Pre-existing invasive fungal infection is not a contraindication for allogeneic HSCT for patients with hematologic malignancies: a CIBMTR study.

Patients with prior invasive fungal infection (IFI) increasingly proceed to allogeneic hematopoietic cell transplantation (HSCT). However, little is known about the impact of prior IFI on survival. Patients with pre-transplant IFI (cases; n=825) were compared with controls (n=10247). A subset analysis assessed outcomes in leukemia patients pre- and post 2001. Cases were older with lower performance status (KPS), more advanced disease, higher likelihood of AML and having received cord blood, reduced intensity conditioning, mold-active fungal prophylaxis and more recently transplanted. Aspergillus spp. and Candida spp. were the most commonly identified pathogens. 68% of patients had primarily pulmonary involvement. Univariate and multivariable analysis demonstrated inferior PFS and overall survival (OS) for cases. At 2 years, cases had higher mortality and shorter PFS with significant increases in non-relapse mortality (NRM) but no difference in relapse. One year probability of post-HSCT IFI was 24% (cases) and 17% (control, P<0.001). The predominant cause of death was underlying malignancy; infectious death was higher in cases (13% vs 9%). In the subset analysis, patients transplanted before 2001 had increased NRM with inferior OS and PFS compared with later cases. Pre-transplant IFI is associated with lower PFS and OS after allogeneic HSCT but significant survivorship was observed. Consequently, pre-transplant IFI should not be a contraindication to allogeneic HSCT in otherwise suitable candidates. Documented pre-transplant IFI is associated with lower PFS and OS after allogeneic HSCT. However, mortality post transplant is more influenced by advanced disease status than previous IFI. Pre-transplant IFI does not appear to be a contraindication to allogeneic HSCT.

Ex Vivo Costimulatory Blockade to Generate Regulatory T Cells From Patients Awaiting Kidney Transplantation.

Short-term outcomes of kidney transplantation have improved dramatically, but chronic rejection and regimen-related toxicity continue to compromise overall patient outcomes. Development of regulatory T cells (Tregs) as a means to decrease alloresponsiveness and limit the need for pharmacologic immunosuppression is an active area of preclinical and clinical investigation. Nevertheless, the immunomodulatory effects of end-stage renal disease on the efficacy of various strategies to generate and expand recipient Tregs for kidney transplantation are incompletely characterized. In this study, we show that Tregs can be successfully generated from either freshly isolated or previously cryopreserved uremic recipient (responder) and healthy donor (stimulator) peripheral blood mononuclear cells using the strategy of ex vivo costimulatory blockade with belatacept during mixed lymphocyte culture. Moreover, these Tregs maintain a CD3(+) CD4(+) CD25(+) CD127(lo) surface phenotype, high levels of intracellular FOXP3 and significant demethylation of the FOXP3 Treg-specific demethylation region on allorestimulation with donor stimulator cells. These data support evaluation of this simple, brief Treg production strategy in clinical trials of mismatched kidney transplantation.

Alloanergization of human T cells results in expansion of alloantigen-specific CD8(+) CD28(-) suppressor cells.

Allostimulation with concurrent costimulatory blockade induces alloantigen-specific hyporesponsiveness in responder T cells ("alloanergization"). Alloanergized responder cells also acquire alloantigen-specific suppressive activity, suggesting this strategy induces active immune tolerance. While this acquired suppressive activity is mediated primarily by CD4(+) FOXP3(+) cells, other cells, most notably CD8(+) suppressor cells, have also been shown to ameliorate human alloresponses. To determine whether alloanergization expands CD8(+) cells with allosuppressive phenotype and function, we used mixed lymphocyte cultures in which costimulatory blockade was provided by belatacept, an FDA-approved, second-generation CTLA-4-immunoglobulin fusion protein that blocks CD28-mediated costimulation, as an in vitro model of HLA-mismatched transplantation. This strategy resulted in an eightfold expansion of CD8(+) CD28(-) T cells which potently and specifically suppressed alloresponses of both CD4(+) and CD8(+) T cells without reducing the frequency of a range of functional pathogen-specific T cells. This CD8-mediated allosuppression primarily required cell-cell contact. In addition, we observed expansion of CD8(+) CD28(-) T cells in vivo in patients undergoing alloanergized HLA-mismatched bone marrow transplantation. Use of costimulatory blockade-mediated alloanergization to expand allospecific CD8(+) CD28(-) suppressor cells merits exploration as an approach to inducing or supporting immune tolerance to alloantigens after allogeneic transplantation.

Attenuation of resting energy expenditure following hematopoietic SCT in children.

Children undergoing hematopoietic SCT (HSCT) typically receive parenteral nutrition (PN) due to gastrointestinal toxicities. Accurate determination of resting energy expenditure (REE) may facilitate optimal energy provision and help avoid unintended overfeeding or underfeeding. A multicenter, prospective cohort study of children undergoing allogeneic HSCT was performed, in which REE was measured by indirect calorimetry at baseline and twice weekly until 30 days after transplantation. Change in percent predicted REE over time from admission was analyzed using repeated measures regression analysis. In all, 26 children (14 females) with a mean (s.d.) age of 14.9 (4.2) years who underwent an HLA-matched sibling or unrelated donor transplantation were enrolled. Mean (s.d.) percent predicted REE at baseline was 92.4 (15.2). Baseline REE was highly correlated with lean body mass measured by dual energy X-ray absorptiometry (r=0.78, P<0.0001). REE decreased significantly over time, following a quadratic curve to a nadir of 79% predicted at 14 days post transplantation (P<0.001) and returned to near baseline by day 30. Children undergoing HSCT exhibit a significant reduction in REE in the early weeks after transplantation, a phenomenon that places them at risk for overfeeding. Serial measurements of REE or reductions in energy intake should be considered when PN is the primary mode of nutrition.

Herpes zoster infection in the post-hematopoietic stem cell transplant pediatric population may be preceded by transaminitis: an institutional experience.

Herpes zoster (HZ), a varicella-zoster virus reactivation, frequently complicates hematopoietic stem cell transplantation (HSCT). Its incidence, complications, and associated risk factors in 310 children undergoing HSCT were reviewed. In all, 61 of 201(32%) patients who had undergone allogeneic and 10 of 109 (9%) patients who had undergone autologous HSCT developed HZ. Of 90 VZV seropositive allogeneic patients, 50 (53%) developed HZ. Seven (17%) of 41 VZV seropositive autologous patients developed HZ. Although a substantial number of patients develop HZ in the early post-HSCT period, risk for HZ persists and HZ can occur up to 5 years post-HSCT. Risk factors for HZ included age >10 years (P<0.0001), allogeneic HSCT (P<0.001), and total body irradiation (TBI) (P<0.059) in allogeneic recipients. Of 37, 22 (59%) patients experienced an elevated alanine aminotransferase (ALT), unassociated with GVHD, in the month preceding HZ. Of the 48/64 patients (75%) hospitalized for treatment (median stay, 6 days; range, 2-39), length of stay was unaffected by donor type but increased by cutaneous dissemination and visceral involvement (P=0.023 and 0.034, respectively) in allogeneic patients. Consideration of HZ infection particularly in patients >10 years of age with elevated ALT after TBI-conditioned allogeneic HSCT may permit earlier diagnosis and therapeutic intervention.

Favorable outcome of allogeneic hematopoietic stem cell transplantation for relapsed or refractory acute promyelocytic leukemia in childhood.

The optimal therapy for children with relapsed or refractory acute promyelocytic leukemia (APL) is unclear. We therefore reviewed our institutional outcomes for children undergoing allogeneic hematopoietic stem cell transplantation (HSCT) for advanced APL. Between 1986 and 2003, 12 allogeneic HSCTs (five related donor, seven unrelated donor) were performed for 11 patients (median age, 13 years) with relapsed (n = 8) or refractory (n = 3) APL. All patients engrafted, after a median of 18.5 days. Grade B-D acute graft-versus-host disease (GVHD) developed after five transplants (42%; 90% CI, 18-68%), and the cumulative incidence of chronic GVHD was 45% (90% CI, 19-71%). The cumulative incidence of overt relapse post-HSCT was 10% (90% CI, 0-28%). The overall 5-year survival was 73% (90% confidence interval (CI), 51-95%), with a median post-HSCT follow-up of 64 months. The Lansky/Karnofsky performance scores are 100% in six of eight survivors. In view of the low risk of subsequent relapse and favorable survival suggested by other reports and our own experience, we continue to recommend allogeneic HSCT for children with advanced APL for whom a suitably HLA-matched donor is identified.

Impact of pharmacy practices on the cost of colony-stimulating factor use in pediatric stem cell transplantation: an institution-based analysis.

PURPOSE: An evaluation of colony-stimulating factor (CSF) use in pediatric stem cell transplantation (SCT) was conducted to identify potential cost-efficiencies while preserving institutional standards of patient care. METHODS: Clinical and pharmacy records of the 55 SCTs performed during fiscal year 1995 were reviewed. Material costs per vial and per microgram, exclusive of preparation or overhead costs, were used. The best costing strategy was defined as the least expensive stocking and dispensing practice to deliver the drug actually used during the study period. RESULTS: CSFs were used in 35 of 55 transplants; 68% of usage was protocol-mandated to enhance engraftment; the remainder was associated with life-threatening complications of SCT. All use was consistent with published evidence-based guidelines. Changes in stocking and dispensing practices would result in an overall annual savings of $48,162 (fiscal year 1995 dollars), a 39% decrease in cost without a change in clinical application. CONCLUSIONS: Our analysis demonstrates that stocking and dispensing practices place significant fiscal burden in the care of pediatric-aged patients and must be carefully considered. This analysis presents a model for evaluating all components of drug cost from a global perspective, highlighting a need for examination of pharmacy and manufacturing as well as clinical practices.

Balancing efficacy with cost: antiemetic control in the pediatric stem cell transplant (SCT) population.

We studied the practice patterns regarding intravenous (i.v.) ondansetron in children receiving stem cell transplants (SCT) at The Children's Hospital, Boston to identify cost efficiencies. The pharmacy provided information on material and preparation costs on 36 patients who received i.v. ondansetron during 41 SCT in 1995. We examined the effects of frequency, duration, and route of administration on costs. There were 498 days of ondansetron administration costing $49,083 (95$). Tremendous variation existed in frequency and duration with one third receiving i.v. ondansetron once daily, despite published evidence of equivalence of once a day and divided dosing. A switch to once daily i.v. dosing for all patients would have resulted in >/=28% savings. The median duration of use was 11 days (range 1-48); placing a cap for 7-10 days based on the length of SCT conditioning regimens, would produce savings of 48-60% over current use. By shifting administration route from i.v. to oral, a savings of 67% over current use, without a cap on duration, would be realized. Identifying areas for cost savings can be achieved after thorough analysis of all the component costs. We demonstrated that significant cost reductions could be realized by simple changes in prescribing practices without jeopardizing efficacy. These savings are achieved by standardizing dosing interval, route of administration and duration of treatment without altering daily dosage or access to an effective antiemetic. Bone Marrow Transplantation (2000) 25, 553-557.

Transplantation of anergic histoincompatible bone marrow allografts.

BACKGROUND: Successful allogeneic bone marrow transplantation relies on global immunosuppression or elimination of T cells. In contrast, the induction of anergy can inactivate specific sets of alloreactive T cells in the donor marrow. Previous work has shown that anergy can be induced by blocking the interaction of the B7 molecule on the surface of antigen-presenting cells with the CD28 molecule on the surface of T cells, thus preventing key signaling events essential for the activation of T cells. To investigate the feasibility of this approach with respect to transplantation of histoincompatible bone marrow, we undertook a clinical trial of ex vivo induction of anergy in T cells present in donor marrow to recipient alloantigens. METHODS: Outcomes in 12 transplant recipients were evaluated. The recipients' peripheral-blood lymphocytes were collected before myeloablation and served as alloantigen-presenting cells. To induce alloantigen-specific anergy, bone marrow from a donor mismatched with the recipient for one HLA haplotype was cocultured with irradiated cells from the recipient for 36 hours in the presence of CTLA-4-Ig, an agent that inhibits B7:CD28-mediated costimulation. After conventional myeloablation and immunoprophylaxis, the treated donor cells were transfused into the recipient. RESULTS: After the induction of anergy, the frequency of T cells capable of recognizing alloantigens of the recipient in donor marrow was sharply reduced (P<0.001), whereas the responsiveness to alloantigens from persons unrelated to the recipient or the donor was unaffected (P=0.51). In the 11 patients who could be evaluated, the haploidentical bone marrow cells engrafted. Of these 11 patients, 3 had acute graft-versus-host disease (GVHD) confined to the gastrointestinal tract. No deaths were attributable to GVHD. Five of the 12 patients were alive and in remission 4.5 to 29 months after transplantation. CONCLUSIONS: Donor bone marrow treated ex vivo to induce anergy to alloantigens from the recipient can reconstitute hematopoiesis in vivo with a relatively low risk of GVHD.

Phase I/II trial of PIXY321 (granulocyte-macrophage colony stimulating factor/interleukin-3 fusion protein) for treatment of inherited and acquired marrow failure syndromes.

Fourteen paediatric patients with advanced amegakaryocytic thrombocytopenia (AMT) or other bone marrow (BM) failure syndromes were enrolled on one of two phase I/II dose escalation studies of PIXY321. PIXY321 was administered subcutaneously in doses ranging from 250 to 750 mg/m2/d. No dose-limiting toxicity was observed. Peak absolute neutrophil count (ANC) was higher than baseline in all patients. Most transfusion-independent patients demonstrated elevation in haematocrit and/or platelet count. Trilineage haemopoietic responsiveness was evident in the three transfusion-independent patients. In these paediatric populations PIXY321 is well tolerated and merits consideration as a potential therapy.

Comparison of multiple immunization schedules for Haemophilus influenzae type b-conjugate and tetanus toxoid vaccines following bone marrow transplantation.

Antibody concentrations to vaccine-preventable diseases decline following BMT and an optimal schedule for vaccination after transplant has not been established. We examined antibody responses to tetanus toxoid (TT) and Haemophilus influenzae type b-conjugate (HIB) vaccines of BMT patients immunized at 6, 12 and 24 months (6 month group, n = 21) and compared them to those previously reported for patients immunized at 3, 6, 12 and 24 months (3 month group, n = 74) or at 12 and 24 months (12 month group, n = 17) following transplantation. Geometric mean total anti-HIB and IgG anti-TT concentrations were significantly higher after the 12 month dose in the 3 and 6 month immunization groups compared to the group who received their first dose at 12 months. Although HIB antibody concentrations were higher in the 3 month and 6 month groups 12 to 24 months after BMT, the proportion of patients with protective levels was not significantly different from the proportion protected in the 12 month group. Following the 24 month immunizations, geometric mean antibody concentrations to HIB and TT were similar for all three immunization groups. The proportion of patients in each group with protective levels of HIB antibody after the 24 month dose was > or = 80%. A two dose schedule of HIB and TT vaccines at 12 and 24 months after BMT should afford protection.

Treatment of severe veno-occlusive disease with defibrotide: compassionate use results in response without significant toxicity in a high-risk population.

Hepatic veno-occlusive disease (VOD) is the most common of the regimen-related toxicities accompanying stem cell transplantation (SCT). Despite aggressive therapies, including the combination of tissue plasminogen activator (t-PA) and heparin, severe VOD is almost uniformly fatal. Defibrotide (DF) is a polydeoxyribonucleotide with activity in several vascular disorders and, unlike t-PA and heparin, produces no systemic anticoagulant effects. Nineteen patients who developed severe VOD after SCT were treated with DF on a compassionate-use basis. Patients had clinically established VOD and met risk criteria predicting progression and fatality. At the initiation of DF, all 19 patients had evidence of multiorgan dysfunction; median bilirubin was 22.3 mg/dL, 12 patients had renal insufficiency (5 dialysis dependent), 14 required oxygen supplementation, and encephalopathy was present in 8 patients. Beginning a median of 6 days after diagnosis of VOD, DF was administered intravenously in doses ranging from 5 to 60 mg/kg/d for a planned minimum course of 14 days. In no case was DF discontinued for attributable toxicity. No severe hemorrhage related to DF administration was observed. Resolution of VOD (bilirubin <2 mg/dL with improvement in other symptoms and signs) was seen in 8 patients (42%). Six of 8 responders survived past day +100, contrasted with the 2% predicted survival reported in comparable patients. The observed response rate, survival to day +100, and absence of significant DF treatment-associated toxicity are compelling and warrant further evaluation.

Inducing amenorrhea during bone marrow transplantation. A pilot study of leuprolide acetate.

OBJECTIVE: To evaluate, in a pilot study, the use and efficacy of a gonadotropin-releasing hormone (GnRH)-agonist in inducing amenorrhea in women undergoing BMT. STUDY DESIGN: We evaluated the use of the GnRH agonist leuprolide acetate (LA) for the induction of amenorrhea in 10 postmenarcheal women prior to BMT. If there was a contraindication to the use of the intramuscular (i.m.) formulation of LA, the subcutaneous (s.c.) formulation was given as a daily intravenous (i.v.) bolus. Once the subject's platelet count was > 50,000/microL, the LA was discontinued. Menstrual bleeding, time from initiation of therapy to amenorrhea, and liver function test results were monitored. RESULTS: All subjects had induction of amenorrhea with the use of LA except for one subject with a large, myomatous uterus, who experienced light spotting. One subject who was thrombocytopenic at the prescribed time of the second dosage of i.m. LA received i.v. LA with documentation of continued pituitary/gonadal suppression. No adverse effects were determined to be directly related to either the i.m. or i.v. LA. CONCLUSION: LA is an option for the induction of amenorrhea in postmenarcheal women undergoing BMT. In thrombocytopenic subjects, administration of the s.c. formulation of LA by an i.v. route served as an alternative to i.m. injection and was documented to maintain gonadotropin suppression.

Antibody responses to tetanus toxoid and Haemophilus influenzae type b conjugate vaccines following autologous peripheral blood stem cell transplantation (PBSCT).

Accelerated granulocyte and platelet recovery following peripheral blood stem cell transplantation (PBSCT) are well documented. We hypothesize that functional immunity may also be enhanced in PBSCT and performed a phase II trial of immunizations in patients with lymphoma undergoing autologous transplantation with peripheral blood stem cells or bone marrow. Seventeen BMT and 10 PBSCT recipients were immunized at 3, 6, 12, and 24-months post-transplantation with Haemophilus influenzae type b (HIB)-conjugate and tetanus toxoid (TT) vaccines. IgG anti-HIB and anti-TT antibody concentrations were measured and compared between the two groups. Geometric mean IgG anti-HIB antibody concentrations were significantly higher for PBSCT recipients compared to BMT recipients at 24 months post-transplantation (11.3 micrograms/ml vs 0.93 microgram/ml, P = 0.051) and following the 24 month immunization (66.2 micrograms/ml vs 1.30 micrograms/ml, P = 0.006). Similar results were noted for IgG anti-TT antibody with significantly higher geometric mean antibody concentrations in the PBSCT group at 24 months post-transplantation (182 micrograms/ml vs 21.6 micrograms/ml, P = 0.039). Protective levels of total anti-HIB antibody were achieved earlier in PBSCT recipients compared with those of BMT recipients. PBSCT recipients had higher antigen-specific antibody concentrations following HIB and TT immunizations. These results suggest enhanced recovery of humoral immunity in PBSCT recipients and earlier protection against HIB with immunization.

Isolated testicular relapse in an adolescent 5 years following allogeneic bone marrow transplantation for acute myelogenous leukemia.

A case of isolated testicular relapse occurring 5 years after allogeneic bone marrow transplantation (BMT) for acute myelogenous leukemia (AML) is reported. The patient presented with M4 AML at age 13 and underwent allogeneic BMT in first remission, 5 months after diagnosis. He had no acute graft-versus-host disease (GVHD) but developed mild chronic GVHD 5 months following transplant and received immunosuppressive therapy for the next 2 years. Five years post-transplant he had an isolated testicular relapse that was treated with chemotherapy and testicular radiation. The patient remains in remission 17 months following relapse and more than 15 months following the cessation of therapy.

Bone marrow transplantation for therapy-related myelodysplasia: comparison with primary myelodysplasia.

Therapy-related myelodysplasia (MDS) is a fatal marrow disorder distinct from primary MDS. We examined the efficacy of bone marrow transplantation (BMT) as a treatment for patients with therapy-related MDS. Eighteen patients with therapy-related MDS and twenty-five patients with primary MDS received an allogeneic, syngeneic, or unrelated donor BMT. Graft-versus-host disease prophylaxis included methotrexate, methotrexate plus cyclosporine, FK-506, or T cell depletion. Conditioning regimens consisted of cyclophosphamide/total body irradiation, with and without cytosine arabinoside, busulfan/cyclophosphamide, and cyclophosphamide/etoposide/carmustine. For patients with therapy-related MDS, the median age was 32 years and the actuarial disease-free survival was 24% (95% confidence interval 6, 42%) with a median follow-up of 3 years. For patients with primary MDS, the median age was 36 years and the actuarial disease-free survival at 3 years was 43% (95% confidence interval 22, 64%). Four of the therapy-related patients and two of the primary patients have relapsed. Three patients experienced graft failure; all three had received T cell-depleted marrow and two had marrow fibrosis. Our results suggest that patients with therapy-related MDS can be successfully transplanted. Transplantation should be considered early in the disease, since long-term disease-free survival is achievable.

Clinical aspects of aplastic anemia.

Severe aplastic anemia is a disorder characterized by peripheral pancytopenia and marrow hypoplasia. Although its pathophysiology is understood poorly, the majority of patients appear to have some immunologic destruction or suppression of hematopoietic cells. The only curative therapy to date is allogeneic stem cell transplantation, although the success of palliative immunosuppressive therapies has improved over the last two decades. Making the best therapy choice is complex and often requires balancing very divergent toxicity profiles, both acute and long-term.

Haemophilus influenzae type b (HIB)-conjugate immunization before bone marrow harvest in autologous bone marrow transplantation.

Immune reconstitution following autologous bone marrow transplantation (ABMT) is characterized by defects in B cell and T cell function and loss of specific antibody. In the late post-transplant period, patients are at risk for infections with polysaccharide encapsulated organisms and respond poorly to polysaccharide vaccines. We examined whether immunizing ABMT patients before bone marrow (BM) harvest enhanced the early recovery of specific antibody. Twelve patients were immunized before BM harvest with Haemophilus influenzae type b (HIB)-conjugate, tetanus toxoid and polysaccharide pneumococcal vaccines. Forty-one comparable ABMT patients not immunized prior to BM harvest were also studied. Following ABMT, both groups of patients were immunized with HIB-conjugate and tetanus toxoid vaccines at 3, 6, 12 and 24 months and with pneumococcal vaccine at 12 and 24 months. Patients immunized before BM harvest had higher HIB antibody concentrations during the first 2 years post-transplant, the differences reaching significance at 3 months (P = 0.0001) and following the 24-month dose (P = 0.048). Tetanus toxoid antibody concentrations were also significantly higher at 3 months (P = 0.001) and 6 months (P = 0.032) in patients immunized before BM harvest. There were no differences in pneumococcal antibody concentrations between the two groups. Immunization of patients before bone marrow harvest resulted in higher anti-HIB antibody concentrations following ABMT and may be an effective strategy to prevent infectious complications.