RESUMEN
Venetoclax + hypomethylating agent (Ven-HMA) is currently the standard frontline therapy for older/unfit patients with newly diagnosed acute myeloid leukemia (ND-AML). Our objective in the current retrospective study of 301 adult patients (median age 73 years; 62% de novo) with ND-AML was to identify molecular predictors of treatment response to Ven-HMA and survival; European LeukemiaNet (ELN) genetic risk assignment was favorable 15%, intermediate 16%, and adverse 69%. Complete remission, with (CR) or without (CRi), count recovery, was documented in 182 (60%) patients. In multivariable analysis, inclusive of mutations only, "favorable" predictors of CR/CRi were NPM1 (86% vs. 56%), IDH2 (80% vs. 58%), and DDX41 (100% vs. 58%) and "unfavorable" TP53 (40% vs. 67%), FLT3-ITD (36% vs. 63%), and RUNX1 (44% vs. 64%) mutations; significance was sustained for each mutation after adjustment for age, karyotype, and therapy-related qualification. CR/CRi rates ranged from 36%, in the presence of unfavorable and absence of favorable mutation, to 91%, in the presence of favorable and absence of unfavorable mutation. At median follow-up of 8.5 months, 174 deaths and 41 allogeneic stem cell transplants (ASCT) were recorded. In multivariable analysis, risk factors for inferior survival included failure to achieve CR/CRi (HR 3.4, 95% CI 2.5-4.8), adverse karyotype (1.6, 1.1-2.6), TP53 mutation (1.6, 1.0-2.4), and absence of IDH2 mutation (2.2, 1.0-4.7); these risk factors were subsequently applied to construct an HR-weighted risk model that performed better than the ELN genetic risk model (AIC 1661 vs. 1750): low (n = 130; median survival 28.9 months), intermediate (n = 105; median 9.6 months), and high (n = 66; median 3.1 months; p < .001); survival in each risk category was significantly upgraded by ASCT. The current study identifies genotype signatures for predicting response and proposes a 3-tiered, CR/CRi-based, and genetics-enhanced survival model for AML patients receiving upfront therapy with Ven-HMA.
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Compuestos Bicíclicos Heterocíclicos con Puentes , Leucemia Mieloide Aguda , Sulfonamidas , Adulto , Humanos , Anciano , Supervivencia sin Enfermedad , Estudios Retrospectivos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Genotipo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
Overall survival and response rates of 270 patients with newly diagnosed acute myeloid leukemia receiving venetoclax (Ven) plus hypomethylating agent, stratified by Ven dosing schedule (Cycle 1 Ven 14 vs. 21 vs. 28 days).
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Compuestos Bicíclicos Heterocíclicos con Puentes , Leucemia Mieloide Aguda , Humanos , Compuestos Bicíclicos Heterocíclicos con Puentes/efectos adversos , Sulfonamidas/efectos adversos , Leucemia Mieloide Aguda/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
BACKGROUND: Myeloid neoplasms (myelodysplastic syndrome [MDS], myelofibrosis, and chronic myelomonocytic [CMML]) are aggressive hematological malignancies for which, despite recent approvals, novel therapies are needed to improve clinical outcomes. The hedgehog (HH) pathway is one of the main pathways for cancer stem cells survival and several HH inhibitors (HHi) are approved in clinical practice. METHODS: Sonidegib (SON), an oral HHi, was tested in this phase 1/1b trial in combination with azacitidine (AZA, 75 mg/m2 days ×7) in patients with newly diagnosed and relapsed/refractory (r/r) chronic MN or acute myeloid leukemia (AML). RESULTS: Sixty-two patients (28 [45%] newly diagnosed) were treated in this study, including 10 patients in the dose-finding component and 52 patients in phase 1b. SON 200 mg oral daily on days 1-28 each cycle was deemed the recommended dose for phase 1b. Out of 21 rrAML patients, two achieved response (one complete response/one morphologic leukemia-free state) with no responses seen in seven r/r MDS/CMML patients. In newly diagnosed AML/MDS, response was seen in six (three had complete remission, two had morphological leukemia-free status) of 27 patients. Median overall survival was 26.4 and 4.7 months for newly diagnosed MDS and AML, respectively. Safety was satisfactory with common (>20%) side effects including fatigue, constipation, nausea, cough, insomnia, and diarrhea. Only 7% of patients died in the study, and none of the deaths were deemed related to treatment. CONCLUSIONS: Our study shows that AZA + SON are a safe combination in a patient with MN. Similar to other hedgehog inhibitors, this combination yielded limited response rate in patients with myeloid neoplasms.
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Protocolos de Quimioterapia Combinada Antineoplásica , Leucemia Mieloide Aguda , Leucemia Mielomonocítica Crónica , Síndromes Mielodisplásicos , Trastornos Mieloproliferativos , Humanos , Azacitidina/uso terapéutico , Proteínas Hedgehog , Leucemia Mielomonocítica Crónica/tratamiento farmacológico , Leucemia Mielomonocítica Crónica/patología , Resultado del Tratamiento , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
Somatic mosaic states in telomere biology disorders are characterized by somatic variants in the spliceosome and DNA damage response and repair pathways. A likely maladaptive response to short telomeres that may lead to increased hematological cancer.
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Telomerasa , Telómero , Humanos , Factor de Empalme U2AF/genética , Telómero/genética , Telómero/metabolismo , Biología , Telomerasa/genética , Telomerasa/metabolismoRESUMEN
We report a comparative analysis of patients with therapy-related acute lymphoblastic leukaemia (tr-ALL) vs de novo ALL. We identified 331 patients with B-ALL; 69 (21%) were classified as tr-ALL. The most common prior malignancies were breast (23·2%) and plasma cell disorders (20·3%). Patients with tr-ALL were older (median 63·2 vs. 46·2 years, P < 0.001), more often female (66·7% vs. 43·5%, P < 0·001), and more likely to have hypodiploid cytogenetics (18·8% vs. 5·0%, P < 0·001). In multivariable analysis, patients with tr-ALL were less likely to achieve complete remission [odds ratio (OR) = 0·16, P < 0·001] and more likely to be minimal residual disease-positive (OR = 4·86, P = 0·01) but had similar OS after diagnosis and allo-haematopoietic cell transplantation.
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Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Persona de Mediana Edad , Adulto JovenRESUMEN
Gilteritinib is approved for the treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML) with an FLT3-mutation (FLT3mut+ ). However, the gilteritinib phase 3 ADMIRAL study (Perl et al NEJM 2019) was conducted prior to widespread adoption of either midostaurin as a component of standard intensive induction and consolidation or posttransplant FLT3 inhibitor maintenance. We performed a retrospective analysis using data from 11 US centers and where we identified 113 patients who received gilteritinib alone or as combination therapy for the treatment of R/R FLT3mut+ AML. The composite complete remission (CR) rate (CRc, defined as CR + CRi + CR with incomplete platelet recovery [CRp]) was 48.7% (n = 55). The CRc rate after treatment with gilteritinib in patients who were treated with only prior 7+3 and midostaurin with or without consolidation was 58% with a median survival of 7.8 months. Survival was longest in patients who obtained a CR, particularly a cMRD (clinical minimal or measurable residual disease) negative response; this remained significant after censoring at the time of stem cell transplant. The mitogen-activated protein kinase pathway activating mutations that are known for gilteritinib resistance (NRAS, KRAS, and PTPN11) had lower CRc (35% vs. 60.5%) and lower median overall survival than patients' whose leukemia did not express these mutations (4.9 months vs. 7.8 months) (HR 2.4; 95% CI 1. 5.4) p value <.01.
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Compuestos de Anilina/administración & dosificación , Leucemia Mieloide Aguda , Mutación , Pirazinas/administración & dosificación , Estaurosporina/análogos & derivados , Tirosina Quinasa 3 Similar a fms , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/enzimología , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Recurrencia , Estudios Retrospectivos , Estaurosporina/administración & dosificación , Tasa de Supervivencia , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Tirosina Quinasa 3 Similar a fms/genéticaRESUMEN
We set out to assess feasibility and safety of allogeneic hematopoietic cell transplant in 17 persons with HIV in a phase II prospective multicenter trial. The primary endpoint was 100-day nonrelapse mortality (NRM). Patients had an 8/8 HLA-matched related or at least a 7/8 HLA-matched unrelated donor. Indications for transplant were acute leukemia, myelodysplasia, and lymphoma. Conditioning was myeloablative or reduced intensity. There was no NRM at 100 days. The cumulative incidence of grades II to IV acute graft-versus-host disease (GVHD) was 41%. At 1 year, overall survival was 59%; deaths were from relapsed/progressive disease (nâ¯=â¯5), acute GVHD (nâ¯=â¯1), adult respiratory distress syndrome (nâ¯=â¯1), and liver failure (nâ¯=â¯1). In patients who achieved complete chimerism, cell-associated HIV DNA and inducible infectious virus in the blood were not detectable. Blood and Marrow Transplant Clinical Trials Network 0903/AIDS Malignancy Consortium 080 was registered at www.clinicaltrials.gov (no. NCT01410344).
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Infecciones por VIH/terapia , VIH-1 , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas , Acondicionamiento Pretrasplante , Adulto , Aloinjertos , Femenino , Enfermedad Injerto contra Huésped/sangre , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/prevención & control , Infecciones por VIH/sangre , Infecciones por VIH/mortalidad , Neoplasias Hematológicas/sangre , Neoplasias Hematológicas/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Síndrome de Dificultad Respiratoria/sangre , Síndrome de Dificultad Respiratoria/etiología , Síndrome de Dificultad Respiratoria/mortalidad , Síndrome de Dificultad Respiratoria/prevención & controlRESUMEN
Although allogeneic hematopoietic cell transplantation (HCT) is an expensive treatment for hematological disorders, little is known about the financial consequences for the patients who undergo this procedure. We analyzed factors associated with its financial burden and its impact on health behaviors of allogeneic HCT recipients. A questionnaire was retrospectively mailed to 482 patients who underwent allogeneic HCT from January 2006 to June 2012 at the Mayo Clinic, to collect information regarding current financial concerns, household income, employment, insurance, out-of-pocket expenses, and health and functional status. A multivariable logistic regression analysis identified factors associated with financial burden and treatment nonadherence. Of the 268 respondents (56% response rate), 73% reported that their sickness had hurt them financially. All patients for whom the insurance information was available (missing, n = 13) were insured. Forty-seven percent of respondents experienced financial burden, such as household income decreased by >50%, selling/mortgaging home, or withdrawing money from retirement accounts. Three percent declared bankruptcy. Younger age and poor current mental and physical functioning increased the likelihood of financial burden. Thirty-five percent of patients reported deleterious health behaviors because of financial constraints. These patients were likely to be younger, have lower education, and with a longer time since HCT. Being employed decreased the likelihood of experiencing financial burden and treatment nonadherence due to concern about costs. A significant proportion of allogeneic HCT survivors experience financial hardship despite insurance coverage. Future research should investigate potential interventions to help at-risk patients and prevent adverse financial outcomes after this life-saving procedure.
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Trasplante de Células Madre Hematopoyéticas/economía , Acondicionamiento Pretrasplante/economía , Trasplante Homólogo/economía , Adolescente , Adulto , Anciano , Femenino , Humanos , Cobertura del Seguro , Masculino , Persona de Mediana Edad , Calidad de Vida , Encuestas y Cuestionarios , Adulto JovenRESUMEN
Novel combinations targeting new molecular vulnerabilities are needed to improve the outcome of patients with acute myeloid leukemia. We recently identified WEE1 kinase as a novel target in leukemias. To identify genes that are synthetically lethal with WEE1 inhibition, we performed a short interfering RNA screen directed against cell cycle and DNA repair genes during concurrent treatment with the WEE1 inhibitor MK1775. CHK1 and ATR, genes encoding two replication checkpoint kinases, were among the genes whose silencing enhanced the effects of WEE1 inhibition most, whereas CDK2 short interfering RNA antagonized MK1775 effects. Building on this observation, we examined the impact of combining MK1775 with selective small molecule inhibitors of CHK1, ATR and cyclin-dependent kinases. The CHK1 inhibitor MK8776 sensitized acute myeloid leukemia cell lines and primary leukemia specimens to MK1775 ex vivo, whereas smaller effects were observed with the MK1775/MK8776 combination in normal myeloid progenitors. The ATR inhibitor VE-821 likewise enhanced the antiproliferative effects of MK1775, whereas the cyclin-dependent kinase inhibitor roscovitine antagonized MK1775. Further studies showed that MK8776 enhanced MK1775-mediated activation of the ATR/CHK1 pathway in acute leukemia cell lines and ex vivo. These results indicate that combined cell cycle checkpoint interference with MK1775/MK8776 warrants further investigation as a potential treatment for acute myeloid leukemia.
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Proteínas de Ciclo Celular/genética , Leucemia Mieloide Aguda/genética , Proteínas Nucleares/genética , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/genética , Proteínas Tirosina Quinasas/genética , Apoptosis/efectos de los fármacos , Apoptosis/genética , Proteínas de la Ataxia Telangiectasia Mutada/antagonistas & inhibidores , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1) , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Perfilación de la Expresión Génica , Silenciador del Gen , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/metabolismo , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Quinasas/metabolismo , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/metabolismo , Pirazoles/farmacología , Pirimidinas/farmacología , Pirimidinonas , Interferencia de ARN , ARN Interferente Pequeño/genética , Transducción de Señal , Ensayo de Tumor de Célula MadreRESUMEN
CONTEXT.: Unlike B-cell acute lymphoblastic leukemia/lymphoma (ALL/LBL), there have been few therapeutic advances in T-cell ALL (T-ALL)/LBL, an aggressive ALL/LBL subtype. OBJECTIVE.: To perform a focused tissue array study to elucidate tumor markers of therapeutic potential in T-ALL/LBL. DESIGN.: Using immunohistochemistry, we evaluated expression of leukemic antigens of interest, specifically CC-chemokine receptor 4 (CCR4), among others, on available remnant diagnostic material, including tumor tissue slides obtained from formalin-fixed, paraffin-embedded preserved tissues. RESULTS.: Our analysis identified, for the first time, expression of CCR4 in T-ALL/LBL in 11 of 27 cases (40.7%) and confirmed common expression of BCL2, CD38, and CD47, as reported previously. We also identified the expression of CD123 in 4 of 26 cases (15.4%), whereas BCL6 and PDL1 were expressed in a small number of T-ALL/LBL cases. The potential novel target CCR4 was significantly more common in the Pre/Pro-T immunophenotypic subtype, 6 of 9 (66.7%, P = .01). No additional differences in clinical and epidemiologic variables were noted among positive or negative CCR4 cases. CONCLUSIONS.: These findings support preclinical and clinical testing of therapies targeting CCR4, CD47, BCL2, CD38, and CD123 in T-ALL/LBL, and may help guide the development of targeted clinical trials in T-ALL/LBL, a rare disease in urgent need of novel therapies.
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Linfoma de Células B , Linfoma , Leucemia-Linfoma Linfoblástico de Células Precursoras , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Adulto , Humanos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Antígeno CD47 , Receptores CCR4 , Subunidad alfa del Receptor de Interleucina-3 , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Linfocitos T/patología , Proteínas Proto-Oncogénicas c-bcl-2RESUMEN
BACKGROUND: Post-transplant cyclophosphamide (PT-Cy) is becoming the standard of care for preventing graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplant (alloHCT). Cyclophosphamide is associated with endothelial injury. We hypothesized that the endothelial activation and stress index (EASIX) score, being a marker of endothelial dysfunction, will predict non-relapse mortality (NRM) in alloHCT patients receiving PT-Cy for GVHD prophylaxis. OBJECTIVE: We evaluate the prognostic ability of the HCT-CI and EASIX scores, and report other factors influencing survival, in patients with hematologic malignancies undergoing alloHCT and receiving PT-Cy based GVHD prophylaxis. STUDY DESIGN: Adult patients with hematologic malignancies who underwent alloHCT and received PT-Cy for GVHD prophylaxis at the three Mayo Clinic locations were included in this study. We retrospectively reviewed the Mayo Clinic database and the available electronic medical records to determine the patient, disease and transplant characteristics. An HCT-CI score of ≥3 was considered high. The EASIX score was calculated from labs available between day -28 (of alloHCT) to the day of starting conditioning and analyzed on log2 transformed values. A log2-EASIX score ≥ 2.32 was considered high. The cumulative incidence of NRM was determined using competing risk analysis, with relapse considered as competing risk. Overall survival (OS) from transplant was determined using Kaplan-Meier and log-rank methods. Cox-proportional hazard method was used to evaluate factors impacting survival. RESULTS: A total of 199 patients were evaluated. Patients with a high log2-EASIX score had a significantly higher cumulative incidence of NRM at 1 years after alloHCT (34.5% vs. 12.3%, Pâ¯=â¯0.003). Competing risk analysis showed that a high log2-EASIX score (HR 2.92, 95% CI 1.38 - 6.17, Pâ¯=â¯0.005) and pre-alloHCT hypertension (HR 2.15, 95% CI 1.06 - 4.36, Pâ¯=â¯0.034) were independently predictive of 1 year-NRM. Accordingly, we combined the two factors to develop a composite risk model stratifying patients in low, intermediate, and high-risk groups: 111 (55.8%) patients were considered low-risk, 76 (38.2%) were intermediate and 12 (6%) were high-risk. Compared to patients in the low-risk group, the intermediate (HR 2.38, 95% CI 1.31 - 4.33, Pâ¯=â¯0.005) and high risk (HR 5.77, 95% CI 2.31 - 14.39, P < 0.001) groups were associated with a significantly inferior 1-year OS. Multiorgan failure (MOF) was among the common causes of NRM (14/32, 43.8%) particularly among patients with prior pulmonary comorbidities [7 (50%) patients]. CONCLUSION: Our study shows that EASIX score is predictive of survival after PT-Cy. The novel EASIX-HTN composite risk model may stratify patients prior to transplant. MOF is a common cause of NRM in patients receiving PT-Cy, particularly among patients with pulmonary comorbidities.
RESUMEN
Although reduced-intensity conditioning has become standard of care for patients with hematologic malignancies undergoing allogeneic hematopoietic cell transplantation (HCT), the optimum regimen has yet to be defined, and may depend on pretransplantation patient- and/or disease-specific risk factors. We report here results in 100 adults, ages 18 to 69, with high-risk hematologic malignancy who received conditioning with fludarabine, carmustine, melphalan, and rabbit antithymocyte globulin (FBM-A). Outcomes were stratified using the disease risk index (DRI) as published by Armand et al. (Blood 2012;120:905-913). Median age was 56, and patients were ineligible for standard myeloablative conditioning because of age, organ dysfunction, or prior autologous HCT. Patients underwent transplantation for myeloid (acute myelogenous leukemia, n = 40; myelodysplastic syndrome, n = 24; myelofibrosis, n = 13; other myeloid, n = 2) or lymphoid (acute lymphoblastic leukemia, n = 8; non-Hodgkin lymphoma, n = 8; Hodgkin lymphoma, n = 4, chronic lymphocytic leukemia, n = 1) malignancy. Donors were related in 26 patients (22 matched, 4 mismatched at 1 antigen) and unrelated in 74 (mismatched at 1 or 2 HLA loci in 33); grafts were peripheral blood stem cells in 97 patients, bone marrow in 2, and double cord in 1. According to the DRI, 68 patients were classified as low (n = 1) or intermediate risk (n = 67), and 32 were classified as high (n = 28) or very high risk (n = 4). With a median follow-up of surviving patients of 18 months, the Kaplan-Meier estimate of overall survival at 2 years for patients in the low/intermediate risk group is 80%, compared with 66% in the high/very high group (P = .11). Two-year cumulative incidence of relapse and nonrelapse mortality in the low/intermediate group are 9.9% and 15%, versus 25% and 19% in the high/very high group (respective P values .07 and .81). The cumulative incidence of acute graft-versus-host (GVHD) grades III to IV at 100 days was 8.1%, and the incidence of National Institutes of Health-defined moderate to severe chronic GVHD was 22% at 2 years. No deaths were attributable to chronic GVHD. Survival was not influenced by age, hematopoietic comorbidity index score, donor type, donor gender, or presence of mismatch. We conclude that FBM-A is an effective and safe conditioning regimen for adults up to age 69 with hematologic malignancies who have low-, intermediate-, or high-risk scores according to the DRI.
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Suero Antilinfocítico/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Melfalán/uso terapéutico , Acondicionamiento Pretrasplante/métodos , Adulto , Factores de Edad , Anciano , Suero Antilinfocítico/administración & dosificación , Suero Antilinfocítico/inmunología , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carmustina/administración & dosificación , Femenino , Neoplasias Hematológicas/tratamiento farmacológico , Neoplasias Hematológicas/cirugía , Humanos , Masculino , Melfalán/administración & dosificación , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Análisis de Supervivencia , Quimera por Trasplante , Trasplante Homólogo , Resultado del Tratamiento , Vidarabina/administración & dosificación , Vidarabina/análogos & derivados , Adulto JovenRESUMEN
Systemic oxalosis is a condition in which calcium oxalate crystals deposit into various bodily tissues. Although this may occur as the result of a rare primary syndrome in which an error of glyoxylate metabolism causes an overproduction of oxalate, it is more often seen as a secondary process characterized by increased enteric oxalate absorption. Here, we describe a patient with short bowel syndrome on long-term parenteral nutrition support who developed a unique manifestation of systemic oxalosis, leading to deposition of oxalate crystals within the bone marrow contributing to pancytopenia. In this report, in addition to reviewing the literature on this presumably rare manifestation of oxalosis, we also discuss its pathogenesis in the setting of short bowel syndrome and its management, including prevention.
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Hiperoxaluria , Pancitopenia , Síndrome del Intestino Corto , Humanos , Pancitopenia/complicaciones , Pancitopenia/patología , Médula Ósea , Síndrome del Intestino Corto/complicaciones , Síndrome del Intestino Corto/terapia , Síndrome del Intestino Corto/metabolismo , Hiperoxaluria/complicaciones , Hiperoxaluria/terapia , Oxalatos/metabolismoRESUMEN
Allogeneic stem cell transplantation (alloSCT) is the only known curative treatment for myelofibrosis (MF). Risk assessment remains important for patient counseling and predicting survival outcomes for relapse and nonrelapse mortality (NRM). Outcome-prediction tools can guide decision-making. Their use in MF has relied on their extrapolation from other malignancies. The primary objective of this study was to assess the performance of the Hematopoietic cell Transplantation Comorbidity Index (HCT-CI), the augmented HCT-CI (aHCT-CI), and the Endothelial Activation and Stress Index (EASIX) in predicting NRM in patients with MF undergoing alloSCT. We retrospectively reviewed patients with MF undergoing alloSCT between 2012 and 2020 at the Mayo Clinic. Data were abstracted from the electronic medical record. EASIX score was calculated before starting conditioning therapy and analyzed based on log2- transformed values. We evaluated the log2-EASIX scores by quartiles to assess the effect of increasing values on NRM. NRM was evaluated using competing risk analyses. We used the Kaplan-Meier and log-rank methods to evaluate OS. The Fine-Gray model was used to determine risk factors for NRM. The performance of HCT-CI and aHCT-CI was compared by evaluation of model concordance given the high correlation between HCT-CI and aHCT-CI (r = .75). A total of 87 patients were evaluated. The median duration of follow-up after alloSCT was 5 years (95% confidence interval [CI], 4.4 to 6.31 years). Patients with a high HCT-CI score had significantly increased cumulative incidence of NRM at 3 years (35.5% versus 11.6%; P = .011) after alloSCT. A progressively increasing 3-year NRM was observed with increasing aHCT-CI risk category, and patients with a high or very high aHCT-CI score had significantly higher 3-year NRM compared to those with intermediate-risk or low-risk aHCT-CI scores at 3 years post-alloSCT (31.9% versus 6.52%; P = .004). An increasing log2-EASIX score quartile was not associated with 3-year NRM (19.0% versus 10.1% versus 25% versus 14.3%; P = .59), and the EASIX score was not found to be a predictor of post-transplantation NRM. A high HCT-CI was associated with significantly worse 3-year overall survival (OS) (hazard ratio [HR], 4.41; 95% CI, 1.97 to 9.87; P < .001). A high or very high aHCT-CI was significantly associated with poor 3-year OS (HR, 3.99; 95% CI, 1.56 to 10.22; P = .004). An increasing log2-EASIX score quartile group was not associated with 3-year OS (3-year OS rate, 66.7% versus 80.4% versus 64.6% versus 76.2%; P = .57). The EASIX score should not be used routinely in patients with MF. Both the HCT-CI and the aHCT-CI are accurate in predicting long-term survival outcomes in this patient population. Further studies are important to validate our findings of the role of EASIX in predicting NRM in patients with MF or other myeloproliferative neoplasms undergoing alloSCT. © 2023 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
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Trasplante de Células Madre Hematopoyéticas , Mielofibrosis Primaria , Humanos , Estados Unidos , Estudios Retrospectivos , Mielofibrosis Primaria/terapia , Mielofibrosis Primaria/etiología , Trasplante Homólogo , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Factores de RiesgoAsunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Mutación , Médicos , Inhibidores de Proteínas Quinasas/uso terapéutico , Encuestas y Cuestionarios , Dasatinib/uso terapéutico , Femenino , Humanos , Mesilato de Imatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/enzimología , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Masculino , Pirimidinas/uso terapéuticoRESUMEN
DDX41 mutations (germline and somatic) are associated with late onset myelodysplastic syndromes/acute myeloid leukemia (MDS/AML). Myeloid neoplasms (MN) with germline predisposition was identified as a distinct category in the 2016 WHO classification revision, including MN with germline DDX41 mutation. We retrospectively analyzed the molecular findings and clinical characteristics of thirty-three DDX41-mutated (mDDX41) patients at our institution. We identified 14 distinct pathogenic DDX41 variants in 32 patients and 8 DDX41 variants of unknown significance (VUS) in 9 patients. Five (16%) patients had a second DDX41 somatic mutation p.R525H and 13 (40%) had at least one additional oncogenic co-mutation in other genes. The median age at the time of diagnosis was 66 years, with male predominance (72%) and the majority of patients had normal cytogenetics (91%). Two-year overall survival (OS) was 86% and 6 (21%) MDS/AML patients with relatively preserved hematopoietic function were observed without further intervention. In comparison to AML patients with prognostically more favorable subtypes [t(8;21), n=27 and inv(16), n=40], mDDX41 patients in our cohort showed similarly favorable OS. Our study highlights that mDDX41-MN patients often have an indolent course and mDDX41-AML has comparable OS to favorable-risk AML.
Asunto(s)
Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Trastornos Mieloproliferativos , ARN Helicasas DEAD-box/genética , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Masculino , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/patología , Trastornos Mieloproliferativos/genética , Estudios RetrospectivosRESUMEN
Vitamin D (VD) deficiency can cause osteomalacia, bone pain, muscle weakness, fatigue, and increased risk of fracture, and may precipitate or exacerbate osteopenia and osteoporosis. Patients receiving treatment for acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) may have limited exposure to sunlight and often experience gastrointestinal side effects that may decrease their ability to maintain an adequate VD level. We hypothesized that patients with AML and ALL would have a low VD level after allogeneic hematopoietic cell transplant (HCT), and that these patients would have a high incidence of osteoporosis/osteopenia. We therefore studied the incidence of low VD level and low bone mineral density after HCT. Of 289 patients with AML or ALL undergoing HCT between January 1, 2000, and January 31, 2009, at the Cleveland Clinic, 58 (20.1%) patients had VD testing after HCT. Of these, 52 (89.7%) patients had a low VD level, and 6 (10.3%) had a normal level. Most patients with VD testing had graft-versus-host disease (GVHD) and were taking corticosteroids (94.8% and 98.3%, respectively). Of the 49 patients with VD testing who also had bone mineral density testing, 65% had abnormal (low bone density) results. Only 21% of patients with VD testing were taking VD supplements prior to testing, and 65% had an elevated parathyroid hormone level. We found that most patients did not have VD testing after HCT, but those that did were very likely to have a low level and have low bone mineral density. Those with a low VD level were likely to have received corticosteroids, have GVHD, and have an elevated parathyroid hormone (PTH) level. Given the potential morbidity of low VD level, VD deficiency should be considered after HCT. Prospective study of VD level and its impact on morbidity and mortality after HCT is warranted.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/sangre , Complicaciones Posoperatorias/etiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Deficiencia de Vitamina D/etiología , Vitamina D/sangre , Adolescente , Corticoesteroides/efectos adversos , Corticoesteroides/uso terapéutico , Adulto , Anciano , Densidad Ósea , Enfermedades Óseas Metabólicas/epidemiología , Enfermedades Óseas Metabólicas/etiología , Suplementos Dietéticos , Femenino , Enfermedades Gastrointestinales/complicaciones , Enfermedad Injerto contra Huésped/epidemiología , Humanos , Incidencia , Tiempo de Internación , Leucemia Mieloide Aguda/cirugía , Masculino , Desnutrición/complicaciones , Persona de Mediana Edad , Osteoporosis/epidemiología , Osteoporosis/etiología , Hormona Paratiroidea/sangre , Complicaciones Posoperatorias/epidemiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/cirugía , Estudios Retrospectivos , Acondicionamiento Pretrasplante , Trasplante Homólogo , Vitamina D/administración & dosificación , Deficiencia de Vitamina D/epidemiología , Adulto JovenRESUMEN
Novel high-risk groups have recently been identified in adult acute lymphoblastic leukemia (ALL), including Philadelphia-like, therapy-related, and measurable residual disease after induction therapy. Furthermore, modern targeted therapies have recently been incorporated into ALL management; rituximab for CD20-positive and blinatumomab for measurable residual disease after induction therapy or relapsed or refractory disease. Allogeneic hematopoietic cell transplantation (allo-HCT) is recommended as consolidation therapy for high-risk ALL; however, its relative benefit for these high-risk groups and after novel therapies is unclear. We performed an analysis of posttransplantation outcomes in a cohort of 261 consecutive patients who underwent allo-HCT for ALL at the 3-site Mayo Clinic Cancer Center (January 1, 2008-December 31, 2018). With a median (range) follow-up of 22.4 months (0.5-135.0), the 100-day and 5-year cumulative incidences of nonrelapse mortality rates were 6.5% and 26.7%, respectively. The 5-year cumulative incidences of relapse and death were 22.6% and 46.2%, respectively. The 1-year estimate of the composite endpoint of graft-versus-host disease/relapse-free survival was 39.3%. We observed no associations of novel high-risk groups or modern targeted therapies with overall survival, nonrelapse mortality, or relapse in multivariable analysis. An increased risk of relapse was observed with T-ALL (hazard ratio, 2.16; 95% confidence interval, 1.14-4.09; P = .02) and hypodiploidy/near-triploidy (hazard ratio, 2.84; 95% confidence interval, 1.06-7.62; P = .04). Our analysis suggests that novel high-risk groups derive a similar benefit from allo-HCT as traditional high-risk adult ALL and that novel targeted therapies do not seem to independently predict for posttransplantation outcomes. It also calls for further exploration of maintenance strategies after Allo-HCT to prevent relapse in high-risk subgroups.