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4.
Leuk Lymphoma ; : 1-9, 2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30943056

RESUMO

Induction chemotherapy in AML patients may have life-threatening side effects requiring intensive care unit (ICU) treatment. We analyzed all AML patients receiving intensive chemotherapy at a single academic center between 01/2006-12/2016. At least one ICU admission was observed in 32% (76/240) patients, and 33% of those died following ICU admission. Whereas the ICU admission proportion remained stable, mortality after ICU admission decreased from 14% (2006-2008) to 3% (2014-2016; p = .056). The number of failing organ systems inversely correlated with surviving ICU admission (p < .001). Sepsis and renal, cardiac and pulmonary failure were each associated with higher mortality. With increasing ICU duration, survival probability decreased (p < .001), but remained >50% even after 14 days of ICU treatment. Progression-free and overall survival were comparable between ICU surviving patients and patients never needing ICU support. In conclusion, outcome after ICU admission of AML patients has substantially improved in recent years.

5.
Swiss Med Wkly ; 149: w20031, 2019 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-30943308

RESUMO

This update on plasma cell myeloma has been elaborated by a Swiss expert panel as a result of the plethora of new data on the treatment of plasma cell myeloma reported recently. It adds new insights to the more extensive review that was published 3 years ago and may help clinicians on decision making for their patients. The new recommendations for distinguishing plasma cell myeloma from smouldering myeloma are briefly presented, including a section on contemporary imaging studies with this respect. Former panel recommendations that remain unchanged by new results will not be discussed in detail as the major focus of this review is on treatment-relevant new developments.

8.
Infect Dis (Lond) ; 51(6): 409-416, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30821562

RESUMO

BACKGROUND: Patients with haematologic malignancies receiving chemotherapy have a high risk of developing febrile neutropenia and bloodstream infections. The benefit of adjunctive gentamicin treatment for enterococcal bloodstream infections is debated. In this study, we compare the treatment outcome of a cell wall-active antibiotic with and without gentamicin for enterococcal bacteraemia in patients with neutropenia. METHODS: The observational study was performed from 1999 through 2016. Patients with bacteraemia due to non-high level gentamicin-resistant enterococci were included. Analyses were performed in two data sets of episodes with enterococcal bacteraemia. One data set consisting of all included episodes (full cohort, n = 154) and one with propensity score-matched episodes (n = 96). The primary endpoint was death within 30 days, and the secondary outcomes were defervescence and persistence of enterococcal bloodstream infection after initiation of anti-enterococcal therapy. RESULTS: Episodes with gentamicin treatment (n = 82, full cohort; n = 48, propensity score-matched cohort) were comparable with episodes without gentamicin treatment (n = 72, full cohort; n = 48, propensity score-matched cohort) with regard to patient- and disease-related characteristics. Enterococcus faecium (40.9%) was the most frequently isolated organism. In the propensity score-matched cohort, there was no difference in 30-days mortality (14.6% in episodes with gentamicin versus 16.7% in episodes without gentamicin, p = 1), median time to defervescence (1 versus 2 days, p = .37) or persistence of enterococcal bloodstream infection for ≥72 h (9.4% versus 7.5%, p = 1). CONCLUSIONS: In our study with neutropenic patients, treatment with a cell wall-active antibiotic without adjunctive gentamicin for episodes with enterococcal bloodstream infection was as effective as combination therapy with gentamicin.

9.
World J Pediatr ; 2019 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-30729445

RESUMO

BACKGROUND: Diffusion-weighted imaging (DWI) of synovitis has been suggested as a possible non-invasive alternative to contrast-enhanced T1w imaging (ce-T1w). We aimed to study DWI for diagnosing synovitis in the knee joint of pediatric patients, to quantify inter-observer agreement on DWI and ce-T1w and to calculate quantitative measures of synovial diffusivity and conspicuity. METHODS: Forty consecutive patients with known or suspected arthritis of the knee (25 girls, median age 12 years) underwent routine 1.5T MRI with ce-T1w and transverse DWI with b values 50 and 800 s/mm2. Mean apparent diffusion coefficient (ADC) values and signal intensity of inflamed synovium, joint effusion and muscle were measured with regions of interest retrospectively. Post-contrast T1w images (diagnostic standard) and diffusion-weighted images at b = 800 s/mm2 with ADC map were separately rated by three independent and blinded readers with different levels of expertise for the presence and degree of synovitis along with the level of diagnostic confidence. RESULTS: Thirty-one (78%) patients showed at least some synovial contrast enhancement, 17 (43%) children were diagnosed with synovitis on ce-T1w. Ratings by the 1st reader on ce-T1w and on DWI for synovitis showed very good agreement (kappa = 0.90). Inter-observer agreement on DWI ranged from moderate to substantial with kappa values between 0.68 and 0.79 (all P < 0.001). Agreement and diagnostic confidence were generally lower in patients with mild and without synovial enhancement, compared to patients with synovitis. DWI yielded higher signal of inflamed synovium vs. muscle tissue, but lower signal vs. joint effusion, compared to ce-T1w (all P < 0.001). CONCLUSIONS: Diffusion-weighted imaging is a promising, though reader-dependent alternative to contrast-enhanced imaging in patients with arthritis of the knee, based on our preliminary findings. It holds potential for increasing patient safety and comfort.

11.
Leukemia ; 33(5): 1102-1112, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30542144

RESUMO

Current risk algorithms are primarily based on pre-treatment factors and imperfectly predict outcome in acute myeloid leukemia (AML). We introduce and validate a post-treatment approach of leukemic stem cell (LSC) assessment for prediction of outcome. LSC containing CD34+CD38- fractions were measured using flow cytometry in an add-on study of the HOVON102/SAKK trial. Predefined cut-off levels were prospectively evaluated to assess CD34+CD38-LSC levels at diagnosis (n = 594), and, to identify LSClow/LSChigh (n = 302) and MRDlow/MRDhigh patients (n = 305) in bone marrow in morphological complete remission (CR). In 242 CR patients combined MRD and LSC results were available. At diagnosis the CD34+CD38- LSC frequency independently predicts overall survival (OS). After achieving CR, combining LSC and MRD showed reduced survival in MRDhigh/LSChigh patients (hazard ratio [HR] 3.62 for OS and 5.89 for cumulative incidence of relapse [CIR]) compared to MRDlow/LSChigh, MRDhigh/LSClow, and especially MRDlow/LSClow patients. Moreover, in the NPM1mutant positive sub-group, prognostic value of golden standard NPM1-MRD by qPCR can be improved by addition of flow cytometric approaches. This is the first prospective study demonstrating that LSC strongly improves prognostic impact of MRD detection, identifying a patient subgroup with an almost 100% treatment failure probability, warranting consideration of LSC measurement incorporation in future AML risk schemes.


Assuntos
Antígenos CD34/metabolismo , Contagem de Células , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Células-Tronco Neoplásicas/metabolismo , ADP-Ribosil Ciclase 1/metabolismo , Adolescente , Adulto , Idoso , Biomarcadores , Feminino , Citometria de Fluxo , Humanos , Imunofenotipagem , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Recidiva , Reprodutibilidade dos Testes , Análise de Sobrevida , Adulto Jovem
12.
Eur J Intern Med ; 58: 28-32, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30527920

RESUMO

Most patients above 60 years with acute myeloid leukemia (AML) will die from their disease. Nevertheless, the treatment concepts in elderly patients with myelodysplastic syndromes (MDS) and AML are rapidly evolving. A number of recent reports have identified better survival rates with intensive induction chemotherapy for patients up to 80 years, with the exception of patients with unfavorable genomic risk abnormalities or with major co-morbidities. Gemtuzumab ozogamicin is increasingly added to induction therapy for AML patients up to 70 years with favorable or intermediate risk profile, and Midostaurin for patients with a FLT3 mutation. The recommended dose of daunorubicin is 60 mg/m2 for 3 + 7 induction therapy. Elderly patients with acute promyelocytic leukemia should receive all-trans retinoic acid and arsenic trioxide, and cytotoxic treatment is limited upfront to patients with initial leukocytosis. Allogeneic transplantation can be recommended to selected patients up to 70-75 years. For patients unfit for intensive treatment, therapeutic options comprise a hypomethylating agent (HMA), low-dose cytarabin and supportive care. HMA treatment is also increasingly applied for relapsed/refractory AML after intensive chemotherapy. A considerable number of candidate compounds are currently being studied in older AML patients, with their potential role in the treatment of elderly AML patients remaining to be clarified.


Assuntos
Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Idoso , Aminoglicosídeos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Daunorrubicina/administração & dosagem , Avaliação Geriátrica , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Indução de Remissão , Estaurosporina/análogos & derivados , Estaurosporina/uso terapêutico
13.
Blood Cancer J ; 8(11): 113, 2018 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-30420667

RESUMO

Given the vast phenotypic and genetic heterogeneity of acute and chronic myeloid malignancies, hematologists have eagerly awaited the introduction of next-generation sequencing (NGS) into the routine diagnostic armamentarium to enable a more differentiated disease classification, risk stratification, and improved therapeutic decisions. At present, an increasing number of hematologic laboratories are in the process of integrating NGS procedures into the diagnostic algorithms of patients with acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and myeloproliferative neoplasms (MPNs). Inevitably accompanying such developments, physicians and molecular biologists are facing unexpected challenges regarding the interpretation and implementation of molecular genetic results derived from NGS in myeloid malignancies. This article summarizes typical challenges (Table 1) that may arise in the context of NGS-based analyses at diagnosis and during follow-up of myeloid malignancies. Table 1 Challenges accompanying the introduction of massive parallel sequencing in clinical routine diagnostics in hemato-oncology Challenge Background Current and future approach Discrimination of leukemia-related mutations from polymorphisms or passenger mutations Driver mutations expected to occur at higher allele frequency in patient samples than passenger mutations; driver mutations more likely to have an impact on protein function than polymorphisms or passenger mutations Optimization of cancer-specific databases including reporting of rare physiological gene variants Implementation of novel bioinformatic algorithms based on prediction of functional impact Quantitative and dynamic VAF monitoring (separately and together with other mutations) at follow-up Discrimination of somatic leukemia-related mutations from CHIP CHIP is presented in ~10% of individuals aged 70 to 80 and in up to 20% in the age group > 80 years Quantitative and dynamic VAF monitoring (separately and together with other mutations) at follow-up Clarifying the significance of CHIP in the context of myeloid malignancies Discrimination of leukemia-related somatic mutations from pathogenic germline alterations Challenge to differentiate acquired somatic mutations from germline pathogenic variants at diagnosis Mutation detection in germline control samples (e.g., skin fibroblasts, saliva) in mutations such as in RUNX1, CEBPA Thorough medical family history followed by molecular genetic tests in relatives if necessary High and stable VAF (e.g., 40-50%) at follow-up despite clinical response to treatment may be indicative for germline alteration Discrimination of true genetic alterations from PCR, sequencing and post-sequencing artifacts Many artefacts are known to arise during NGS library preparation, sequencing and data analysis Error correction using molecular identifiers that individually label original input DNA molecules Refinement of error-correction computational methods in post-sequencing NGS data analysis Confirmation using Sanger sequencing Limited sensitivity of NGS for minimal residual disease (MRD) assessment Mutations detected at diagnosis may be re-identified at best to a VAF of 1-2% Error-corrected sequencing using molecular identifiers Complementation of NGS by established MRD tools like real-time PCR and flow cytometry High financial burden; demand on interdisciplinary approaches Expensive technical and staff equipment, sophisticated data interpretation Complex translation of NGS results into therapeutic decisions Development of continuously updated NGS interpretation sets and algorithms for well-established mutational profiles within distinct hematological malignancies Interdisciplinary leukemia boards VAF variant allele frequency, CHIP clonal hematopoiesis of indeterminate significance, bp base pairs, G guanine, C cytosine, ITDs internal tandem duplication.

14.
Artigo em Inglês | MEDLINE | ID: mdl-30390061

RESUMO

The optimal melphalan dose prior to autologous stem cell transplantation (ASCT) is not known for elderly multiple myeloma (MM) patients. We analyzed data of all MM patients ≥65 years (n = 388) enrolled in the observational Swiss Blood Stem Cell Transplantation Registry. The median age was 67 years (65-77). Single ASCT was performed in 344 (88.7%) patients, with 259 patients (75.3%) receiving a melphalan dose of 200 mg/m2 (MEL200), and 85 patients (24.7%) receiving lower doses (MELlow) (median 140 mg/m2, range 70-180 mg/m2). MEL200 patients were slightly younger, and had a better renal function, but did not differ with regards to ISS stage, cytogenetic risk, remission status, and KPS. Overall mortality at day 100 was 1.5% without differences between the MEL groups (p = 0.621). Median progression-free survival (PFS) in the MEL200 and the MELlow group was 27.7 and 22.1 months, respectively (p = 0.294). Median overall survival (OS) in the MEL200 and in MELlow group was 91.2 and 61.2 months (p = 0.015). However, multivariate analysis showed no significant association of the melphalan dose and OS (HR 0.734; CI95% 0.264-2.038; p = 0.553). In conclusion, our data reveal no significant differences in safety and PFS for elderly myeloma patients treated with MEL200 or with lower MEL doses.

15.
Artigo em Inglês | MEDLINE | ID: mdl-30353065

RESUMO

Collection of peripheral blood progenitor cells by leukapheresis is the preferred method to obtain grafts for autologous transplantation. Optimizing this procedure is important to warrant sufficient cell yield and reduce associated risks. To obtain sufficient to optimal yields of ≥ 2 to ≥ 5 × 106 CD34+ cells/kg body weight with a single leukapheresis procedure, success rates between 83 and 92% have been reported in children. In this retrospective study, we describe an improved protocol for autologous stem cell collection with an extraordinarily high success rate applied in 122 consecutive pediatric patients treated at the University Hospital Bern between 2004 and 2017. By comparing our data with previous studies, we identify two main optimizing factors: higher pre-apheresis CD34+ cell counts with a median of 130/µl and higher blood flow rates of 42-100 ml/min. Consequently, blood volumes processed were increased, duration of leukapheresis was shorter and CD34+ cell yields with a median of 19.0 × 106/kg body weight were higher than previously described. Safety in our study was comparable to previous studies. Based on our data, we present an innovative algorithm for determination of the necessary blood volume and time of pediatric leukapheresis procedure.

16.
Lancet Haematol ; 5(10): e462-e473, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30290903

RESUMO

BACKGROUND: Although intensified chemotherapy regimens have improved tumour control and survival in advanced-stage Hodgkin's lymphoma, data on the long-term sequelae are scarce. We did preplanned follow-up analyses of the German Hodgkin Study Group (GHSG) trials HD9 and HD12 to assess whether the primary results of these trials-which had shown that intensive initial therapy in advanced-stage Hodgkin's lymphoma has a beneficial effect on treatment outcomes-would continue with longer follow-up. METHODS: In HD9 (Feb 1, 1993, to March 10, 1998), 1282 patients with newly diagnosed, histology-proven, advanced-stage Hodgkin's lymphoma received eight alternating cycles of COPP and ABVD (COPP/ABVD), eight cycles of bBEACOPP, or eight cycles of eBEACOPP. In HD12 (Jan 4, 1999, to Jan 13, 2003; registered with ClinicalTrials.gov [NCT00265031]), 1670 patients with newly diagnosed, histology-proven, advanced-stage Hodgkin's lymphoma received eight cycles of eBEACOPP or four cycles of eBEACOPP plus four cycles of bBEACOPP (4 + 4), plus consolidation radiotherapy to initial bulk and residual disease or no radiotherapy, to analyse two non-inferiority objectives. In both trials, randomisation was done centrally in the GHSG trial coordination centre using the minimisation method including a random component, stratified according to centre, age, stage, international prognostic score, the presence or absence of a large mediastinal mass, and bulky disease. Patients and investigators were not masked to treatment allocation. All analyses were done on the intention-to-treat principle. The primary endpoint of this follow-up analysis was progression-free survival (time from first diagnosis to progressive disease, relapse, or death from any cause or censoring at the date of last information on disease status). To assess whether long-term outcome might be impaired by long-term sequelae, we analysed overall survival and second primary malignant neoplasm incidence as key secondary endpoints. FINDINGS: Median observation time was 141 months (IQR 101-204) in HD9 and 97 months (69-143) in HD12. For HD9 trial patients, 15-year progression-free survival was 57·0% (95% CI 50·0-64·0) for COPP/ABVD, 66·8% (61·9-71·8) for bBEACOPP, and 74·0% (69·0-79·0) for eBEACOPP, 15-year overall survival was 72·3% (95% CI 66·5-78·1), 74·5% (70·1-78·9), and 80·9% (76·7-85·0), respectively. Progression-free survival and overall survival in the eBEACOPP group remained significantly better than in the COPP/ABVD group (hazard ratio [HR] 0·53, 95% CI 0·41-0·69, p<0·0001, and 0·68, 0·50-0·93, p=0·015, respectively). The 15-year cumulative incidence of second primary malignant neoplasms was 7·2% (95% CI 3·7-10·7) after COPP/ABVD, 13·0% (9·1-16·9) after bBEACOPP, and 11·4% (7·6-15·1) after eBEACOPP. For HD12 trial patients, non-inferiority of 4 + 4 was shown, with 10-year progression-free survival of 82·6% (95% CI 79·6-85·6) for eBEACOPP and 80·6% (77·4-83·7) for 4 + 4 (HR 1·13 [0·89-1·43], within non-inferiority margin of 1·50), and 10-year overall survival of 87·3% (95% CI 84·7-89·9) and 86·8% (84·2-89·4), respectively (HR 1·02 [95% CI 0·77-1·36]). Among 555 (37%) patients with residual disease after chemotherapy, omission of radiotherapy was associated with significantly worse 10-year progression-free survival (89·7% [95% CI 85·8-93·6] radiotherapy vs 83·4% [78·2-88·5] for no radiotherapy; p=0·027) and 10-year overall survival (94·4% [91·4-97·3] vs 88·4% [83·8-93·0]; p=0·025). 10-year cumulative second primary malignant neoplasms incidence was 6·4% (95% CI 3·3-9·5) for 4 + 4 and 8·8% (5·2-12·4) for eBEACOPP. INTERPRETATION: Long-term follow-up of HD9 and HD12 shows an ongoing benefit of intensive first-line treatment and consolidation radiotherapy to residual disease in terms of progression-free survival and overall survival. Our results support the use of eBEACOPP in advanced-stage Hodgkin's lymphoma. However, because late toxicities such as second primary malignant neoplasms contribute to mortality, less toxic but equally effective treatments need to be developed to further improve overall survival. FUNDING: Deutsche Krebshilfe e.V.


Assuntos
Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/patologia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica , Ciclofosfamida , Feminino , Humanos , Masculino , Estadiamento de Neoplasias , Prednisona , Procarbazina , Análise de Sobrevida , Resultado do Tratamento , Vincristina , Adulto Jovem
18.
Transfusion ; 58(10): 2365-2373, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30203418

RESUMO

BACKGROUND: Patients with acute myeloid leukemia (AML) undergoing consolidation with autologous stem cell transplantation (ASCT) depend on the successful mobilization of peripheral blood stem cells. However, the factors affecting the mobilization potential in AML patients and, in particular, the effect of transfusion-related iron overload on peripheral blood stem cell mobilization are largely unknown. STUDY DESIGN AND METHODS: We investigated the association of varying levels of iron overload and stem cell mobilization efficacy in consecutive AML patients after two induction cycles. RESULTS: A total of 113 AML patients in early first complete remission underwent the mobilization procedure. While 84 (74.3%) patients had serum ferritin levels exceeding 1000 µg/L, 26 (23.0%) patients had levels even higher than 2000 µg/L. Iron overload correlated with the number of preceding red blood cell transfusions and inversely correlated with circulating CD34+ cell levels (p = 0.04) at apheresis. Finally, the median progression-free and overall survival rates of patients with ferritin levels of higher than 2000 µg/L were shorter with 332 days versus 2156 days (p = 0.04) and 852 days versus 2235 days (p = 0.04), respectively. CONCLUSION: Our data suggest that transfusion-related iron overload is suppressing the mobilization potential and is associated with inferior outcome in AML.

19.
Cancers (Basel) ; 10(9)2018 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-30235847

RESUMO

While the majority of patients with acute myeloid leukemia (AML) are above the age of 65 years at diagnosis, the outcome of older AML patients remains disappointing. Even if standard intensive chemotherapy induces morphologic complete remission (CR1), relapses in older AML patients are common leading to poor long-term survival outcomes. Since autologous hematopoietic stem cell transplantation (HCT) offers distinct anti-leukemic effectiveness while avoiding graft-versus-host disease associated with allogeneic transplantation, it represents an option for consolidation treatment in selected older AML patients. However, prospective studies in older AML patients assessing the benefit of autologous HCT compared to chemotherapy consolidation or allogeneic transplantation are lacking. Consequently, clinicians face the dilemma that there is considerable ambiguity on the most appropriate consolidation treatment for older AML patients in CR1. This review highlights the possible role of autologous HCT for consolidation in older AML patients reaching CR1 after induction treatment.

20.
Hematol Oncol ; 36(4): 671-678, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30110717

RESUMO

Consolidation in myeloma patients with high-dose melphalan chemotherapy (Mel HDCT) and autologous transplantation (ASCT) is standard of care since more than 2 decades. However, definite cure remains exceptional despite intensive treatment, and improving effectiveness of HDCT remains an unmet clinical need. Combining intensified bendamustine with melphalan may represent an option. We analyzed safety and efficacy of combining dose-intensified bendamustine (200 mg/m2 on days -4/-3) with high-dose melphalan (100 mg/m2 on days -2/-1) before a second (tandem) ASCT in adverse risk myeloma patients after Mel HDCT/ASCT1. Twelve patients received BenMel conditioning before ASCT2 because of high-risk cytogenetics and/or failure to achieve complete remission (CR) after Mel HDCT/ASCT1. Comparing Mel HDCT/ASCT1 and BenMel HDCT/ASCT2, we observed no differences in hematologic recovery and tolerance. Acute renal injury after BenMel conditioning occurred in 3 (25%) patients, but was reversible in all patients, and there were no treatment related deaths. Complete remission rates were increasing from 42% after Mel/ASCT1 to 75% after BenMel/ASCT2. PFS 1 year after ASCT2 was 67%, and OS was 83%. These data suggest that dose-intensified bendamustine with melphalan conditioning is safe and warrants a prospective randomized comparison to standard melphalan HDCT in myeloma patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Transplante de Células-Tronco Hematopoéticas/métodos , Mieloma Múltiplo/terapia , Condicionamento Pré-Transplante/métodos , Adulto , Idoso , Antígenos CD34/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cloridrato de Bendamustina/administração & dosagem , Cloridrato de Bendamustina/efeitos adversos , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Estimativa de Kaplan-Meier , Masculino , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Condicionamento Pré-Transplante/efeitos adversos , Transplante Autólogo
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