Non-Hodgkin’s Lymphoma: Five-year Survival in a Historical Cohort of Patients who Underwent Stem Cell Transplantationin Brazil / Linfoma No-Hodgkin: Supervivencia de Cinco Años en una Cohorte Histórica dePacientes Sometidos a Trasplante de Células Madre en Brasil / Linfoma Não-Hodgkin: Sobrevida de Cinco Anos em uma Coorte Histórica dePacientes Submetidos a Transplante de Células-Tronco no Brasil

Introduction: Several studies have shown the benefits of stem cell transplantation in the treatment of Non-Hodgkin’s lymphoma. Objective: To evaluate survival and associated factors in transplanted Non-Hodgkin’s lymphoma patients in Brazil. Method: We conducted a retrospective analysis of 100 adult patients with Non-Hodgkin’s lymphoma transplanted in a national reference center for hematopoietic stem cell transplantation between 1997 and 2009. Data was obtained from medical charts and included besides socio-demographic and lifestyle variables, others relatedto diagnosis and transplantation. The five-year survival probability was estimated using the Kaplan-Meier method and differences between curves were tested with the log-rank test, assuming statistical significance level of 5%. Cox regression was performed for multivariate analysis. Results: Median age at diagnosis was 43 years (17-65) and 45 years (18-66) at transplantation. Median time between diagnosis and transplantation was 17 months (4-173). The probability of survival at 5 years was 50.8% with a median survival time of 22.5 months. In multivariate analysis, evidence of disease 12 months after transplant (HR: 4.49; 95% CI 2.15-9.39), chemo-sensitivity to the last regimenbefore transplant (HR: 2.92; 95% CI 1.35-6.32) and advanced stage at diagnosis (HR: 1.96, 95% CI 1.02-3.80)were prognostic factors for survival. Conclusion: Median age at transplantation in this cohort was similar to that of other studies but median time between diagnosis and transplantation was higher. Although overall survival (5 years) approached that reported in other studies, different treatment protocols and specific characteristics of each populationlimit comparisons

Comparison between horse and rabbit antithymocyte globulin as first-line treatment for patients with severe aplastic anemia: a single-center retrospective study.

The best antithymocyte globulin preparation for first-line immune suppression in patients with severe aplastic anemia is still not clear. The aim of this study was to compare hematological response and overall survival in patients submitted to horse or rabbit antithymocyte globulin as first-line treatment for severe aplastic anemia. We retrospectively compared 71 consecutive patients with severe aplastic anemia, classified according to the antithymocyte globulin preparation. Analyses included variables related to patients and to immune suppression. Forty two patients (59.1%) received horse and 29 (40.9%) rabbit antithymocyte globulin. Response rates were higher at 6 months in patients submitted to horse in comparison to rabbit antithymocyte globulin (59.5% versus 34.5% respectively, p = 0.05). Median time to response was similar between the two groups (99 versus 88.5 days, respectively, for horse and rabbit antithymocyte globulin; p = 0.98). Overall survival at 2 years was significantly higher in patients submitted to horse in comparison to rabbit antithymocyte globulin (78.4% versus 55.4%, p = 0.03). Post-treatment response was strongly associated with survival at 2 years (97% in responders versus 41.2% in non-responders, p < 0.001). Use of rabbit antithymocyte globulin was an independent predictor of death (odds ratio 2.5; 95% confidence interval 1.03-6.04; p = 0.04). Rabbit antithymocyte globulin was associated with a significant and prolonged lymphopenia in comparison with horse antithymocyte globulin. Our data suggest the superiority of horse over rabbit antithymocyte globulin as first-line treatment for severe aplastic anemia, both regarding hematological response and survival.

Serum ferritin as risk factor for sinusoidal obstruction syndrome of the liver in patients undergoing hematopoietic stem cell transplantation.

Hepatic sinusoidal obstruction syndrome (SOS) is a serious complication in hematopoietic stem cell transplant (HSCT) recipients. To determine the impact of pretransplantation hyperferritinemia on the risk of SOS after HSC transplantation, we retrospectively studied 427 HSCT recipients (179 autologous and 248 allogeneic). Serum ferritin levels were measured before transplantation. Patients with and without a diagnosis of SOS were compared regarding demographics; underlying disease; transplant characteristics; receipt of imatinib, busulfan, total body irradiation, gemtuzumab, vancomycin, acyclovir, or methotrexate; and baseline serum ferritin. Univariate and multivariate (stepwise logistic regression) analyses were performed. SOS was diagnosed in 88 patients (21%) at a median of 10 days (range, 2-29 days) after transplantation. By multivariate analysis, allogeneic HSC transplantation (odds ratio [OR] = 8.25; 95% confidence interval [95% CI], 3.31-20.57), receipt of imatinib (OR = 2.60; 95% CI, 1.16-5.84), receipt of busulfan (OR = 2.18; 95% CI, 1.25-3.80), and ferritin serum level higher than 1000 ng/dL (OR = 1.78; 95% CI, 1.02-3.08) were risk factors for SOS. A ferritin serum level higher than 1000 ng/dL in the pretransplantation period is an independent risk factor for SOS. The results suggest the need for prospective studies addressing the use of iron chelation in the pretransplantation period.

High CD8+ lymphocyte dose in the autograft predicts early absolute lymphocyte count recovery after peripheral hematopoietic stem cell transplantation.

Early lymphocyte recovery (ELR) after autologous peripheral hematopoietic stem cell transplantation (ASCT) is an independent predictor for survival in patients with hematological and non-hematological cancers. Sixty-five ASCT for hematological cancers were retrospectively analyzed to identify the factors associated with ELR and to assess the impact of different mobilization regimens on the pre-collection absolute lymphocyte count (ALC). The CD8+ lymphocyte dose in the autograft and the pre-mobilization ALC were independently associated with ELR (P < 0.001 and P = 0.008, respectively). CD8+ lymphocyte doses higher than 0.1 x 10(9)/kg were strongly associated with ELR [P < 0.001, odds ratio 25.22, 95% confidence interval (CI) 4.98-127.69] and this cutoff may be used to predict ELR (P = 0.001, area under the curve 0.75, 95% CI 0.62-0.88). Mobilization with granulocyte colony-stimulating factor (G-CSF) alone, the pre-collection ALC and the number of apheresis sessions were independently associated with the CD8+ lymphocyte dose (P = 0.04, P = 0.001, and P < 0.001, respectively). The number of aphereses was the variable with the strongest correlation to the CD8+ lymphocyte dose (r(s) = 0.68, P < 0.001). Median pre-mobilization ALC was higher than pre-collection ALC in the subgroup of patients without ELR mobilized with chemotherapy followed by G-CSF (1090 vs. 758 lymphocytes/microL; P < 0.001). This reduction was not significant in the subgroup with ELR mobilized with chemotherapy plus G-CSF (1920 vs. 1539/microL, respectively; P = 0.23). These results suggest that the CD8+ lymphocyte dose in the autograft is critical for ELR after ASCT and also demonstrates that mobilization with chemotherapy followed by G-CSF significantly decreases the pre-collection ALC, especially in patients with low pre-mobilization ALC.

The impact of addictional chromosomal abnormalities in response to imatinib mesylate therapy for chronic myeloid leukemia

Imatinib induces a complete cytogenetic response in more than 80% of newly diagnosed patients with chronicmyeloid leukemia (CML) in the chronic phase (CP) and in 41% of patients in the first chronic phase after failureof interferon- treatment. However, some patients do not respond completely. Therefore, according to moststudies, drug resistance in CML patients treated with imatinib is correlated with cytogenetic abnormalities acquiredduring treatment. In this study we analyzed 48 CML patients treated with imatinib mesylate after interferon- resistance in order to elucidate the impact of additional chromosomal abnormalities prior to imatinib in response to therapy. Cytogenetic abnormalities in addition to the Philadelphia chromosome (Ph) were detected in 33.3% of patients. Patients with Ph as the sole cytogenetic abnormality prior to imatinib therapy presented a major cytogeneticresponse and significantly longer median overall survival (p=0.006) than patients with additional chromosomalabnormalities. Therefore, in this group of patients, another choice of treatment should be considered, such as stemcell transplantation or combination regimens as appropriate. The present study indicates the importance of detecting a double Ph chromosome prior to imatinib therapy. Patients showing this abnormality did not respond to imatinib, thus indicating the abnormality's association with resistance. Our study suggests that classical cytogenetic analysisis still an important tool prior to and during follow-up of CML patients treated with imatinib.

Imatinibe induz à resposta citogenética completa em cerca de 80 por cento dos pacientes diagnosticados com leucemia mielóide crônica (LMC) em fase crônica (FC), e em 41 por cento dos pacientes em primeira FC após falha do tratamento com interferon-alfa. Alguns pacientes, entretanto, não respondem completamente. Em muitos estudos, a resistência à droga em pacientes tratados com imatinibe é correlacionada a alterações cromossômicas adquiridas durante o tratamento. No presente estudo, foram analisados 48 pacientes tratados com imatinibe após resistência ao interferon-alfa, com o objetivo de verificar o impacto das alterações cromossômicas adicionais ao Philadelphia (Ph), prévias à terapia com imatinibe. Alterações adicionais foram detectadas em 33,3 por cento dos pacientes. Pacientes com somente o cromossomo Ph apresentaram melhor taxa de resposta citogenética e sobrevida global significativa maior quando comparados com os pacientes que apresentavam alterações cromossômicas adicionais antes do início da terapia com imatinibe. Assim, nesse grupo de pacientes, a escolha de outra conduta terapêutica, como o transplante de células tronco-hematopoéticas ou regime de combinação de drogas, pode ser indicada. O presente estudo indica a importância do duplo Ph antesdo início da terapia com imatinibe. Todos os pacientes com esta alteração não responderam ao tratamento, sendo a mesma associada à resistência à droga. Este estudo sugere que a citogenética clássica permanece como uma ferramenta importante no monitoramento de pacientes portadores de LMC tratados com imatinibe.

Karyotype abnormalities and their clinical significance in a group of chronic myeloid leukemia patients treated with hematopoietic stem cell transplantation.

CONTEXT AND OBJECTIVE: Following hematopoietic stem cell transplantation (HSCT), karyotyping is a valuable tool for monitoring engraftment and disease status. Few studies have examined the prognostic significance of karyotypes in patients who underwent HSCT for chronic myeloid leukemia (CML). The objective of this study was to evaluate the significance of pretransplantation cytogenetic status in relation to outcomes following HSCT in CML patients. DESIGN AND SETTING: Case series study at Instituto Nacional do Câncer (INCA), Rio de Janeiro, Brazil. METHODS: Cytogenetic analysis was performed by G banding on 39 patients treated with HSCT. RESULTS: Thirty-one patients were in the chronic phase and eight were in the accelerated phase. Prior to HSCT, additional chromosomal abnormalities on the Philadelphia (Ph) chromosome were found in 11 patients. The most frequent additional abnormality was a double Ph, which was observed in four cases. Following HSCT, full chimeras were observed in 31 patients (79.5%). Among these, 23 (82.3%) had presented Ph as the sole abnormality. Mixed chimeras were observed in seven patients, of which three had additional abnormalities. Only one case did not present any cytogenetic response. Five patients presented cytogenetic relapse associated with clinical relapse following HSCT. Twenty-seven patients are still alive and present complete hematological and cytogenetic remission. CONCLUSION: In our study, the presence of additional abnormalities was not associated with worse outcome and relapse risk. Also, no differences in survival rates were observed. Our study supports the view that classical cytogenetic analysis remains an important tool regarding HSCT outcome.

Karyotype abnormalities and their clinical significance in a group of chronic myeloid leukemia patients treated with hematopoietic stem cell transplantation

CONTEXT AND OBJECTIVE: Following hematopoietic stem cell transplantation (HSCT), karyotyping is a valuable tool for monitoring engraftment and disease status. Few studies have examined the prognostic significance of karyotypes in patients who underwent HSCT for chronic myeloid leukemia (CML). The objective of this study was to evaluate the significance of pretransplantation cytogenetic status in relation to outcomes following HSCT in CML patients. DESIGN AND SETTING: Case series study at Instituto Nacional do Câncer (INCA), Rio de Janeiro, Brazil. METHODS: Cytogenetic analysis was performed by G banding on 39 patients treated with HSCT. RESULTS: Thirty-one patients were in the chronic phase and eight were in the accelerated phase. Prior to HSCT, additional chromosomal abnormalities on the Philadelphia (Ph) chromosome were found in 11 patients. The most frequent additional abnormality was a double Ph, which was observed in four cases. Following HSCT, full chimeras were observed in 31 patients (79.5 percent). Among these, 23 (82.3 percent) had presented Ph as the sole abnormality. Mixed chimeras were observed in seven patients, of which three had additional abnormalities. Only one case did not present any cytogenetic response. Five patients presented cytogenetic relapse associated with clinical relapse following HSCT. Twenty-seven patients are still alive and present complete hematological and cytogenetic remission. CONCLUSION: In our study, the presence of additional abnormalities was not associated with worse outcome and relapse risk. Also, no differences in survival rates were observed. Our study supports the view that classical cytogenetic analysis remains an important tool regarding HSCT outcome.

RESUMO CONTEXTO E OBJETIVO: Após o transplante de células tronco-hematopoéticas (TCTH), o cariótipo é uma ferramenta valiosa para monitorar o status do enxerto e da doença. Poucos estudos investigaram o significado prognóstico do cariótipo nos pacientes que se submeteram ao TCTH para leucemia mielóide crônica (LMC). O objetivo desse estudo foi verificar o significado dos achados citogenéticos pré-TCTH em pacientes portadores de LMC. TIPO DE ESTUDO E LOCAL: Série de casos. Instituto Nacional do Câncer (INCA), Rio de Janeiro, Brasil. METODOLOGIA: Foram realizados estudos citogenéticos por bandeamento G em 39 pacientes submetidos ao TCTH. RESULTADOS: Trinta e um pacientes estavam em fase crônica e oito em fase acelerada. Pré-TCTH, alterações cromossômicas adicionais ao cromossomo Philadelphia (Ph) foram observadas em 11 pacientes. A mais freqüente foi o duplo Ph observado em quatro casos. Após o TCTH, quimerismo total foi observado em 31 pacientes (79,5 por cento). Desses, 23 (82,3 por cento) apresentavam somente o cromossomo Ph. Quimerismo misto foi observado em sete pacientes, sendo três com alterações adicionais ao Ph. Um caso não apresentou resposta ao TCTH. Recaída citogenética associada com recaída clínica foi observada em cinco pacientes. Após o TCTH, 27 pacientes permanecem vivos e com remissão clínica e citogenética. CONCLUSÃO: Em nosso estudo a presença de alterações cromossômicas adicionais ao Ph, prévias ao TCTH, não foi associada com pior evolução, com risco de recaída, bem como não foi observada diferença entre as taxas de sobrevida. Nosso estudo sugere que a citogenética clássica permanece uma grande ferramenta no monitoramento do TCTH.

Low-power laser in the prevention of induced oral mucositis in bone marrow transplantation patients: a randomized trial.

We investigated the clinical effects of low-power laser therapy (LPLT) on prevention and reduction of severity of conditioning-induced oral mucositis (OM) for hematopoietic stem cell transplantation (HSCT). We randomized 38 patients who underwent autologous (AT) or allogeneic (AL) HSCT. A diode InGaAlP was used, emitting light at 660 nm, 50 mW, and 4 J/cm2, measured at the fiberoptic end with 0.196 cm2 of section area. The evaluation of OM was done using the Oral Mucositis Assessment Scale (OMAS) and the World Health Organization (WHO) scale. In the LPLT group, 94.7% of patients had an OM grade (WHO) lower than or equal to grade 2, including 63.2% with grade 0 and 1, whereas in the controls group, 31.5% of patients had an OM grade lower than or equal to grade 2 (P < .001). Remarkably, the hazard ratio (HR) for grades 2, 3, and 4 OM was 0.41 (range, 0.22-0.75; P = .002) and for grades 3 and 4 it was 0.07 (range, 0.11-0.53; P < .001). Using OMAS by the calculation of ulcerous area, 5.3% of the laser group presented with ulcers of 9.1 cm2 to 18 cm2, whereas 73.6% of the control group presented with ulcers from 9.1 cm2 to 18 cm2 (P = .003). Our results indicate that the use of upfront LPLT in patients who have undergone HSCT is a powerful instrument in reducing the incidence of OM and is now standard in our center.

Validation of the EBMT risk score in chronic myeloid leukemia in Brazil and allogeneic transplant outcome.

BACKGROUND AND OBJECTIVES: The management of chronic myeloid leukemia (CML) has changed radically since the introduction of imatinib therapy. The decision of whether to offer a patient a hematopoietic stem cell transplant (HSCT) must be based on the probability of success of the procedure. The aim of this retrospective analysis of 1,084 CML patients who received an allogeneic HSCT in 10 Brazilian Centers between February 1983 and March 2003 was to validate the EBMT risk score. DESIGN AND METHODS: The study population comprised 647 (60%) males and 437 (40%) females, with a median age of 32 years old (range 1 - 59); 898 (83%) were in chronic phase, 146 (13%) were in accelerated phase and 40 (4%) were in blast crisis; 151 (14%) were younger than 20 years old, 620 (57%) were between 20 and 40 and 313 (29%) were older than 40; 1,025 (94%) received an HLA fully matched sibling transplant and only 59 (6%) received an unrelated transplant. In 283 cases (26%) a male recipient received a graft from a female donor. The interval from diagnosis to transplantation was less than 12 months in 223 (21%) cases and greater in 861 (79%). The overall survival, disease-free survival, transplant-related mortality and relapse incidence were 49%, 50%, 45% and 25%, respectively. RESULTS: Of the 1084 patients, 179 (17%) had a risk score of 0 or 1, 397 (37%) had a score of 2, 345 (32%) had a score of 3, 135 (12%) had a score of 4 and 28 (2%) a score of 5 or 6. The overall survival (OS) rate in patients with risk scores 0-1 and 2 was similar (58% and 55%, respectively) but significantly better than that in patients with scores 3 or more (score 3 - 44%, 4 - 36 % and 5-6 - 27%, respectively) pp<0.001). Disease-free survival (DFS) and transplant related mortality (TRM) in a patients with a score of 3 or more were 46% and 49%, respectively and the relapse rate beyond score 5-6 was 77%. Disease status had a negative impact on all outcomes (OS, DFS, TRM, and relapse). The OS rate for male recipients of a graft from a female donor was 40% compared to 52% among the other donor-recipient pairs (p=0.004). DFS and TRM were significant for disease phase and female donor-male recipient (p<0.001 and p<0.003, respectively). In our experience, age and interval between diagnosis and transplant did influence OS, DFS, TRM, and relapse rate. INTERPRETATION AND CONCLUSIONS: Our results validate the EBMT risk score in the context of a developing country and confirm its usefulness for making point decisions in the imatinib era.

Successful treatment of oral lesions of chronic lichenoid graft-vs.-host disease by the addition of low-level laser therapy to systemic immunosuppression.

We report a case of severe oral stomatitis caused by lichenoid chronic graft-vs.-host disease in which low-level laser therapy applied to the oral mucosa, in addition to standard systemic immunosuppressive treatment, resulted in quick healing and symptomatic relief.

Estudo multicêntrico randomizado comparando o uso do fator estimulador de colônias de granulócitos a partir do dia +1 ou dia +5 do transplante autólogo de células progenitoras de sangue periférico

O G-CSF acelera a recuperação neutrofílica quando administrado a partir do D+1 após transplante autólogo de células progenitoras de sangue periférico (CPSP). Alguns estudos sugerem que o uso do G-CSF pode ser iniciado mais tardiamente com a mesma eficácia, mas o melhor momento para o início do G-CSF permanece mal definido. Objetivo. Comparar a eficácia do G-CSF administrado após o transplante autólogo de CPSP a partir do D+ 1 ou D+5, em um ensaio clínico randomizado, multicêntrico. Métodos. Noventa receptores de transplante autólogo de CPSP em quatro instituições foram randomizados para receber G-CSF 5 ug/kg/dia a partir do D+ 1 (grupo A) ou D+5 (grupo B). Foram analisados a duração da neutropenia, a documentação de infecções, a duração da antibioticoterapia e o tempo até a alta hospitalar após o transplante. Resultados. Entre 86 pacientes analisados, 44 receberam G-CSF a partir do dia + 1 e 42 a partir do dia +5. A duração mediana da neutropenia foi um dia mais curta no grupo A (7 dias contra 8 dias; p = 0,02). O tempo para recuperação dos neutrófilos (> 500/ul) e plaquetas (> 50.000/ul) foi semelhante. Em análise estratificada, a duração reduzida da neutropenia observada no grupo A foi estatisticamente significativa apenas nos pacientes que receberam uma dose de CD34+ > 3,0 x 106/kg e condicionamento com melfalano (MEL200). Nestes pacientes, a neutropenia iniciou-se mais tardiamente em relação ao dia do transplante. A freqüência de febre, a documentação de infecções e a mortalidade geral foram iguais. A duração mediana da antibioticoterapia e o tempo para a alta hospitalar foram menores no grupo A, mas o dia de início do G-CSF não foi um fator independentemente preditivo dessas diferenças em análises multivariadas. A duração do tratamento com G-CSF foi três dias menor no grupo B. Conclusões. O uso do G-CSF a partir do dia + 1 reduziu a duração da neutropenia em pacientes que receberam uma dose de CD34+ > 3,0 x 106/kg e o regime MEL200. Nestes pacientes, o uso precoce do G-CSF associou-se a um início mais tardio da neutropenia. A maior duração da antibioticoterapia e da intenação, observadas no grupo B, foram associadas a outros fatores que não o uso tardio do G-CSF em análises multivariadas

Introduction. G-CSF accelerates neutrophil recovery when given from day + 1 after autologous peripheral blood progenitor cell (PBPC) transplants. Some studies suggest that it is possible to delay the start of G-CSF without loss of efficacy, but the best timing for the initiation of G-CSF remains ill-defined. Objective. To compare the efficacy of G-CSF administration starting on day + 1 or day + 5 after autologous PBPC transplantation, in a randomized, multicentric clinical trial. Methods. Ninety recipients of autologous PBPC transplants from four institutions were randomized to receive G-CSF 5 ug/kg/day starting either on day + 1 (group A) or day +5 (group B). The main endpoints were duration of neutropenia, documentation of infections, duration of antibiotic treatment and time to hospital discharge. Results. Among 86 evaluated patients, 44 received G-CSF starting on day + 1 and 42 on day +5. The median duration of neutropenia was one day shorter in group A (7 days versus 8 days; p = 0.02). Time to recovery of neutrophils (> 500/ul) and platelets (> 5O,OOO/ul) was comparable. In stratified analyses, the reduced duration of neutropenia in group A was statistically significant only in patients who received a CD34+ cell dose> 3.0 x 106/kg and conditioning with melphalan (MEL200). In these patients, neutropenia had a later day of onset after the transplant There was no difference in the rates of fever, documentation of infection, and overall mortality. The median duration of antibiotic treatment and time to hospital discharge were shorter in group A, but the day of G-CSF initiation was not an independent predictor of these differences in multivariate analyses. The duration of treatment with G-CSF was three days shorter in group B. Conclusions. The use of G-CSF starting on day + 1 reduced the duration of neutropenia in patients who received a CD34+ cell dose> 3.0 x 106/kg and the MEL200 regimen. In these patients, the earlier initiation of G-CSF resulted in later onset of neutropenia. The longer duration of antimicrobial treatment and of hospital stay observed in group B were associated with factors other than the delayed initiation of G-CSF in multivariate analyses

Micobacteriose Atípica Pós Transplante Alogênico de Medula Ossea / Mycobacteriosis atypical transplant from

Os autores apresentam um raro caso de micobacteriose atípica bem como complicaçöes imunológicas, em um paciente portador de LMC fase crônica submetido a um TMO alogênico com célula-tronco periférica de doador HLA idêntico. Säo discutidas as características clínicas do paciente ao diagnóstico, a terapêutica instituída e as possíveis causas de óbito