A retrospective comparison of cyclophosphamide plus antithymocyte globulin with cyclophosphamide plus busulfan as the conditioning regimen for severe aplastic anemia.

Allogeneic hematopoietic stem cell transplantation (AHSCT) is the treatment of choice for young patients with severe aplastic anemia (SAA). The association of antithymocyte globulin (ATG) and cyclophosphamide (CY) is the most frequently used conditioning regimen for this disease. We performed this retrospective study in order to compare the outcomes of HLA-matched sibling donor AHSCT in 41 patients with SAA receiving cyclophosphamide plus ATG (ATG-CY, N = 17) or cyclophosphamide plus busulfan (BU-CY, N = 24). The substitution of BU for ATG was motivated by the high cost of ATG. There were no differences in the clinical features between the two groups, including age, gender, cytomegalovirus status, ABO match, interval between diagnosis and transplant, and number of total nucleated cells infused. No differences were observed in the time to neutrophil and platelet engraftment, or in the risk of veno-occlusive disease and hemorrhage. However, there was a higher risk of mucositis in the BU-CY group (71 vs 24%, P = 0.004). There were no differences in the incidence of neutrophil and platelet engraftment, acute and chronic graft-versus-host disease, and transplant-related mortality. There was a higher incidence of late rejection in the ATG-CY group (41 vs 4%, P = 0.009). Although the ATG-CY group had a longer follow-up (101 months) than the BU-CY group (67 months, P = 0.04), overall survival was similar between the groups (69 vs 58%, respectively, P = 0.32). We conclude that the association BU-CY is a feasible option to the conventional ATG-CY regimen in this population.

A retrospective compariso of cyclophosphamide plus antithymocyte globulin with cyclophosphamide plus busulfan as the conditioning regimen for severe aplastic anemia

Allogeneic hematopoietic stem cell transplantation (AHSCT) is the treatment of choice for young patients with severe aplastic anemia (SAA). The association of antithymocyte globulin (ATG) and cyclophosphamide (CY) is the most frequently used conditioning regimen for this disease. We performed this retrospective study in order to compare the outcomes of HLA-matched sibling donor AHSCT in 41 patients with SAA receiving cyclophosphamide plus ATG (ATG-CY, N = 17) or cyclophosphamide plus busulfan (BU-CY, N = 24). The substitution of BU for ATG was motivated by the high cost of ATG. There were no differences in the clinical features between the two groups, including age, gender, cytomegalovirus status, ABO match, interval between diagnosis and transplant, and number of total nucleated cells infused. No differences were observed in the time to neutrophil and platelet engraftment, or in the risk of veno-occlusive disease and hemorrhage. However, there was a higher risk of mucositis in the BU-CY group (71 vs 24 percent, P = 0.004). There were no differences in the incidence of neutrophil and platelet engraftment, acute and chronic graft-versus-host disease, and transplant-related mortality. There was a higher incidence of late rejection in the ATG-CY group (41 vs 4 percent, P = 0.009). Although the ATG-CY group had a longer follow-up (101 months) than the BU-CY group (67 months, P = 0.04), overall survival was similar between the groups (69 vs 58 percent, respectively, P = 0.32). We conclude that the association BU-CY is a feasible option to the conventional ATG-CY regimen in this population.

Comparison between hybrid MOPPABV and ABVD chemotherapy protocols for Hodgkin's lymphoma in public hospitals of the largest South American city: a retrospective 14-year study.

The behavior of Hodgkin's lymphoma (HL) is different in developing countries, perhaps due to differences in epidemiology and population access to health care. We performed a retrospective study comparing the efficacy of mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, and vinblastine (MOPPABV) versus adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy protocols as first-line therapy for HL in a Brazilian population. A hundred and eighty-six HL patients were retrospectively analyzed regarding their first-line treatment with MOPPABV and ABVD at two public hospitals in São Paulo, Brazil. Eligible patients were either previously untreated or at first relapse after being treated with only radiotherapy with confirmed HL diagnosis. At a median follow-up of 9 years, complete remission is 89.5 and 85.9 (P = 0.3), overall survival 93.8% and 89.6% (P = 0.68), disease-free survival 85.6% and 81.6% (P = 0.41), and relapse ratios 20.9% and 26.4% (P = 0.17) for ABVD and MOPPABV, respectively. Extended-field radiation therapy postchemotherapy was mostly used in the MOPPABV group. There were three cases of secondary neoplasm (colon adenocarcinoma, myeloid chronic leukemia, and non-Hodgkin's lymphoma), all associated with MOPPABV. ABVD and MOPPABV protocols as first-line treatment for HL resulted in similar therapeutic outcomes and did not influence overall survival, disease-free survival, and relapse ratio. MOPPABV was related to a higher risk of secondary malignancy and, therefore, ABVD should be considered a better option for HL therapy. These findings corroborate recent data in literature.

Fludarabine induces apoptosis in chronic lymphocytic leukemia - the role of P53, Bcl-2, Bax, Mcl-1, and Bag-1 proteins

The expression of P53, Bcl-2, Bax, Bag-1, and Mcl-1 proteins in CD5/CD20-positive B-chronic lymphocytic leukemia (B-CLL) cells from 30 typical CLL patients was evaluated before and after 48 h of incubation with 10-6 M fludarabine using multiparametric flow cytometric analysis. Protein expression was correlated with annexin V expression, Rai modified clinical staging, lymphocyte doubling time, and previous treatment. Our main goal was to determine the predictive value of these proteins in CLL cells in terms of disease evolution. Bcl-2 expression decreased from a median fluorescence index (MFI) of 331.71 ± 42.2 to 245.81 ± 52.2 (P < 0.001) after fludarabine treatment, but there was no difference between viable cells (331.57 ± 44.6 MFI) and apoptotic cells (331.71 ± 42.2 MFI) before incubation (P = 0.859). Bax expression was higher in viable cells (156.24 ± 32.2 MFI) than in apoptotic cells (133.56 ± 35.7 MFI) before incubation, probably reflecting defective apoptosis in CLL (P = 0.001). Mcl-1 expression was increased in fludarabine-resistant cells and seemed to be a remarkable protein for the inhibition of the apoptotic process in CLL (from 233.59 ± 29.8 to 252.04 ± 35.5; P = 0.033). After fludarabine treatment, Bag-1 expression was increased in fludarabine-resistant cells (from 425.55 ± 39.3 to 447.49 ± 34.5 MFI, P = 0.012), and interestingly, this higher expression occurred in patients who had a short lymphocyte doubling time (P = 0.022). Therefore, we could assume that Bag-1 expression in such situation might identify CLL patients who will need treatment earlier.

Fludarabine induces apoptosis in chronic lymphocytic leukemia--the role of P53, Bcl-2, Bax, Mcl-1, and Bag-1 proteins.

The expression of P53, Bcl-2, Bax, Bag-1, and Mcl-1 proteins in CD5/CD20-positive B-chronic lymphocytic leukemia (B-CLL) cells from 30 typical CLL patients was evaluated before and after 48 h of incubation with 10(-6) M fludarabine using multiparametric flow cytometric analysis. Protein expression was correlated with annexin V expression, Rai modified clinical staging, lymphocyte doubling time, and previous treatment. Our main goal was to determine the predictive value of these proteins in CLL cells in terms of disease evolution. Bcl-2 expression decreased from a median fluorescence index (MFI) of 331.71 +/- 42.2 to 245.81 +/- 52.2 (P < 0.001) after fludarabine treatment, but there was no difference between viable cells (331.57 +/- 44.6 MFI) and apoptotic cells (331.71 +/- 42.2 MFI) before incubation (P = 0.859). Bax expression was higher in viable cells (156.24 +/- 32.2 MFI) than in apoptotic cells (133.56 +/- 35.7 MFI) before incubation, probably reflecting defective apoptosis in CLL (P = 0.001). Mcl-1 expression was increased in fludarabine-resistant cells and seemed to be a remarkable protein for the inhibition of the apoptotic process in CLL (from 233.59 +/- 29.8 to 252.04 +/- 35.5; P = 0.033). After fludarabine treatment, Bag-1 expression was increased in fludarabine-resistant cells (from 425.55 +/- 39.3 to 447.49 +/- 34.5 MFI, P = 0.012), and interestingly, this higher expression occurred in patients who had a short lymphocyte doubling time (P = 0.022). Therefore, we could assume that Bag-1 expression in such situation might identify CLL patients who will need treatment earlier.

Refractory chronic GVHD emerging after splenectomy in a marrow transplant recipient with accelerated phase CML.

We report a 39-year-old female patient who underwent HLA-identical sibling allogeneic BMT for CML in accelerated phase. Severe pancytopenia refractory to G-CSF associated with progressive splenomegaly and RBC/platelet transfusion dependency were present from day +60 after BMT. MRD assessed by FISH and RT-PCR multiplex for BCR-ABL rearrangement was negative, and complete chimerism was documented by VNTR on days +100, +180, +360 and 2 years after BMT. Splenectomy was performed on day +225 and pancytopenia resolved but chronic extensive graft-versus-host disease developed, with hepatic cholestasis, diffuse scleroderma and sicca-like syndrome. She was sequentially and progressively treated with different immunosuppressive therapy combinations with no clear benefit. On day +940, she presented with infection over the previously present ulcers on both limbs, which culminated in septic shock and death on day +1041. We conclude that, although splenectomy may reverse poor graft function after allogeneic BMT, hyposplenism may trigger or worsen chronic extensive GVHD leading to increased morbidity and mortality.

Fungal infections in marrow transplant recipients under antifungal prophylaxis with fluconazole.

Fungal infection is one of the most important causes of morbidity and mortality in bone marrow transplant (BMT) recipients. The growing incidence of these infections is related to several factors including prolonged granulocytopenia, use of broad-spectrum antibiotics, conditioning regimens, and use of immunosuppression to avoid graft-versus-host disease (GvHD). In the present series, we report five cases of invasive mold infections documented among 64 BMT recipients undergoing fluconazole antifungal prophylaxis: 1) A strain of Scedosporium prolificans was isolated from a skin lesion that developed on day +72 after BMT in a chronic myeloid leukemic patient. 2) Invasive pulmonary aspergillosis (Aspergillus fumigatus) was diagnosed on day +29 in a patient with a long period of hospitalization before being transplanted for severe aplastic anemia. 3) A tumoral lung lesion due to Rhizopus arrhizus (zygomycosis) was observed in a transplanted patient who presented severe chronic GvHD. 4) A tumoral lesion due to Aspergillus spp involving the 7th, 8th and 9th right ribs and local soft tissue was diagnosed in a BMT patient on day +110. 5) A patient with a history of Ph1-positive acute lymphocytic leukemia exhibited a cerebral lesion on day +477 after receiving a BMT during an episode of severe chronic GvHD. At that time, blood and spinal fluid cultures yielded Fusarium sp. Opportunistic infections due to fungi other than Candida spp are becoming a major problem among BMT patients receiving systemic antifungal prophylaxis with fluconazole.

Fungal infections in marrow transplant recipients under antifungal prophylaxis with fluconazole

Fungal infection is one of the most important causes of morbidity and mortality in bone marrow transplant (BMT) recipients. The growing incidence of these infections is related to several factors including prolonged granulocytopenia, use of broad-spectrum antibiotics, conditioning regimens, and use of immunosuppression to avoid graft-versus-host disease (GvHD). In the present series, we report five cases of invasive mold infections documented among 64 BMT recipients undergoing fluconazole antifungal prophylaxis: 1) A strain of Scedosporium prolificans was isolated from a skin lesion that developed on day +72 after BMT in a chronic myeloid leukemic patient. 2) Invasive pulmonary aspergillosis (Aspergillus fumigatus) was diagnosed on day +29 in a patient with a long period of hospitalization before being transplanted for severe aplastic anemia. 3) A tumoral lung lesion due to Rhizopus arrhizus (zygomycosis) was observed in a transplanted patient who presented severe chronic GvHD. 4) A tumoral lesion due to Aspergillus spp involving the 7th, 8th and 9th right ribs and local soft tissue was diagnosed in a BMT patient on day +110. 5) A patient with a history of Ph1-positive acute lymphocytic leukemia exhibited a cerebral lesion on day +477 after receiving a BMT during an episode of severe chronic GvHD. At that time, blood and spinal fluid cultures yielded Fusarium sp. Opportunistic infections due to fungi other than Candida spp are becoming a major problem among BMT patients receiving systemic antifungal prophylaxis with fluconazole

Doença do enxerto contra hospedeiro pós-transfusional-guia para irradiaçäo gama de hemocomponentes / Transfusion-associated graft-versus-host disease guideline on gamma irradiation of blood components

A doença enxerto contra hospedeiro transfusional (DECHT) é síndrome rara e geralmente fatal. É caracterizada por febre, eritema cutâneo, náuseas, vômitos, diarréia, hepatite e pancitopenia. Pode ocorrer em pacientes com imunossupressão severa e em pacientes com imunossupressão severa e em pacientes imunocompetentes após a transfusão de hemocomponente celular de doador homozigoto para proteínas HLA às quais o receptor é heterozigoto. O diagnóstico é feito pelo quadro clínico e exame histopatológico da pele. A gamaglobulina antitimocítica associada a altas doses de corticosteróides é a terapêutica mais empregada. O desconhecimento da síndrome, o retardo no diagnóstico, o curso rápido e a ausência de resposta ao tratamento estão relacionados à má evolução dos pacientes. A melhor forma de abordagem da DECHT é a prevenção através da irradiação gama dos hemocomponentes. A dose necessária para completa inativação dos linfócitos T é de 2500 cGy. A principal alteração decorrente da irradiação é o aumento da concentração de potassio nos concentrados de hemácias. Os filtros de leucócitos não previnem o desenvolvimento da DECHT e a irradiação não previne a aloimunização e as reações transfusionais. Apenas hemocomponentes celulares como sangue total, cencentrado de hemácias, concentrado de plaquetas e concentrado de granulócitos, necessitam ser irradiados. Devem ser irradiados os hemocomponentes para transfusão entre familiares, transfusões HLA compatíveis, pacientes submetidos a trasnplante de medula óssea, portadores de doença de Hodgkin, pacientes tratados com análogos da purina, transfusões intra-útero, recém nascidos pré-termo e pacientes com síndrome de imunodeficiência congênita. É recomendável a irradiação de hemocomponentes destinados a pacientes com doenças neoplásicas quando submetidos a protocolos de quimioterapia agressivos.

Granuloma letal da linha média: abordagem clínica e terapêutica de três casos / Lethal midline granuloma: clinical management of three cases

Objetivo. Relato de três casos do GLLM acompanhados pela Disciplina de Hematologia e Hemoterapia da Unifesp-EPM que tiveram boa resposta à terapêutica e evoluçao favorável. Métodos. Após confirmaçao histológica e histoquímica, os pacientes foram submetidos à tratamento quimio e radioterápico com boa resposta terapêutica. Resultados. Atualmente estes pacientes encontram-se em remissao total da doença, com sobrevida média de 45 meses. Conclusao. Levando-se em consideraçao nossa pequena experiência, acreditamos que o tratamento radioterápico e a abordagem quimioterápica inicial agressiva sao fundamentais para uma boa evoluçao deste tipo de linfoma.

Linfoma primário de pulmäo associado a artrite reumatóide e seqüela de tuberculose: a propósito de um caso / Primary lymphoma of the lung associated with rheumatoid arthritis and tuberculosis sequelae: report of a case

Mostramos o caso de uma paciente de 40 anos, portadora de quadro de artrite reumatóide e dispnéia aos esforços. A radiografia de tórax evidenciava infiltrado intersticial bilateral e a pesquisa de BAAR foi positiva em quatro amostras consecutivas. Após 12 meses de suspensäo do tratamento com esquema tríplice, apresentou febre de evoluçäo prolongada, sem melhora com cefalosporina. O quadro radiológico era de condensaçäo de base direita e nódulos de limites imprecisos em bases e campos médios bilateralmente. Após cinco meses de estado febril, submeteu-se à pesquisa de foco infeccioso e atividade inflamatória da artrite reumatóide, com resultados negativos. Evoluiu com nítida piora do estado geral, febre diária e vespertina e extensäo dos nódulos pulmonares. Após biopsia transbrônquica, fez-se o diagnóstico de linfoma linfocítico pouco diferenciado difuso em parênquima pulmonar. Foi a óbito 24 horas após o início do tratamento quimioterápico

Histopatologia da medula óssea na síndrome de imunodeficiência adquirida / Histopathology of the marrow in acquired immunodeficiency syndrome

Apresentamos as alteraçöes hematológicas e de histologia de medula óssea em 15 portadores de síndrome de imunodeficiência adquirida em fase considerada final da doença. Treze de 15 pacientes apresentavam-se anêmicos; linfopenia periférica absoluta (linfócitos abaixo de 2.500/mm3) ocorreu em 14/15 casos e plaquetopenia (abaixo 100.000/mm3) em 2/15. A velocidade de hemossedimentaçäo foi superior a 40mm/h em todos os casos. O ferro medular estava aumentado em 6/13 anêmicos, sendo que em 4 deles havia hipoplasia da série vermelha; em 5/13 o ferro medular estava diminuído (três com hiperplasia da série vermelha e dois com normoplasia). A série branca foi hipercelular em seis casos, normocelular em quatro e hipocelular em cinco. A série plaquetária mostrava-se hiperplásica em oito casos (três deles com megacariócitos hiperlobulados, quatro com micromegacariócitos hipolobulados e dois com disposiçöes em grumos e associaçäo com fibrose de medular); hipoplasia megacariocítica ocorreu em cinco casos. Depressäo dos três setores ocorreu em um caso e depressäo de dois setores em três. Em 13/15 o número de linfócitos na medula óssea estava aumentado e, na maioria das vezes, tinham morfologia de linfócitos transformados, sendo que em 11 dos doentes havia aumento de plasmócitos intersticiais ou peritrabeculares. Em dois casos havia formaçäo de nódulos linfóides hiperplásicos peritrabeculares. Em um caso portador de toxoplasmose generalizada observou-se formaçäo granulomatosa, BAAR negativo, e em necrose caseosa. Em 12/15 casos havia eosinofilia medular sem correspondência com o sangue periférico. Fibras reticulínicas aumentadas foram vistas em 11/15 casos e em dois deles o aspecto era de fibrose medular