Marco A. Salvino

Consenso brasileiro em transplante de células-tronco hematopoéticas: comitê de hemoglobinopatias

Os disturbios hereditarios das hemoglobinas sao as doencas geneticas mais frequentes do homem e mais difundidas no mundo, abrangendo sobretudo continentes como Africa, Americas, Europa e extensas regioes da Asia. Estima-se que haja 270 milhoes de portadores de hemoglobinopatias no mundo, dos quais 80 milhoes sao portadores de talassemia. Aproximadamente 60 mil criancas nascem anualmente no mundo com talassemia e 250 mil com anemia falciforme, dando uma frequencia de 2,4 criancas afetadas para cada 1.000 nascimentos. No Brasil, a doenca falciforme e a doenca hereditaria monogenica mais comum, estimando-se que haja entre 20 a 30 mil pacientes portadores desta doenca. O transplante de celulas-tronco hematopoeticas alogenico (TCTH alo) e atualmente a unica modalidade terapeutica capaz de curar pacientes com hemoglobinopatias. Neste artigo discutiremos os dados disponiveis na literatura e sugerimos os criterios para a indicacao do TCTH nas hemoglobinopatias.

Hematopoietic progenitor cell mobilization for autologous transplantation - a literature review

The use of high-dose chemotherapy with autologous support of hematopoietic progenitor cells is an effective strategy to treat various hematologic neoplasms, such as non-Hodgkin lymphomas and multiple myeloma. Mobilized peripheral blood progenitor cells are the main source of support for autologous transplants, and collection of an adequate number of hematopoietic progenitor cells is a critical step in the autologous transplant procedure. Traditional strategies, based on the use of growth factors with or without chemotherapy, have limitations even when remobilizations are performed. Granulocyte colony-stimulating factor is the most widely used agent for progenitor cell mobilization. The association of plerixafor, a C-X-C Chemokine receptor type 4 (CXCR4) inhibitor, to granulocyte colony stimulating factor generates rapid mobilization of hematopoietic progenitor cells. A literature review was performed of randomized studies comparing different mobilization schemes in the treatment of multiple myeloma and lymphomas to analyze their limitations and effectiveness in hematopoietic progenitor cell mobilization for autologous transplant. This analysis showed that the addition of plerixafor to granulocyte colony stimulating factor is well tolerated and results in a greater proportion of patients with non-Hodgkin lymphomas or multiple myeloma reaching optimal CD34+ cell collections with a smaller number of apheresis compared the use of granulocyte colony stimulating factor alone.

Repeat course of rabbit antithymocyte globulin as salvage following initial therapy with rabbit antithymocyte globulin in acquired aplastic anemia

The treatment for the majority of patients with acquired aplastic anemia (AA) who are not suitable for hematopoietic stem cell transplant (HSCT) is immunosuppression with standard horse antithymocyte globulin (h-ATG) and cyclosporine (CSA) where hematologic responses are observed in 60–70%.[1][1]

Acquired cutis laxa with an interstitial granulomatous reaction associated with IgG lambda monoclonal gammopathy.

Acquired cutis laxa (ACL) is a rare connective tissue disorder that affects the skin elastic fibers, resulting in the loss of elasticity. In 50% of cases, this condition is associated with other diseases, particularly plasma-cell dyscrasias. This report describes a case of ACL with unusual clinical and histopathological characteristics. A 29-year-old man presented with diffuse erythematous plaques that had first appeared 5 months previously. Examination revealed multiple flaccid erythematous plaques on his trunk, neck, and skinfolds. Immunophenotyping of bone marrow aspirate revealed 7% of monoclonal plasma cells with lambda light chain expression. Skin biopsy histology revealed foci of interstitial granulomatous reaction. Weigert stain showed a loss of elastic fibers in the dermis, areas with thickened fibers and elastophagocytosis. Immunohistochemistry was positive for CD68. The cutaneous findings enabled an early diagnosis of IgG lambda monoclonal gammopathy to be made. Microscopic examination revealed an interstitial granulomatous reaction and severe alterations in the elastic fibers that varied in intensity in the different biopsies. Curiously, little has been mentioned in the literature regarding the presence of an interstitial granulomatous reaction in ACL. It is our belief that this reaction is secondary to the degenerative process of the elastic fibers.

Nilotinib dose-optimization in newly diagnosed chronic myeloid leukaemia in chronic phase: final results from ENESTxtnd

The Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Extending Molecular Responses (ENESTxtnd) study was conducted to evaluate the kinetics of molecular response to nilotinib in patients with newly diagnosed chronic myeloid leukaemia in chronic phase and the impact of novel dose‐optimization strategies on patient outcomes. The ENESTxtnd protocol allowed nilotinib dose escalation (from 300 to 400 mg twice daily) in the case of suboptimal response or treatment failure as well as dose re‐escalation for patients with nilotinib dose reductions due to adverse events. Among 421 patients enrolled in ENESTxtnd, 70·8% (95% confidence interval, 66·2–75·1%) achieved major molecular response (BCR‐ABL1 ≤ 0·1% on the International Scale) by 12 months (primary endpoint). By 24 months, 81·0% of patients achieved major molecular response, including 63·6% (56 of 88) of those with dose escalations for lack of efficacy and 74·3% (55 of 74) of those with dose reductions due to adverse events (including 43 of 54 patients with successful re‐escalation). The safety profile of nilotinib was consistent with prior studies. The most common non‐haematological adverse events were headache, rash, and nausea; cardiovascular events were reported in 4·5% of patients (grade 3/4, 3·1%). The study was registered at clinicaltrials.gov (NCT01254188).

An Unusual Association of Adult T-Cell Leukemia/Lymphoma With Hyalohyphomycosis.

Infection by human T-cell lymphotropic virus (HTLV-1) causes deregulation of the immune system, which makes the infected individuals more susceptible to infectious diseases. Immune deregulation is even more pronounced in HTLV-1 carriers with adult T-cell leukemia/lymphoma (ATLL), which results in frequent opportunistic infections. Hyalohyphomycosis is a rare subcutaneous mycosis which is more commonly associated with immunocompromised patients. We report a case of a HTLV-1-infected man with skin tumors, inguinal lymphadenomegaly, and lymphocytosis. Histopathological examination of skin biopsies revealed a T-cell lymphoma intermingled with a granulomatous process with abscesses and hyaline-septated hyphae. The lymph node showed only a T-cell lymphoma. The patient was diagnosed with acute ATLL and hyalohyphomycosis. He was treated with itraconazole for the subcutaneous mycosis and with chemotherapy for ATLL. A few months later, despite the treatment, he died because of progression of ATLL.

TP53 and p16INK4A mutations in adult-T cell leukemia/lymphoma (ATL) in Bahia (Brazil)

ATL is an aggressive malignancy associated with the HTLV-1. The development of ATL is believed to involve a multitude of factors that include the accumulation of genetic alterations. The aim of this study was to analyze the presence of mutations in the TP53, p16INK4A, p15INK4B, K-ras, PI3K and EGFR genes in ATL patients from Bahia (Brazil) with the acute and chronic subtypes. Fourteen patients with acute ATL and five with chronic ATL were included. Exons 4-9 of the TP53 gene, exons 1-3 of the p16INK4A gene, exons 1-2 of the p15INK4B gene, exons 18-21 of the EGFR gene and exons 9 and 21 of the PI3Ka gene were investigated using PCR followed by sequencing. Mutations at codons 12 and 13 of the K-ras gene were analyzed by RFLP following PCR amplification. In 5 of the 19 ATL patients (26%), missense mutations were observed in the TP53 gene. All of these patients had the acute subtype. Alterations were detected in exon 5 (codons 155 and 181), exon 7 (codon 248) and exon 8 (codon 282). Mutations in codons 155, 181 and 282 had not previously been described in ATL. Missense mutation was observed in p16INK4A in only one patient with acute ATL who did not have alterations in the TP53 gene. Point mutations in p15INK4B, K-ras, EGFR and PI3Ka genes were not found. These results are in agreement with the findings of previous studies suggesting that mutations of the TP53 and p16INK4A genes may play a role in aggressive ATL.