RESUMEN
BACKGROUND: Mutations in the gene encoding isocitrate dehydrogenase 1 ( IDH1) occur in 6 to 10% of patients with acute myeloid leukemia (AML). Ivosidenib (AG-120) is an oral, targeted, small-molecule inhibitor of mutant IDH1. METHODS: We conducted a phase 1 dose-escalation and dose-expansion study of ivosidenib monotherapy in IDH1-mutated AML. Safety and efficacy were assessed in all treated patients. The primary efficacy population included patients with relapsed or refractory AML receiving 500 mg of ivosidenib daily with at least 6 months of follow-up. RESULTS: Overall, 258 patients received ivosidenib and had safety outcomes assessed. Among patients with relapsed or refractory AML (179 patients), treatment-related adverse events of grade 3 or higher that occurred in at least 3 patients were prolongation of the QT interval (in 7.8% of the patients), the IDH differentiation syndrome (in 3.9%), anemia (in 2.2%), thrombocytopenia or a decrease in the platelet count (in 3.4%), and leukocytosis (in 1.7%). In the primary efficacy population (125 patients), the rate of complete remission or complete remission with partial hematologic recovery was 30.4% (95% confidence interval [CI], 22.5 to 39.3), the rate of complete remission was 21.6% (95% CI, 14.7 to 29.8), and the overall response rate was 41.6% (95% CI, 32.9 to 50.8). The median durations of these responses were 8.2 months (95% CI, 5.5 to 12.0), 9.3 months (95% CI, 5.6 to 18.3), and 6.5 months (95% CI, 4.6 to 9.3), respectively. Transfusion independence was attained in 29 of 84 patients (35%), and patients who had a response had fewer infections and febrile neutropenia episodes than those who did not have a response. Among 34 patients who had a complete remission or complete remission with partial hematologic recovery, 7 (21%) had no residual detectable IDH1 mutations on digital polymerase-chain-reaction assay. No preexisting co-occurring single gene mutation predicted clinical response or resistance to treatment. CONCLUSIONS: In patients with advanced IDH1-mutated relapsed or refractory AML, ivosidenib at a dose of 500 mg daily was associated with a low frequency of grade 3 or higher treatment-related adverse events and with transfusion independence, durable remissions, and molecular remissions in some patients with complete remission. (Funded by Agios Pharmaceuticals; ClinicalTrials.gov number, NCT02074839 .).
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Inhibidores Enzimáticos/administración & dosificación , Glicina/análogos & derivados , Isocitrato Deshidrogenasa/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Piridinas/administración & dosificación , Administración Oral , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Recuento de Células , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/farmacocinética , Femenino , Estudios de Seguimiento , Glicina/administración & dosificación , Glicina/efectos adversos , Glicina/farmacocinética , Hemoglobinas/análisis , Humanos , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Mutación , Piridinas/efectos adversos , Piridinas/farmacocinética , Recurrencia , Inducción de Remisión , Tasa de Supervivencia , Adulto JovenRESUMEN
BACKGROUND: Rare DNA breakage repair disorders predispose to infection and lymphoreticular malignancies. Hematopoietic cell transplantation (HCT) is curative, but coadministered chemotherapy or radiotherapy is damaging because of systemic radiosensitivity. We collected HCT outcome data for Nijmegen breakage syndrome, DNA ligase IV deficiency, Cernunnos-XRCC4-like factor (Cernunnos-XLF) deficiency, and ataxia-telangiectasia (AT). METHODS: Data from 38 centers worldwide, including indication, donor, conditioning regimen, graft-versus-host disease, and outcome, were analyzed. Conditioning was classified as myeloablative conditioning (MAC) if it contained radiotherapy or alkylators and reduced-intensity conditioning (RIC) if no alkylators and/or 150 mg/m2 fludarabine or less and 40 mg/kg cyclophosphamide or less were used. RESULTS: Fifty-five new, 14 updated, and 18 previously published patients were analyzed. Median age at HCT was 48 months (range, 1.5-552 months). Twenty-nine patients underwent transplantation for infection, 21 had malignancy, 13 had bone marrow failure, 13 received pre-emptive transplantation, 5 had multiple indications, and 6 had no information. Twenty-two received MAC, 59 received RIC, and 4 were infused; information was unavailable for 2 patients. Seventy-three of 77 patients with DNA ligase IV deficiency, Cernunnos-XLF deficiency, or Nijmegen breakage syndrome received conditioning. Survival was 53 (69%) of 77 and was worse for those receiving MAC than for those receiving RIC (P = .006). Most deaths occurred early after transplantation, suggesting poor tolerance of conditioning. Survival in patients with AT was 25%. Forty-one (49%) of 83 patients experienced acute GvHD, which was less frequent in those receiving RIC compared with those receiving MAC (26/56 [46%] vs 12/21 [57%], P = .45). Median follow-up was 35 months (range, 2-168 months). No secondary malignancies were reported during 15 years of follow-up. Growth and developmental delay remained after HCT; immune-mediated complications resolved. CONCLUSION: RIC HCT resolves DNA repair disorder-associated immunodeficiency. Long-term follow-up is required for secondary malignancy surveillance. Routine HCT for AT is not recommended.
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Roturas del ADN de Doble Cadena , Trastornos por Deficiencias en la Reparación del ADN/genética , Trastornos por Deficiencias en la Reparación del ADN/terapia , Reparación del ADN , Trasplante de Células Madre Hematopoyéticas , Adolescente , Alelos , Niño , Preescolar , Trastornos por Deficiencias en la Reparación del ADN/diagnóstico , Trastornos por Deficiencias en la Reparación del ADN/mortalidad , Femenino , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/diagnóstico , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Lactante , Estimación de Kaplan-Meier , Masculino , Mutación , Pronóstico , Resultado del Tratamiento , Virosis , Adulto JovenRESUMEN
The prognostic importance of genetic information in primary myelofibrosis (PMF) was recently highlighted in a study of over 1000 cytogenetically-annotated patients; 5-year survival rates were 8% for very high risk (VHR), 27% "unfavorable" and 45% "favorable" karyotype. The current study addresses the practice-relevant question of whether or not allogeneic hematopoietic stem cell transplant (HCT) can overcome the detrimental survival effect of VHR or unfavorable karyotype. The study included 67 patients with PMF or secondary MF who received HCT at the Mayo Clinic and in whom pretransplant cytogenetic information was available. Dynamic international prognostic scoring system (DIPSS) risk distribution was 13% high, 66% intermediate-2 and 21% intermediate-1. Cytogenetic risk distribution was 11% VHR, 34% unfavorable and 55% favorable. At median post-HCT follow-up of 60 months for living patients (range 34-170), 28 (42%) deaths were recorded. Five-year survival was 62% and was not affected by VHR or unfavorable karyotype (P = .68). The salutary effect of HCT in patients with VHR or unfavorable karyotype was also apparent during analysis of a combined dataset that included a nontransplant cohort of 383 patients with PMF; multivariable analysis of the combined dataset (n = 450) resulted in HRs (95% CI) of 2.4 (1.6-3.6) for absence of transplant, 3.3 (2.2-4.8) for VHR karyotype, 1.6 (1.2-2.1) for unfavorable karyotype, 2.9 (2.0-4.2) for DIPSS high and 1.7 (1.4-2.2) for DIPSS intermediate-2. These observations were further confirmed by analysis of more stringently matched case-control subset cohorts and provide the evidence for the therapeutic preference of HCT in cytogenetically high risk patients with MF.
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Trasplante de Células Madre Hematopoyéticas/métodos , Cariotipo , Mielofibrosis Primaria/terapia , Anciano , Aloinjertos , Estudios de Casos y Controles , Citogenética , Femenino , Trasplante de Células Madre Hematopoyéticas/mortalidad , Trasplante de Células Madre Hematopoyéticas/normas , Humanos , Masculino , Persona de Mediana Edad , Mielofibrosis Primaria/genética , Mielofibrosis Primaria/mortalidad , Pronóstico , Medición de Riesgo , Análisis de Supervivencia , Adulto JovenRESUMEN
Cytogenetic evolution (CGE) in patients with myeloid neoplasms who relapsed after an allogeneic (allo) hematopoietic cell transplantation (HCT) has been evaluated by only few studies. The effect of the CGE on survival of relapsed allo-HCT recipients is not clear. The effect of previously received chemotherapy to induce CGE in this patient population has not been studied. The aims of our study are to (1) characterize the patterns of cytogenetic change in patients with myeloid neoplasms who relapsed after an allo-HCT, (2) evaluate the effect of CGE on survival, and (3) explore the association of CGE with previous chemotherapy (including the lines of salvage therapy, type of induction, and conditioning therapy). Of 49 patients with a myeloid malignancy (27 acute myeloid leukemia [AML], 19 myelodysplastic syndrome [MDS]/myeloproliferative neoplasm [MPN], and 3 chronic myelogenous leukemia) who relapsed after an allo-HCT, CGE was observed in 25 (51%), whereas 24 patients had unchanged cytogenetic findings at relapse. The CGE group carried more cytogenetic abnormalities at original diagnosis. The most frequent cytogenetic change was the acquisition of 3 or more new chromosomal abnormalities followed by acquisition of unbalanced abnormalities, aneuploidy, and emergence of apparently new clones unrelated to the original clone. The CGE cohort had higher proportion of MDS and MPN and fewer patients with de novo AML. Disease risk assessment category showed a trend to higher frequency of high-risk patients in the CGE group, though the difference was not statistically significant. Time from diagnosis to transplantation and time from transplantation to relapse were not different between the CGE and non-CGE groups. CGE and non-CGE cohorts had similar exposures to salvage therapy and to induction chemotherapy, as well as similar conditioning regimens; thus, no particular type of chemotherapy emerged as a predisposing factor to CGE. CGE was associated with significantly shortened post-transplantation and postrelapse survival when compared with those of the non-CGE group (P = .004 and P < .001, respectively). Our results underscore the significance of CGE in progression of myeloid malignancies after an allo-HCT.
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Transformación Celular Neoplásica/genética , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Leucemia Mieloide/genética , Leucemia Mieloide/patología , Adulto , Anciano , Aneuploidia , Antineoplásicos/farmacología , Estudios de Casos y Controles , Transformación Celular Neoplásica/inducido químicamente , Aberraciones Cromosómicas , Células Clonales , Citogenética , Progresión de la Enfermedad , Femenino , Humanos , Leucemia Mieloide/mortalidad , Leucemia Mieloide/terapia , Masculino , Persona de Mediana Edad , Recurrencia , Estudios Retrospectivos , Tasa de Supervivencia , Factores de Tiempo , Trasplante Homólogo/efectos adversos , Adulto JovenRESUMEN
PURPOSE: Stem cell transplant (SCT) recipients commonly undergo bronchoalveolar lavage (BAL) collection as an infectious pulmonary work-up. Previous studies report the utility and overall diagnostic yield of fiberoptic bronchoscopy with BAL in this vulnerable population, though none focused purely on microbiologic yield or made comparisons with less invasive means of pathogen detection. We sought to determine and elaborate on the microbiologic yield of BAL in SCT recipients, assess a correlation between BAL studies and less invasive means of pathogen detection, and assess the utility of repeating a BAL within 30 days. METHODS: Between January 1, 2009, and July 31, 2013, we reviewed medical records of 125 SCT recipients who underwent 179 BALs. In addition to demographic information and details pertaining to their SCT, a comprehensive review of their microbiologic data was performed and recorded. RESULTS: Our study showed an overall BAL microbiologic yield of 40%, despite 92% of patients receiving broad-spectrum antimicrobial therapy at the time of the BAL procedure. CONCLUSIONS: Although an initial BAL sample in this population provides crucial microbiologic information, repeating the procedure within 30 days may have minimal additional microbiologic yield. BAL continues to be an essential diagnostic tool in SCT recipients undergoing an infectious pulmonary work-up.
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Antibacterianos/uso terapéutico , Líquido del Lavado Bronquioalveolar/microbiología , Neoplasias/terapia , Infecciones del Sistema Respiratorio/microbiología , Trasplante de Células Madre/efectos adversos , Adulto , Anciano , Lavado Broncoalveolar/instrumentación , Lavado Broncoalveolar/métodos , Broncoscopía/instrumentación , Broncoscopía/métodos , Femenino , Humanos , Huésped Inmunocomprometido , Masculino , Persona de Mediana Edad , Infecciones del Sistema Respiratorio/diagnóstico , Infecciones del Sistema Respiratorio/prevención & control , Estudios Retrospectivos , Tomografía Computarizada por Rayos X , Trasplante Autólogo/efectos adversos , Trasplante Homólogo/efectos adversosRESUMEN
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
To identify rational therapeutic combinations with cytarabine (Ara-C), we developed a high-throughput, small-interference RNA (siRNA) platform for myeloid leukemia cells. Of 572 kinases individually silenced in combination with Ara-C, silencing of 10 (1.7%) and 8 (1.4%) kinases strongly increased Ara-C activity in TF-1 and THP-1 cells, respectively. The strongest molecular concepts emerged around kinases involved in cell-cycle checkpoints and DNA-damage repair. In confirmatory siRNA assays, inhibition of WEE1 resulted in more potent and universal sensitization across myeloid cell lines than siRNA inhibition of PKMYT1, CHEK1, or ATR. Treatment of 8 acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myeloid leukemia (CML) cell lines with commercial and the first-in-class clinical WEE1 kinase inhibitor MK1775 confirmed sensitization to Ara-C up to 97-fold. Ex vivo, adding MK1775 substantially reduced viability in 13 of 14 AML, CML, and myelodysplastic syndrome patient samples compared with Ara-C alone. Maximum sensitization occurred at lower to moderate concentrations of both drugs. Induction of apoptosis was increased using a combination of Ara-C and MK1775 compared with using either drug alone. WEE1 is expressed in primary AML, ALL, and CML specimens. Data from this first siRNA-kinome sensitizer screen suggests that inhibiting WEE1 in combination with Ara-C is a rational combination for the treatment of myeloid and lymphoid leukemias.
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Antimetabolitos Antineoplásicos/farmacología , Proteínas de Ciclo Celular/metabolismo , Citarabina/farmacología , Leucemia Mieloide/enzimología , Proteínas Nucleares/metabolismo , Fosfotransferasas/análisis , Proteínas Tirosina Quinasas/metabolismo , Western Blotting , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Ensayos Analíticos de Alto Rendimiento , Humanos , Fosfotransferasas/metabolismo , ARN Interferente Pequeño , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
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
Few studies have examined the outcome of large numbers of patients with the microgranular variant (M3V) of acute promyelocytic leukemia (APL) in the all-trans retinoic acid era. Here, the outcome of 155 patients treated with all-trans retinoic acid-based therapy on 3 clinical trials, North American Intergroup protocol I0129 and Programa para el Estudio de la Terapéutica en Hemopatía Maligna protocols LPA96 and LPA99, are reported. The complete remission rate for all 155 patients was 82%, compared with 89% for 748 patients with classical M3 disease. The incidence of the APL differentiation syndrome was 26%, compared with 25% for classical M3 patients, and the early death rate was 13.6% compared with 8.4% for patients with classical M3 morphology. With a median follow-up time among survivors of 7.6 years (range 3.6-14.5), the 5-year overall survival, disease-free survival, and cumulative incidence of relapse for patients with M3V were 70%, 73%, and 24%, respectively. With a median follow-up time among survivors of 7.6 years (range 0.6-14.3), the 5-year overall survival, disease-free survival, and cumulative incidence of relapse among patients with classical M3 morphology were 80% (P = .006 compared with M3V), 81% (P = .07), and 15% (P = .005), respectively. When outcomes were adjusted for the white blood cell count or the relapse risk score, none of these outcomes were significantly different between patients with M3V and classical M3 APL.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Promielocítica Aguda/tratamiento farmacológico , Leucemia Promielocítica Aguda/patología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Citarabina/administración & dosificación , Daunorrubicina/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Lactante , Leucemia Promielocítica Aguda/clasificación , Masculino , Persona de Mediana Edad , Inducción de Remisión , Tasa de Supervivencia , Resultado del Tratamiento , Tretinoina/administración & dosificación , Adulto JovenRESUMEN
Anti-thymocyte globulin (ATG) has been associated with decreased rates graft versus host disease (GVHD) but with a potential risk of increasing risk of infection and relapse. We retrospectively studied the impact of single dose low dose (2.5 mg/kg) ATG in patients undergoing allogenic hematopoietic cell transplantation (HCT) from 8/8 matched unrelated donors (MUD). Of the total 209 patients identified, 129 received ATG. At baseline, the ATG group had more intermediate and high disease risk index (DRI) (64.6% vs. 54.3%) (28.3% vs. 23.7%) p < .001, respectively, and who received reduced intensity or non-myeloablative conditioning (RIC) (69.0% vs. 47.5%, p .003). There was no significant difference in the overall survival (OS) HR = 1.3, 95% CI [0.99, 1.0], p = .350 or relapse-free survival (RFS) HR = 1.2, 95% CI [0.74, 1.8], p = .526 between the two groups. Patients receiving ATG had a lower incidence of chronic GVHD (cGVHD) (10.1% vs. 25%, p = .007) and less moderate to severe cGVHD (8.5% vs. 25%, p = .002). ATG was associated with a reduced incidence of moderate to severe cGVHD OR = 0.28, 95% CI [0.12, 0.61], p < .01. There was no difference in the incidence of Epstein-Barr Virus (EBV) or cytomegalovirus (CMV) reactivation, CMV disease, invasive fungal infection, or grade III-IV acute GVHD (aGVHD). Our study shows that low dose ATG results in similar OS and RFS with lower rates of cGVHD. Additional prospective studies are needed to confirm these findings.
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Infecciones por Virus de Epstein-Barr , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Suero Antilinfocítico , Enfermedad Injerto contra Huésped/epidemiología , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Herpesvirus Humano 4 , Humanos , Recurrencia Local de Neoplasia , Estudios Prospectivos , Estudios Retrospectivos , Acondicionamiento Pretrasplante , Donante no EmparentadoRESUMEN
Factors predicting allogeneic hematopoietic cell transplantation (HCT) outcomes in myelofibrosis in the early post-HCT period have not been defined thus far. We attempt to study such factors that can help identify patients at a higher risk of relapse or death. This retrospective study included 79 patients who underwent first HCT for myelofibrosis at three centers between 2005 and 2016. Univariate analysis showed that red blood cell (RBC) transfusion dependence (HR 9.02, 95% CI 4.0-20.35), platelet transfusion dependence (HR 8.17, 95%CI 3.83-17.37), 100% donor chimerism in CD33 + cells (HR 0.21, 95%CI 0.07-0.62), unfavorable molecular status (HR 4.41, 95%CI 1.87-10.39), normal spleen size (HR 0.42, 95%CI 0.19-0.94), grade ≥ 2 bone marrow fibrosis (vs. grade ≤ 1; HR 2.7, 95%CI 1.1-6.93) and poor graft function (HR 2.6, 95%CI 1.22-5.53) at day +100 were statistically significantly associated with relapse-free survival (RFS). RBC transfusion dependence and unfavorable molecular status were also statistically significant in the multivariate analysis. Patients in whom both of these factors were present had a significantly worse RFS when compared to those with one or none. While limited by a small sample size, we demonstrate the significance of transfusion dependence and molecular status at day +100 in predicting outcomes.
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Trasplante de Células Madre Hematopoyéticas/métodos , Mielofibrosis Primaria/mortalidad , Acondicionamiento Pretrasplante/métodos , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mielofibrosis Primaria/terapia , Factores de Riesgo , Análisis de Supervivencia , Adulto JovenRESUMEN
BACKGROUND: This two-stage, multi-institutional, randomized phase 2 trial assessed the toxicity and response rate associated with two treatment schedules of the histone deacetylase inhibitor, vorinostat (suberoylanilide hydroxamic acid; SAHA) in patients with relapsed acute myeloid leukemia and in selected untreated patients with high-risk acute myeloid leukemia. DESIGN AND METHODS: Patients with relapsed or untreated acute myeloid leukemia who were not candidates for chemotherapy entered one of the two treatment arms. In both arms a total dose of 8400 mg of vorinostat was delivered in each 21-day cycle of treatment: in arm A the dose regimen was 400 mg daily whereas in arm B the dose regimen was 200 mg three times daily for 14 days followed by 1 week rest. RESULTS: Data from all 37 patients were used for the analyses. In arm A (n=15), the confirmed complete remission rate was 0% (95% CI, 0% to 23%); this arm was closed at the planned interim analysis. In arm B (n=22), the confirmed complete remission rate was 4.5% (1 response; 95% CI, 0.4% to 24%), with a duration of response exceeding 398 days. The median time to treatment failure in arm A was 42 days (95% CI, 26 to 57); although a minimum of four cycles of treatment were planned, 11 patients (79%) received no more than two cycles. The median time to treatment failure in arm B was 46 days (95% CI, 20 to 71); 13 patients (59%) received no more than two cycles of treatment. CONCLUSIONS: Vorinostat monotherapy demonstrated minimal activity in this group of patients with acute myeloid leukemia. Therapy was discontinued in many patients before the planned four cycles had been administered, either because of failure of vorinostat to control the leukocyte count or patients' and physicians' preference. Future studies of vorinostat in acute myeloid leukemia should focus on combinations with other drugs with which it might interact pharmacodynamically. ClinicalTrials.gov Identifier: NCT00305773.
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Ácidos Hidroxámicos/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Leucemia Mieloide Aguda/sangre , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , VorinostatRESUMEN
Testicular germ cell tumors (TGCTs) are unique amongst solid tumors in terms of the high cure rates using chemotherapy for metastatic disease. Nevertheless, TGCTs still kill approximately 400 men per year, at a median age of 30 years, in the United States. This young age of mortality dramatically amplifies the impact of these deaths for the patients and their often young families. Furthermore the high cure rate makes it difficult to conduct further clinical trials of non curable disease. TGCTs are characterized by a marked aneuploidy and the presence of gain of chromosomal region 12p. Genomic testing may offer the ability to identify potentially lethal TGCTs at the time of initial diagnosis. However sequencing based studies have shown a paucity of somatic mutations in TGCT genomes including those that drive refractory disease. Furthermore these studies may be limited by genetic heterogeneity in primary tumors and the evolution of sub populations during disease progression. Herein we applied a systematic approach combining DNA content flow cytometry, whole genome copy number and whole exome sequence analyses to interrogate tumor heterogeneity in primary and metastatic refractory TGCTs. We identified both known and novel somatic copy number aberrations (12p, MDM2, and RHBDD1) and mutations (XRCC2, PIK3CA, RITA1) including candidate markers for platinum resistance that were present in a primary tumor of mixed histology and that remained after tandem autologous stem cell transplant.
Asunto(s)
Biomarcadores de Tumor/genética , Cisplatino/farmacología , Células Clonales/patología , Resistencia a Antineoplásicos/genética , Genoma Humano , Neoplasias de Células Germinales y Embrionarias/genética , Neoplasias Testiculares/genética , Antineoplásicos/farmacología , Células Clonales/efectos de los fármacos , Células Clonales/metabolismo , Humanos , Masculino , Metástasis de la Neoplasia , Neoplasias de Células Germinales y Embrionarias/tratamiento farmacológico , Neoplasias de Células Germinales y Embrionarias/patología , Neoplasias Testiculares/tratamiento farmacológico , Neoplasias Testiculares/patología , Células Tumorales CultivadasRESUMEN
The aim of this study is to compare clinical outcomes of patients who underwent allogeneic stem cell transplantation (HCT) for myelofibrosis with reduced intensity conditioning (RIC) using either Busulfan Fludarabine (BuFlu), Fludarabine Bis-chlorethyl-nitroso-urea/ carmustine Melphalan (FBM) or Fludarabine Melphalan (FluMel) regimens. Sixty-one patients were identified who underwent HCT with one of these RIC regimens. Overall survival (OS) was not different in the 3 groups. However, 100% donor chimerism was seen in more frequently at day +30 and day +100 in patients who received FBM or FluMel than BuFlu, in both CD3 and CD33 fractions. For instance, 100% donor chimerism in CD33 fraction was present in 100% patients in FBM cohort, 90% in FluMel cohort while 44% in BuFlu cohort at day +100. Acute graft-versus host disease, grade 2-4 and grade 3-4, was not statistically different in the 3 groups (BuFlu 47 and 35%, FBM 68 and 27%, FluMel 68 and 46%; p = 0.31 and 0.45). Relapses and non-relapse mortality was also not statistically significantly different. Our study shows similar OS with these 3 RIC regimens in myelofibrosis; although donor chimerism at day +30 and day +100 was better in patients who received FBM and FluMel.
Asunto(s)
Antineoplásicos/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Agonistas Mieloablativos/uso terapéutico , Mielofibrosis Primaria/terapia , Acondicionamiento Pretrasplante/métodos , Adulto , Anciano , Antineoplásicos/efectos adversos , Busulfano/uso terapéutico , Carmustina/uso terapéutico , Quimerismo , Femenino , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Masculino , Melfalán/uso terapéutico , Persona de Mediana Edad , Agonistas Mieloablativos/efectos adversos , Mielofibrosis Primaria/complicaciones , Mielofibrosis Primaria/mortalidad , Análisis de Supervivencia , Acondicionamiento Pretrasplante/efectos adversos , Acondicionamiento Pretrasplante/mortalidad , Acondicionamiento Pretrasplante/normas , Trasplante Homólogo , Vidarabina/análogos & derivados , Vidarabina/uso terapéuticoRESUMEN
Epstein-Barr virus (EBV) reactivation is an unresolved medical issue after allogeneic hematopoietic stem cell transplantation (HSCT). Rituximab treatment is recommended for EBV reactivation after HSCT but the number of doses of rituximab to use is unclear. In this study, risk factors and outcomes of patients who needed 1 dose vs >1 doses of preemptive rituximab to clear EBV viremia were compared. A higher viral load was more likely to be associated with higher doses of rituximab. Patients whose EBV viremia cleared with 1 dose of rituximab were more likely to have a preceding reduction of immunosuppression. Overall survival (OS) in these 2 cohorts was not different (18.7 vs 26.6 months, respectively, p = .96). Since rituximab can have side effects and is fairly costly, a predictive model to determine the number of rituximab doses using viral load would be a useful and cost-effective manner to utilize rituximab for this indication.
Asunto(s)
Infecciones por Virus de Epstein-Barr/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trastornos Linfoproliferativos/terapia , Rituximab/administración & dosificación , Viremia/prevención & control , Adolescente , Adulto , Anciano , Toma de Decisiones Clínicas/métodos , Esquema de Medicación , Infecciones por Virus de Epstein-Barr/epidemiología , Infecciones por Virus de Epstein-Barr/etiología , Femenino , Estudios de Seguimiento , Herpesvirus Humano 4/efectos de los fármacos , Herpesvirus Humano 4/aislamiento & purificación , Herpesvirus Humano 4/fisiología , Humanos , Trastornos Linfoproliferativos/mortalidad , Masculino , Persona de Mediana Edad , Modelos Biológicos , Selección de Paciente , Estudios Retrospectivos , Factores de Riesgo , Análisis de Supervivencia , Trasplante Homólogo/efectos adversos , Resultado del Tratamiento , Carga Viral/efectos de los fármacos , Viremia/epidemiología , Viremia/etiología , Activación Viral/efectos de los fármacos , Adulto JovenRESUMEN
Therapeutic dose monitoring is widely adopted for determination of busulfan (Bu) dose for use as a conditioning regimen. However, while dose adjustments are being incorporated, transient fluctuations of Bu levels may occur. We aim to understand if these fluctuations affect clinical outcomes of these patients. We compared outcomes in patients in whom the absolute dose changes and fluctuation of AUC were ≥ median% versus < median%. Rates of sinusoidal obstructive syndrome, grades 2-4/grades 3-4 acute and chronic graft versus host disease were not different between the two cohorts. The Kaplan-Meier curves for overall survival showed no significant differences. Six patients required >50% dose adjustment and four had a fluctuation in AUC of >50%. One of these patients died of sinusoidal obstruction syndrome and two died of infections. In our study, the transient fluctuations in Bu levels did not affect clinical outcomes; hence obviating the need for test dose strategy.
Asunto(s)
Busulfano/administración & dosificación , Busulfano/farmacocinética , Trasplante de Células Madre Hematopoyéticas , Agonistas Mieloablativos/administración & dosificación , Agonistas Mieloablativos/farmacocinética , Acondicionamiento Pretrasplante , Adulto , Anciano , Monitoreo de Drogas , Femenino , Supervivencia de Injerto , Enfermedad Injerto contra Huésped/diagnóstico , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Pronóstico , Recurrencia , Acondicionamiento Pretrasplante/efectos adversos , Acondicionamiento Pretrasplante/métodos , Trasplante Homólogo , Resultado del Tratamiento , Adulto JovenAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Pancreatitis/inducido químicamente , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Enfermedad Aguda , Adolescente , Adulto , Asparaginasa/efectos adversos , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Estudios Retrospectivos , Factores de Riesgo , Adulto JovenRESUMEN
Decitabine is a pyrimidine analogue of nucleoside cytidine, used for the treatment of myelodysplastic syndromes, chronic myelogenous leukemia, and acute myelogenous leukemia. We present a case of cardiomyopathy associated with decitabine used for secondary acute myelogenous leukemia. The patient presented with new heart failure symptoms and an ejection fraction decline.
RESUMEN
We present the first scalable algorithm that supports the composition of successive rectilinear deformations. Earlier systems that provided stretch and squish navigation could only handle small datasets. More recent work featuring rubber sheet navigation for large datasets has focused on rendering and on application-specific issues. However, no algorithm has yet been presented for carrying out such navigation methods; our paper addresses this problem. For maximum flexibility with large datasets, a stretch and squish navigation algorithm should allow for millions of potentially deformable regions. However, typical usage only changes the extents of a small subset k of these n regions at a time. The challenge is to avoid computations that are linear in n, because a single deformation can affect the absolute screen-space location of every deformable region. We provide an O(klogn) algorithm that supports any application that can lay out a dataset on a generic grid, and show an implementation that allows navigation of trees and gene sequences with millions of items in sub-millisecond time.