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.

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.

Cytomegalovirus as a cause of very late interstitial pneumonia after bone marrow transplantation.

Cytomegalovirus (CMV) infection is an important cause of morbidity and mortality after allogeneic transplant. Interstitial pneumonia (IP) is the most common manifestation of CMV in BMT patients, with a 30-48% mortality rate despite adequate treatment. Most CMV infection occurs in the first 100 days. However, prolonged ganciclovir (GCV) prophylaxis has favored the occurrence of late CMV IP, probably by inhibition of the development of CMV-specific T cell lymphocyte responses. We report the case of a patient treated with an allogeneic BMT who received pre-emptive GCV until day +100 because of CMV-positive antigenemia. He developed a CMV IP on day +811 post BMT, which responded to treatment. We intend to alert clinicians that even at long-term (>1 year) post-BMT, CMV is a possible cause of IP in high-risk patients.

Primary renal aspergillosis: extremely uncommon presentation in patients treated with bone marrow transplantation.

Invasive aspergillosis affects 3 to 11% of BMT patients with a high mortality rate (60 to 95%). Extra-pulmonary disease is an unusual event, and primary renal aspergillosis is extremely uncommon. A patient with CML treated with BMT, who developed primary renal and subsequently hepatic aspergillosis, is described. Dysfunction of the mucosal barrier secondary to conditioning therapy, was a possible portal of entry for the fungus. Fine needle aspiration was very useful, as is direct microscopic examination of the urine, for diagnosis of the fungal infection. Surgical drainage of the abscess followed by antifungal therapy is the treatment of choice. Unconducive situations, such as refractory thrombocytopenia, are associated with the worst outcome in these patients.

Second bone marrow transplantation for severe aplastic anemia: analysis of 34 cases.

Severe aplastic anemia (sAA) is a bone marrow failure disorder which is mostly a consequence of immunologically mediated stem cell destruction. Allogeneic bone marrow transplantation (BMT) from a compatible donor provides long-term survival in 60 to 80% of sAA patients. However, graft rejection still remains a major problem, and a second allograft is an alternative for these patients. We retrospectively analyzed 34 patients who received a second BMT (BMT2), nine with primary graft failure (PGF) and 25 with transient engraftment (TE). The probability of survival at 13 years among PGF patients was 22% vs 60% for the TE group (P = 0.0068). Age (<17 vs>17 years), number of mononuclear cells (<3 vs >3 x 10(8)/kg) and year of transplant (1986-1991 vs 1992-1998) at BMT2 had no statistical influence on survival. A significant survival advantage was noted among TE patients (P = 0.0068), which was probably because of a longer intertransplant interval (>90 days). Furthermore, 90% of patients with positive blood cultures at BMT2 did not survive the procedure. We conclude that early detection of primary graft failure (PGF), followed by measures attempting to promote hematopoietic recovery (eg use of growth factors, further infusion of stem cells) may decrease mortality.

Disseminated Fusarium sp. infection affecting the brain of a child after bone marrow transplantation.

A case of Fusarium sp. infection of the brain in a 6-year-old child who underwent allogeneic BMT is reported. As far as the authors know, this is the first report of Fusarium sp. encephalitis in a BMT patient. Fusarium sp. infection is a rare but emerging fungal pathogen after BMT and, because of several similarities, it is often mistaken for other mold infections, such as Aspergillus sp. The importance of early identification of this fungus as a cause of disseminated fungal infection in BMT patients, and some new modalities of Fusarium sp disseminated infection treatment are discussed here.

Neuropathological findings after bone marrow transplantation: an autopsy study of 180 cases.

We prospectively evaluated the neuropathological complications of 180 patients who underwent autopsy studies following bone marrow transplantation (BMT) (177 allogeneic, three autologous). The most frequent underlying disorders included severe aplastic anemia (n = 55), chronic myelogenous leukemia (n = 53), acute myelogenous leukemia (n = 24) and Fanconi anemia (n = 16). There were 114 males and 66 females. Neuropathological findings were detected in 90.55% of the patients. The most frequent findings were subarachnoid hemorrhages (SAH) (n = 57), intraparenchymal hemorrhages (IHP) (n = 49), fungal infections (n = 16), Wernicke's encephalopathy (n = 10), microglial nodular encephalopathy (n = 10) and neurotoxoplasmosis (n = 8). In only 17 patients was the brain within normal limits. Survival time after BMT averaged 5.4 months and the majority of patients died in the first 3 months post BMT (n = 105). Central nervous system (CNS) pathology was the main cause of death in 17% of the patients (n = 31), with a predominance of IHP in this particular group. Furthermore, the survival time of these patients who died of CNS causes (96.3 days) was almost half of the survival time of those who died of extra-cerebral causes (177.8 days) (P = 0.0162). IHP (70. 96 vs27.22%) (P < 0.001), fungal infections (25.8 vs 8.88%) (P < 0. 001) and toxoplasmosis (9.67 vs 4.44%) (P < 0.001) were significantly more frequent in the group of patients who died due to CNS causes than in the control group. The findings of this work provide a possible guide to the possible causes of neurological syndromes following BMT. Bone Marrow Transplantation (2000) 25, 301-307.

Iatrogenic Wernicke's encephalopathy in allogeneic bone marrow transplantation: a study of eight cases.

Wernicke's encephalopathy (WE) is a neuropsychiatric condition generally caused by acute thiamine deficiency and classically involves the triad of altered mentation, ataxia and ophthalmoplegia. It is most common among alcoholics, but several other causes have been identified, including total parenteral nutrition (TPN) use. We present eight cases of WE in patients undergoing allogeneic BMT, where thiamine deficiency was caused by a lack of vitamin supplementation during TPN administration. Clinically, WE presented as a severe refractory metabolic acidosis, preceded by 'raspberry tongue', and ophthalmologic and neurologic dysfunction. The sites most affected were the periventricular structures and the thalamus, and no mammilary bodies lesions were found.

Intracranial hemorrhage following bone marrow transplantation: an autopsy study of 58 patients.

Autopsy files of 180 patients were reviewed, who died after BMT between July 1987 and June 1998 and 58 (32.2%) cases, who had experienced intracranial hemorrhage (ICH) were selected. Age, sex, underlying disease, preparatory regimens, immunoprophylaxis, chronic and acute GVHD, survival of the patients and localization and size of hemorrhages were evaluated. There were 33 males and 25 females, with a mean age of 23.4 years. The main underlying disorders for which BMT was performed included SAA (n = 21), CML (n = 13) and AML (n = 10). Forty patients were found to have intraparenchymal hemorrhage, 35 had subarachnoid hemorrhage and eight patients had subdural hemorrhage. In 16 cases the CNS hemorrhage was so extensive that it was considered to be the main cause of death. There was no significant statistical difference concerning sex (P = 0.217), age (P = 0.296), underlying disease (P= 0.352), preparatory regimens (P = 0.07), immunoprophylaxis (P = 0.914), chronic and acute graft-versus-host disease (P = 0.107 and P = 0.631, respectively) and survival (P = 0.701) when comparing patients with or without ICH. However, the number of cases in which the CNS was defined as the main cause of death was higher among patients with ICH than in patients without ICH (n = 16 vs 15) (P = 0.011). We conclude that ICH is common and has a significant mortality rate following BMT.

Effect of all-trans retinoic acid on newly diagnosed acute promyelocytic leukemia patients: results of a Brazilian center.

Thirty-seven patients with acute promyelocytic leukemia (APL) were treated with all-trans retinoic acid (ATRA). Patients received 45 mg m-2 day-1 po of ATRA until complete remission (CR) was achieved, defined as: a) presence of less than 5% blasts in the bone marrow, with b) white blood cells > 10(3)/mm3, c) platelets > 10(5)/mm3 and d) hemoglobin concentration > 8 g/dl, with no blood or platelet transfusions. Thirty-one (83.7%) patients achieved CR by day 50, and 75% of these before day 30. Correction of the coagulopathy, achieved between days 2 and 10 (mean, 3 days), was the first evidence of response to treatment. Only one patient had been previously treated with chemotherapy and three had the microgranular variant M3 form. Dryness of skin and mucosae was the most common side effect observed in 82% of the patients. Thrombosis, hepatotoxicity and retinoid acid syndrome (RAS) were observed in 7 (19%), 6 (16%) and 4 (11%) patients, respectively. Thirteen (35%) patients had to be submitted to chemotherapy due to hyperleukocytosis (above 40 x 10(3)/mm3) and six of these presented with new signs of coagulopathy after chemotherapy. Four (11%) patients died secondarily to intracerebral hemorrhage (IH) and two (5.4%) dropped out of the protocol due to severe ATRA side effects (one RAS and one hepatotoxicity). RAS and IH were related strictly to hyperleukocytosis. The reduced use of platelets and fresh frozen plasma probably lowered the total cost of treatment. We conclude that ATRA is an effective agent for inducing complete remission in APL patients.

Long-term outcome of 25 children and adolescents with severe aplastic anemia treated with antithymocyte globulin.

Severe aplastic anemia (SAA) is probably an immune-mediated disorder, and immunosuppressive therapy is recommended for patients with no available donor for bone marrow transplant. Between October 1984 and November 1987, 25 consecutive children and adolescents with SAA with no HLA-compatible marrow donor received equine antithymocyte globulin (ATG) (15 mg kg-1 day-1) for 10 days. The patients were evaluated 6 weeks, 6 months, and 12 months after starting ATG treatment. Thereafter, patients were evaluated yearly until July 1998. Median age was 10 years (range, 1.5-20 years), granulocyte counts on referral ranged from 0.032 to 1.4 x 10(9)/l (median 0.256 x 10(9)/l), and 12 patients had granulocyte counts <0.2 x 10(9)/l. At a median follow-up of 9.6 years (range, 8.6-11.8 years), 10 patients (40%) remained alive with good marrow function. No morphologic evidence of hematological clonal disorders has been observed, although two patients probably have acquired clonal chromosomal abnormalities (trisomy 8 and del(6)q21, respectively). Responses to ATG were observed between 6 weeks and 6 months from the start of treatment in 60% of evaluable patients. The response rate was not different in patients whose granulocyte count at diagnosis was <0.2 x 10(9)/l, or in those who were <10 years of age. This study supports the view that, when compared with supportive measures, ATG is an effective treatment for children or adolescents with SAA. Although these results are inferior to those reported for marrow transplantation or more intensive immunosuppressive regimens, these patients who responded to ATG are long-term survivors with stable peripheral blood counts and a low rate of relapse.

Reversible posterior leucoencephalopathy syndrome associated with bone marrow transplantation.

Reversible posterior leucoencephalopathy syndrome (RPLS) has previously been described in patients who have renal insufficiency, eclampsia, hypertensive encephalopathy and patients receiving immunosuppressive therapy. The mechanism by which immunosuppressive agents can cause this syndrome is not clear, but it is probably related with cytotoxic effects of these agents on the vascular endothelium. We report eight patients who received cyclosporine A (CSA) after allogeneic bone marrow transplantation or as treatment for severe aplastic anemia (SSA) who developed posterior leucoencephalopathy. The most common signs and symptoms were seizures and headache. Neurological dysfunction occurred preceded by or concomitant with high blood pressure and some degree of acute renal failure in six patients. Computerized tomography studies showed low-density white matter lesions involving the posterior areas of cerebral hemispheres. Symptoms and neuroimaging abnormalities were reversible and improvement occurred in all patients when given lower doses of CSA or when the drug was withdrawn. RPLS may be considered an expression of CSA neurotoxicity.

Cholestasis secondary to Hodgkin's disease: report of 2 cases of vanishing bile duct syndrome.

Only a small percentage of patients with Hodgkin's disease become clinically Jaundiced during their disease. This Jaundice may be secondary to biliary obstruction, hemolysis, direct hepatic infiltration by the disease, drug toxicity or viral hepatitis. Vanishing bile duct syndrome secondary to Hodgkin's disease is a rare cause of cholestasis in these patients, only 13 cases having been reported so far. The authors describe 2 patients who developed severe Jaundice secondary to Hodgkin's disease due to vanishing bile duct syndrome affecting small intrahepatic bile ducts.

Disseminated toxoplasmosis after bone marrow transplantation: report of 9 cases.

Toxoplasma infection following bone marrow transplantation (BMT) is infrequently reported. We report 9 cases of disseminated Toxoplasma gondii infection in BMT recipients documented during an 11-year period at our institution. The incidence of T. gondii infection in our institution (1.14 per 100 allogeneic BMT) is higher than previously reported. The most frequently affected sites were the brain, lungs, and heart. Findings common to most patients who developed toxoplasmosis were positive pre-transplant serology, allogeneic transplant and graft-versus-host disease and its treatment, as well as BMT from matched unrelated donors. All 9 patients died and 8 were diagnosed only after autopsy. Heightened awareness of the occurrence of toxoplasmosis in marrow recipients, especially in highly endemic areas, and early diagnosis and therapy are needed for a better outcome.