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In the version of this article initially published, a source of funding (Deutsche José Carreras Leukämie-Stiftung e.V. (DJCLS R12/29 to C.K. and I.P.)) was not included in the Acknowledgments section. The correct statement is as follows: "Supported by Deutsche Forschungsgemeinschaft, (SFB900/B8 to C.K. and I.P.; and PR727/4-1 to I.P.), Deutsche José Carreras Leukämie-Stiftung e.V. (DJCLS R12/29 to C.K. and I.P.) and the German Federal Ministry of Education and Research (01EO1302 to C.S.-F., C.K. and I.P.)." The error has been corrected in the HTML and PDF versions of the article.
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To investigate how the human γδ T cell pool is shaped during ontogeny and how it is regenerated after transplantation of hematopoietic stem cells (HSCs), we applied an RNA-based next-generation sequencing approach to monitor the dynamics of the repertoires of γδ T cell antigen receptors (TCRs) before and after transplantation in a prospective cohort study. We found that repertoires of rearranged genes encoding γδ TCRs (TRG and TRD) in the peripheral blood of healthy adults were stable over time. Although a large fraction of human TRG repertoires consisted of public sequences, the TRD repertoires were private. In patients undergoing HSC transplantation, γδ T cells were quickly reconstituted; however, they had profoundly altered TCR repertoires. Notably, the clonal proliferation of individual virus-reactive γδ TCR sequences in patients with reactivation of cytomegalovirus revealed strong evidence for adaptive anti-viral γδ T cell immune responses.
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Evolución Clonal , Infecciones por Citomegalovirus/inmunología , Trasplante de Células Madre Hematopoyéticas , Receptores de Antígenos de Linfocitos T gamma-delta/genética , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Evolución Clonal/genética , Evolución Clonal/inmunología , Infecciones por Citomegalovirus/genética , Infecciones por Citomegalovirus/virología , Reordenamiento Génico de Linfocito T , Supervivencia de Injerto , Humanos , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Trasplante HomólogoRESUMEN
ABSTRACT: Most patients with acute myeloid leukemia (AML) develop refractory/relapsed (R/R) disease even in the presence of novel and targeted therapies. Given the biological complexity of the disease and differences in frontline treatments, there are therapies approved for only subgroups of R/R AML, and enrollment in clinical trials should be first priority. Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative strategy for most patients. Therapeutic approaches, including allogeneic HCT, triggered by the presence of measurable residual disease (MRD), have recently evolved to prevent overt hematologic relapse. Salvage therapy with chemotherapy or targeted therapy is frequently administered before HCT to reduce the leukemic burden. Gilteritinib is approved by the Food and Drug Administration and European Medicines Agency for patients with relapsed FLT3 mutated AML, whereas targeted therapy for relapsed IDH1/2 mutated AML has only FDA approval. Patients who are R/R after azacitidine and venetoclax (AZA/VEN) have a dismal outcome. In this setting, even available targeted therapies show unsatisfactory results. Examples of ongoing developments include menin inhibitors, a targeted therapy for patients with mutated NPM1 or KMT2A rearrangements, antibodies targeting the macrophage immune checkpoint CD47, and triple combinations involving AZA/VEN. The latter cause significant myelosuppressive effects, which make it challenging to find the right schedule and dose.
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Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Humanos , Azacitidina/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/tratamiento farmacológico , Terapia RecuperativaRESUMEN
ABSTRACT: Patients with acute myeloid leukemia (AML) who experience relapse following allogeneic hematopoietic cell transplantation (alloHCT) face unfavorable outcomes regardless of the chosen relapse treatment. Early detection of relapse at the molecular level by measurable residual disease (MRD) assessment enables timely intervention, which may prevent hematological recurrence of the disease. It remains unclear whether molecular MRD assessment can detect MRD before impending relapse and, if so, how long in advance. This study elucidates the molecular architecture and kinetics preceding AML relapse by using error-corrected next-generation sequencing (NGS) in 74 patients with AML relapsing after alloHCT, evaluating 140 samples from peripheral blood collected 0.6 to 14 months before relapse. At least 1 MRD marker became detectable in 10%, 38%, and 64% of patients at 6, 3, and 1 month before relapse, respectively. By translating these proportions into monitoring intervals, 38% of relapses would have been detected through MRD monitoring every 3 months, whereas 64% of relapses would have been detected with monthly intervals. The relapse kinetics after alloHCT are influenced by the functional class of mutations and their stability during molecular progression. Notably, mutations in epigenetic modifier genes exhibited a higher prevalence of MRD positivity and greater stability before relapse, whereas mutations in signaling genes demonstrated a shorter lead time to relapse. Both DTA (DNMT3A, TET2, and ASXL1) and non-DTA mutations displayed similar relapse kinetics during the follow-up period after alloHCT. Our study sets a framework for MRD monitoring after alloHCT by NGS, supporting monthly monitoring from peripheral blood using all variants that are known from diagnosis.
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Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Neoplasia Residual , Trasplante Homólogo , Humanos , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/diagnóstico , Masculino , Persona de Mediana Edad , Femenino , Neoplasia Residual/diagnóstico , Adulto , Anciano , Mutación , Secuenciación de Nucleótidos de Alto Rendimiento , Recurrencia , Adulto Joven , AdolescenteRESUMEN
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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BACKGROUND: Human metapneumovirus (hMPV) epidemiology, clinical characteristics and risk factors for poor outcome after allogeneic stem cell transplantation (allo-HCT) remain a poorly investigated area. METHODS: This retrospective multicenter cohort study examined the epidemiology, clinical characteristics, and risk factors for poor outcomes associated with human metapneumovirus (hMPV) infections in recipients of allo-HCT. RESULTS: We included 428 allo-HCT recipients who developed 438 hMPV infection episodes between January 2012 and January 2019. Most recipients were adults (93%). hMPV infections were diagnosed at a median of 373 days after allo-HCT. The infections were categorized as upper respiratory tract disease (URTD) or lower respiratory tract disease (LRTD), with 60% and 40% of cases, respectively. Patients with hMPV LRTD experienced the infection earlier in the transplant course and had higher rates of lymphopenia, neutropenia, corticosteroid use, and ribavirin therapy. Multivariate analysis identified lymphopenia and corticosteroid use (>30 mg/d) as independent risk factors for LRTD occurrence. The overall mortality at day 30 after hMPV detection was 2% for URTD, 12% for possible LRTD, and 21% for proven LRTD. Lymphopenia was the only independent risk factor associated with day 30 mortality in LRTD cases. CONCLUSIONS: These findings highlight the significance of lymphopenia and corticosteroid use in the development and severity of hMPV infections after allo-HCT, with lymphopenia being a predictor of higher mortality in LRTD cases.
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Trasplante de Células Madre Hematopoyéticas , Linfopenia , Metapneumovirus , Infecciones por Paramyxoviridae , Infecciones del Sistema Respiratorio , Adulto , Humanos , Estudios de Cohortes , Estudios Retrospectivos , Infecciones del Sistema Respiratorio/epidemiología , Infecciones del Sistema Respiratorio/etiología , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Infecciones por Paramyxoviridae/epidemiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Corticoesteroides/uso terapéuticoRESUMEN
The treatment of acute myeloid leukaemia (AML) has changed fundamentally in the last decade with many new targeted therapies entering clinics. Some of the most interesting agents under development are Menin inhibitors which interfere with the interaction of Menin with wild-type (wt) KMT2A or a KMT2A-fusion protein and thereby downregulate the leukaemic gene expression (MEIS1, PBX3, HOX) in NPM1 mutant or KMT2A-rearranged leukaemia. Other HOX and MEIS1 expressing leukaemias may also be sensitive to Menin inhibition. Following the encouraging results as monotherapy in refractory and relapsed AML, the combination of Menin inhibitors with chemotherapeutic agents and other targeted drugs is being investigated clinically.
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Allogeneic haematopoietic cell transplantation (allo-HCT) remains an option for tyrosine kinase inhibitor-resistant chronic myeloid leukaemia (CML) in first chronic phase (CP1) and high-risk patients with advanced disease phases. In this European Society for Blood and Marrow Transplantation (EBMT) registry-based study of 1686 CML patients undergoing first allo-HCT between 2012 and 2019, outcomes were evaluated according to donor type, particularly focusing on mismatched related donors (MMRDs). Median age at allo-HCT was 46 years (IQR 36-55). Disease status was CP1 in 43%, second CP (CP2) or later in 27%, accelerated phase in 12% and blast crisis in 18%. Donor type was matched related (MRD) in 39.2%, MMRD in 8.1%, matched unrelated (MUD) in 40.2%, and mismatched unrelated (MMUD) in 12.6%. In 4 years, overall survival (OS) for MRD, MMRD, MUD and MMUD was 61%, 56%, 63% and 59% (p = 0.21); relapse-free survival (RFS) was 48%, 42%, 52% and 46% (p = 0.03); cumulative incidence of relapse (CIR) was 33%, 37%, 27% and 30% (p = 0.07); non-relapse mortality (NRM) was 19%, 21%, 21% and 24% (p = 0.21); and graft-versus-host disease (GvHD)-free/relapse-free survival (GRFS) was 16%, 18%, 22% and 15% (p = 0.05) respectively. On multivariate analysis, MMRD use associated with longer engraftment times and higher risk of graft failure compared to MRD or MUD. There was no statistical evidence that MMRD use associated with different OS, RFS and incidence of GvHD compared to other donor types.
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Trasplante de Células Madre Hematopoyéticas , Leucemia Mielógena Crónica BCR-ABL Positiva , Humanos , Trasplante de Células Madre Hematopoyéticas/métodos , Persona de Mediana Edad , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Adulto , Masculino , Femenino , Estudios Retrospectivos , Enfermedad Injerto contra Huésped/etiología , Trasplante Homólogo , Sistema de Registros , Donantes de Tejidos , Donante no EmparentadoRESUMEN
Treatment options for relapsed and refractory acute myeloid leukemia patients (R/R AML) are limited. This retrospective cohort study compares safety and efficacy of fludarabine, cytarabine, and idarubicin (FLA-IDA) without or with venetoclax (FLAVIDA) in patients with R/R AML. Thirty-seven and 81 patients received one course FLA-IDA with or without a 7-day course of venetoclax, respectively. The overall response rate (ORR) was significantly higher in FLAVIDA compared to FLAIDA- treated patients (78% vs. 47%; P=0.001), while measurable residual disease was negative at a similar proportion in responding patients (50% vs. 57%), respectively. Eighty-one percent and 79% of patients proceeded to allogeneic hematopoietic cell transplantation or donor lymphocyte infusion after FLAVIDA and FLA-IDA, respectively. Event-free and overall survival were similar in FLAVIDA- and FLA-IDA-treated patients. Refractory patients could be salvaged more successfully after FLA-IDA compared to FLAVIDA pretreatment. Neutrophil and platelet recovery times were similar in the venetoclax and the control group. In conclusion, short-term venetoclax in combination with FLA-IDA represents an effective treatment regimen in R/R AML identifying chemosensitive patients rapidly and inducing measurable residual disease-negative remission in a high proportion of R/R AML patients.
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Idarrubicina , Leucemia Mieloide Aguda , Humanos , Idarrubicina/uso terapéutico , Citarabina , Estudios Retrospectivos , Factor Estimulante de Colonias de Granulocitos , Leucemia Mieloide Aguda/tratamiento farmacológico , Vidarabina , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
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
We report 5 cases of prothrombotic immune thrombocytopenia after exposure to the ChAdOx1 vaccine (AZD1222, Vaxzevria) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients presented 5 to 11 days after first vaccination. The spectrum of clinical manifestations included cerebral venous sinus thrombosis, splanchnic vein thrombosis, arterial cerebral thromboembolism, and thrombotic microangiopathy. All patients had thrombocytopenia and markedly elevated D-dimer. Autoantibodies against platelet factor 4 (PF4) were detected in all patients, although they had never been exposed to heparin. Immunoglobulin from patient sera bound to healthy donor platelets in an AZD1222-dependent manner, suppressed by heparin. Aggregation of healthy donor platelets by patient sera was demonstrated in the presence of buffer or AZD1222 and was also suppressed by heparin. Anticoagulation alone or in combination with eculizumab or intravenous immunoglobulin (IVIG) resolved the pathology in 3 patients. Two patients had thromboembolic events despite anticoagulation at a time when platelets were increasing after IVIG. In summary, an unexpected autoimmune prothrombotic disorder is described after vaccination with AZD1222. It is characterized by thrombocytopenia and anti-PF4 antibodies binding to platelets in AZD1222-dependent manner. Initial clinical experience suggests a risk of unusual and severe thromboembolic events.
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Vacunas contra la COVID-19/efectos adversos , COVID-19/prevención & control , Púrpura Trombocitopénica Idiopática/etiología , Trombosis/etiología , Adulto , Anciano , Autoanticuerpos/inmunología , COVID-19/inmunología , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/uso terapéutico , ChAdOx1 nCoV-19 , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factor Plaquetario 4/inmunología , Púrpura Trombocitopénica Idiopática/inmunología , SARS-CoV-2/inmunología , Trombosis/inmunologíaRESUMEN
Adult patients with relapsed B-cell precursor acute lymphoblastic leukemia (BCP-ALL) have a dismal prognosis. To improve pharmacotherapy, we analyzed induction of apoptosis by venetoclax and inotuzumab ozogamicin in terms of cytotoxicity and mode of action. Flow cytometry-based analyses of mitochondrial outer membrane permeabilization (MOMP) and ataxia telangiectasia mutated activation demonstrate rapid induction of MOMP by venetoclax and DNA damage signaling by inotuzumab ozogamicin, respectively. In primary ALL samples and patient-derived xenograft (PDX) models, venetoclax and inotuzumab ozogamicin cooperated and synergized in combination with dexamethasone in vitro in all tested samples of ALL. In murine PDX models, inotuzumab ozogamicin, but not venetoclax, induced complete remission in a dose-dependent manner but constantly failed to achieve relapse-free survival. In contrast, combination therapy with venetoclax, dexamethasone, and inotuzumab ozogamicin induced long-term leukemia-free survival and treatment-free survival in all 3 ALL-PDX models tested. These data demonstrate synergistic and highly efficient pharmacotherapy in preclinical models that qualify for evaluation in clinical trials.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Daño del ADN , ADN de Neoplasias/efectos de los fármacos , Dexametasona/farmacología , Inotuzumab Ozogamicina/farmacología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Sulfonamidas/farmacología , Adolescente , Adulto , Anciano , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Apoptosis/efectos de los fármacos , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Calicheamicinas/farmacología , Roturas del ADN de Doble Cadena , Dexametasona/administración & dosificación , Sinergismo Farmacológico , Femenino , Humanos , Inotuzumab Ozogamicina/administración & dosificación , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Persona de Mediana Edad , Membranas Mitocondriales/efectos de los fármacos , Recurrencia , Sulfonamidas/administración & dosificación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
In the international randomized phase 3 RATIFY (Randomized AML Trial In FLT3 in patients less than 60 Years old) trial, the multikinase inhibitor midostaurin significantly improved overall and event-free survival in patients 18 to 59 years of age with FLT3-mutated acute myeloid leukemia (AML). However, only 59% of patients in the midostaurin arm achieved protocol-specified complete remission (CR), and almost half of patients achieving CR relapsed. To explore underlying mechanisms of resistance, we studied patterns of clonal evolution in patients with FLT3-internal tandem duplications (ITD)-positive AML who were entered in the RATIFY or German-Austrian Acute Myeloid Leukemia Study Group 16-10 trial and received treatment with midostaurin. To this end, paired samples from 54 patients obtained at time of diagnosis and at time of either relapsed or refractory disease were analyzed using conventional Genescan-based testing for FLT3-ITD and whole exome sequencing. At the time of disease resistance or progression, almost half of the patients (46%) became FLT3-ITD negative but acquired mutations in signaling pathways (eg, MAPK), thereby providing a new proliferative advantage. In cases with FLT3-ITD persistence, the selection of resistant ITD clones was found in 11% as potential drivers of disease. In 32% of cases, no FLT3-ITD mutational change was observed, suggesting either resistance mechanisms bypassing FLT3 inhibition or loss of midostaurin inhibitory activity because of inadequate drug levels. In summary, our study provides novel insights into the clonal evolution and resistance mechanisms of FLT3-ITD-mutated AML under treatment with midostaurin in combination with intensive chemotherapy.
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Evolución Clonal/efectos de los fármacos , Leucemia Mieloide Aguda , Mutación , Estaurosporina/análogos & derivados , Tirosina Quinasa 3 Similar a fms , Adolescente , Adulto , Anciano , Evolución Clonal/genética , Femenino , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Masculino , Persona de Mediana Edad , Estaurosporina/administración & dosificación , Secuencias Repetidas en Tándem , Secuenciación del Exoma , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/metabolismoRESUMEN
Patients with R/M HNSCC treated with palliative first-line therapy at Hannover Medical School between October 2005 and December 2016 have been included to show changes in survival following broad utilization of cetuximab. Treatment periods were defined from 10/2005 to 12/2008 (Period A) and 01/2009 to 12/2016. Overall survival did not improve over time. However, in subgroup analysis cetuximab utilized at any time vs. never showed a significant improve of overall survival (11.3 vs. 6.3 months, HR: 0.55, 95%-CI: 0.4-0.8, p = 0.04). Therefore, this study supports the application of cetuximab in this real-world population.
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Neoplasias de Cabeza y Cuello , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Cetuximab/uso terapéutico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/etiologíaRESUMEN
Survival after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for severe idiopathic aplastic anemia (SAA) has improved in recent years, approaching 75% at 5 years. However, an SAA-adapted composite endpoint, graft-versus-host disease (GvHD) and relapse/rejection-free survival (GRFS), may more accurately assess patient outcomes beyond survival. We analyzed GRFS to identify risk factors and specific causes of GRFS failure. Our retrospective analysis from the Severe Aplastic Anemia Working Party of the European Society for Blood and Marrow Transplantation included 479 patients with idiopathic SAA who underwent allo-HSCT in two conventional situations: i) upfront allo-HSCT from a matched related donor (MRD) (upfront cohort), and ii) allo-HSCT for relapsed or refractory SAA (rel/ref cohort). Relevant events for GRFS calculation included graft failure, grade 3-4 acute GvHD, extensive chronic GvHD, and death. In the upfront cohort (n=209), 5-year GRFS was 77%. Late allo-HSCT (i.e., >6 months after SAA diagnosis) was the main poor prognostic factor, specifically increasing the risk of death as the cause of GRFS failure (hazard ratio [HR]=4.08; 95% confidence interval [CI]: 1.41-11.83; P=0.010). In the rel/ref cohort (n=270), 5-year GRFS was 61%. Age was the main factor significantly increasing the risk of death (HR=1.04; 95% CI: 1.02-1.06; P<0.001), acute GvHD (HR=1.03; 95% CI: 1.00-1.07; P=0.041), and chronic GvHD (HR=1.04; 95% CI: 1.01-1.08; P=0.032) as the cause of GRFS failure. GRFS after upfront MRD allo-HSCT was very good, notably with early allo-HSCT, confirming that younger patients with an MRD should be transplanted immediately. GRFS was worse in cases of salvage allo-HSCT, most notably in older patients, questioning the utility of allo-HSCT earlier in the disease course.
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Anemia Aplásica , Síndrome de Bronquiolitis Obliterante , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Humanos , Anciano , Anemia Aplásica/complicaciones , Estudios Retrospectivos , Supervivencia sin Enfermedad , Enfermedad Injerto contra Huésped/diagnóstico , Enfermedad Injerto contra Huésped/etiología , Trasplante Homólogo/efectos adversos , Trasplante de Células Madre Hematopoyéticas/efectos adversosRESUMEN
The role of autologous-allogeneic tandem stem cell transplantation (alloTSCT) followed by maintenance as upfront treatment for multiple myeloma (MM) is controversial. Between 2008 and 2014 a total of 217 MM patients with a median age of 51 years were included by 20 German centers within an open-label, parallel-group, multi-center clinical trial to compare alloTSCT to auto tandem transplantation TSCT (autoTSCT) followed by a 2-year maintenance therapy with thalidomide (100 mg/d) in both arms with respect to relapse/progression-free survival (PFS) and other relevant outcomes. A total of 178 patients underwent second SCT (allo n = 132 and auto n = 46). PFS at 4 years after the second SCT was 47% (CI: 38-55%) for alloTSCT and 35% (CI: 21-49%) for autoTSCT (p = 0.26). This difference increased to 22% at 8 years (p = 0.10). The cumulative incidences of non-relapse mortality (NRM) and of relapse at 4 years were 13% (CI: 8-20%) and 2% (CI: 0.3-2%) (p = 0.044) and 40% (CI: 33-50%) and 63% (CI: 50-79%) for alloTSCT and autoTSCT (p = 0.04), respectively. The difference for relapse/progression increased to 33% (alloTSCT: 44%, autoTSCT: 77%) at a median follow-up of 82 months (p = 0.002). Four-year OS was 66% (CI: 57-73%) for alloTSCT and 66% (CI: 50-78%) for auto TSCT (p = 0.91) and 8-year OS was 52% and 50% (p = 0.87), respectively. AlloTSCT followed by thalidomide maintenance reduced the rate of recurrence or progression during a follow-up period of up to 10 years but failed to improve PFS significantly.
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Therapeutic donor lymphocyte infusions (tDLI) are used to reinforce the graft-versus-leukemia (GvL) effect in relapse after allogeneic stem cell transplantation (alloSCT). In contrast, the role of prophylactic DLI (proDLI) in preventing leukemia relapse has been less clearly established, although supported by retrospective, case-control, and registry analyses. We report a prospective, monocentric, ten year cohort of patients with high risk acute leukemias (AL) or myelodysplasia (MDS) in whom proDLI were applied beyond day +120 post alloSCT to compensate for lack of GvL.272 consecutive allotransplanted AL or MDS patients in complete remission and off immunosuppression at day +120 were stratified according to the prior appearance of relevant GvHD (acute GvHD °II-IV or extensive chronic GvHD) as a clinical indicator for GvL. Escalating doses of unmodified proDLI were applied to 72/272 patients without prior relevant GvHD. Conversely, 157/272 patients with prior spontaneous GvHD did not receive proDLI, nor did 43/272 patients with contraindications (uncontrolled infections, patient refusal, DLI unavailability).By day 160-landmark analysis (median day of first DLI application), proDLI recipients had significantly higher five-year overall (OS) and disease free survival (DFS) (77% and 67%) than patients with spontaneous GvHD (54% and 53%) or with contraindications (46% and 45%) (p=0.003). Relapse incidence for patients with proDLI (30%) or spontaneous GvHD (29%) was significantly lower than in patients with contraindications (39%; p=0.021). With similar GvHD incidence beyond day +160, non-relapse mortality (NRM) was less with proDLI (5%) than without proDLI (18%; p=0.036).In conclusion, proDLI may be able to compensate for lack of GvL in alloSCT recipients with high risk AL or MDS.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Humanos , Prevención Secundaria , Estudios Retrospectivos , Estudios Prospectivos , Transfusión de Linfocitos/efectos adversos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Leucemia Mieloide Aguda/complicaciones , Síndromes Mielodisplásicos/terapia , Síndromes Mielodisplásicos/complicaciones , Enfermedad Crónica , LinfocitosRESUMEN
Relapse in patients with acute myeloid leukemia (AML) is common and is associated with a dismal prognosis. Treatment options are limited and the understanding of molecular response patterns is still challenging. We analyzed the clonal response patterns of 15 patients with relapsed/refractory AML treated with selinexor in a phase II trial (SAIL). DNA was analyzed at three time points and showed a decline of mutated alleles in FLT3, SF3B1, and TP53 under SAIL treatment. Overall survival (OS) was similar between patients with declining versus persisting clones. We show an interesting long-term course of a patient who relapsed after allogeneic stem cell transplantation (alloHCT) with SF3B1- and SRSF2-mutated AML and received selinexor as maintenance treatment for 4 years. Measurable residual disease (MRD) remained detectable for 2 weeks after donor lymphocyte infusion (DLI) in this patient and then remained negative under selinexor maintenance treatment. Selinexor was tolerated well and was stopped after 4 years of SAIL treatment. We present an exploratory study and identify subclonal patterns of patients treated with selinexor.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Pronóstico , RecurrenciaRESUMEN
Evolution of erythrocyte transfusion-dependent (RBC-TD) anaemia associated with haploinsufficiency of the ribosomal protein subunit S14 gene (RPS14) is a characteristic complication of myelodysplastic syndromes (MDS) with del(5q) [MDS.del(5q)]. Evaluating 39 patients with MDS.del(5q), <5% of anaemia progression was attributable to RPS14-dependent alterations of normoblasts, pro-erythroblasts, or CD34+ CD71+ precursors. Ninety-three percent of anaemia progression and 70% of the absolute decline in peripheral blood Hb value were attributable to disappearance of erythroblastic islands (Ery-Is). Ery-Is loss occurred independently of blast excess, TP53 mutation, additional chromosome aberrations and RPS14-dependent alterations of normoblasts and pro-erythroblasts. It was associated with RPS14-dependent intrinsic (S100A8+ ) and extrinsic [tumour necrosis factor α (TNF-α)-overproduction] alterations of (CD169+ ) marrow macrophages (p < 0.00005). In a mouse model of RPS14 haploinsufficiency, Ery-Is disappeared to a similar degree: approximately 70% of Ery-Is loss was related to RPS14-dependent S100A8 overexpression of marrow macrophages, less than 20% to that of CD71high Ter119- immature precursors, and less than 5% to S100A8/p53 overexpression of normoblasts or pro-erythroblasts. Marked Ery-Is loss predicted reduced efficacy (erythrocyte transfusion independence) of lenalidomide therapy (p = 0.0006). Thus, erythroid hypoplasia, a characteristic complication of MDS.del(5q), seems to result primarily from a macrophage-associated failure of the erythropoietic niche markedly reducing the productive capacity of erythropoiesis as the leading factor in anaemia progression and evolution of RBC-TD in MDS.del(5q).
Asunto(s)
Anemia , Síndromes Mielodisplásicos , Anemia/complicaciones , Animales , Aberraciones Cromosómicas , Deleción Cromosómica , Cromosomas Humanos Par 5/genética , Humanos , Lenalidomida , Macrófagos/metabolismo , Ratones , Síndromes Mielodisplásicos/patología , TalidomidaRESUMEN
Monitoring of measurable residual disease (MRD) provides prognostic information in patients with Nucleophosmin1-mutated (NPM1mut) acute myeloid leukemia (AML) and represents a powerful tool to evaluate treatment effects within clinical trials. We determined NPM1mut transcript levels (TLs) by quantitative reverse-transcription polymerase chain reaction and evaluated the prognostic impact of NPM1mut MRD and the effect of gemtuzumab ozogamicin (GO) on NPM1mut TLs and the cumulative incidence of relapse (CIR) in patients with NPM1mut AML enrolled in the randomized phase 3 AMLSG 09-09 trial. A total of 3733 bone marrow (BM) samples and 3793 peripheral blood (PB) samples from 469 patients were analyzed. NPM1mut TL log10 reduction ≥ 3 and achievement of MRD negativity in BM and PB were significantly associated with a lower CIR rate, after 2 treatment cycles and at end of treatment (EOT). In multivariate analyses, MRD positivity was consistently revealed to be a poor prognostic factor in BM and PB. With regard to treatment effect, the median NPM1mut TLs were significantly lower in the GO-Arm across all treatment cycles, resulting in a significantly greater proportion of patients achieving MRD negativity at EOT (56% vs 41%; P = .01). The better reduction in NPM1mut TLs after 2 treatment cycles in MRD positive patients by the addition of GO led to a significantly lower CIR rate (4-year CIR, 29.3% vs 45.7%, P = .009). In conclusion, the addition of GO to intensive chemotherapy in NPM1mut AML resulted in a significantly better reduction in NPM1mut TLs across all treatment cycles, leading to a significantly lower relapse rate.