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There is little long-term outcome data on the efficacy of autologous hematopoietic stem cell transplantation (ASCT) in light chain deposition disease (LCDD). We identified 51 LCDD patients in the European Society for Blood and Bone Marrow transplantation registry who had undergone upfront ASCT between 1995 and 2021. The median serum creatinine was 280 µmol/L and 45% required renal replacement therapy (RRT) at time of transplant. The melphalan dose was 100 mg/m2 in 23%, 140 mg/m2 in 55% and 200 mg/m2 in 21%. The rate of very good partial response or better improved from 41% pretransplant to 66% at day +100 post- ASCT. In RRT-independent patients, there was a modest improvement in renal function within the first 3 months; the median estimated glomerular filtration rate increased from 44 to 51 mL/min/1.73 m2. There was no further change between 3 and 12 months post-ASCT. No patient who was RRT-independent at ASCT became RRT dependent by day + 100 post-ASCT. Median follow- up post-ASCT was 84 months (interquartile range [IQR]: 46-122). At 6-years post ASCT, overall survival was 88% (95% confidence interval [CI]: 78-98) and PFS was 44% (95% CI: 28-60). The 2-year cumulative incidence of relapse and non-relapse mortality was 17% (95% CI: 6-27) and 2% (95% CI: 0-6), respectively. The cumulative incidence of renal transplantation at 4 years after ASCT was 27% (95% CI: 13-41) with renal transplantation performed between 6.3 and 52.9 months post-ASCT (median 24.7 months). ASCT represents a feasible option for LCDD patients even if RRT dependent at time of transplant. Outcomes are favorable with low non-relapse mortality and good long-term overall survival.
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Trasplante de Células Madre Hematopoyéticas , Trasplante Autólogo , Humanos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto , Resultado del Tratamiento , Anciano , Tasa de Filtración Glomerular , Cadenas Ligeras de Inmunoglobulina/sangre , Paraproteinemias/terapia , Paraproteinemias/mortalidad , Paraproteinemias/diagnóstico , Estudios de Seguimiento , Europa (Continente) , Sistema de Registros , Acondicionamiento Pretrasplante/métodosRESUMEN
OBJECTIVES: Hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for various diseases. The measurement of CD34+ cells is crucial to schedule the peripheral blood stem cell collection and assess the engraftment potential of the apheresis product. The AQUIOS STEM system has been introduced as a novel application on the AQUIOS CL, a fully automated flow cytometer, for the enumeration of CD34+ hematopoietic progenitor cells (HPCs) in accordance with the The International Society for Hematotherapy and Graft Engineering guidelines. This study aimed to assess the potential of the novel AQUIOS STEM system versus currently used systems including the FACSCanto-II and the FACS Lyric flow cytometer in a multicenter study. METHODS: A total of 91 samples were used for the validation of the AQUOIS STEM system, including an analytical performance evaluation by means of assessing precision, sample stability, intersample carryover, and linearity and a method comparison with the present FACS systems in use to assess analytical and clinical decision agreement. RESULTS: Results showed excellent precision, with coefficient of variations <15% for dedicated quality control material and patient samples. There was no significant carry over. The fresh apheresis samples were stable when stored overnight at room temperature and at 4°C. Analytical comparison with the current systems demonstrated good correlation in peripheral blood, and minimal, clinically neglectable systematic and proportional bias in fresh apheresis products but a low correlation coefficient in cryopreserved products. CONCLUSIONS: The STEM system on AQUIOS CL allows automated enumeration of CD34+ stem cells, demonstrating good analytical performance and promising overall outcomes in peripheral blood and fresh apheresis products.
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Antígenos CD34 , Citometría de Flujo , Células Madre Hematopoyéticas , Humanos , Antígenos CD34/análisis , Eliminación de Componentes Sanguíneos/métodos , Citometría de Flujo/métodos , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/citología , Reproducibilidad de los ResultadosRESUMEN
OBJECTIVES: Patients treated for hematologic malignancies are at higher risk for blood stream infections (BSI) and multidrug-resistant organisms (MDRO) are increasingly involved. Studies showed a significant association between rectal colonization status and a higher risk of subsequent MDRO BSI. The objective of our study was to probe the practice of surveillance cultures in Belgian hematology centers. METHODS: A questionnaire was sent to the 13 hematology centers participating in the acute leukemia board of the Belgian Hematology Society. 21 questions probed for the method of surveillance cultures, MDRO screened, antimicrobial prophylaxis, and empirical therapy and their relationship with colonization status. RESULTS: All centers completed the questionnaire in full. Routine gastrointestinal surveillance cultures in hematologic patients are taken in 10 hospitals. Organisms tested for included mostly ESBL (n = 9) and carbapenem-resistant (n = 8) Enterobacterales. All centers with a screening strategy adapt empiric antibiotic therapy based on MDRO colonization. Prophylaxis strategies are variable, only two centers adapt prophylaxis upon documentation of fluoroquinolone resistance. CONCLUSIONS: The majority of the Belgian centers perform routine surveillance cultures and adapt empiric therapy for neutropenic fever accordingly. Other reasons for testing include to gain insight into local epidemiology and to prevent in-hospital transmission. In general, there was significant variability in surveillance dimensions.
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Neoplasias Hematológicas , Leucemia Mieloide Aguda , Humanos , Farmacorresistencia Bacteriana Múltiple , Antibacterianos/uso terapéutico , Antibacterianos/farmacología , Carbapenémicos , Neoplasias Hematológicas/complicaciones , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/tratamiento farmacológico , Estudios RetrospectivosRESUMEN
BACKGROUND: Patients with newly diagnosed high-risk Burkitt lymphoma are treated with high-intensity immune-chemotherapy regimens such as R-CODOX-M/R-IVAC or with lower-intensity regimens such as DA-EPOCH-R. The aim of this study was to make a formal comparison between these regimens. METHODS: This multicentre, phase 3, open-label, randomised study was done in 26 clinical centres in the Netherlands, Belgium, and Switzerland. Eligible patients were aged 18-75 years with newly diagnosed high-risk Burkitt lymphoma without CNS involvement. Patients were randomly assigned to two cycles of R-CODOX-M/R-IVAC (R-CODOX-M: rituximab 375 mg/m2 on day 1 and 9, cyclophosphamide 800 mg/m2 on day 1, cyclophosphamide 200 mg/m2 on days 2-5, vincristine 1·5 mg/m2 on days 1 and 8, doxorubicin 40 mg/m2 on day 1, and methotrexate 3000 mg/m2 on day 10; R-IVAC: rituximab 375 mg/m2 on days 3 and 7, iphosphamide 1500 mg/m2 on days 1-5, etoposide 60 mg/m2 on days 1-5, and cytarabin 2000 mg/m2 on day 1 and 2) or six cycles of DA-EPOCH-R (dose-adjusted etoposide 50-124 mg/m2 on days 1-4, prednisolone 120 mg/m2 on days 1-5, vincristine 0·4 mg/m2 on days 1-4, dose-adjusted cyclophosphamide 480-1866 mg/m2 on day 5, dose-adjusted doxorubicin 10-24·8 mg/m2 on days 1-4, rituximab 375 mg/m2 on days 1 and 5). Patients older than 65 years received a dose modified R-CODOX-M/R-IVAC. All drugs were intravenous except for prednisolone, which was oral. Patients also received four intrathecal CNS administrations with cytarabin (70 mg) and four with methotrexate (15 mg). Patients were stratified by centre, leukemic disease, and HIV-positivity. The primary endpoint was progression-fee survival. All analyses were done by modified intention-to-treat, excluding randomly assigned patients who were subsequently found to have CNS involvement or diagnosis other than Burkitt lymphoma at study entry. This study is registered with the European Clinical Trial Register, EudraCT2013-004394-27. FINDINGS: Due to a slow accrual, the study was closed prematurely on Nov 15, 2021. Between Aug 4, 2014, and Sept 17, 2021, 89 patients were enrolled and randomly assigned to receive R-CODOX-M/R-IVAC (n=46) or DA-EPOCH-R (n=43). Five patients were excluded after random assignment (three in the R-CODOX-M/R-IVAC group [one diagnosis other than Burkitt lymphoma at study entry according to local pathology and two CNS involvement] and two in the DA-EPOCH-R group [one diagnosis other than Burkitt lymphoma at study entry according to local pathology and one CNS involvement]. 84 remaining patients were included in the modified intention-to-treat analysis. 73 (87%) of 84 patients were male, 76 (90%) presented with stage III or IV disease, and nine (11%) had HIV-positive Burkitt lymphoma. Median patient age was 52 years (IQR 37-64). With a median follow-up of 28·5 months (IQR 13·2-43·7), 2-year progression-free survival was 76% (95% CI 60-86%) in the R-CODOX-M/R-IVAC group and 70% (54-82%) in the DA-EPOCH-R group (hazard ratio 1·42, 95% CI 0·63-3·18; p=0·40). There were two deaths in the R-CODOX-M/R-IVAC group (one infection [treatment related] and one due to disease progression [not treatment related]) and one death in the DA-EPOCH-R group (COVID-19 infection [treatment related]). In the R-CODOX-M/R-IVAC group, four patients went off-protocol because of toxic effects, versus none in the DA-EPOCH-R group. Patients treated with R-CODOX-M/R-IVAC had more infectious adverse events (24 [56%] of 43 patients had at least one grade 3-5 infection vs 14 [34%] of 41 patients in the DA-EPOCH-R group). INTERPRETATION: The trial stopped early, but the available data suggest that while DA-EPOCH-R did not result in superior progression-free survival compared with R-CODOX-M/R-IVAC, it was associated with fewer toxic effects and need for supportive care. DA-EPOCH-R appears to be an additional valid therapeutic option for patients with high-risk Burkitt lymphoma without CNS involvement. FUNDING: The Dutch Cancer Society and the Schumacher-Kramer Foundation.
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Linfoma de Burkitt , Humanos , Masculino , Femenino , Linfoma de Burkitt/diagnóstico , Linfoma de Burkitt/tratamiento farmacológico , Etopósido , Vincristina , Rituximab/uso terapéutico , Metotrexato , Citarabina , Ciclofosfamida/efectos adversos , Doxorrubicina , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Prednisolona/uso terapéuticoRESUMEN
Introduction: Diffuse large B-cell lymphoma (DLBCL) and primary mediastinal B-cell lymphoma (PMBCL) are aggressive histological subtypes of non-Hodgkin's lymphoma. Improved understanding of the underlying molecular pathogenesis has led to new classification and risk stratification tools, including the development of cell-free biomarkers through liquid biopsies. The goal of this study was to investigate cell-free RNA (cfRNA) biomarkers in DLBCL and PMBCL patients. Materials and methods: Blood plasma samples (n=168) and matched diagnostic formalin-fixed paraffin-embedded (FFPE) tissue samples (n=69) of DLBCL patients, PMBCL patients and healthy controls were collected between 2016-2021. Plasma samples were collected at diagnosis, at interim evaluation, after treatment, and in case of refractory or relapsed disease. RNA was extracted from 200 µl plasma using the miRNeasy serum/plasma kit and from FFPE tissue using the miRNeasy FFPE kit. RNA was subsequently sequenced on a NovaSeq 6000 instrument using the SMARTer Stranded Total RNA-seq pico v3 library preparation kit. Results: Higher cfRNA concentrations were demonstrated in lymphoma patients compared to healthy controls. A large number of differentially abundant genes were identified between the cell-free transcriptomes of DLBCL patients, PMBCL patients, and healthy controls. Overlap analyses with matched FFPE samples showed that blood plasma has a unique transcriptomic profile that significantly differs from that of the tumor tissue. As a good concordance between tissue-derived gene expression and the immunohistochemistry Hans algorithm for cell-of-origin (COO) classification was demonstrated in the FFPE samples, but not in the plasma samples, a 64-gene cfRNA classifier was developed that can accurately determine COO in plasma. High plasma levels of a 9-gene signature (BECN1, PRKCB, COPA, TSC22D3, MAP2K3, UQCRHL, PTMAP4, EHD1, NAP1L1 pseudogene) and a 5-gene signature (FTH1P7, PTMAP4, ATF4, FTH1P8, ARMC7) were significantly associated with inferior progression-free and overall survival in DLBCL patients, respectively, independent of the NCCN-IPI score. Conclusion: Total RNA sequencing of blood plasma samples allows the analysis of the cell-free transcriptome in DLBCL and PMBCL patients and demonstrates its unexplored potential in identifying diagnostic, cell-of-origin, and prognostic cfRNA biomarkers.
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The WAA apheresis registry contains data on more than 140,000 apheresis procedures conducted in 12 different countries. The aim is to give an update of indications, type and number of procedures and adverse events (AEs). MATERIAL AND METHODS: The WAA-registry is used for registration of apheresis procedures and is free of charge. The responsible person for a center can apply at the site www.waa-registry.org RESULTS: Data includes reported AEs from 2012 and various procedures and diagnoses during the years 2018-2022; the latter in total from 27 centers registered a total of 9500 patients (41% women) that began therapeutic apheresis (TA) during the period. A total of 58,355 apheresis procedures were performed. The mean age was 50 years (range 0-94). The most common apheresis procedure was stem cell collection for which multiple myeloma was the most frequent diagnosis (51%). Donor cell collection was done in 14% and plasma exchange (PEX) in 28% of patients; In relation to all performed procedures PEX, using a centrifuge (35%) and LDL-apheresis (20%) were the most common. The main indication for PEX was TTP (17%). Peripheral veins were used in 56% as the vascular access. The preferred anticoagulant was ACD. AEs occurred in 2.7% of all procedures and were mostly mild (1%) and moderate 1.5% (needed supportive medication) and, only rarely, severe (0.15%). CONCLUSION: The data showed a wide range of indications and variability in apheresis procedures with low AE frequency.
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Eliminación de Componentes Sanguíneos , Humanos , Femenino , Recién Nacido , Lactante , Preescolar , Niño , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Masculino , Eliminación de Componentes Sanguíneos/métodos , Intercambio Plasmático/efectos adversos , Plasmaféresis , Sistema de Registros , Donantes de TejidosRESUMEN
Treatment choice according to the individual conditions remains challenging, particularly in older patients with acute myeloid leukemia (AML) and high risk myelodysplastic syndrome (MDS). The impact of performance status, comorbidities, and physical functioning on survival is not well defined for patients treated with hypomethylating agents. Here we describe the impact of performance status (14% ECOG performance status 2), comorbidity (40% HCT-comorbidity index ≥ 2), and physical functioning (41% short physical performance battery < 9 and 17% ADL index < 6) on overall survival (OS) in 115 older patients (age ≥ 66 years) treated on a clinical trial with a 10-day decitabine schedule. None of the patient-related variables showed a significant association with OS. Multivariable analysis revealed that age > 76 years was significantly associated with reduced OS (HR 1.58; p = 0.043) and female sex was associated with superior OS (HR 0.62; p = 0.06). We further compared the genetic profiles of these subgroups. This revealed comparable mutational profiles in patients younger and older than 76 years, but, interestingly, revealed significantly more prevalent mutated ASXL1, STAG2, and U2AF1 in male compared to female patients. In this cohort of older patients treated with decitabine age and sex, but not comorbidities, physical functioning or cytogenetic risk were associated with overall survival.
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Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Humanos , Masculino , Femenino , Anciano , Decitabina/uso terapéutico , Síndromes Mielodisplásicos/genética , Leucemia Mieloide Aguda/genética , Mutación , Resultado del TratamientoRESUMEN
We report the case of a 32-year-old man receiving chemotherapeutics for an acute B-lymphoblastic leukemia who developed proven cerebral and pulmonary aspergillosis with Aspergillus flavus. Because of progressive fungal disease with neurological deterioration despite adequate systemic antifungal therapy and surgical debridement, intracerebral administration of liposomal amphotericin B was initiated at 5 mg twice weekly. This led to improvement of the cerebral infection. Surgical debridement of a pleural Aspergillus empyema was necessary, and pleural trough level of isavuconazole was found to be subtherapeutic despite adequate blood trough levels, which led us to increase the dose of isavuconazole. We conclude that intralesional amphotericin B might be beneficial at 5 mg twice weekly in cerebral aspergillosis if systemic antifungals and surgical debridement fail. In Aspergillus empyema, measurement of pleural isavuconazole trough levels should be considered.
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OBJECTIVES: Serum free light chain (sFLC) measurements have inherent analytical limitations impacting sFLC clinical interpretation. We evaluated analytical and diagnostic performance of three polyclonal sFLC assays on four analytical platforms. METHODS: sFLC concentration was measured using Diazyme FLC assays (Diazyme) on cobas c501/c503 analyzer (Roche); Freelite assays (The Binding Site) on Optilite analyzer (The Binding Site) and cobas c501 analyzer and Sebia FLC ELISA assays (Sebia) on AP22 ELITE analyzer (DAS). Imprecision, linearity, method comparison vs. Freelite/Optilite, antigen excess detection and reference value verification were assessed. Diagnostic performance was compared on 120 serum samples and on follow-up samples of five patients with κ and λ monoclonal gammopathy. RESULTS: Method comparison showed excellent correlation with Freelite/Optilite method for all assays. A large proportional negative bias was shown for both Sebia κ and λ ELISA and a significant positive proportional bias for λ in the low (<10 mg/L) Freelite/cobas c501 method. Clinically relevant underestimation of κ sFLC levels due to antigen excess was shown for 7% of each Diazyme/cobas application and for 11 and 32.1% of λ sFLC assay of respectively Diazyme/cobas and Sebia/AP22. sFLC reference values revealed application specific. Cohen's κ values were (very) good for κ sFLC but only moderate to good for λ sFLC. In 4/10 follow-up patients, significant differences in clinical interpretation between sFLC assays were noticed. CONCLUSIONS: Important analytical limitations remain for all sFLC applications. Differences in reference values and diagnostic performance hamper interchangeability of sFLC assays. Assay specific sFLC decision guidelines are warranted.
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Cadenas Ligeras de Inmunoglobulina , Paraproteinemias , Ensayo de Inmunoadsorción Enzimática , Humanos , Cadenas kappa de Inmunoglobulina , Cadenas lambda de Inmunoglobulina , Paraproteinemias/diagnósticoRESUMEN
The phase 3 MIRROS (MDM2 antagonist Idasanutlin in Relapsed or Refractory acute myeloid leukemia [AML] for Overall Survival) trial (NCT02545283) evaluated the efficacy and safety of the small-molecule MDM2 antagonist idasanutlin plus cytarabine in patients with relapsed/refractory (R/R) AML. Adults (n = 447) with R/R AML whose disease relapsed or was refractory after ≤2 prior induction regimens as initial treatment or following salvage chemotherapy regimen, with Eastern Cooperative Oncology Group performance status ≤2 were enrolled regardless of TP53 mutation status and randomly assigned 2:1 to idasanutlin 300 mg or placebo orally twice daily plus cytarabine 1 g/m2 IV on days 1 to 5 of 28-day cycles. At primary analysis (cutoff, November 2019), 436 patients were enrolled, including 355 in the TP53 wild-type intention-to-treat (TP53WT-ITT) population. The primary endpoint, overall survival in the TP53WT-ITT population, was not met (median, 8.3 vs 9.1 months with idasanutlin-cytarabine vs placebo-cytarabine; stratified hazard ratio [HR], 1.08; 95% confidence interval [CI], 0.81-1.45; P = .58). The complete remission (CR) rate, a key secondary endpoint, was 20.3% vs 17.1% (odds ratio [OR], 1.23; 95% CI, 0.70-2.18). The overall response rate (ORR) was 38.8% vs 22.0% (OR, 2.25; 95% CI, 1.36-3.72). Common any-grade adverse events (≥10% incidence in any arm) were diarrhea (87.0% vs 32.9%), febrile neutropenia (52.8% vs 49.3%), and nausea (52.5% vs 31.5%). In summary, despite improved ORR, adding idasanutlin to cytarabine did not improve overall survival or CR rates in patients with R/R AML.
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Citarabina , Leucemia Mieloide Aguda , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Humanos , Pirrolidinas , para-Aminobenzoatos/uso terapéuticoRESUMEN
BACKGROUND: Acute graft-versus-host disease (GVHD) is a common and life-threatening complication of allogeneic haematopoietic stem cell transplantation (HSCT); there is an urgent unmet need for effective therapies. We aimed to evaluate the Janus kinase 1 inhibitor itacitinib versus placebo, both in combination with corticosteroids, for initial treatment of acute GVHD. METHODS: GRAVITAS-301 was an international, double-blind, adaptive (group sequential design) phase 3 study conducted at 129 hospitals and community practices in 19 countries. Eligible patients were aged 18 years or older, had previously received allogeneic HSCT for a haematological malignancy, developed grades II-IV acute GVHD, and received up to 2 days of systemic corticosteroids. Patients were stratified by clinical standard-risk or high-risk acute GVHD and randomly assigned (1:1), via a centralised interactive voice response system, to receive either oral itacitinib (200 mg) or placebo once daily, both in addition to corticosteroids. The primary endpoint was overall response rate (ORR) at day 28 (defined as the proportion of patients with complete response, very good partial response, or partial response 28 days after the start of treatment). For sample size determination, an absolute improvement in ORR at day 28 over standard therapy of 16% was considered clinically meaningful. Efficacy analyses were performed in the intention-to-treat population; safety analyses included patients who received at least one dose of study drug. GRAVITAS-301 is registered with ClinicalTrials.gov (NCT03139604) and is complete. FINDINGS: Between July 19, 2017, and Oct 3, 2019, 439 patients were randomly assigned to receive either itacitinib plus corticosteroids (n=219; itacitinib group) or placebo plus corticosteroids (n=220; placebo group). 173 (39%) patients were female and 390 (89%) were White. At baseline, 107 (24%) of 439 patients (itacitinib 51 [23%] of 219; placebo 56 [25%] of 220) had clinical high-risk acute GVHD. The ORR at day 28 was 74% (95% CI 67·6-79·7; 162 of 219; complete response 53% [116 of 219]) for itacitinib and 66% (59·7-72·6; 146 of 220; complete response, 40% [89 of 220]) for placebo (odds ratio for ORR 1·45, 95% CI 0·96-2·20; two-sided p=0·078). Grade 3 or worse adverse events occurred in 185 (86%) of 215 itacitinib recipients and 178 (82%) of 216 placebo recipients, and most commonly included thrombocytopenia or platelet count decreased (78 [36%] vs 68 [31%]), neutropenia or neutrophil count decreased (49 [23%] vs 45 [21%]), anaemia (42 [20%] vs 26 [12%]), and hyperglycaemia (26 [12%] vs 28 [13%]). Treatment-related deaths occurred in three of 215 patients (1%) in the itacitinib group and four of 216 (2%) in the placebo group. INTERPRETATION: The observed improvement in ORR at day 28 with the addition of itacitinib versus placebo to corticosteroids did not reach the prespecified significance level. Further studies might provide additional insight into the utility of selective JAK1 inhibition for the treatment of acute GVHD. FUNDING: Incyte.
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Enfermedad Injerto contra Huésped , Acetonitrilos/efectos adversos , Corticoesteroides/uso terapéutico , Método Doble Ciego , Femenino , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Humanos , Pirazoles/efectos adversos , Pirimidinas/efectos adversos , Pirroles/efectos adversos , Resultado del TratamientoRESUMEN
Clofarabine (CLO) is a nucleoside analog with efficacy in relapsed/refractory acute lymphoblastic leukemia (ALL). This randomized phase 3 study aimed to evaluate whether CLO added to induction and whether consolidation would improve outcome in adults with newly diagnosed ALL. Treatment of younger (18-40 years) patients consisted of a pediatric-inspired protocol, and for older patients (41-70 years), a semi-intensive protocol was used. Three hundred and forty patients were randomized. After a median follow-up of 70 months, 5-year event-free survival (EFS) was 50% and 53% for arm A and B (CLO arm). For patients ≤40 years, EFS was 58% vs 65% in arm A vs B, whereas in patients >40 years, EFS was 43% in both arms. Complete remission (CR) rate was 89% in both arms and similar in younger and older patients. Minimal residual disease (MRD) was assessed in 200 patients (60%). Fifty-four of 76 evaluable patients (71%) were MRD- after consolidation 1 in arm A vs 75/81 (93%) in arm B (P = .001). Seventy (42%) patients proceeded to allogeneic hematopoietic stem cell transplantation in both arms. Five-year overall survival (OS) was similar in both arms: 60% vs 61%. Among patients achieving CR, relapse rates were 28% and 24%, and nonrelapse mortality was 16% vs 17% after CR. CLO-treated patients experienced more serious adverse events, more infections, and more often went off protocol. This was most pronounced in older patients. We conclude that, despite a higher rate of MRD negativity, addition of CLO does not improve outcome in adults with ALL, which might be due to increased toxicity. This trial was registered at www.trialregister.nl as #NTR2004.
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Trasplante de Células Madre Hematopoyéticas , Adulto , Anciano , Niño , Clofarabina , Humanos , Neoplasia Residual , Recurrencia , Inducción de RemisiónRESUMEN
PURPOSE: Proteasome inhibitors are effective in Waldenström's macroglobulinemia (WM) but require parenteral administration and are associated with polyneuropathy. We investigated efficacy and toxicity of the less neurotoxic oral proteasome inhibitor ixazomib combined with rituximab, in patients with relapsed WM. METHODS: We conducted a multicenter phase I/II trial with ixazomib, rituximab, and dexamethasone (IRD). Induction consisted of eight cycles IRD wherein rituximab was started in cycle 3, followed by rituximab maintenance. Phase I showed feasibility of 4 mg ixazomib. Primary end point for phase II was overall response rate (ORR [≥ minimal response]) after induction. RESULTS: A total of 59 patients were enrolled (median age, 69 years; range, 46-91 years). Median number of prior treatments was 2 (range, 1-7); 70% had an intermediate or high WM-IPSS (International Prognostic Scoring System for WM) score. After eight cycles, ORR was 71% (42 out of 59) (14% very good partial response [PR], 37% PR, and 20% minor response). Depth of response improved until month 12 (best ORR 85% [50 out of 59]: 15% very good PR, 46% PR, and 24% minor response). Median duration of response was 36 months. The average hematocrit level increased significantly (0.33-0.38 L/L) after induction (P < .001). After two cycles of ixazomib and dexamethasone, immunoglobulin M levels decreased significantly (median 3,700-2,700 mg/dL, P < .0001). Median time to first response was 4 months. Median progression-free survival and overall survival were not reached. After median follow-up of 24 months (range, 7.4-54.3 months), progression-free survival and overall survival were 56% and 88%, respectively. Toxicity included mostly grade 2 or 3 cytopenias, grade 1 or 2 neurotoxicity, and grade 2 or 3 infections. No infusion-related reactions or immunoglobulin M flare occurred with use of subcutaneous rituximab. Quality of life improved significantly after induction. In total, 48 patients (81%) completed at least six cycles of IRD. CONCLUSION: Combination of IRD shows promising efficacy with manageable toxicity in patients with relapsed or refractory WM.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Compuestos de Boro/administración & dosificación , Dexametasona/administración & dosificación , Glicina/análogos & derivados , Inhibidores de Proteasoma/administración & dosificación , Rituximab/administración & dosificación , Macroglobulinemia de Waldenström/tratamiento farmacológico , Administración Oral , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Compuestos de Boro/efectos adversos , Dexametasona/efectos adversos , Europa (Continente) , Estudios de Factibilidad , Femenino , Glicina/administración & dosificación , Glicina/efectos adversos , Humanos , Infusiones Subcutáneas , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Inhibidores de Proteasoma/efectos adversos , Rituximab/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Macroglobulinemia de Waldenström/diagnósticoAsunto(s)
Hematología , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Azacitidina/farmacología , Azacitidina/uso terapéutico , Bélgica , Humanos , Leucemia Mieloide Aguda/terapia , Transfusión de Linfocitos , Linfocitos , Síndromes Mielodisplásicos/terapia , Estudios Prospectivos , Recurrencia , Estudios RetrospectivosRESUMEN
Shallow-depth sequencing of cell-free DNA, a cheap and standardized approach to obtain molecular information on tumors non-invasively, is insufficiently explored for lymphoma diagnosis and disease follow-up. This study collected 318 samples, including longitudinal liquid and paired solid biopsies, from a prospectively recruited cohort of 38 Hodgkin lymphoma (HL) and 85 aggressive B-cell non- HL patients, represented by 81 diffuse large B-cell lymphoma (DLBCL) cases. Following sequencing, copy number alterations and viral read fractions were derived and analyzed. At diagnosis, liquid biopsies showed detectable copy number alterations in 84.2% of HL (88.6% for classical HL) and 74.1% of DLBCL patients. Copy number profiles between liquid-solid pairs were highly concordant within DLBCL (r=0.815±0.043); and, compared to tissue, HL liquid biopsies had abnormalities with higher amplitudes (P=.010), implying that tumor DNA is more abundant in plasma. Additionally, 39.5% of HL and 13.6% of DLBCL cases had a significantly elevated number of plasmatic Epstein-Barr virus DNA fragments, achieving a sensitivity of 100% compared to current standard. Longitudinal analysis determined that, when detectable, copy number patterns were similar across (re)staging moments in refractory/relapsed patients. Moreover, the overall profile anomaly highly correlated with the total metabolic tumor volume (P.
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Ácidos Nucleicos Libres de Células , Infecciones por Virus de Epstein-Barr , Enfermedad de Hodgkin , Linfoma de Células B Grandes Difuso , Herpesvirus Humano 4/genética , Enfermedad de Hodgkin/diagnóstico , Enfermedad de Hodgkin/genética , Humanos , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/genéticaRESUMEN
BACKGROUND: Hyperproliferative crises with hyperleukocytosis occur frequently in the disease course of refractory or relapsed acute myeloid leukemia (AML). Palliative cytoreduction aims to control blast count in order to avoid life-threatening complications and preserve quality of life in patients unfit for intensive treatment. In our center, low-dose intravenous melphalan is sometimes used with this intent. METHODS: We performed a retrospective analysis of patients with AML who were treated with low-dose intravenous melphalan (15-30 mg/m2) in a palliative setting. RESULTS: Thirty patients with AML who received low-dose melphalan (15-25 mg/m2) were identified. In total, 63 administrations of low-dose melphalan were counted. A clear cytoreductive effect (>50%) was seen within a few days in 78% of melphalan administrations. The median duration of response after an individual dose was 17 days (interquartile range [IQR] 10-26). The median overall survival was 29 days (IQR 16-73). Most common side effects were worsening pancytopenia with neutropenic fever and an increase in transfusion dependency and tumor lysis syndrome. CONCLUSION: Intravenous low-dose melphalan is effective, quick and safe as palliative cytoreductive therapy in patients with hyperproliferative AML. It can be considered in palliative care of patients refractory to prior treatment with preserving acceptable quality of life. Our small retrospective cohort is the first to report the use of low-dose intravenous melphalan as palliative cytoreductive treatment in this population.
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Leucemia Mieloide Aguda , Melfalán , Protocolos de Quimioterapia Combinada Antineoplásica , Procedimientos Quirúrgicos de Citorreducción , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Melfalán/uso terapéutico , Cuidados Paliativos , Calidad de Vida , Estudios RetrospectivosRESUMEN
Therapeutic apheresis (TA) is prescribed to patients that suffer from a severe progressive disease that is not sufficiently treated by conventional medications. A way to gain more knowledge about this treatment is usually by the local analysis of data. However, the use of large quality assessment registries enables analyses of even rare findings. Here, we report some of the recent data from the World Apheresis Association (WAA) registry. Data from >104,000 procedures were documented, and TA was performed on >15,000 patients. The main indication for TA was the collection of autologous stem cells (45% of patients) as part of therapy for therapy. Collection of stem cells from donors for allogeneic transplantation was performed in 11% of patients. Patients with indications such as neurological diseases underwent plasma exchange (28%). Extracorporeal photochemotherapy, lipid apheresis, and antibody removal were other indications. Side effects recorded in the registry have decreased significantly over the years, with approximately only 10/10,000 procedures being interrupted for medical reasons. CONCLUSION: Collection of data from TA procedures within a multinational and multicenter concept facilitates the improvement of treatment by enabling the analysis of and feedback on indications, procedures, effects, and side effects.
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In this phase 3 trial, older patients with acute myeloid leukemia ineligible for intensive chemotherapy were randomized 2:1 to receive the polo-like kinase inhibitor, volasertib (V; 350 mg intravenous on days 1 and 15 in 4-wk cycles), combined with low-dose cytarabine (LDAC; 20 mg subcutaneous, twice daily, days 1-10; n = 444), or LDAC plus placebo (P; n = 222). Primary endpoint was objective response rate (ORR); key secondary endpoint was overall survival (OS). Primary ORR analysis at recruitment completion included patients randomized ≥5 months beforehand; ORR was 25.2% for V+LDAC and 16.8% for P+LDAC (n = 371; odds ratio 1.66 [95% confidence interval (CI), 0.95-2.89]; P = 0.071). At final analysis (≥574 OS events), median OS was 5.6 months for V+LDAC and 6.5 months for P+LDAC (n = 666; hazard ratio 0.97 [95% CI, 0.8-1.2]; P = 0.757). The most common adverse events (AEs) were infections/infestations (grouped term; V+LDAC, 81.3%; P+LDAC, 63.5%) and febrile neutropenia (V+LDAC, 60.4%; P+LDAC, 29.3%). Fatal AEs occurred in 31.2% with V+LDAC versus 18.0% with P+LDAC, most commonly infections/infestations (V+LDAC, 17.1%; P+LDAC, 6.3%). Lack of OS benefit with V+LDAC versus P+LDAC may reflect increased early mortality with V+LDAC from myelosuppression and infections.
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Data on clinical use of ponatinib are limited. This prospective registry aimed to evaluate outcomes of ponatinib treatment in routine practice over 3 years (2016-2019) in Belgium (NCT03678454). Patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) were treated with ponatinib per current label. Fifty patients (33 CML and 17 Ph+ ALL) were enrolled. Fifty-five percent of CML and 29% of Ph+ ALL patients had received ≥3 prior tyrosine kinase inhibitors (TKIs). Reasons for starting ponatinib were intolerance (40%), relapse or refractoriness (28%) to previous TKIs, progression (16%), or T315I mutation (16%). Median follow-up was 15 months for CML and 4.5 months for Ph+ ALL patients. Best response was a major molecular response in 58% of CML and 41% of Ph+ ALL patients. Of 20 patients who started ponatinib due to intolerance to previous TKIs, 9 (64%) CML and 4 (67%) Ph+ ALL achieved a major molecular response. Three-year estimates of overall survival were 85.3% and 85.6%, respectively, in CML and Ph+ ALL patients; estimated progression-free survival was 81.6% and 48.9%. Adverse reactions were reported in 34 patients (68%); rash (26%) and dry skin (10%) were most common. Reported cardiovascular adverse reactions included vascular stenosis (3), arterial hypertension (2), chest pain (1), palpitations (1), and vascular occlusion (1). This Belgian registry confirms results from the PACE clinical trial and supports routine ponatinib use in CML and Ph+ ALL patients who are resistant or intolerant to previous TKIs or with the T315I mutation.
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Antineoplásicos/uso terapéutico , Imidazoles/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridazinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Bélgica , Enfermedades Cardiovasculares/inducido químicamente , Erupciones por Medicamentos/etiología , Sustitución de Medicamentos , Femenino , Estudios de Seguimiento , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Humanos , Ictiosis/inducido químicamente , Imidazoles/efectos adversos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Estudios Prospectivos , Inhibidores de Proteínas Quinasas/efectos adversos , Piridazinas/efectos adversos , Sistema de Registros , Terapia Recuperativa , Resultado del Tratamiento , Adulto JovenRESUMEN
Treatment results of AML in elderly patients are unsatisfactory. We hypothesized that addition of tosedostat, an aminopeptidase inhibitor, to intensive chemotherapy may improve outcome in this population. After establishing a safe dose in a run-in phase of the study in 22 patients, 231 eligible patients with AML above 65 years of age (median 70, range 66-81) were randomly assigned in this open label randomized Phase II study to receive standard chemotherapy (3+7) with or without tosedostat at the selected daily dose of 120 mg (n = 116), days 1-21. In the second cycle, patients received cytarabine 1000 mg/m2 twice daily on days 1-6 with or without tosedostat. CR/CRi rates in the 2 arms were not significantly different (69% (95% C.I. 60-77%) vs 64% (55-73%), respectively). At 24 months, event-free survival (EFS) was 20% for the standard arm versus 12% for the tosedostat arm (Cox-p = 0.01) and overall survival (OS) 33% vs 18% respectively (p = 0.006). Infectious complications accounted for an increased early death rate in the tosedostat arm. Atrial fibrillation was more common in the tosedostat arm as well. The results of the present study show that the addition of tosedostat to standard chemotherapy does negatively affect the therapeutic outcome of elderly AML patients.