Impact of mother donor, peripheral blood stem cells and measurable residual disease on outcomes after haploidentical hematopoietic cell transplantation with post-transplant cyclophosphamide in children with acute leukaemia.

Haploidentical hematopoietic-cell transplantation using post-transplant cyclophosphamide(Haplo-PTCy) is a feasible procedure in children with haematologic malignancies. However, data of a large series of children with acute leukaemia(AL) in this setting is missing. We analysed 144 AL Haplo-PTCy paediatric recipients; median age was 10 years. Patients had acute lymphoblastic(ALL; n = 86) or myeloblastic leukaemia(AML; n = 58) and were transplanted in remission(CR1: n = 40; CR2: n = 57; CR3+: n = 27) or relapse (n = 20). Bone marrow was the graft source in 57%; donors were father (54%), mother (35%), or sibling (11%). Myeloablative conditioning was used in 87%. Median follow-up was 31 months. At day +100, cumulative incidence (CI) of neutrophil recovery and acute GVHD (II-IV) were 94% and 40%, respectively. At 2-years, CI of chronic GVHD and relapse, were 31%, 40%, and estimated 2-year overall survival (OS), leukaemia-free survival (LFS) and graft-versus-host-relapse-free survival (GRFS) were 52%, 44% and 34% respectively. For patients transplanted in remission, positive measurable residual disease (MRD) prior to transplant was associated with decreased LFS (p = 0.05) and GRFS (p = 0.003) and increased risk of relapse (p = 0.02). Mother donor was associated with increased risk of chronic GVHD (p = 0.001), decreased OS (p = 0.03) and GRFS (p = 0.004). Use of PBSC was associated with increased risk of chronic GVHD (p = 0.04). In conclusion, achieving MRD negativity pre-transplant, avoiding use of mother donors and PBSC as graft source may improve outcomes of Haplo-PTCy in children with AL.

Successful Allogenic Stem Cell Transplantation in Patients with Inherited CARD9 Deficiency.

Autosomal recessive (AR) CARD9 (caspase recruitment domain-containing protein 9) deficiency underlies invasive infections by fungi of the ascomycete phylum in previously healthy individuals at almost any age. Although CARD9 is expressed mostly by myeloid cells, the cellular basis of fungal infections in patients with inherited CARD9 deficiency is unclear. Therapy for fungal infections is challenging, with at least 20% premature mortality. We report two unrelated patients from Brazil and Morocco with AR CARD9 deficiency, both successfully treated with hematopoietic stem cell transplantation (HSCT). From childhood onward, the patients had invasive dermatophytic disease, which persisted or recurred despite multiple courses of antifungal treatment. Sanger sequencing identified homozygous missense CARD9 variants at the same residue, c.302G>T (p.R101L) in the Brazilian patient and c.301C>T (p.R101C) in the Moroccan patient. At the ages of 25 and 44 years, respectively, they received a HSCT. The first patient received a HLA-matched HSCT from his CARD9-mutated heterozygous sister. There was 100% donor chimerism at D + 100. The other patient received a T cell-depleted haploidentical HSCT from his CARD9-mutated heterozygous brother. A second HSCT from the same donor was performed due to severe amegakaryocytic thrombocytopenia despite achieving full donor chimerism (100%). At last follow-up, more than 3 years after HSCT, both patients have achieved complete clinical remission and stopped antifungal therapy. HSCT might be a life-saving therapeutic option in patients with AR CARD9 deficiency. This observation strongly suggests that the pathogenesis of fungal infections in these patients is largely due to the disruption of leukocyte-mediated CARD9 immunity.

Gill metazoan parasites of the spotted goatfish Pseudupeneus maculatus (Ostheichthyes: Mullidae) from the Coast of Pernambuco, northeastern Brazil / Metazoários parasitos de brânquias do saramunete Pseudupeneus maculatus (Ostheichthyes: Mullidae) da costa de Pernambuco, Nordeste do Brasil

Abstract This study evaluated the parasite fauna on the gills of spotted goatfish Pseudupeneus maculatus captured in the dry and rainy seasons in the coast of the State of Pernambuco, Brazil. Eight parasite species were identified belonging to the following taxa: Monogenea (Haliotrema caraïbensis, Haliotrema caballeroi and Haliotrema golvani); Crustacea (Rocinela signata, Hamaticolax scutigerulus and Caligidae gen. sp.) and Cestoda (Nybelinia indica and Pseudolacistorhynchus noodti). The most prevalent parasites were: Monogenea (100%), H. scutigerulus (35%), N. indica (11.7%), R. signata (8.3%), Caligidae gen. sp. (3.33%) and P. noodti (0.83%). Values of infestation are compared to other studies, and the uncommon occurrence of Trypanorhyncha on the gills suggests that the spotted goatfish could be an intermediate host for the parasite.

Resumo O presente estudo investigou a fauna parasitária das brânquias do peixe conhecido como saramunete Pseudupeneus maculatus, capturados nas estações seca e chuvosa na costa do estado de Pernambuco, Brasil. Oito espécies de parasitos foram identificadas, pertencentes aos seguintes táxons: Monogenea (Haliotrema caraïbensis, Haliotrema caballeroi e Haliotrema golvani); Crustacea (Rocinela signata, Hamaticolax scutigerulus e Caligidae gen. sp.) e Cestoda (Nybelinia indica e Pseudolacistorhynchus noodti). Os parasitos mais prevalentes foram: Monogenea (100%), H. scutigerulus (35%), N. indica (11,7%), R. signata (8,3%), Caligidae gen. sp. (3,33%) e P. noodti (0,83%). Os valores de infestação são comparados a outros estudos, e a ocorrência incomum de cestóides Trypanorhyncha sugere que o saramunete pode ser um hospedeiro intermediário para o parasito.

Latin America: the next region for haematopoietic transplant progress.

Haematopoietic cell transplant activity in the 28 countries comprising Latin America is poorly defined. We conducted a voluntary survey of members of the Latin American Bone Marrow Transplantation Group regarding transplant activity 2009-2012. Collated responses were compared with data of transplant rates from the Worldwide Network for Blood and Marrow Transplantation for other geographic regions. Several socio-economic variables were analysed to determine correlations with transplant rates. In total, 94 teams from 12 countries reported 11 519 transplants including 7033 autotransplants and 4486 allotransplants. Annual activity increased from 2517 transplants in 2009 to 3263 in 2012, a 30% increase. Median transplants rate (transplant per million inhabitants) in 2012 was 64 (autotransplants, median 40; allotransplants, median 24). This rate is substantially lower than that in North America and European regions (482 and 378) but higher than that in the Eastern Mediterranean and Asia Pacific regions (30 and 45). However, the Latin America transplant rate is 5-8-fold lower than that in America and Europe, suggesting a need to increase transplant availability. Transplant team density in Latin America (teams per million population; 1.8) is 3-4-fold lower than that in North America (6.2) or Europe (7.6). Within Latin America, there is substantial diversity in transplant rates by country partially explained by diverse socio-economic variables including per capita gross national income, health expenditure and physician density. These data should help inform future health-care policy in Latin America.

The Salivary Microbiome and Oral Cancer Risk: a Pilot Study in Fanconi Anemia.

Fanconi anemia (FA) is a rare genetic disease characterized by chromosomal instability and impaired DNA damage repair. FA patients develop oral squamous cell carcinoma (OSCC) earlier and more frequently than the general population, especially after hematopoietic stem cell transplantation (HSCT). Although evidence of an etiological role of the local microbiome and carcinogenesis has been mounting, no information exists regarding the oral microbiome of FA patients. The aim of this study was to explore the salivary microbiome of 61 FA patients regarding their oral health status and OSCC risk factors. After answering a questionnaire and receiving clinical examination, saliva samples were collected and analyzed using 16S rRNA sequencing of the V3-V4 hypervariable region. The microbial profiles associated with medical and clinical parameters were analyzed using general linear models. Patients were young (mean age, 22 y) and most had received HSCT ( n = 53). The most abundant phyla were Firmicutes [mean relative abundance (SD), 42.1% (10.1%)] and Bacteroidetes [(25.4% (11.4%)]. A history of graft-versus-host disease (GVHD) ( n = 27) was associated with higher proportions of Firmicutes (43.8% × 38.5%, P = 0.05). High levels of gingival bleeding were associated with the genera Prevotella (22.25% × 20%), Streptococcus (19.83% × 17.61%), Porphyromonas (3.63% × 1.42%, P = 0.03), Treponema (1.02% × 0.28%, P = 0.009), Parvimonas (0.28% × 0.07%, P = 0.02) and Dialister (0.27% × 0.10%, P = 0.04). Finally, participants transplanted over 11 y ago showed the highest levels of Streptococcus (18.4%), Haemophilus (12.7%) and Neisseria (6.8%). In conclusion, FA patients that showed poor oral hygiene harbored higher proportions of the genera of bacteria compatible with gingival disease. Specific microbial differences were associated with a history of oral GVHD and a history of oral mucositis.

Gill metazoan parasites of the spotted goatfish Pseudupeneus maculatus (Ostheichthyes: Mullidae) from the Coast of Pernambuco, northeastern Brazil

Abstract This study evaluated the parasite fauna on the gills of spotted goatfish Pseudupeneus maculatus captured in the dry and rainy seasons in the coast of the State of Pernambuco, Brazil. Eight parasite species were identified belonging to the following taxa: Monogenea (Haliotrema caraïbensis, Haliotrema caballeroi and Haliotrema golvani); Crustacea (Rocinela signata, Hamaticolax scutigerulus and Caligidae gen. sp.) and Cestoda (Nybelinia indica and Pseudolacistorhynchus noodti). The most prevalent parasites were: Monogenea (100%), H. scutigerulus (35%), N. indica (11.7%), R. signata (8.3%), Caligidae gen. sp. (3.33%) and P. noodti (0.83%). Values of infestation are compared to other studies, and the uncommon occurrence of Trypanorhyncha on the gills suggests that the spotted goatfish could be an intermediate host for the parasite.

Resumo O presente estudo investigou a fauna parasitária das brânquias do peixe conhecido como saramunete Pseudupeneus maculatus, capturados nas estações seca e chuvosa na costa do estado de Pernambuco, Brasil. Oito espécies de parasitos foram identificadas, pertencentes aos seguintes táxons: Monogenea (Haliotrema caraïbensis, Haliotrema caballeroi e Haliotrema golvani); Crustacea (Rocinela signata, Hamaticolax scutigerulus e Caligidae gen. sp.) e Cestoda (Nybelinia indica e Pseudolacistorhynchus noodti). Os parasitos mais prevalentes foram: Monogenea (100%), H. scutigerulus (35%), N. indica (11,7%), R. signata (8,3%), Caligidae gen. sp. (3,33%) e P. noodti (0,83%). Os valores de infestação são comparados a outros estudos, e a ocorrência incomum de cestóides Trypanorhyncha sugere que o saramunete pode ser um hospedeiro intermediário para o parasito.

Haematopoietic cell transplants in Latin America.

Haematopoietic cell transplants are done by more than 1500 transplant centres in 75 countries, mostly for life-threatening haematological disorders. However, transplant technology and access are not uniformly distributed worldwide. Most transplants are done predominately in Europe, North America and some Asian countries. We review transplant activity in Latin America, a geographic region with a population of >600 million persons living in countries with diverse economic and social development levels. These data indicate a 20-40-fold lower frequency of transplants in Latin America compared with Europe and North America. We show that although economics, infrastructure and expertise are important limitations, other variables also operate. Changes in several of these variables may substantially increase transplant activity in Latin America.

Haploidentical BMT and post-transplant Cy for severe aplastic anemia: a multicenter retrospective study.

Patients with refractory severe aplastic anemia (SAA) who lack a matched sibling or unrelated donor need new therapeutic approaches. Hematopoietic SCT (HSCT) using mismatched or haploidentical related donors has been used in the past, but was associated with a significant risk of GVHD and mortality. Recently, the use of post-transplant cyclophosphamide (Cy) has been shown to be an effective strategy to prevent GVHD in recipients of haploidentical HSCT, but the majority of reports have focused on patients with hematology malignancies. We describe the outcome of 16 patients who underwent haploidentical transplantation using a reduced-intensity conditioning regimen with post-transplant Cy. Stem cell sources were BM (N=13) or PBSCs (N=3). The rate of neutrophil engraftment was 94% and of platelet engraftment was 75%. Two patients had secondary graft failure and were successfully salvaged with another transplant. Three patients developed acute GVHD being grades 2-4 in two. Five patients have died and the 1-year OS was 67.1% (95% confidence interval: 36.5-86.4%). In our small series, the use of a reduced-intensity conditioning with post-transplant Cy in haploidentical BMT was associated with high rates of engraftment and low risk of GVHD in patients with relapsed/refractory SAA.

Severe combined immunodeficiency in Brazil: management, prognosis, and BCG-associated complications.

BACKGROUND: Severe combined immunodeficiency (SCID) is one of the most severe forms of primary immunodeficiency. The objectives of this study were to analyze the diagnosis, treatment, and prognosis of SCID in Brazil and to document the impact of BCG vaccine. METHODS: We actively searched for cases by contacting all Brazilian referral centers. RESULTS: We contacted 23 centers and 70 patients from 65 families. Patients were born between 1996 and 2011, and 49 (70%) were male. More than half (39) of the diagnoses were made after 2006. Mean age at diagnosis declined from 9.7 to 6.1 months (P = .058) before and after 2000, respectively, and mean delay in diagnosis decreased from 7.9 to 4.2 months (P = .009). Most patients (60/70) were vaccinated with BCG before the diagnosis, 39 of 60 (65%) had complications related to BCG vaccine, and the complication was disseminated in 29 of 39 (74.3%). Less than half of the patients (30, 42.9%) underwent hematopoietic stem cell transplantation (HSCT). Half of the patients died (35, 50%), and 23 of these patients had not undergone HSCT. Disseminated BCG was the cause of death, either alone or in association with other causes, in 9 of 31 cases (29%, no data for 4 cases). CONCLUSIONS: In Brazil, diagnosis of SCID has improved over the last decade, both in terms of the number of cases and age at diagnosis, although a much higher number of cases had been expected. Mortality is higher than in developed countries. Complications of BCG vaccine are an important warning sign for the presence of SCID and account for significant morbidity during disease progression.

Cyclophosphamide-based in vivo T-cell depletion for HLA-haploidentical transplantation in Fanconi anemia.

Allogeneic hematopoietic cell transplantation (HCT) is the only known cure for patients with Fanconi anemia (FA) who develop aplasia or leukemia. However, transplant regimens typically contain high-dose alkylators, which are poorly tolerated in FA patients. Furthermore, as many patients lack human leukocyte antigen (HLA)-matched family donors, alternative donors are used, which can increase the risk of both graft rejection and graft-versus-host disease (GVHD). To improve on these three concerns, we developed a multi-institutional clinical trial using a fludarabine (FLU)-based conditioning regimen with limited alkylators/low-dose radiation, HLA-haploidentical marrow, followed by reduced-dose cyclophosphamide (CY) to treat three FA patients with aplasia. All three patients engrafted with 100% donor CD3 chimerism at 1 month. One patient died early from disseminated toxoplasmosis infection. Of the two survivors, one had significant pretransplant co-morbidities and inadequate immunosuppression, and developed severe acute GVHD. The other patient had only mild acute and no chronic GVHD. With a follow-up of 2 and 3 years, respectively, both patients are doing well, are transfusion-independent, and maintain full donor chimerism. The patient with severe GVHD has resolving oral GVHD and good quality of life. We conclude that using low-intensity conditioning, HLA-haploidentical marrow, and reduced-dose CY for in vivo T-cell depletion can correct life-threatening aplasia in FA patients.

Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation.

Advances in hematopoietic cell transplantation (HCT) technology and supportive care techniques have led to improvements in long-term survival after HCT. Emerging indications for transplantation, introduction of newer graft sources (eg, umbilical cord blood) and transplantation of older patients using less intense conditioning regimens have also contributed to an increase in the number of HCT survivors. These survivors are at risk for developing late complications secondary to pre-, peri-, and posttransplant exposures and risk factors. Guidelines for screening and preventive practices for HCT survivors were published in 2006. An international group of transplantation experts was convened in 2011 to review contemporary literature and update the recommendations while considering the changing practice of transplantation and international applicability of these guidelines. This review provides the updated recommendations for screening and preventive practices for pediatric and adult survivors of autologous and allogeneic HCT.

Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation.

Advances in hematopoietic cell transplantation (HCT) technology and supportive care techniques have led to improvements in long-term survival after HCT. Emerging indications for transplantation, introduction of newer graft sources (for example, umbilical cord blood) and transplantation of older patients using less intense conditioning regimens have also contributed to an increase in the number of HCT survivors. These survivors are at risk for developing late complications secondary to pre-, peri- and post-transplant exposures and risk factors. Guidelines for screening and preventive practices for HCT survivors were published in 2006. An international group of transplant experts was convened in 2011 to review contemporary literature and update the recommendations while considering the changing practice of transplantation and international applicability of these guidelines. This report provides the updated recommendations for screening and preventive practices for pediatric and adult survivors of autologous and allogeneic HCT.

High prevalence of oral human papillomavirus infection in Fanconi's anemia patients.

BACKGROUND: Fanconi's anemia (FA) is a rare recessive genetic disorder characterized by bone marrow failure, developmental and congenital abnormalities, which frequently evolves to aplastic anemia and neoplasias, primarily acute leukemia and head-neck carcinomas. Risk of malignancies increases after hematopoietic stem cell transplantation (HSCT), and the role of human papillomavirus (HPV) in FA carcinogenesis have been proposed. OBJECTIVE: To investigate prevalence of oral HPV in FA patients without oral malignant lesions. MATERIALS AND METHODS: After oral examination, 76 subjects without detectable oral malignant lesions were included and classified in four groups: 20 FA submitted to HSCT (I), 22 FA not submitted to HSCT (II), 18 severe aplastic anemia (SAA) submitted to HSCT (III) and 16 healthy subjects (IV). Liquid-based cytology sampling, HPV screening by polymerase chain reaction and genotyping by reverse hybridization were performed. RESULTS: The HPV detection rates were: group I 35%, group II 27.3%, group III 38% and group IV 6.25%. Prevalence of high risk HPV types, mainly HPV16, was detected. Compared with control group, suggestions for increased likelihood of being HPV infected in SAA (OR = 9.55, 95% CI: 1.01-125.41) and FA patients submitted to HSCT (OR = 8.08, 0.83-72.29) emerged. CONCLUSION: Patients without oral malignant lesions submitted to HSCT, have high prevalence of oral HPV. HPV screening and close follow up should be considered in these patients.

Analysis of risk factors influencing outcome in children with myelodysplastic syndrome after unrelated cord blood transplantation.

We describe 70 children with myelodysplastic syndrome (MDS) (refractory cytopenia (n=31) and refractory anemia with excess blasts (n=30) or blasts in transformation (n=9)) who received umbilical cord blood (UCB) transplantation with a single UCB unit and a myeloablative conditioning regimen. Approximately 20% of children had secondary MDS. Median age at transplantation was 7 years and the median follow-up was 3 years. The day-60 probability of neutrophil recovery was 76%; recovery was faster after transplantation of matched or 1-locus mismatched UCB, irradiation-containing conditioning regimen, cell dose >6 × 10(7)/kg and monosomy 7. Risks of treatment failure (recurrent disease or death) were lower in patients with monosomy 7 and transplantations after 2001. The 3-year disease-free survival (DFS) was 50% for transplantations after 2001 compared with 27% for the earlier period (P=0.018). Transplantations after 2001 occurred within 6 months after diagnosis and used UCB units with higher cell dose. DFS was highest in patients with monosomy 7 (61%) compared with other karyotypes (30%), P=0.017. These data suggest that transplantation of mismatched UCB graft is an acceptable alternative for children without a matched sibling or suitably matched unrelated adult donor.

Human metapneumovirus infection in hematopoietic stem cell transplant recipients.

UNLABELLED: Human metapneumovirus (hMPV) was described in 2001 and has been associated with both upper and lower respiratory tract infection (URTI and LRTI, respectively), especially in children, the elderly, and in immunocompromised patients. The objective of this study was to identify hMPV as the etiological agent of acute respiratory infection in hematopoietic stem cell transplant (HSCT) patients and to determine the clinical features of hMPV infection in these patients. METHODS: The study was performed retrospectively in 769 respiratory samples obtained from immunocompromised patients submitted to HSCT over a period of 6 years. RNA was extracted by the guanidinium thiocyanate method, and reverse transcription polymerase chain reaction assay was performed to amplify a 928pb fragment of the hMPV N gene. RESULTS: hMPV was present in 19 (2.5%) samples. The mean age of infected patients was 18.3+/-10.8 (range, 3-41). Sixty-six percent of hMPV infections occurred during autumn, winter, and spring months. Three episodes showed co-infection with more than 1 virus. Two patients (11.1%) were infected a few days into the conditioning period and 9 (50%) in the first 3 months after the transplant. The majority of patients (72.2%) presented URTI alone with flu-like symptoms (cough, fever, headache, wheezing), while 5 patients (27.8%) had LRTI (pneumonia). No patient died from complications associated with the hMPV infection. CONCLUSIONS: hMPV has been reported as a respiratory pathogen in HSCT patients. We suggest that hMPV infection should be routinely investigated in this population, mainly in children, to prevent nosocomial transmission during transplant proceedings and to avoid the risk of progressing to complications due to LRTI.

Engraftment and survival following hematopoietic stem cell transplantation for osteopetrosis using a reduced intensity conditioning regimen.

Autosomal recessive osteopetrosis (OP) is a disease characterized by osteoclast dysfunction, leading to multisystem morbidity and death of most affected children. Hematopoietic stem cell transplantation (HSCT) is the treatment of choice for OP, but this patient population is particularly prone to post-transplant complications and death after myeloablative conditioning. To determine the potential of achieving improved overall outcomes in these patients by decreasing pre-transplant mortality, we investigated engraftment and survival following a reduced intensity regimen including busulfan, fludarabine and total lymphoid irradiation. We report outcomes in 11 patients. All six patients who received a bone marrow or peripheral stem cell graft engrafted with >75% donor chimerism. In contrast, all five recipients of unrelated cord blood as a stem cell source for a first graft failed to demonstrate donor hematopoietic chimerism. The day 100 and 6-month mortality was low at 9%. One year after HSCT, six of 11 patients (55%) were surviving. Our data suggest that this regimen results in low peri-transplant mortality without compromising engraftment when a marrow or peripheral stem cell graft is used. An umbilical cord blood graft, however, should be used with caution for patients with OP when this or a similar reduced intensity regimen is used.

Allogeneic hematopoietic stem cell transplantation from an alternative stem cell source in Fanconi anemia patients: analysis of 47 patients from a single institution.

We transplanted 47 patients with Fanconi anemia using an alternative source of hematopoietic cells. The patients were assigned to the following groups: group 1, unrelated bone marrow (N = 15); group 2, unrelated cord blood (N = 17), and group 3, related non-sibling bone marrow (N = 15). Twenty-four patients (51%) had complete engraftment, which was not influenced by gender (P = 0.87), age (P = 0.45), dose of cyclophosphamide (P = 0.80), nucleated cell dose infused (P = 0.60), or use of anti-T serotherapy (P = 0.20). Favorable factors for superior engraftment were full HLA compatibility (independent of the source of cells; P = 0.007) and use of a fludarabine-based conditioning regimen (P = 0.046). Unfavorable factors were > or = 25 transfusions pre-transplant (P = 0.011) and degree of HLA disparity (P = 0.007). Intensity of mucositis (P = 0.50) and use of androgen prior to transplant had no influence on survival (P = 0.80). Acute graft-versus-host disease (GVHD) grade II-IV and chronic GVHD were diagnosed in 47 and 23% of available patients, respectively, and infections prevailed as the main cause of death, associated or not with GVHD. Eighteen patients are alive, the Kaplan-Meyer overall survival is 38% at approximately 8 years, and the best results were obtained with related non-sibling bone marrow patients. Three recommendations emerged from the present study: fludarabine as part of conditioning, transplant in patients with < 25 transfusions and avoidance of HLA disparity. In addition, an extended family search (even when consanguinity is not present) seeking for a related non-sibling donor is highly recommended.

Allogeneic hematopoietic stem cell transplantation from an alternative stem cell source in Fanconi anemia patients: analysis of 47 patients from a single institution

We transplanted 47 patients with Fanconi anemia using an alternative source of hematopoietic cells. The patients were assigned to the following groups: group 1, unrelated bone marrow (N = 15); group 2, unrelated cord blood (N = 17), and group 3, related non-sibling bone marrow (N = 15). Twenty-four patients (51 percent) had complete engraftment, which was not influenced by gender (P = 0.87), age (P = 0.45), dose of cyclophosphamide (P = 0.80), nucleated cell dose infused (P = 0.60), or use of anti-T serotherapy (P = 0.20). Favorable factors for superior engraftment were full HLA compatibility (independent of the source of cells; P = 0.007) and use of a fludarabine-based conditioning regimen (P = 0.046). Unfavorable factors were > or = 25 transfusions pre-transplant (P = 0.011) and degree of HLA disparity (P = 0.007). Intensity of mucositis (P = 0.50) and use of androgen prior to transplant had no influence on survival (P = 0.80). Acute graft-versus-host disease (GVHD) grade II-IV and chronic GVHD were diagnosed in 47 and 23 percent of available patients, respectively, and infections prevailed as the main cause of death, associated or not with GVHD. Eighteen patients are alive, the Kaplan-Meyer overall survival is 38 percent at ~8 years, and the best results were obtained with related non-sibling bone marrow patients. Three recommendations emerged from the present study: fludarabine as part of conditioning, transplant in patients with <25 transfusions and avoidance of HLA disparity. In addition, an extended family search (even when consanguinity is not present) seeking for a related non-sibling donor is highly recommended.

Therapy for severe refractory acute graft-versus-host disease with basiliximab, a selective interleukin-2 receptor antagonist.

Basiliximab is a chimeric monoclonal antibody that binds to the alpha chain of IL-2R on activated cytotoxic T-cells, inhibiting lymphocyte proliferation. We report 34 patients with refractory acute GVHD (grade III-IV) who received basiliximab from December 1998 to October 2003. Adults received 40 mg weekly (2-3 doses) and children received half of this dose. Median age was 13 years. Twenty-five donors were unrelated. The stem cell source was bone marrow in 30 and cord blood in four. Complete responses were seen in 27/32 patients (84%) with skin, 12/25 (48%) with gut and 6/23 (26%) with liver GVHD. Median duration of response was 38 days (5-1103). Overall survival at 5 years was 20%. Eleven patients (32%) are alive. The main causes of death were CMV (n=4), fungus (n=6), sepsis (n=8), hemorrhage (n=2), and relapse (n=2). Graft-versus-host disease flares were observed in 14 patients (41%), half being rescued by other therapies. In conclusion, basiliximab was able to induce complete responses in patients with refractory acute GVHD. Prospective studies are necessary to evaluate the optimal treatment schedule.