Bone Marrow Transplantation For Leukemia Research Articles

Effect of nucleated marrow cell dose on relapse and survival in identical twin bone marrow transplants for leukemia

AbstractThe impact of cell dose (number of nucleated donor cells per kilogram recipient weight) on transplantation outcome is controversial and may differ for allogeneic and identical twin (syngeneic) bone marrow transplants. We studied the association between cell dose and outcome in 100 unmanipulated identical twin bone marrow transplantations for leukemia, reported to the International Bone Marrow Transplant Registry between 1985 and 1994, using Cox proportional hazards regression for multivariate analyses. Cell doses ranged from 0.3 to 7.4 × 108 nucleated cells/kg (median, 3.0 × 108cells/kg). Median follow-up was 75 months. Five-year cumulative incidences of transplant-related mortality with high (more than 3 × 108 cells/kg) versus low (less than or equal to 3 × 108 cells/kg) cell doses were 2% (95% confidence interval [CI], 0% to 8%) versus 10% (95% CI, 4% to 20%), respectively. Five-year probabilities of leukemia-free survival were 53% (95% CI, 39% to 67%) and 37% (95% CI, 23% to 52%), respectively. In multivariate analysis, among patients surviving in remission at least 9 months after transplantation, those receiving high cell doses were at significantly lower risk for treatment failure (relapse or death) than those receiving low cell doses (RR, 0.27; 95% CI, 0.12 to 0.6;P = .001). Lower treatment failure resulted from fewer relapses in the high cell dose group (RR for relapse, 0.28; 95% CI, 1.2 to 0.66; P = .003). These findings suggest that outcomes after syngeneic bone marrow transplantation could be improved by transplanting more than 3 × 108 nucleated cells per kilogram. The benefit of high cell dose on relapse may represent a delayed graft-versus-leukemia effect.

T-cell depletion of bone marrow transplants for leukemia from donors other than HLA-identical siblings: advantage of T-cell antibodies with narrow specificities

AbstractT-cell depletion of donor marrow decreases graft–versus–host disease resulting from transplants from unrelated and human leukocyte antigen (HLA)-mismatched related donors. However, there are diverse strategies for T-cell–depleted transplantation, and it is uncertain whether any improve leukemia-free survival (LFS). To compare strategies for T-cell–depleted alternative donor transplants and to compare T-cell depleted with non-T-cell–depleted transplants, we studied 870 patients with leukemia who received T-cell–depleted transplants from unrelated or HLA-mismatched related donors from 1982 to 1994. Outcomes were compared with those of 998 non-T-cell–depleted transplants. We compared LFS using different strategies for T-cell–depleted transplantation considering T-cell depletion technique, intensity of pretransplant conditioning, and posttransplant immune suppression using proportional hazards regression to adjust for other prognostic variables. Five categories of T-cell depletion techniques were considered: narrow-specificity antibodies, broad-specificity antibodies, Campath antibodies, elutriation, and lectins. Strategies resulting in similar LFS were pooled to compare T-cell–depleted with non-T-cell–depleted transplants. Recipients of transplants T-cell depleted by narrow-specificity antibodies had lower treatment failure risk (higher LFS) than recipients of transplants T-cell depleted by other techniques. Compared with non-T-cell–depleted transplants (5-year probability ± 95% confidence interval [CI] of LFS, 31% ± 4%), 5-year LFS was 29% ± 5% (P = NS) after transplants T-cell depleted by narrow-specificity antibodies and 16% ± 4% (P < .0001) after transplants T-cell depleted by other techniques. After alternative donor transplantation, T-cell depletion of donor marrow by narrow-specificity antibodies resulted in LFS rates that were higher than those for transplants T-cell depleted using other techniques but similar to those for non-T-cell–depleted transplants.

New principles of cancer therapy give new hope for oncological patients.

The Nobel Prize in Physiology or Medicine 2018 was awarded jointly to James P. Allison and Tasuku Honjo "for their discovery of cancer therapy by inhibition of negative immune regulation". A number of therapeutic approaches are available for cancer treatment, including surgery, radiation, and other strategies, some of which have been awarded previous Nobel Prizes. These include methods for hormone treatment for prostate cancer (Huggins, 1966), chemotherapy (Elion and Hitchins, 1988), and bone marrow transplantation for leukemia (Thomas, 1990). Many scientists engaged in intense basic research and uncovered fundamental mechanisms regulating immunity and also showed how the immune system can recognize cancer cells. T-cells were shown to have receptors that bind to structures recognized as non-self and such interactions trigger the immune system to engage in defense. However, additional proteins acting as T-cell accelerators are also required to trigger a full-blown immune response. Many scientists contributed to this important basic research and identified other proteins that function as brakes on the T-cells, inhibiting immune activation. This intricate balance between the accelerators and inhibitors is essential for a tight control. New strategy was developed into a therapy for humans. Promising results soon emerged from several groups, and in 2010 an important clinical study showed striking effects in patients with advanced melanoma. In several patients, signs of remaining cancer disappeared. The results were dramatic, leading to long-term remission and possible cure in several patients with metastatic cancer, a condition that had previously been considered essentially untreatable. Such remarkable results had never been seen in this patient group before (Fig. 2, Ref. 12). Keywords: Nobel Prize, physiology, medicine, immune system, inhibition, cancer therapy.

Juniper Subtle Energy Healing: A Case Study

This pilot case study sought to examine the efficacy of subtle energy treatments as conducted by Buddhist healing master Segyu Rinpoche at his Juniper Integrative Clinic in Northern California. Over the course of a year, this study followed two patients with terminal diagnoses, their treating physicians, and Segyu Rinpoche as the patients underwent treatment at the Juniper Clinic. The patients entering the study had exhausted all known medical options. One patient suffered from chronic lymphocytic leukemia [CLL] and the other from bronchiolitis obliterans [BOS] brought about by graft versus host disease following a bone marrow transplant for leukemia. Their treating physicians are prominent members of two different teaching/research hospitals. This was an IRB approved study conducted in conformity with HIPAA standards. The patients participated in treatments with Segyu Rinpoche twice a month at his clinic and engaged in daily meditation as instructed by Rinpoche. The study followed both patients through in-depth, face-to-face interviews, wellness surveys, weekly journal entries, and medical records. The study also followed the physicians and Segyu Rinpoche through face-to-face interviews. Both patients and physicians identified significant shifts in patient wellbeing, including less pain, greater happiness and more ease. In addition, both physicians and patients reported a reduced need for medication. Some aspects of the design were more or less successful in tracking patient experience (i.e., health and wellness survey vs. personal journals). The success of the pilot indicates that more qualitative case studies are needed. Patients and physicians identified a significant increase in overall patient wellbeing. Hence, on an anecdotal level, the study demonstrated the usefulness of subtle energy healing as practiced by Segyu Rinpoche and the Juniper Clinic. The success of the pilot indicates the potential value of full qualitative studies for this modality.

703. Development of RD-MolPack-trLNGFR/dCK.DM.S74E Stable Packaging Cells

The efficacy of several clinical approaches of adoptive T cell therapy (ACT) can be compromised by the insurgence of severe unfavorable events as graft-versus host disease (GvHD) secondary to bone marrow transplantation unless ex-vivo manipulation endow transplantable T cells with safety system. Introduction of drug-induced suicide genes, as for example the herpes simplex virus thymidine kinase (HSV-TK) transgene in T cells during bone marrow transplantation for leukemia and lymphoma treatment, represents a valid approach to control gene-modified cell proliferation and survival overtime. Transplanted modified cells are selectively deleted in vivo by specific activation of an otherwise inactive prodrug in those cells. Despite the well-documented utility of this approach, some limitations arose in terms of poor prodrug activation kinetics, escape from drug selection and immunological rejection.Engineered variants targeting the active site of the human deoxyCytidine Kinase (dCK) suicide enzyme were described as a powerful alternative to current strategies being able to activate a large variety of nucleoside analogue-based prodrugs, having low immunogenicity and permitting in vivo imaging of genetically modified cells. Lentiviral vector (LV)-mediated delivery of the triple mutant dCK.R104M.D133A.S74E (dCK.DM.S74E) fused to the truncated low density nerve growth factor receptor (LNGFR) selection marker renders human cells highly sensitive to the prodrugs bromovinyl-deoxyuridine (brivudine or BVdU), l-deoxythymidine (LdT), and l-deoxyuridine (LdU) via induction of apoptosis. MolMed has developed the proprietary RD-MolPack technology for the stable production of both second and third generation LVs, pseudotyped with the RD114-TR envelope that, in contrast to inducible systems based on VSV-G envelope, permits the generation of a simple, constitutive, no-toxic LV packaging system. We thus exploited the RD-MolPack technology to obtain several colonies of RD-MolPack-trLNGFR/dCK.DM.S74E producer cells by stable transfection of a SIN transfer vector plasmid carrying the trLNGFR/dCK.DM.S74E transgene followed by zeocin selection. The average titer calculated on CEM A3.01 target cells of several colonies is 1.9 × 105 ± 8.15 × 104 TU/106 cells/day, in line with the previous results obtained with the previously established RD2-MolPack-Chim3 and RD3-MolPack-GFP producer cells. These preliminary data suggest that the human suicide gene trLNGFR/dCK.DM.S74E can be constitutively produced in LV stable packaging cells without toxicity and its use can be therefore considered a valid option in the scenario of prodrug convertase enzymes.

Safety and effectiveness of percutaneous cholecystostomy in critically ill children who are immune compromised.

Acalculous cholecystitis is known to develop in critically ill patients without cystic duct obstruction. In the past, treatment for acalculous cholecystitis has been cholecystectomy; however, many children who are critically ill are Percutaneous cholecystostomy is likely the procedure of choice in this subgroup of patients. To assess the safety and effectiveness of percutaneous cholecystostomy in critically ill and immune-compromised children with acalculous cholecystitis. Retrospective review of immune-compromised and critically ill children who underwent percutaneous cholecystostomy between 2006 and 2013. Diagnostic imaging performed included ultrasound, CT and hepatobiliary scintigraphy. Every percutaneous cholecystostomy was performed using imaging guidance. Ten critically ill and immune-compromised children with acalculous cholecystitis underwent percutaneous cholecystostomy. Seven boys and 3 girls, ranging in age from 10months to 15years 8months, were treated. Six of the immune-compromised children had received a bone marrow transplant for leukemia (5 children) or severe combined immunodeficiency (SCID) (1 child), and ranged from 18 to 307days post bone marrow transplant at the time of their percutaneous cholecystostomy. Of the remaining four immune-compromised children with acalculous cholecystitis who underwent percutaneous cholecystostomy, two had leukemia, one had SCID and lymphoma, and the fourth was undergoing treatment for undifferentiated germ cell tumor. The 10 percutaneous gallbladder drains were placed using a transhepatic approach, except one unintentional transperitoneal approach. There were no complications. Three gallbladder drains were removed in Interventional Radiology. Those three patients had a return to normal gallbladder function and didn't require cholecystectomy. Two drains were removed during cholecystectomy and another as an outpatient. Four patients died in the hospital due to multiorgan system failure, with indwelling gallbladder drains. Percutaneous cholecystostomy is a safe procedure in immune-compromised and critically ill children with acalculous cholecystitis. Percutaneous cholecystostomy may obviate the need for future cholecystectomy.

Whole Genome and Transcriptome Analysis of Genetic Alterations in Context of Busulfan in Vitro Resistance in Pediatric Acute Leukemias

INTRODUCTIONBusulfan (BUS) is bifunctional cell cycle non-specific alkylating antineoplastic agent. High-dose busulfan in combination with cyclophosphamide is an effective preparative regimen for patients undergoing allogeneic or autologous bone marrow transplantation for leukemias and solid tumors. The main mechanism of action involves the interference of DNA replication and RNA transcription (by alkylation and cross-linking of strands), which results in the disruption of nucleic acid functions. Alterations in drug transport and metabolism, increased activity of glutathione S-transferase and aldehyde dehydrogenase activity or enhanced DNA repair may also play a role in the resistance to this alkylator. OBJECTIVE: The aim of this study was to elucidate candidate genes and molecular pathways involved in ex vivo resistance to busufan in childhood acute leukemias. METHODS: In order to determine the in vitro BUS resistance profile, MTT cytotoxicity assay was performed on mononuclear cells, collected from 153 patients. All samples were processed for RNA and DNA extraction, using standard protocols. Templates provided as suitable for hybridization were assessed with 2100 Bioanalyzer (Agilent Technologies, Santa Clara, CA, USA). Oligonucleotide array-CGH was performed using the Agilent SurePrint G3 Human CGH Microarray Kit, 6×60K. Experiments were done according to the standard protocol (Agilent Oligonucleotide Array-Based CGH for Genomic DNA Analysis). Commercially available genomic DNA (Promega, Madison, WI, USA) was used as the control. Microarray data were extracted with Feature Extraction Software. Data analysis and chromosome segmentation were performed with CytoGenomics Software. Gene expression profiles were prepared on the basis of cRNA hybridization to oligonucleotide arrays of the human genome (Affymetrix, Santa Clara, CA, USA) for 51 patients with ALL and 16 patients with AML. Hierarchical clustering, assignment location and biological function were performed. Real time PCR was performed on a LightCycler® 480 instrument (Roche, Mannheim, Germany) using specific primers and Universal ProbeLibrary set for 20 target and 3 reference genes. RESULTS: Expression analysis level highlighted some of the most relevant biological processes and molecular functions. These included also the apoptosis (eg. APC, STAT1,3, FGF2, MAPK14, PRKCG, ANGPT2, PDGFC), p53 (CDC25C, CDK2, SFN, GADD45G), WNT signallig (eg. APC, CTBP2, CSNK2A2, TBLX1), EGF receptor signaling (eg. STAT5A, BTC, AREG) and B-cell activation (eg. LYN, BLK, PTPN6) pathways. Three genomic segments were frequently and exclusively changed: del3q26, del9p21 and amp14q23 (Table 1). Deletion of the 3q26 segment was primarily associated with TBL1XR1 decrease expression (data from GEP and qPCR). Homozygous deletions were identified for sensitive cells in 9p21 (extended over a 1.8 Mb region and affecting CDKN2A/CDKN2B). Genomic amplification in 14p23 was seen in 5 cases and encompassing ADAM 6 and long intergenic non-protein coding RNA 226Table 1Genomic imbalances characteristic for BUS response.Chromosome nameCytogenetic bandSize (Mb)Type of change-log10(PVal)GenesRESISTANT CELLSchr3q26.321.31loss region0.007TBL1XR1SENSITIVE CELLSchr9q21.31.80loss region0.046FOCAD, IFN, KLHL9, MTAB, CDKN2A, CDKN2Bchr14q23.330.05gain region0.021ADAM6, human gene LINC00226 (uc021seu.1) CONCLUSIONIn this study, we employed high-throughput approaches to profile the transcriptome and genome of leukemic blasts and an integrative bioinformatics approach to elucidate the molecular pathways associated with the BUS resistance phenotype. The results suggest that lack of sensitivity is multifactorial and includes constitutively up-regulated expression of genes involved in anti-apoptotis, drug metabolism and DNA repair. By combining genomic and expression profiles we could show that deletion in 3q26 was associated with decreased TBL1XR1 expression level. The presented data indicates TBL1X and its receptor as a possible target genes.This study was supported by Grant from the National Science Centre No. DEC-2011/03/D/NZ5/05749 DisclosuresNo relevant conflicts of interest to declare.

ICD USE IN ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY: PROPHYLACTIC V SECONDARY INDICATION

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) causes fibro-fatty scarring predominantly in the right ventricle and can lead to ventricular arrhythmias and sudden death. The role of prophylactic ICD therapy is unknown. We report our long-term follow-up of ICD use for prophylactic and secondary indications in a cohort of patients with ARVC. A retrospective chart review of all ARVC patients undergoing ICD implantation at a tertiary care center was performed, including both primary and secondary indications. Primary prevention ICDs were implanted based on suspected risk factors associated with an increased risk for sudden death including: sudden death in a first degree relative, marked RV involvement, LV involvement or TMEM43 genetic mutation. Patients with less than one year follow-up were excluded. All ICD events were adjudicated by two electrophysiologists. 48 ARVC patients at our centre were included. Diagnosis of ARVC was made between the ages of 9.8 to 70.2 (mean 40.1) years in 31 males and 17 females. Follow-up after ICD implantation was for a mean of 9.5 years (range 1 - 20.3 yrs). ICD was indicated secondary to VT/VF in 19 (39.6%) and prophylactic in 29 (60.4%) pts. The table shows the results. Thirteen of 19 (68.4%) patients with prior VT/VF had appropriate ICD use due to recurrence of sustained VT or VF. Four of 29 (13.8%) of primary prophylactic patients had appropriate ICD use. The prophylactic group is divided into those with (12) and those without (17) the TMEM43 genetic mutation. Three of the 12 TMEM43 mutation group had ICD use (25%). One of the non TMEM43 pts of the prophylactic group (1 of 17; 5.8%) had ICD use. Two patients underwent cardiac transplantation. Nine secondary ICD patients and one prophylactic patient had catheter ablation for frequent VT/VF. There was one death (post bone marrow transplantation for leukemia). ARVC patients with secondary ICD implantation for VT/VF had very frequent VT/VF recurrence with appropriate ICD use. Prophylactic ICD patients had VT/VF treated by ICD less frequently (13%) over 8.7 years of follow-up. Appropriate prophylactic ICD use was common with TMEM43 genetic mutation (25%). Primary prophylactic ICD use in ARVC patients without TMEM43 mutations requires further evaluation of risk factors for sudden death and outcomes with ICD use.

The Impact Of a Standardized Protocol On Thromboprophylaxis, Venous Thromboembolism and Bleeding Rates In Hospitalized Patients With Hematological Malignancies

BackgroundVenous thromboembolism (VTE) is a frequent complication in patients with underlying cancer. This risk is higher during hospitalization for acute medical conditions. Consequently, routine thromboprophylaxis is recommended in hospitalized cancer patients. A retrospective review of admissions to the Leukemia/Bone Marrow Transplant (LBMT) unit at our institution between January and June 2010 demonstrated that VTE prophylaxis was prescribed in only 6.6% of admissions. In March 2012, a mandatory VTE risk assessment and thromboprophylaxis protocol was introduced in the LBMT unit as part of a hospital-wide policy to improve thromboprophylaxis compliance for all hospitalized patients. ObjectivesThe primary goal is to assess the impact of the VTE thromboprophylaxis protocol on the use of thromboprophylaxis in the LBMT unit. Secondary aims of this study are to evaluate the incidence of VTE (including catheter-related thrombosis [CRT]) and bleeding after the introduction of the protocol. MethodsA retrospective chart review of all admissions to the Vancouver General Hospital LBMT unit between March 1, 2012 and February 28, 2013 was performed (intervention cohort [IC]). Only the first admission for each patient during the study period was included in the analysis. Data were extracted from electronic medical records using standardized forms. The primary outcome, rate of VTE prophylaxis, was compared to historical data from January 2010 to June 2010 (historical cohort [HC]). Results361 patients were included in the IC and 166 patients were included in the HC. All baseline patient characteristics, thrombotic risk factors and bleeding risk factors were similar between the cohorts with the exception of the presence of thrombocytopenia (82.0% IC vs. 68.7% HC, p=0.001) (Table 1). At least one dose of thromboprophylaxis was prescribed in 14.0% of admissions in the IC vs. 6.6% of admissions in the HC. This increase was statistically significant (p=0.01). Despite the low prophylaxis prevalence, VTE was uncommon, occurring in only 1.9% patients in the IC (pulmonary embolism [PE] in 5 patients, CRT in 1 patient and left ventricular thrombus in 1 patient) vs. 2.4% patients in the HC (deep vein thrombosis +/- PE in 3 patients, CRT and PE in 1 patient) (p=0.7). In contrast, bleeding complications were frequent (even in the absence of anticoagulants), with 13.3% of patients in the IC and 19.3% of patients in the HC experiencing at least one bleeding episode (p=0.08). 22 patients (6.1%) in the IC and 8 patients (4.8%) in the HC died during the study period. While fatal bleeding events occurred in 2 patients in each cohort in the absence of anticoagulation, no deaths due to VTE were observed. ConclusionsAfter introduction of a standardized protocol, VTE prophylaxis rate in hospitalized LBMT patients significantly increased by over 2-fold but remains low. No changes in bleeding and VTE rates were observed despite the increase in prophylaxis compliance. Although thrombocytopenia is likely the prime reason for withholding prophylaxis, further review is ongoing to elucidate the reasons why thromboprophylaxis was not prescribed in the majority of patients. Disclosures:No relevant conflicts of interest to declare.

Ex vivo fucosylation improves human cord blood engraftment in NOD-SCID IL-2Rγnull mice

Delayed engraftment remains a major hurdle after cord blood (CB) transplantation. It may be due, at least in part, to low fucosylation of cell surface molecules important for homing to the bone marrow microenvironment. Because fucosylation of specific cell surface ligands is required before effective interaction with selectins expressed by the bone marrow microvasculature can occur, a simple 30-minute ex vivo incubation of CB hematopoietic progenitor cells with fucosyltransferase-VI and its substrate (GDP-fucose) was performed to increase levels of fucosylation. The physiologic impact of CB hematopoietic progenitor cell hypofucosylation was investigated in vivo in NOD-SCID interleukin (IL)-2Rγ(null) (NSG) mice. By isolating fucosylated and nonfucosylated CD34(+) cells from CB, we showed that only fucosylated CD34(+) cells are responsible for engraftment in NSG mice. In addition, because the proportion of CD34(+) cells that are fucosylated in CB is significantly less than in bone marrow and peripheral blood, we hypothesize that these combined observations might explain, at least in part, the delayed engraftment observed after CB transplantation. Because engraftment appears to be correlated with the fucosylation of CD34(+) cells, we hypothesized that increasing the proportion of CD34(+) cells that are fucosylated would improve CB engraftment. Ex vivo treatment with fucosyltransferase-VI significantly increases the levels of CD34(+) fucosylation and, as hypothesized, this was associated with improved engraftment. Ex vivo fucosylation did not alter the biodistribution of engrafting cells or pattern of long-term, multilineage, multi-tissue engraftment. We propose that ex vivo fucosylation will similarly improve the rate and magnitude of engraftment for CB transplant recipients in a clinical setting.

Comparison of Unrelated Cord Blood Transplantation and HLA-Mismatched Unrelated Bone Marrow Transplantation for Adults with Leukemia

Recent advances in unrelated cord blood transplantation (UCBT) and high-resolution typing of human leukocyte antigen (HLA) from an unrelated donor have increased choices in alternative donor/stem cell source selection. We assessed HLA-mismatched locus-specific comparison of the outcomes of 351 single-unit UCB and 1,028 unrelated bone marrow (UBM) adult recipients 16 years old or older at the time of transplantation who received first stem cell transplantation with myeloablative conditioning for acute leukemia or myelodysplastic syndromes. With adjusted analyses, HLA 0 to 2 mismatched UCBT showed similar overall mortality (relative risk [RR] = 0.85, 95% confidence interval [CI], 0.68-1.06; P = .149) compared with that of single-HLA-DRB1-mismatched UBMT. UCBT showed inferior neutrophil recovery (RR = 0.50, 95% CI, 0.42-0.60; P < .001), lower risk of acute graft-versus-host disease (RR = 0.55, 95% CI, 0.42-0.72; P < .001), and lower risk of transplantation-related mortality (RR = 0.68, 95% CI, 0.50-0.92; P = .011) compared with single-HLA-DRB1-mismatched UBMT. No significant difference was observed for risk of relapse (RR = 1.28, 95% CI, 0.93-1.76; P = .125). HLA 0 to 2 antigen-mismatched UCBT is a reasonable second alternative donor/stem cell source with a survival outcome similar to that of single-HLA-DRB1-mismatched or other 7 of 8 UBMT.

A Bayesian analysis for the Block and Basu bivariate exponential distribution in the presence of covariates and censored data

In this paper, we introduce a Bayesian Analysis for the Block and Basu bivariate exponential distribution using Markov Chain Monte Carlo (MCMC) methods and considering lifetimes in presence of covariates and censored data. Posterior summaries of interest are obtained using the popular WinBUGS software. Numerical illustrations are introduced considering a medical data set related to the recurrence times of infection for kidney patients and a medical data set related to bone marrow transplantation for leukemia.

Outcomes of pediatric bone marrow transplantation for leukemia and myelodysplasia using matched sibling, mismatched related, or matched unrelated donors

Outcomes of pediatric bone marrow transplantation for leukemia and myelodysplasia using matched sibling, mismatched related, or matched unrelated donors

Outcomes of pediatric bone marrow transplantation for leukemia and myelodysplasia using matched sibling, mismatched related, or matched unrelated donors

AbstractAlthough some trials have allowed matched or single human leukocyte antigen (HLA)–mismatched related donors (mmRDs) along with HLA-matched sibling donors (MSDs) for pediatric bone marrow transplantation in early-stage hematologic malignancies, whether mmRD grafts lead to similar outcomes is not known. We compared patients < 18 years old reported to the Center for International Blood and Marrow Transplant Research with acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, and myelodysplastic syndrome undergoing allogeneic T-replete, myeloablative bone marrow transplantation between 1993 and 2006. In total, patients receiving bone marrow from 1208 MSDs, 266 8/8 allelic-matched unrelated donors (URDs), and 151 0-1 HLA-antigen mmRDs were studied. Multivariate analysis showed that recipients of MSD transplants had less transplantation-related mortality, acute graft-versus-host disease (GVHD), and chronic GVHD, along with better disease-free and overall survival than the URD and mmRD groups. No differences were observed in transplant-related mortality, acute and chronic GVHD, relapse, disease-free survival, or overall survival between the mmRD and URD groups. These data show that mmRD and 8/8 URD outcomes are similar, whereas MSD outcomes are superior to the other 2 sources. Whether allele level typing could identify mmRD recipients with better outcomes will not be known unless centers alter practice and type mmRD at the allele level.

Superior Graft-versus-Leukemia Effect Associated with Transplantation of Haploidentical Compared with HLA-Identical Sibling Donor Grafts for High-Risk Acute Leukemia: An Historic Comparison

The outcomes of an historic comparison of 117 consecutive, high-risk, acute leukemia patients undergoing hematopoietic stem cell transplantation (HSCT) from HLA-mismatched/haploidentical donors (HID, n = 81) or HLA-identical sibling donors (ISD, n = 36) without the use of in vitro T cell depletion (TCD), between the period of January 2005 and April 2009 were compared. Full engraftment was achieved in 98% of patients in the HID group and 97% in the ISD group. The cumulative incidences of grades II-IV acute graft-versus-host disease (aGVHD) in the HID and ISD cohorts were 49% and 24%, respectively (P = .014) with a relative risk (RR) of 2.99 (1.25-7.21) (P = .014). The incidence of chronic GVHD (cGVHD) did not differ significantly between the 2 cohorts. The 2-year cumulative incidence of relapse was significantly lower in HID (26%) than in ISD patients (49%) (P = .008). The 2-year cumulative incidence of nonrelapse mortality (NRM) was comparable in recipients of HID (34%) and ISD grafts (38%) (P = .85). The 3-year probability of overall survival (OS) was higher in HID patients (42%) than in ISD (20%) (P = .048) patients. Our comparisons suggest that HID transplants can achieve a stronger graft-versus-leukemia (GVL) effect than ISD for high-risk acute leukemia patients.

Zygomycotic invasion of the central nervous system

Zygomycosis is an opportunistic fungal infection that affects the central nervous system (CNS). In this report, we present three cases of zygomycosis with CNS involvement. In two patients zygomycosis developed after neurosurgery, and in the third patient zygomycosis developed after bone marrow transplantation for leukemia. All patients developed persistent fever and neurological deficits. They presented with progressive cerebral infarction accompanied by hemorrhage. Intraoperative findings and histopathological examinations revealed that zygomycotic hyphae caused mycotic aneurysm, vasculitis, and venous occlusion.

Predictive factors for outcomes after reduced intensity conditioning hematopoietic stem cell transplantation for hematological malignancies: a 10-year retrospective analysis from the Société Française de Greffe de Moelle et de Thérapie Cellulaire

This retrospective study analyzed the impact of demographic and transplantation variables on outcomes of 1108 patients who have undergone allogeneic hematopoietic stem cell transplantation after reduced intensity conditioning (RIC HSCT) for hematological malignancies and were reported to the Société Française de Greffe de Moelle et de Thérapie Cellulaire registry between November 1994 and December 2004. Only 442 patients (40%) were in complete remission (CR) at time of transplantation. Peripheral blood stem cells were used in the majority of patients (n = 878; 79%), 255 patients received fludarabine and low-dose total body irradiation, while 465 patients (42%) fludarabine and busulfan with rabbit anti-thymocyte globulins (ATG). The impact of demographic and transplant variables was studied on overall (OS) and event-free survival (EFS) in univariate and multivariate analysis. With a median follow-up of 21 months, 3-year probability of OS and EFS was 42% and 30%, respectively, and treatment-related mortality was 15% at 2 years. The multivariate analysis showed a significant negative impact on OS and EFS of the absence of CR status before transplantation; conditioning regimen, including >10 mg/kg ATG; and minor ABO incompatibility. In conclusion, this study highlights the major impact on RIC HSCT outcome of disease status before transplantation, ATG dose and ABO incompatibility.

Surgical resection of persistent pulmonary fungus nodules and secondary prophylaxis are effective in preventing fungal relapse in patients receiving chemotherapy or bone marrow transplantation for leukemia

Antifungal therapy may be unable to eradicate invasive mycosis in leukemia patients. The presence of persisting pulmonary nodules owing to mycosis seems to increase the risk of fungal relapse after chemotherapy and transplant procedures. Between 1997 and 2004, 10 acute leukemia patients underwent pulmonary surgery for invasive mycosis. The median time from diagnosis of mycosis to surgery was 135 days (range 21-147). Three patients underwent emergency surgery, owing to hemoptysis. In the other seven patients with nodule/cavitation remaining after antifungal treatment, surgery (three wedge resections, four lobectomies) was scheduled before transplant. Pathologic examination confirmed two aspergillosis and three zygomycosis. The only side effect was pneumothorax in one case. Nine patients were considered cured. Six patients underwent bone marrow transplantation (three allogeneic, three autologous) with antifungal prophylaxis without relapse during the transplant procedure. In selected patients scheduled for bone marrow transplantation, surgical resection of localized pulmonary fungus nodules combined with antifungal prophylaxis seem to be an effective treatment for preventing mycotic relapse.

Acute disseminated encephalomyelitis mimicking late CNS relapse of acute lymphoblastic leukaemia: case report

BackgroundAcute encephalomyelopathy occurring after an allogeneic bone marrow transplant for leukaemia is a diagnostic emergency. The diagnosis can be challenging since there is a wide set of alternative diagnoses, including opportunistic infections and relapse of the leukaemia.Case presentationA 13-year old girl presented with a severe acute myelopathy and encephalopathy. She was in prolonged remission from a central nervous system and bone marrow relapse of an acute lymphoblastic leukaemia, treated with allogeneic bone marrow transplantation. Neuroimaging showed multifocal grey and white matter lesions of demyelinating appearance in the brain and entire spine. Immunophenotyping and cytogenetic investigations of the girl's cerebrospinal fluid lymphocytosis excluded a late central nervous system relapse of her leukaemia. The diagnosis was acute disseminated encephalomyelitis. With standard immunosuppressive therapy, the girl had early cerebral recovery but a prolonged period of recovery from her myelopathy.ConclusionAcute disseminated encephalomyelitis should be considered in the differential diagnosis of acute encephalomyelopathy after bone marrow transplantation for leukaemia. Demyelinating syndromes such as acute disseminated encephalomyelitis may be late sequelae of bone marrow transplantation.

Comparative Analysis of Clinical Outcomes between Unrelated Donor Peripheral Blood Stem Cell Transplantation and Bone Marrow Transplantation for Leukemia.

Objective To evaluate hematopoietic reconstitution, immune reconstitution, infection, incidence of graft-versus-host disease (GVHD) and other complications between unrelated donor peripheral blood stem cell (PBSC) transplantation and bone marrow (BM) transplantation.Methods The clinical results in 21 patients receiving a PBSC graft mobilized by granulocyte colony stimulating factor (G-CSF) from unrelated donors were compared to 32 patients receiving unrelated BM transplants.Results The PBSC graft contained significantly more nucleated cells (P=0.000), and resulted in a significantly shorter time-to-neutrophil (12.43±3.67 versus 16.16±2.99 days) and platelet engraftment (14.67±6.19 versus 21.23±8.25 days), compared to the BM group (P=0.000, 0.003, respectively). T cell reconstitution between the two groups differed little after transplantation. The incidences of early-stage infection were 42.86% and 53.13% (not significant [NS]) in the PBSC and BM groups, respectively. Probabilities of acute graft-versus-host disease (aGVHD) were 61.90% and 71.88% (NS), of grades III to IV aGVHD 23.81% and 15.63% (NS) and of chronic GVHD 47.06% and 43.48% (NS) in the PBSC and BM groups, respectively. The probabilities of relapse were 6.90% and 12.50% (NS) in the PBSC and BM groups, respectively. The 2-year disease free survival (DFS) rates of the two groups were (50.14±12.00) % and (59.81±8.99) %( NS), respectively.Conclusion G-CSF-mobilized PBSCs engraft rapidly in unrelated donor recipients compared to conventional BM, but T cell reconstitution and the incidence of infection between the two groups differed little. There were no significant differences of the incidence and severity of aGVHD and cGVHD, and 2-year DFS rates between the two groups.