Allogeneic Blood And Marrow Transplantation Research Articles

A Comparison of Measured Creatinine Clearance versus Calculated Glomerular Filtration Rate for Assessment of Renal Function before Autologous and Allogeneic BMT

Common blood and marrow transplantation (BMT) eligibility criteria include a minimum glomerular filtration rate (GFR) that may vary by regimen intensity. GFR is often estimated by measurement of creatinine clearance in a 24-hour urine collection (24-hr CrCl), an inconvenient and error-prone method that overestimates GFR. The study objectives were to determine which of 6 GFR calculations: Cockroft-Gault (CG), modified CG (mCG), Modification of Diet in Renal Disease 1 (MDRD1), MDRD2, Jelliffe, and Wright, consistently underestimated measured 24-hr CrCl pre-BMT. We retrospectively analyzed 98 consecutive allogeneic (n = 48) or autologous (n = 50) adult BMT patients from January 2006 to April 2007. All 6 formulas were significantly ( P < .001) correlated with 24-hr CrCl with R = 0.64 (Wright), 0.63 (CG), 0.61 (mCG), 0.61 (Jelliffe), 0.54 (MDRD2), and 0.50 (MDRD1). When compared to the measured 24-hr CrCl, MDRD2 consistently underestimated it in the highest proportion of patients (66%, P < .001), compared with MDRD1 (65%, P < .001), Jelliffe (61%, P = NS), mCG (55%, P = NS), Wright (34%, P < .001), and CG (34%, P = .001). Measured 24-hr CrCl, pre-BMT serum Cr, and all 6 equations were not predictive of renal regimen-related toxicity (RRT) post-BMT. The Wright and CG formulas are closest to, but overestimate 24-hr CrCl in 66% of patients. In comparison, MDRD2 consistently underestimates 24-hr CrCl in 66%. Although MDRD2 is the most conservative formula, all 6 formulas gave reasonable estimates of GFR and any of the 6 equations can replace the measured 24-hr CrCl. Larger analyses and transplantation of patients with GFR <50 mL/min may better define subgroups at risk for renal RRT.

Clinical and Genetic Factors Underlying Acute Bone Mineral Density Loss by 100 Days after Blood and Marrow Transplantation: A Potential Early Regimen-Related Complication

Accelerated bone mineral density (BMD) loss after blood and marrow transplantation (BMT) has been described, with corticosteroid dose as the most important risk factor. Loss of BMD exponentially increases fracture risk, where a 10–15% decrease in BMD approximately doubles the risk. Our preliminary study [BMT 41:393–398, 2008] demonstrated that BMD loss frequently occurs even among patients with little to no steroid exposure. In the general population, common genetic variations are estimated to contribute as much as 50–80% of the phenotypic variation in bone-related traits, however genetic factors have not been examined in relation to BMD loss post-BMT. In the current study, we prospectively measured BMD by dual energy X-ray absorptiometry (DXA) scans at the lumbar spine and dual femur on all adult (≥18 yrs) first autologous or allogeneic BMT patients at our center. Pre- and post-BMT serum levels of 25(OH)D, parathyroid hormone (PTH) and Ca++ were collected within 2 weeks of each DXA scan. From 1/2006 and 4/2008, 151/157 (96%) BMT patients had a DXA scan a median 22 days pre-BMT, and 106/151 had a second DXA scan a median 100 days post-BMT. Reasons for not having a second DXA were early mortality (n=32) or medically unfit (n=13). Median age was 51 yrs, 61% were male, and 92% were White. The diseases included ALL (5%), AML (23%), lymphoma (39%), MDS/aplastic anemia (9%), and myeloma/amyloidosis (25%). BMT type was 57% autologous and 43% allogeneic, with 86% receiving blood stem cells. Conditioning and treatment regimens were myeloablative (74%) or reduced intensity (26%). While BMD for the majority remained in the normal range, there was a significantly accelerated BMD loss in most patients. After standardizing the time between pre- and post-BMT DXAs to 100 days, the median BMD change was −0.031 g/cm2 at the spine and −0.043 g/cm2 at the femur, which equates to a median annual loss rate of 9.2% and 14.4%, respectively. In men and premenopausal women, the average annual BMD loss rate is 0.2–0.4% per year, and increases after menopause to 1–2% per year. When compared to the expected BMD loss rates among healthy adults and adjusted for gender and age, the loss seen in BMT patients measured in a 4 month period was equivalent to aging their bones by approximately 12 yrs at the spine and 9 yrs at the femur. Serum levels of 25(OH) D, PTH, or Ca++ were not associated with BMD measured pre- or post-BMT nor with BMD loss. Multivariate analysis demonstrated the following significant risk factors for BMD loss at the spine: steroid dose, baseline BMD, and conditioning regimen; and at the femur: steroid dose, baseline BMD, age, gender, BMI and stem cell type. The multivariate models did not demonstrate a difference between autologous and allogeneic BMT. To estimate the performance of these clinical factors in explaining the variance in BMD loss, we calculated R2 of the best multivariate models. Although statistically significant (P<0.0001), our best model explained only 17% of the variance in BMD loss at the spine and 44% at the femur. We are currently analyzing 170 genetic polymorphisms selected from 46 candidate genes from 6 pathways: vitamin D-related genes, cytokines and their receptors, bone matrix genes, estrogen-related genes, PTH and steroid-related genes, and other genes. Gene-based and pathway-based approaches will be used to identify genetic factors that play an important role in BMD loss related to BMT. Finally, a complete model integrating clinical and genetic factors will be built to predict risk of bone loss, and early interventions can therefore be tailored to patients at high risk. It is clear that accelerated BMD loss occurs early after BMT which increases the risk of osteopenia, osteoporosis and fractures at an earlier age in the BMT population than in the general population. Thus, BMD loss could be considered a regimen-related toxicity due to its close proximity to and association with BMT.

Philadelphia Chromosome Negative (Ph-) Very High Risk (VHR) Acute Lymphoblastic Leukemia (ALL) in Children and Adolescents: The Impact of Intensified Chemotherapy on Early Event Free Survival (EFS) in Children's Oncology Group (COG) Study AALL0031.

Background: VHR patients eligible for COG AALL0031 had an expected 5-year EFS ≤ 40% and consisted of those with Ph+ ALL, severe hypodiploidy (<44 chromosomes), and induction failure (IF) with >25% blasts at the end of standard induction therapy. Patients with hypodiploidy and IF are the subject of this report. Ph+ patients were reported previously (Blood Schultz KR, et. al. Blood 2006; 108:87a.).Methods: Between 10/14/02 and 10/20/06, 63 evaluable patients (41 hypodiploidy and 22 IF) were enrolled in AALL0031 after completion of a 3- or 4-drug induction, and begun on an intensive chemotherapy regimen. Induction failure patients not entering complete remission (CR) after the first two chemotherapy cycles, ifosfamide and etoposide (cycle 1) and IV cyclophosphamide, IV etoposide) followed by high dose methotrexate and high dose cytarabine (cycle 2), were removed from study. Remission patients were assigned to 8 cycles of standard maintenance. All patients received triple intrathecal chemotherapy followed by cranial irradiation. An HLA-identical blood and marrow transplantation (BMT), by donor availability or to an intensive ~2.2 year chemotherapy regimen. The intensive chemotherapy regimen included a reinduction block (daunomycin, cyclophosphamide, vincristine, L-asparaginase, dexamethasone), intensification block [IV methotrexate (Mtx), etoposide, cyclophosphamide, high dose cytarabine, L-asparaginase], with each block repeated followed by 4 cycles of intensive maintenance (high dose Mtx, PO Mtx, IV vincristine, PO 6-MP). Unrelated donor BMT was not an option on AALL0031.Results: Twenty-one of 22 (95%) IF patients achieved CR after two cycles of therapy. Of these, 12 continued chemotherapy, 2 underwent BMT, and 7 were taken off protocol for an unrelated donor BMT. At 2-years, the EFS for IF patients was chemotherapy (46±17%) or related/unrelated donor BMT (67±17%; p = 0.50). Twenty-eight hypodiploidy patients continued chemotherapy, 12 underwent related donor BMT and 1 was taken off protocol for an unrelated donor BMT. For hypodiploid patients, the 2 year EFS was 57±10% for those receiving chemotherapy compared to related/unrelated donor BMT (67±14%, p=0.74). These outcomes compared favorably with COG historical controls (n=16, 44±12%; p=0.30). We lack a COG historical control for a comparison with IF patients. We examined minimal residual disease (MRD) at the end of cycle 2 in patients undergoing related/unrelated BMT and those receiving chemotherapy. With MRD > 0.01% (n=9) and < 0.01% (n=6), 2-year EFS was 56±19% and 83±15% (p=0.27), respectively. Chemotherapy groups showed a 2 year EFS for > 0.01% of 57±22% (N = 7) compared to 53±12% for ≤ 0.01% (N=19; p =0.83).Conclusions: The AALL0031 regimen attained a very high CR (95%) for IF patients. Small number severely limited statistical power. We found better outcomes for AALL0031 versus historical data, for allogeneic BMT versus chemotherapy, and MRD negativity versus positivity in BMT patients, although none were statistically significant. Future strategies focused on inducing lower MRD early in therapy may improve outcomes for both chemotherapy and BMT. International collaborations to allow for higher patient accrual should be considered.

Results of a Randomized, Double-Blind Trial of Fluconazole (FLU) vs. Voriconazole (VORI) for the Prevention of Invasive Fungal Infections (IFI) in 600 Allogeneic Blood and Marrow Transplant (BMT) Patients.

A multi-center, randomized, double blind trial was performed to determine the impact of FLU (400 mg daily in adults) vs. VORI (200 mg twice daily in adults) on the prevention of IFIs in standard risk allogeneic BMT patients receiving full-intensity conditioning regimens. 600 patients with AML (n=230), ALL (n=122), CML (n=103), MDS (n=98), lymphoma (n=43) and other diseases (n=4) were randomized; 295 to FLU, 305 to VORI between 2003 and 2006 (1 not transplanted). Study drugs were given for 100 days; in those receiving prednisone at a dose of ≥1 mg/kg/day at day 100 or for recipients of T cell depleted grafts with CD4+ counts <200 at day 100, drugs were administered for 180 days. All patients had serum galactomannan (GM) assayed twice weekly for 60 days, then once to twice weekly until day 100, depending on severity of graft versus host disease (GVHD). Positive GM, radiology or the presence of suspicious symptoms or signs triggered intensive evaluation for IFI. Empirical antifungal therapy was permitted for suspected IFI during diagnostic assessment but was limited to ≤14 days. The primary endpoint was freedom from IFI or death at 6 months (fungal-free survival) in the intent to treat cohort. Median recipient age was 43 years (range, 3-66) with 92% >18 years; 55% male; 95% with HLA A, B, and DRB1 matched donor; stem cell graft was related donor marrow or PBSC in 56%. There were no significant differences between the two arms in patient, disease type or risk, or transplant characteristics. Rates of engraftment, acute or chronic GVHD, non-fungal infections, expected or unexpected severe adverse events, and rates of premature study drug withdrawal were similar in both arms (p=NS). At a median follow-up of 12 months, overall survival was 80% at 6 months and 67% at 12 months. A blinded data review committee reviewed source documents of all reported fungal infections, deaths, patients with a positive GM and those given empirical antifungal therapy. There were 25 proven, 30 probable, 15 presumptive, and 74 possible IFIs. The cumulative rates of proven, probable and presumptive IFI were similar in the two arms: 10.6% for FLU and 6.6% for VORI at 6 months (p=0.11) and 13.1% and 11.6% at 12 months (p=0.50), respectively. Microbiologically documented IFIs at 6 months in each arm (FLU and VORI) were caused by Aspergillus (16 and 7, p=0.05), Candida (3 and 3), Zygomycetes (3 and 2), and other (1 and 1). Fungal-free survival rates were similar: 76% for FLU and 78% for VORI at 6 months (p=NS) and 65% and 63% at 12 months (p=NS), respectively. Event-free and overall survival rates also were similar in both arms at 6 and 12 months (p=NS). There were no differences in fungal-free survival rates in patients who received prophylactic fluconazole or voriconazole when intensive monitoring and early empirical therapy were employed in standard risk allogeneic BMT recipients.

Glutathione-S-Transferase M1 (GSTM1) and T1 (GSTT1) Single Nucleotide Polymorphisms (SNPs) Predict Regimen-Related Toxicity after Autologous and Allogeneic Blood and Marrow Transplantation (BMT).

Mortality due to conditioning regimen-related toxicity (RRT) has decreased over the past decade, but still remains a major limitation for autologous and allogeneic BMT. In addition, morbidity due to moderate or severe but non-fatal toxicity has a major impact on increased length of stay, cost and therapeutic intervention to treat toxicity while decreasing acute quality-of-life for post-BMT patients. Clinical prognostic factors for treatment-related mortality (TRM) have been described in various reports, however these account for only 40–70% of the variability in TRM, and most of the published prognostic models have evaluated only toxic mortality, not morbidity. Several reports have found associations with individual SNPs and survival, TRM and hepatic toxicity. We hypothesized that genetic variability affecting activity of enzymes that metabolize and detoxify chemotherapeutic drugs and radiation could explain some of the inter-individual variability in TRM and RRT. The glutathione-S-transferase (GST) isoenzymes respond to oxidative stress by detoxifying the reactive oxygen species produced by many chemotherapeutic drugs and radiation therapy. We retrospectively reviewed 496 patients treated with a first myeloablative autologous or allogeneic BMT from 1/1/1996 to 12/31/2002 at RPCI for moderate to fatal (grade 2–4 Bearman RRT criteria) toxicity in association with GSTM1 and GSTT1 genotype. 290 patients (58% of cohort) had procured pre-BMT samples available in the specimen repository, of which 268 patients (92%) yielded amplifiable DNA. DNA was extracted from thawed blood or marrow samples previously stored in liquid nitrogen, using Gentra Puregene DNA isolation kits according to the manufacturer's instructions, and genotypes were examined using multiplex PCR and visualized by 1.5% agarose gel electrophoresis. 130/268 (49%) patients were homozygous null for GSTM1, 50/268 (19%) were homozygous null for GSTT1, and 17/268 (6%) were homozygous null for both GSTM1 and GSTT1. GSTM1 and GSTT1 individually did not predict overall survival (OS) in autologous or allogeneic BMT patients. However patients who were homozygous null for both genes had a trend toward increased OS in allogeneic but decreased OS in autologous BMT patients, suggesting a differential response to regimen intensity and/or the immunomodulatory effects of graft-versus-host disease. 152/268 patients (57%) developed grade 2–4 RRT in any one or more organ sites. GSTM1 deletion was associated with a significantly increased risk of overall grade 2–4 RRT (RR=1.7, 95%CI 1.02, 2.7; p=0.04), with the same trend seen in both autologous and allogeneic BMT subgroups. GSTT1 deletion alone or in combination with GSTM1 null was not significantly associated with grade 2–4 RRT. Individual organ toxicity was also assessed: GSTM1 deletion was associated with an increased risk of grade 2–4 Stomatitis RRT (RR=1.6, 95%CI 0.99, 2.6; p=0.056); GSTT1 deletion was associated with an increased risk of grade 2–4 GI RRT (RR=3.7, 95% CI 0.96, 14.3; p=0.058). Genotype analysis of SNPs in additional metabolic enzyme gene pathways is ongoing, as well as additional multivariate statistical analyses. The ability to predict moderate to severe RRT after myeloablative autologous and/or allogeneic BMT may improve outcomes by allowing for individualized conditioning regimens.

Effect of Bone Marrow Hypoplasia Secondary to Reinduction Therapy for Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) on Outcomes after Blood and Marrow Transplantation (BMT).

Refractory AML and MDS are difficult diseases to manage, even with allogeneic BMT, due to recurrent disease. In an attempt to cytoreduce prior to BMT, but also avoid the toxicities associated with multiple reinduction attempts, we altered our treatment practice to offer allogeneic BMT while the patient is hypoplastic after reinduction therapy. We retrospectively reviewed 47 consecutive patients (22 males, 25 females; median age 47 years, range 6–68,) with AML (n=36) or MDS (n=11) who received a first related (n=23) or unrelated (n=24) allogeneic BMT between 4/1/2003 and 3/31/2006 at Roswell Park Cancer Institute to compare outcomes by pre-BMT disease status. Bone marrow hypoplasia post-reinduction therapy was defined as a particulate biopsy with <20% cellularity and <5% myeloblasts within 1 to 4 weeks before BMT. Fourteen patients met this definition and were compared to 33 patients who had untreated MDS or AML in CR (n=25) or were relapsed/primary induction failure (n=8). We analyzed the association of the following characteristics with hypoplasia post-reinduction/pre-BMT: diagnosis, conditioning regimen, donor relation, HLA-matching, KPS, stem cell source, donor-recipient gender matching, age, ejection fraction, DLCO, FEV1, and time from diagnosis to BMT. In the univariate analysis, KPS was the only significant factor associated with hypoplastic status at time of BMT with all hypoplastic patients having a KPS ≤80 pre-BMT (p=0.002). Patients who were transplanted while hypoplastic had shorter overall survival (OS) compared to non-hypoplastic patients (p=0.0088) and also had a trend toward shorter leukemia free survival (LFS) (p=0.0936). Additionally, patients with active disease at BMT had poorer OS than patients who were untreated or in CR, and patients who were hypoplastic fared worse than those with active disease (1 year OS was 54% vs. 69% vs. 30%; p=0.027). Multivariate analysis of OS used a Cox proportional hazards model with forward stepwise selection conditional on the likelihood ratio with p<0.05 to enter and p>0.10 to remove each factor from the model. Since KPS correlated with hypoplastic status, both factors could not be added into the model simultaneously. Factors that were considered in the first model: KPS (≥90 vs. ≤80), conditioning regimen (FluMel vs. BuC vs. CT vs. FluC), donor (related vs. unrelated), age at BMT (continuous), and FEV1 (continuous). KPS was the only significant predictor of OS (RR=20.5; 95% confidence interval 2.7, 156; p=0.004). Substituting hypoplastic (yes vs. no) for KPS in the model yielded hypoplastic as the only significant factor (RR=3.06; 95% CI 1.3, 7.38; p=0.013). This study demonstrates that patients transplanted with bone marrow hypoplastia secondary to reinduction therapy have a compromised performance status, but that a low KPS is a stronger predictor of poor LFS and OS. Reducing the intensity of the reinduction regimen may increase performance status at BMT and improve overall outcome post-transplant.

The Comparison of In Vitro and In Vivo Anti-Host Responses as a Predictor of T Cell Reactivity after Allogeneic-BMT as Determined by TCR Vb Spectratype Analysis.

Immunotherapeutic strategies have gained recognition as viable alternatives to more conventional therapeutic modalities for the treatment of cancer. In this regard, adoptive T cell therapy through allogeneic blood and marrow transplantation (BMT) has offered the first evidence to demonstrate that anti-tumor effects could be achieved against hematological malignancies. However, complications which include graft failure, opportunistic infections, leukemic relapse and graft-versus-host disease (GVHD) underscore the importance for the development of more targeted strategies in order to promote the successful implementation of allogeneic-BMT as a long term curative approach. It is well understood that mature donor T cells present in the donor inoculum must be an integral part of any such strategy as they play a pivotal role in all of the above mentioned complications. The incidence of the first three complications is diminished by the presence of mature donor T cells while, unfortunately, the transplantation of mature alloreactive donor T cells also directly induces the latter complication of acute GVHD, which can be directed against either HLA or minor histocompatibility antigen (miHA) disparities. Efforts to pan deplete donor marrow inoculum of T cells have been successful in minimizing the development of disease but have been associated with increased leukemic relapse. Thus, one approach to solve this problem would be to identify and then selectively deplete alloreactive donor T cells while allowing the residual T cells to provide protection against infection and to mediate a leukemia-specific GVL response. We hypothesized that an in vitro culture system using a one-way mixed lymphocyte reaction generated between a potential allogeneic BMT donor and their respective recipient could give rise to many of the alloreactive T cell responses that would be predictive of those that would be generated in vivo, following BMT. We proceeded to test the predictive value of the in vitro culture system through the use of TCR CDR3 Vβ spectratype analysis in the clinical BMT setting. To this end we compared, by spectratype analysis, the in vitro and post-transplant in vivo responses of nine donor patient pairs. The results indicated a high association of overlapping Vβ CDR3-size skewing as defined by the reactive Vβ families in the patient post-transplant also found to be reactive in the in vitro culture system (range of overlap 50–100%, median 72.5%). Thus, in vitro spectratyping analysis may be useful in guiding the manipulation of the donor T cell inoculum in order to provide improved BMT outcomes.

Long-Term Survival after Blood and Marrow Transplantation: Comparison with an Age- and Gender-Matched Normative Population

A plateau in long-term survival patterns of patients undergoing blood and marrow transplantation (BMT) from allogeneic donors is apparent, but whether their expected survival ever parallels that of the normative population is unclear. This study attempts to identify a cutoff time for classifying BMT patients as long-term survivors and compares their actual survival with the expected survival of an age- and gender-matched “normal” population. In this study, the records of 1386 patients who underwent allogeneic BMT at Princess Margaret Hospital between 1970 and 2002 were reviewed. Hazard rates (HRs), Kaplan-Meier survival estimates, and loess curves were used to propose a cutoff time classifying patients as long-term survivors. Factors predictive of overall survival and survival for long-term survivors were investigated. Actual survival for these patients was compared with the expected survival of the Canadian “normal” population. A cutoff time of 6 years post-BMT was proposed to define long-term survivors based on loess curves of hazard ratios and yearly survival statistics. The only statistically significant predictor of survival among long-term survivors was having a male donor (HR = 0.39; 95% confidence interval [CI] = 0.17–0.88). Although only 62% of patients survived the first year post-BMT, 98.5% of patients alive after 6 years survived at least another year. Almost 1/3 (31%) of the deaths in long-term survivors resulted from causes unrelated to transplantation or relapse. The observed number of deaths among BMT patients exceeded the expected number from the Canadian population; however, the difference in life expectancy decreased the longer that a patient survived. The 95% CIs for the observed/expected number of deaths cover 1, indicative of no difference, after the tenth year post-BMT. A cutoff of 6 years is proposed to define long-term survivorship after BMT. Life expectancy remained reduced compared with that of the “normal” population; however, this difference decreased the longer that a patient survived. Known risk factors of short-term survival disappeared, with only donor gender predictive of survival among long-term survivors.

Adenovirus Isolation Post Blood and Marrow Transplant (BMT) in Australia and New Zealand- Results of a 4 Year Clinical Multi -Institutional Prospective Cohort Study.

Adenovirus (AdV) infection is an important cause of morbidity and mortality post BMT in both children and adults. The incidence of AdV in retrospective or single-centre prospective studies is reported between 4.9% and 41%. There are no published multi-institutional prospective clinical studies. We conducted a prospective cohort study from January 2001 to December 2004 in Australia and New Zealand for allogeneic and autologous BMT in children and adults, to find the incidence of AdV and disease post BMT and confirm risk factors for developing AdV.The 37 centres involved in the study completed a brief questionnaire every month to capture all recognized cases of AdV, and were periodically contacted to collect detailed data on patients who had AdV post transplant. The centres did not change their current practice of surveillance for AdV for this study. No centres were prospectively monitoring for adenoviraemia by polymerase chain reaction (PCR) in blood.We found an overall incidence of AdV disease or infection of 52/3468 (1.5%; 95% Confidence Interval [CI] 1.1 to 2.0), with 46/596, (7.7%; CI 5.7 to 10.2) in the paediatric population and 6/2872 (0.21%; CI 0.1 to 0.45) in the adult population. Although only 596/3468 (17%) of transplants were performed in children, 48% (CI 39 to 69) of all patients with AdV infection were 5 years of age or under. Using the established criteria1 of 52 patients with AdV infection, 14 had definite adenoviral disease and 27 probable adenoviral disease. Four (7.6%) patients died of adenovirus, two of multi-organ failure, one of liver failure and one of pneumonitis.There was a greater risk of developing AdV with an allogeneic transplant than an autologous transplant (RR 9.48, CI 4.2 to 20.9 p<0.001). In autologous transplants none of 1795 adults and only 7 of the 272 children had AdV.Children who had an allogeneic transplant with a T cell depleted graft were at greater risk of developing AdV than those with a T cell replete graft (RR 2.2, CI 1.20 to 4.1, p=0.02) as were those who had an unrelated compared to a related donor (RR 1.99, CI 1.02 to 3.85, p=0.05). Unrelated cord BMT compared to other unrelated transplants was not a statistically significant risk factor for developing AdV in this study (RR 1.1 CI 0.55 to 2.14 p = 0.98).The median day of detection of an AdV isolate for all patients was day 38 post transplant. However, there was a biphasic pattern, with 23.4% of all patients having the first AdV isolate identified greater than Day 100. 38.5% (CI 25.3– 53.0) of patients had isolation of AdV in more than one site. The most common site of an isolate was the gastrointestinal tract in 71% of patients, followed by positive blood PCR in 25%. 31 out of the 52 patients with AdV had another virus isolated apart from AdV; in 15 out of these 31 patients this virus was CMV, either reactivation or CMV disease.This prospective population-based study confirms the importance of AdV in BMT, particularly in paediatric T cell depleted unrelated donor BMT and highlights the occurrence of AdV infection greater than 100 days after transplant.

Outcome of Patients with Secondary Leukemias Managed with Different Treatment Strategies at a Single Center.

134 patients with a prior diagnosis of a malignant solid tumor presented between 1 Jan 95 and 31 Dec 04 to the leukemia service at PMH for management of a secondary hemopoietic malignancy or aplasia (AML n=99, MDS n=22, ALL n=11, AA n=2). The cohort included 65 males (median age 70 years, ranging from 18–94 years) and 69 females (median age 60 years, ranging from 25–87 years). The tumor types showed the expected gender based variation. Based on age, performance status and patient preference 81 individuals received remission induction therapy, while 53 patients were managed with supportive care. 49 of the patients undergoing induction therapy met the age criteria (70 years) for a blood and marrow transplant (BMT) and survived at least 70 days post initiation of induction therapy. 25 of the 49 patients underwent allogeneic BMT from related (n=20) or unrelated donors (n=5). The median survival of all 134 patients amounted to 314 days with an overall survival (OS) at 2 and 3 years of 25% and 20%. The respective values for patients undergoing induction therapy and supportive care were 413 days,36%,28% and 192 days, 9%,7% (p= 0.0002). Survival was strongly influenced by age (p= 0.0017), while gender (p=0.1436) and FAB subtype (p=0.219) did not contribute significantly to outcome. Subset analysis of the 25 BMT recipients showed a median survival of 922 days, with a 51% and 39.5 % OS at 2 and 3 years. The respective data for the remaining 24 not transplanted patients were not significantly different (p= 0.7508) with 522 days, 42% and 35%. Both subgroups however differed significantly in their causes of death favoring a lower relapse rate for transplant recipients and lower treatment related mortality (TRM) for non-transplanted patients (p=0.0012). In conclusion, this single center study confirms the relatively poor outcome for patients with secondary leukemias but is consistent with the view that patients able to undergo intensive therapy including transplantation may derive a significant survival benefit. The low relapse rate observed for BMT patients compared to patients not transplanted may translate into a survival benefit provided TRM can be reduced

A prognostic model for prolonged event-free survival after autologous or allogeneic blood or marrow transplantation for relapsed and refractory Hodgkin's disease

There are several prognostic models for Hodgkin's disease (HD) patients, but none evaluating patient characteristics at time of blood and marrow transplantation (BMT). We developed a prognostic model for event-free survival (EFS) post-BMT based on HD patient characteristics measured at the time of autologous (auto) or allogeneic (allo) BMT. Between 1/1991 and 12/2001, 64 relapsed or refractory HD patients received an auto (n=46) or allo (n=18) BMT. A multivariate prognostic model was developed measuring time to relapse, progression or death. Median follow-up was 51.7 months; median EFS for auto and allo BMT was 36 and 3 months, respectively (P=0.001). Significant multivariate predictors of shorter EFS were chemotherapy-resistant disease, KPS <90 and > or =3 chemotherapy regimens pre-BMT. Patients with two to three adverse factors had significantly shorter EFS at 2 years (58 vs 11% in auto; 38 vs 0% in allo BMT patients). Despite a selection bias favoring auto BMT, the model was valid in both auto and allo BMT groups. We were able to differentiate patients at high vs low risk for adverse outcomes post-BMT. This prognostic model may prove useful in predicting patient outcomes and identifying high-risk patients for novel treatment strategies. Validation of this model in a larger cohort of patients is warranted.

Thrombotic Microangiopathy after Allogeneic Blood and Marrow Transplantation Is Associated with Dose-Intensive Myeloablative Conditioning Regimens, Unrelated Donor, and Methylprednisolone T-Cell Depletion

Allogeneic blood and marrow transplantation (BMT)-associated thrombotic microangiopathy (TM) contributes to transplant-related morbidity and mortality. This report examines the incidence of and risk factors for allogeneic BMT-associated TM in two patient cohorts treated before and after changes in myeloablative conditioning regimen intensity (high vs. standard intensity). Cohort 1 includes 153 consecutive allogeneic BMT patients who underwent transplantation between April 1994 and October 1997 with an allogeneic BMT-associated TM crude incidence of 12%. Cohort 2 includes 75 consecutive allogeneic BMT patients who underwent transplantation from November 1997 to November 2000 with an allogeneic BMT-associated TM crude incidence of 1%. In cohort 1, matched unrelated donor transplant and methylprednisolone (MP) T-cell depletion (TCD) of donor bone marrow were significantly associated with allogeneic BMT-associated TM by univariate analysis; therefore, a logistic model incorporating these effects was constructed to calculate the expected number of allogeneic BMT-associated TM cases in cohort 2. Seven cases would have been expected, but only one was observed (P = 0.003; bayesian predictive test). The multivariate analysis of both cohorts yielded MP-TCD (P<0.001), high-intensity myeloablative conditioning regimens used in cohort 1 (P = 0.02), and matched unrelated donor (P = 0.03) as significant predictors of time to allogeneic BMT-associated TM. Avoidance of high-intensity conditioning regimens may decrease the incidence of allogeneic BMT-associated TM.

Lymphocyte recovery after allogeneic bone marrow transplantation predicts risk of relapse in acute lymphoblastic leukemia.

Allogeneic blood and marrow transplantation (BMT) is curative for many patients with high-risk and relapsed acute lymphoblastic leukemia (ALL). However, relapse is an important cause of post-transplantation failure, and there are no reliable markers to predict relapse. A retrospective review of patients with ALL who underwent matched related allogeneic BMT was carried out to examine whether the rate of lymphocyte recovery after transplantation had any prognostic value in ALL. The absolute lymphocyte count (ALC) at days 21 and 30 after transplantation was obtained for 43 patients who received transplants during an 18-year period. Patients with an ALC of 175 x 10(6)/l or less on day 21 were more likely to relapse than those with ALC greater than 175 x 10(6)/l (relative risk, 4; 95% confidence interval, 1.5-11.2). Patients with slower lymphocyte recovery had significantly lower relapse-free survival than those with faster recovery (P=0.0028). There was also a trend toward poorer overall survival among those with a slow lymphocyte recovery (log-rank test; P=0.028). The rate of lymphocyte recovery is prognostic in patients with ALL undergoing allogeneic BMT, and this should be integrated with other predictors to identify patients at high risk of relapse. Such patients could be considered for interventions aimed at prevention of relapse, including rapid withdrawal of immunosuppressive medication or donor lymphocyte infusion.

Veno-occlusive Disease of the Liver after Blood and Marrow Transplantation: Analysis of Pre- and Post-transplant Risk Factors Associated with Severity and Results of Therapy with Tissue Plasminogen Activator

We reviewed our blood and marrow transplantation (BMT) database from April 1982 to July 1996 and identified 111 of 474 patients with serum bilirubin concentration (SBR) ≥ 34 µ mol/l for two consecutive days within the first 20 days after related allogeneic or autologous BMT. Of the 111, 73 fulfilled the Seattle criteria for veno-occlusive disease of the liver (VOD) and had no other obvious cause for liver dysfunction. The patients were 16-60 years old (median, 39 years), and 41 were male (56%). Fourteen patients (19%) had autologous BMT, and 59 (81%) had allogeneic BMT. Twenty-eight (38%), 12 (16%), and 33 (45%) patients had severe, moderate, and mild VOD, respectively, by Seattle criteria. None of 23 patients with maximum (max) SBR ≥ 257 µ mol/l survived, all patients with max SBR ≤ 128 µ mol/l survived, and 7 of 15 patients (47%) with max SBR 128-257 µ mol/l survived. The only pre-transplantation risk factor predictive of severe VOD was advanced disease state (P =0.035), and the only transplant factors that predicted severe VOD were max SBR (P =0.01) and maximum blood urea level (P =0.03). Ten patients (all with creatinine levels ≥ 150 µ mol/l) were treated with tissue plasminogen activator; only two had a significant response and only one survived beyond day 120.

Prolonged fluconazole prophylaxis is associated with persistent protection against candidiasis-related death in allogeneic marrow transplant recipients: long-term follow-up of a randomized, placebo-controlled trial

AbstractTwo randomized, placebo-controlled trials previously showed that fluconazole (400 mg/d) administered prophylactically decreases the incidence of candidiasis in blood and marrow transplant (BMT) recipients. However, there exists conflicting data regarding the optimal duration of fluconazole administration, specifically whether prophylaxis through acute graft-versus-host disease (GVHD) results in improved survival in allograft recipients. Reported here are the results of long-term follow-up and a detailed analysis of invasive candidiasis and candidiasis-related death in 300 patients who received fluconazole (400 mg/d) or placebo for 75 days after BMT at the Fred Hutchinson Cancer Research Center. Patients in both treatment arms were compared for survival, causes of death, and the incidence of invasive fungal infections early (less than 110 days) and late (more than 110 days) after BMT. After 8 years of follow-up, survival is significantly better in fluconazole recipients compared with placebo recipients (68 of 152 vs 41 of 148,P = .0001). The overall incidence of invasive candidiasis was increased in patients who received placebo compared with fluconazole (30 of 148 vs 4 of 152, P < .001). More patients who received placebo died with candidiasis early (13 of 148 vs 1 of 152, P = .001) and late (8 of 96 vs 1 of 121,P = .0068) after BMT. The incidence of severe GVHD involving the gut was higher in patients who did not receive fluconazole (20 of 143 vs 8 of 145, P = .02), and fewer patients who received fluconazole died with this complication. Thus, administration of fluconazole (400 mg/d) for 75 days after BMT appears to be associated with decreased gut GVHD, a persistent protection against disseminated candidal infections and candidiasis-related death, resulting in an overall survival benefit in allogeneic BMT recipients.

Prolonged fluconazole prophylaxis is associated with persistent protection against candidiasis-related death in allogeneic marrow transplant recipients: long-term follow-up of a randomized, placebo-controlled trial

Two randomized, placebo-controlled trials previously showed that fluconazole (400 mg/d) administered prophylactically decreases the incidence of candidiasis in blood and marrow transplant (BMT) recipients. However, there exists conflicting data regarding the optimal duration of fluconazole administration, specifically whether prophylaxis through acute graft-versus-host disease (GVHD) results in improved survival in allograft recipients. Reported here are the results of long-term follow-up and a detailed analysis of invasive candidiasis and candidiasis-related death in 300 patients who received fluconazole (400 mg/d) or placebo for 75 days after BMT at the Fred Hutchinson Cancer Research Center. Patients in both treatment arms were compared for survival, causes of death, and the incidence of invasive fungal infections early (less than 110 days) and late (more than 110 days) after BMT. After 8 years of follow-up, survival is significantly better in fluconazole recipients compared with placebo recipients (68 of 152 vs 41 of 148,P = .0001). The overall incidence of invasive candidiasis was increased in patients who received placebo compared with fluconazole (30 of 148 vs 4 of 152, P &lt; .001). More patients who received placebo died with candidiasis early (13 of 148 vs 1 of 152, P = .001) and late (8 of 96 vs 1 of 121,P = .0068) after BMT. The incidence of severe GVHD involving the gut was higher in patients who did not receive fluconazole (20 of 143 vs 8 of 145, P = .02), and fewer patients who received fluconazole died with this complication. Thus, administration of fluconazole (400 mg/d) for 75 days after BMT appears to be associated with decreased gut GVHD, a persistent protection against disseminated candidal infections and candidiasis-related death, resulting in an overall survival benefit in allogeneic BMT recipients.