from diagnosis to death or last follow-up. Outpatient resource use, reimbursement, frequency and duration of hospitalization, and transfusion burden were assessed. Forty-six patients with a median age of 64 years were included. Anthracycline plus cytarabine regimens were the most common induction treatment (39 patients, 85%). The ratio of the total days hospitalized between the total follow-up was 29%, with a sum of 204 hospitalizations (average four/patient; average duration 21 days). The total average reimbursement was EUR 90,008 per patient, with the majority (EUR 77,827) related to hospital admissions (EUR 17,403/hospitalization). Most hospitalizations (163, mean 22 days) occurred in the period before the first allogeneic hematopoietic stem cell transplant (alloHSCT), costing EUR 59,698 per patient and EUR 15,857 per hospitalization. The period after alloHSCT (in only 10 patients) had 41 hospitalizations (mean 21 days), and a mean reimbursement cost of EUR 99,542 per patient and EUR 24,278 per hospitalization. In conclusion, there is a high consumption of economic and healthcare resources in elderly patients with sAML receiving active treatments in Spain.
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Secondary acute myeloid leukemia (sAML) comprises a heterogeneous group of patients and is associated with poor overall survival (OS). We analyze the characteristics, treatment patterns, and outcomes of adult patients with sAML in the Programa Español de Tratamientos en Hematología (PETHEMA) registry. Overall, 6211 (72.9%) were de novo and 2310 (27.1%) had sAML, divided into myelodysplastic syndrome AML (MDS-AML, 44%), MDS/myeloproliferative AML (MDS/MPN-AML, 10%), MPN-AML (11%), therapy-related AML (t-AML, 25%), and antecedent neoplasia without prior chemotherapy/radiotherapy (neo-AML, 9%). Compared with de novo, patients with sAML were older (median age, 69 years), had more Eastern Cooperative Oncology Group ≥2 (35%) or high-risk cytogenetics (40%), less FMS-like tyrosine kinase 3 internal tandem duplication (11%), and nucleophosmin 1 (NPM1) mutations (21%) and received less intensive chemotherapy regimens (38%) (all P < .001). Median OS was higher for de novo than sAML (10.9 vs 5.6 months; P < .001) and shorter in sAML after hematologic disorder (MDS, MDS/MPN, or MPN) compared with t-AML and neo-AML (5.3 vs 6.1 vs 5.7 months, respectively; P = .04). After intensive chemotherapy, median OS was better among patients with de novo and neo-AML (17.2 and 14.6 months, respectively). No OS differences were observed after hypomethylating agents according to type of AML. sAML was an independent adverse prognostic factor for OS. We confirmed high prevalence and adverse features of sAML and established its independent adverse prognostic value. This trial was registered at www.clinicaltrials.gov as #NCT02607059.
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Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Neoplasias Primarias Secundarias , Adulto , Anciano , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/etiología , Síndromes Mielodisplásicos/terapia , Neoplasias Primarias Secundarias/epidemiología , Neoplasias Primarias Secundarias/etiología , Sistema de Registros , Inducción de RemisiónRESUMEN
In acute myeloid leukemia (AML) internal tandem duplications of the FLT3 gene (FLT3-ITD) are associated with poor prognosis. Retrospectively, we investigated the prognostic and predictive impact of FLT3-ITD insertion site (IS) in 452 patients randomized within the RATIFY trial, which evaluated midostaurin additionally to intensive chemotherapy. Next-generation sequencing identified 908 ITDs, with 643 IS in the juxtamembrane domain (JMD) and 265 IS in the tyrosine kinase domain-1 (TKD1). According to IS, patients were categorized as JMDsole (n = 251, 55%), JMD and TKD1 (JMD/TKD1; n = 117, 26%), and TKD1sole (n = 84, 19%). While clinical variables did not differ among the 3 groups, NPM1 mutation was correlated with JMDsole (P = 0.028). Overall survival (OS) differed significantly, with estimated 4-year OS probabilities of 0.44, 0.50, and 0.30 for JMDsole, JMD/TKD1, and TKD1sole, respectively (P = 0.032). Multivariate (cause-specific) Cox models for OS and cumulative incidence of relapse using allogeneic hematopoietic cell transplantation (HCT) in first complete remission as a time-dependent variable identified TKD1sole as unfavorable and HCT as favorable factors. In addition, Midostaurin exerted a significant benefit only for JMDsole. Our results confirm the distinct molecular heterogeneity of FLT3-ITD and the negative prognostic impact of TKD1 IS in AML that was not overcome by midostaurin.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Leucemia Mieloide Aguda/patología , Mutagénesis Insercional , Secuencias Repetidas en Tándem , Tirosina Quinasa 3 Similar a fms/genética , Terapia Combinada , Femenino , Estudios de Seguimiento , Trasplante de Células Madre Hematopoyéticas , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Trasplante HomólogoRESUMEN
In this article, we discuss the history of acute promyelocytic leukemia (APL) from the pre-therapeutic era, which began after its recognition by Hillestad in 1947 as a nosological entity, to the present day. It is a paradigmatic history that has transformed the "most malignant leukemia form" into the most curable one. The identification of a balanced reciprocal translocation between chromosomes 15 and 17, resulting in fusion between the promyelocytic leukemia gene and the retinoic acid receptor alpha, has been crucial in understanding the mechanisms of leukemogenesis, and responsible for the peculiar response to targeted therapy with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). We review the milestones that marked successive therapeutic advances, beginning with the introduction of the first successful chemotherapy in the early 1970s, followed by a subsequent incorporation of ATRA and ATO in the late 1980s and early 1990s which have revolutionized the treatment of this disease. Over the past two decades, treatment optimization has relied on the combination of ATRA, ATO, and chemotherapy according to risk-adapted approaches, which together with improvements in supportive therapy have paved the way for cure for most patients with APL.
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Irruption of decitabine and azacitidine has led to profound changes in the upfront management of older acute myeloid leukaemia (AML). However, they have not been directly compared in a randomised clinical trial. In addition, there are no studies comparing the optimal treatment schedule of each drug in AML. A systematic review and meta-analysis on the efficacy of decitabine and azacitidine monotherapy in newly diagnosed AML was conducted. Randomised controlled trials and retrospective studies were included. A total of 2743 patients from 23 cohorts were analysed (10 cohorts of azacitidine and 13 of decitabine). Similar response rates were observed for azacitidine (38%, 95% CI: 30-47%) compared to decitabine (40%, 95% CI: 32-48%) (p = 0.825). Overall survival (OS) between azacitidine (10.04 months, 95% CI: 8.36-11.72) and decitabine (8.79 months, 95% CI: 7.62-9.96) was also similar (p = 0.386). Patients treated with azacitidine showed a lower median OS when azacitidine was administered for 5 days (6.28 months, 95% CI: 4.23-8.32) compared to the standard 7-day schedule (10.83 months, 95% CI: 9.07-12.59, p = 0.002). Among patients treated with decitabine, response rates and OS were not significantly different between 5-day and 10-day decitabine regimens. Despite heterogeneity between studies, we found no differences in response rates and OS in AML patients treated with azacitidine or decitabine.