Autologous Blood And Marrow Transplantation Research Articles

Beating the Benchmark: Adopting a Learning Organization Approach to Clabsi Reduction in BMT

Topic Significance & Study Purpose/Background/Rationale Preventing central line-associated blood stream infections (CLABSIs) is a priority in blood and marrow transplantation (BMT). A central line infection is both costly and potentially a fatal event. Our hybrid unit of 33 inpatient beds and seven outpatient rooms is designed for hematology/oncology patients receiving autologous and allogeneic BMT. According to the National Healthcare Safety Network (2013), our unit is classified as a hematology/oncology unit, with a CLABSI benchmark of 1.4 per 1000 central line days, not a BMT unit with a rate of 2.6 (NHSN, 2013). In 2016, an analysis of our practice identified opportunities for improvement based on a BMT CLABSI rate of 2.5. The goal of this quality improvement initiative was to reduce the CLABSI rate below the benchmark of 1.4, a 44% reduction. Methods, Intervention, & Analysis Our approach included: a collaborative unit-based task force of direct care nurses, nursing assistants, nurse managers, advanced practice providers, infection preventionists and quality specialists; standardizing central line catheters for BMT patients; and clinical surveillance with a focus on line care. Nurse-sensitive practice changes included: education of BMT nurses and assistants, focused risk awareness and practice “musts”; continual review of data at all task force and staff meetings; minimizing intravenous tubing disconnections; product changes for line care; and focused patient education. Findings & Interpretation Subsequent to interventions outlined below, we achieved a remarkable improvement, achieving a rate much less than the national benchmark of 1.4. With the exception of mucosal barrier injury-related CLABSIs, the 2016 CLABSI rate of 2.5 was reduced to zero in 2017, and 0.59 in 2018 (attributed to an increase in allogeneic transplant volume and acuity). The current 2019 rate is zero! Discussion & Implications CLABSI prevention is best accomplished by creating a team environment, where everyone involved is a stakeholder. Reflection and shared decision-making can result in a significant, sustained CLABSI rate reduction in BMT.

Bone Marrow Transplantation in Patients With Acute Leukemia In Cuba: Results From the Last 30 Years and New Opportunities Through International Collaboration.

Blood and marrow transplantation (BMT) has been performed in Cuba for over 30 years with limited resources and without international relationships. Researchers from University of Illinois at Chicago and Hermanos Ameijeiras Hospital (HAH) in Havana collaborated on retrospectively analyzing 101 consecutive patients with adult acute leukemia who received BMT at HAH from June 1986 to January 2016. Of these, 82 had acute myeloid leukemia (AML) and 19 had acute lymphoblastic leukemia (ALL). BMT eligibility criteria included prior morphologic complete remission, no severe comorbidities, and age between 16 and 60 years. Patients with an HLA-matched donor received an allogeneic BMT, whereas the others received an autologous BMT. All patients received fresh stem cells from marrow (80%) or mobilized peripheral blood (19%). Of 82 patients with AML, 35 received an allogeneic (AML-allo) and 47 an autologous (AML-auto) BMT. Both groups had comparable median age (37 years) and follow-up of survivors. Overall survival (OS) was 34% in AML-allo and 38% in AML-auto. The transplant-related mortality rate was 40% in AML-allo and 17% in AML-auto, whereas the relapse-related mortality rates were 25% and 40%, respectively. Of the 19 patients with ALL, six received an allogeneic transplant. Of these, transplant-related mortality occurred in one patient and three died after disease relapse (OS, 33%). Of 13 patients who received autologous transplants, transplant-related mortality occurred in three and six died after disease relapse (OS, 31%). To our knowledge, this is the first scientific report on BMT performed in patients with acute leukemia in Cuba. The collaboration between University of Illinois at Chicago and HAH will further develop capacity building in research and implementation of new diagnostic and therapeutic strategies in Cuba.

Blood and Marrow Transplantation (BMT) in Acute Leukemia Patients in Cuba: Current Results and Future Opportunities through International Collaboration

In the majority of low-middle-income countries (LMIC) worldwide, cancer care is limited by lack of patients' access to care and/or unaffordable cost of treatment. In contrast with many other LMIC, Cuban government provides cancer therapy to every citizen. Therefore, any standard treatment for acute leukemias, including BMT, is available for free. However, because of limited financial resources laboratories do not always provide immunophenotypic, cytogenetic or molecular tests to support the diagnosis or the management of leukemias, and only standard chemotherapy protocols are available.In this retrospective study we analyzed the results of BMT in adult acute leukemia patients transplanted at the Hermanos Ameijeiras Hospital in Havana (Cuba) from June 1986 to January 2016. A total of 101 consecutive cases (83 acute myeloid leukemia [AML] and 18 acute lymphoblastic leukemia [ALL]) were transplanted. Eligibility criteria for BMT included: age >16 and <60; achievement of morphologic complete remission after induction and consolidation chemotherapy and no severe comorbidities according to standard BMT criteria. Because of lack of access to international donor registries, only patients who had an HLA matched related donor (MRD) received an allogeneic BMT, whereas the others received a further consolidation with an autologous BMT. Stem cell source was fresh bone marrow in 80% of patients, fresh G-CSF mobilized peripheral blood (PBSC) in 19%, and only 1 cord blood transplant was attempted in a patient without a MRD. Of 83 AML patients, 36 received an allogeneic (AML-allo) and 47 an autologous (AML-auto) stem cell transplant. Median age in AML-allo and AML-auto groups was 37 (range:22-54) and 36 (range: 18-58) years, respectively. Median follow-up was 50.4 months (range:1-288) in AML-allo and 50.7 months (range: 1-324) in AML-auto. This is in part due to the policy that patients from outside Havana return to their primary hematologist within 1-2 years after transplant. In addition, some patients left Cuba soon after transplant. Of 36 AML-allo 36% died of transplant-related-mortality (TRM) and 25% of relapse. On the contrary, of 47 AML-auto 17% died of TRM and 40% of relapse. Overall survival (OS) was 38% in AML-allo and 42% in AML-auto. Of 18 ALL patients, 7 received an allogeneic (ALL-allo) and 11 and autologous (ALL-auto) transplant. Median age in the two groups was 36 (range: 18-47) and 27 (range:17-34) years, respectively. Of 7 ALL-allo cases, 1 died of TRM and 3 of relapse (OS 43%). Of 11 ALL-auto cases 4 patients died, all due to relapse (OS 64%). In conclusion, BMT is available for acute leukemia patients in Cuba. Despite limited resources, we envision that through an active collaboration with UIC the BMT program at the Hermanos Ameijeiras Hospital may rapidly expand its activity by developing disease risk assessment through cytogenetic and molecular technologies, implementing cryopreservation of stem cells from PBSC, introducing haploidentical transplantation for patients without a MRD, offering reduced intensity conditioning regimens to patients >60 years old. Support of training and development of research infrastructures remain of key importance in global health cancer care and global BMT. DisclosuresNo relevant conflicts of interest to declare.

A Novel Health Information Technology Communication System to Increase Caregiver Activation in the Context of Hospital-Based Pediatric Hematopoietic Cell Transplantation: A Pilot Study.

BackgroundPediatric hematopoietic cell transplantation (HCT), commonly referred to as blood and marrow transplantation (BMT), is an intense treatment modality that requires the involvement of engaged caregivers during the patient’s (child’s) prolonged hospitalization. The ubiquity of electronic health records (EHRs) and a trend toward patient-centered care could allow a novel health information technology (IT) system to increase parental engagement. The paucity of research on acute care, hospital-based (inpatient) health IT applications for patients or caregivers provides an opportunity for testing the feasibility of such applications. The pediatric BMT population represents an ideal patient group to conduct an evaluation due to the lengthy inpatient stays and a heightened need for patient activation.ObjectiveThe primary objective of this study is to assess the feasibility of implementing the BMT Roadmap in caregivers as an intervention during their child’s inpatient hospitalization. The BMT Roadmap is an inpatient portal prototype optimized for tablet with a user-centered design. It integrates patient-specific laboratory and medication data from the EHR in real-time and provides support in terms of discharge goals, home care education, and other components. Feasibility will be proven if (1) the BMT Roadmap functions and can be managed by the study team without unexpected effort, (2) the system is accessed by users at a defined minimum threshold, and (3) the qualitative and quantitative research conducted provides quality data that address the perceived usefulness of the BMT Roadmap and could inform a study in a larger sample size.MethodsThis will be a single-arm, nonrandomized feasibility study. We aim to enroll 10 adult caregivers (age ≥ 18 years) of pediatric patients (aged 0-25 years) undergoing autologous (self-donor) or allogeneic (alternative donor) BMT. Assenting minors (aged 10-18) will also be invited to participate. Recruitment of study participants will take place in the outpatient pediatric BMT clinic. After signing an informed consent, the research study team will provide participants with the BMT Roadmap, available on an Apple iPad, which will used throughout the inpatient hospitalization. To measure the study outcomes, approximately 6-8 semistructured qualitative interviews will be conducted periodically from pre-BMT to 100 days post-BMT and an additional 15-20 semistructured interviews will be conducted among BMT health care providers to assess perceived usefulness and usability of the system, as well as any associated workflow impacts. Quantitative survey instruments will only be administered to adult participants (age ≥ 18 years).ResultsRecruitment will begin in September 2015, and preliminary findings are expected in 2016.ConclusionsThis protocol offers a framework for the design and analysis of a personalized health IT system that has the potential to increase patient and caregiver engagement in acute care, hospital-based contexts.

Quality of Care in Blood and Marrow Transplantation – a Systematic Review in Order to Define a Quality Framework and Develop Quality Indicators

Introduction: Quality of health care is a major focus for providers, patients, payers and accreditors. Blood and marrow transplantation (BMT) is a complex and specialized process with unique quality needs. Accreditation bodies for BMT programs expect an implemented and coordinated management system. Currently, hospitals performing BMT have many tiers of quality evaluation from hospital accreditation, BMT accreditation, self-evaluation and in Ontario, provincial quality measurement. Hence, a quality framework with a clearly defined process of quality indicator (QI) prioritization, development and measurement is required.Methods: At Princess Margaret Cancer Centre, we conducted a structured review of the literature to identify published QI for BMT. The literature review from 1999 to 2014 focused on BMT with MESH terms including quality improvement/assurance, quality of health care, benchmarking, performance measures/indicators and standards of care. Focus was on the clinical aspects of care and laboratory/cell collection was excluded. We included Medline, Pubmed, Embase and CINAHL databases and a structured “grey zone” literature review. The identified QI were evaluated by a core expert panel and like concepts were merged and quality domains identified. Thereafter, end user engagement of the multidisciplinary team was completed through a modified Delphi Process. QI definitions were evaluated as medidata tables to link to data collection sources. Management/operational related and hospital accreditation QI were evaluated by the expert panel for relevance. A quality framework was then modeled off the Cancer System Quality Index to include the domains of safe, effective, efficient, integrated, equitable, responsive, accessible and innovative. QI were aligned to relevant domains in the framework to give an overall program evaluation and future direction.Results: Structured literature review identified 2211 citations with 111 abstracts meeting the inclusion criteria and only 20 full papers reporting on 114 QI. Grey zone literature review revealed a further 10 sources reporting on 100 QI. Of the 214 QI, 120 were quality domains or quality concepts (“Big Dot”) and not clearly defined QI. With consensus review, 214 QI were merged into 22 clinical and 12 operational/managerial “Big Dot” QI. Of the clinical QI, there were 8 only relevant to allogeneic BMT and 14 were relevant to both autologous and allogeneic BMT (see Table 1). Concurrently, mapping of QI within the framework as well as, alignment of both hospital and provincial BMT QI to the framework and to the 22 clinical QI indicators was done. .Conclusions: An integrated and comprehensive quality management plan is required for BMT which is standards based. We report a framework and strategy to align all quality endeavors occurring at local-regional to national levels as it relates to BMT. We also present a detailed literature review of QI in BMT and the need for more detailed, reproducible indicators in this area. As end-user engagement in quality improvement is necessary, the clinical multidisciplinary team will set QI prioritization for near term and future reporting though a modified Delphi exercise.Table 1:Big Dot Clinical QI in BMT for Prioritization and DevelopmentApheresis Not Performed Due to Insufficient MobilizationApheresis Not Performed Due to Other Reasons (i.e. progression)Appropriate Donor Screening and TestingComplications During ApheresisComplications During Bone Marrow HarvestDonor Outcomes (i.e. adverse events)Incidence and Measurement of Acute and Chronic Graft vs Host DiseaseIncidence of ICU TransfersLength of Stay in HospitalRoutine Chimerism AnalysisMedian Time to Engraftment (in days)Number of Patients who enter the program that are not transplantedNurse Sensitive Outcomes i.e. central venous catheter complicationsNeed for Stem Cell Boost or Second Transplant for Graft FailurePatient Satisfaction at Discharge and at TransitionsRate of Serious Bacterial, Viral and Fungal InfectionsReadmissions within 30 Days of DischargeRelapse RateOverall SurvivalTime to Find an Unrelated Compatible DonorTreatment Related MortalityWhether a Product was Collected From a Donor and Not Infused DisclosuresNo relevant conflicts of interest to declare.

Comparing peripheral blood stem cell collection using the COBE Spectra, Haemonetics MCS+, and Baxter Amicus

Peripheral blood stem cells (PBSC) have become the most common source of hematopoietic cells for allogeneic or autologous blood and marrow transplantation (BMT). We performed an evaluation of PBSC collections using three different apheresis systems in two major transplantation centers in Singapore. Patients undergoing autologous BMT and donors collecting for allogeneic BMT were harvested using the COBE Spectra, Haemonetics MCS+, or Baxter Amicus. There were 99 Spectra collections (61 were autologous), 81 MCS+ collections (35 were autologous) and 38 Amicus collections (33 were autologous). Our data shows that the Amicus not only processed larger peripheral blood volumes but also yielded larger PBSC volume (P-value<0.05). In terms of PBSC products, the Spectra produced more WBC, WBC/liter blood processed, and WBC/kg (P-value<0.05). The Spectra and MCS+ produced comparable amount of CD34+ cells. Amicus collected 50% less platelets compared to Spectra and MCS+. The total CD34+ cells in the PBSC products was linearly correlated to the circulating CD34+ cells using Spectra, MCS+, and Amicus. Our results suggest that, compared to MCS+ and Amicus, collecting PBSC using the COBE Spectra can produce more WBC with a similar number of CD34+ cells. With a linear correlation of circulating CD34+ cells to the total CD34+ cells in the products, the availability of an automated procedure, no rotating seal, and a small extracorporeal volume, the Spectra appears to be the preferred machine for PBSC collection.

A Deletion Polymorphism in Glutathione-S-Transferase Mu (GSTM1) and/or Theta (GSTT1) Is Associated with an Increased Risk of Toxicity after Autologous Blood and Marrow Transplantation

Toxicity after blood and marrow transplantation (BMT) has interindividual variability that may be explained by common genetic polymorphisms in critical pathways. The glutathione-S-transferase (GST) isoenzymes detoxify the reactive oxygen species generated by chemotherapy agents and radiation. We investigated whether deletion polymorphisms in 2 GST genes (GSTM1 and GSTT1) were associated with toxicity after autologous or allogeneic BMT. The study population was selected from 699 consecutive BMT patients from 2 centers in Buffalo, NY, and Moscow, Russia, of whom 321 (203 autologous, 118 allogeneic BMT) had available banked samples and amplifiable DNA. Fifty percent of patients were homozygous null for GSTM1, which did not vary by center; however, the GSTT1 homozygous null deletion polymorphism occurred more frequently in patients treated in Moscow (38% versus 18%, P < .001). Overall grade 2-4 regimen-related toxicity occurred in 56%, with nearly 1 in 5 patients having 2 or more organ systems affected. Among autologous BMT patients, a deletion polymorphism in 1 or both genes was significantly associated with increased occurrence of overall toxicity (71% versus 56%, P = .034) and mucositis (74% versus 55%, P = .006). GSTM1 and/or GSTT1 deletion polymorphisms were not associated with toxicity after allogeneic BMT. Future studies may allow for individualized genetic risk stratification.

Myxoma Virus Targets Primary Human Leukemic Stem and Progenitor Cells While Sparing Normal Hematopoietic Stem and Progenitor Cells.

Abstract 14High dose chemotherapy followed by autologous blood and marrow transplantation (ABMT) has been used to treat patients with acute myeloid leukemia (AML), but leukemia relapse rates remain high. One reason is the potential contamination of marrow with leukemic stem and progenitor cells (LSPCs). Purging autologous hematopoietic grafts of LSPCs prior to transplant serves as a viable strategy for increasing transplant efficacy in these cases; however, previous attempts using cytotoxic agents and cell culture techniques have generally resulted in loss of normal stem and progenitor cell numbers and/or functionality. Oncolytic poxviruses, such as myxoma virus (MYXV), are promising new instruments in targeting human cancer. MYXV has normal tropism towards European rabbits (Oryctolagus cuniculus) while remaining nonpathogenic for all other vertebrate species tested including humans and mice. Despite this host specificity, we have shown that MYXV is capable of infecting and killing a wide variety of human cancer cell lines. In light of these observations, we investigated whether MYXV could specifically target and eliminate LSPCs from primary AML using an ex vivo purging technique as assessed using both in vitro and in vivo functional analyses. Using a MYXV construct that expresses GFP upon cell infection, we observed GFP+ cells in leukemia exposed to MYXV at a concentration of 10 MOI over a 3-day period. No GFP expression was observed in normal bone marrow (BM) or mock (vehicle only) treated controls. GFP+ AML cells also began to undergo apoptosis shown by positive Annexin V staining. For myxoma to be a viable therapeutic for leukemia, it must not only target primary leukemia but also spare normal hematopoietic stem and progenitor cells (HSPCs). To test normal progenitor cell function following exposure to MYXV, normal BM cells were incubated with and without MYXV and tested for colony forming cell (CFC) content. Following incubation with MYXV, we observed differentiated colonies forming after 14 days indicating that the CFC potential of normal HSPCs was not adversely affected by MYXV. The frequency of the different colonies formed was also similar between mock and MYXV treated groups. When AML cells were mock treated pleomorphic colonies formed consistent with AML-colony forming units (AML-CFUs). Conversely, when exposed to MYXV, AML cells did not form recognizable AML-CFU colonies and instead remained heterodispersed suggesting impairment of progenitor cell function in vitro. To assess functional effects of MYXV on leukemia engraftment, sublethally irradiated NOG mice were transplanted with either mock treated primary AML (n=7) or primary AML pre-treated with MYXV for 3 hours (n=10). After 8 weeks, the percentage of engrafted mice was 100% after mock treated AML transplant but dropped to 10% after MYXV treatment. Significantly lower mean engraftment was observed in the group that received MYXV treated AML in comparison to mock treated samples (4.5% vs. 24% respectively; p < 0.05). Moreover, we show susceptibility of a primary AML specimen harboring an activating internal tandem duplication (ITD) mutation in FLT3, which represents an aggressive malignancy well-known for insensitivity to conventional chemotherapy. In animals showing leukemia engraftment by FACS, PCR was positive for the FLT3 ITD mutation. However, molecular remissions were evident in mice receiving MYXV treated samples. Efficacy against this leukemia signifies opportunity for disease eradication in an otherwise grim clinical setting. Finally, to assess functional effects of MYXV on normal HSPC engraftment, sublethally irradiated NOG mice were transplanted with either mock treated normal BM (n=10) or MYXV treated BM (n=9). After 8 weeks, there was no difference in the numbers of mice that engrafted between mock treated or MYXV treated groups (70% vs. 78% respectively; p = 0.72). There was also no difference in mean levels of engraftment per animal (1% vs. 2%; p = 0.41) suggesting that MYXV does not adversely affect the in vivo engraftment potential of normal HSPCs. In these studies, primary human LSPCs were targeted by MYXV purging, while normal human HSPCs showed no response maintaining both in vitro and in vivo functional potential. Given this demonstrated efficacy and safety, ex vivo purging of autologous hematopoietic grafts with MYXV may be feasible in cancer patients undergoing high dose chemotherapy followed by ABMT. Disclosures:No relevant conflicts of interest to declare.

Syngeneic Blood and Marrow Transplantation: A Report of 94 Cases From Chinese Society of Blood and Marrow Transplantation (CSBMT).

Abstract 4295Syngeneic blood and marrow transplantation (BMT) has been applied in the treatment of many malignant or nonmalignant hematologic disorders with no or minimal and transient graft-versus-host disease (GVHD), much less transplant-related mortality (TRM) in contrast to allogeneic BMT, and lower relapse rate compared with autologous BMT. However, limited data in a single BMT center is not sufficient for statistical analysis. To evaluate the clinical outcomes of syngeneic BMT, CSBMT has performed a cooperative survey among BMT centers in mainland, Taiwan, and Hong Kong. From January 1964 to May 2009, 94 transplants from syngeneic donors have been performed in 32 BMT centers. The median age was 20 (1.5 to 51) years old. The diagnosis included AML (29 cases), SAA (26 cases), ALL (17 cases), CML (12 cases), lymphoma (3 cases), MDS (4 cases), neuroblastoma (2 cases), and large granular lymphocytosis (1 case). The main conditioning regimens were CYTBI or BUCY for malignant diseases, none or CY plus ATG for SAA. Bone marrow (BM, 34) or peripheral blood (PB, 49) or both BM and PB (11) as grafts were used. Five patients (SAA 2, AML 3) underwent the same donor's syngeneic BMT twice. One patient with large granular lymphocytosis and 1 case with SAA underwent the same donor's syngeneic BMT thrice. The median follow-up time was 28 months (1 month to 45 years). The median time for white blood cells > 1.0 × 109/L, and platelets > 20 × 109/L was 11 (2-30) days, 13 (0-122) days, respectively. Two patients (2.1%) had grade I acute GVHD (aGVHD), and 4 cases (4.3%) had grade II aGVHD. However, only one patient's specimen was consulted by pathologist. All aGVHD was controlled easily with low-dose steroid. No chronic GVHD was noted. Three-year disease-free survival (DFS) for the patients with nonmalignant disorders was 88.5%. Among them, the longest survivor was living and well for 45 years after transplant. Three-year DFS for the patients with malignant diseases was 62.9%. The overall survival rates at 3 years were 87.9%, and 69.5% for nonmalignant, and malignant diseases, respectively. 22 of 94 patients died after BMT (nonmalignant 3, malignant 19). The only cause of death for the patients with nonmalignant disorders was rejection. Relapse was the main cause of death in patients with malignancies (17/19). TRM was 2.1%. In conclusion, syngeneic BMT is a safe and effective therapeutic option for both nonmalignant and malignant hematologic disorders. Syngeneic donor, if available, should be the first choice in all cases of AA and hematological malignancies in general. The longest survivor of 45 years post-BMT is presented in this series. The good results and advantage of syngeneic BMT cast light on the potential utility of stored autologous placental-cord blood which is shared by the identical twin through the same placenta. Disclosures:No relevant conflicts of interest to declare.

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.

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.

Explaining Family Caregiver Role Strain Following Autologous Blood and Marrow Transplantation

This research project explores family caregiving processes during the first 100 days following autologous blood and marrow transplantation (ABMT). In this paper, we (1) explore patterns in care-giving, and ABMT recipient function early recovery from ABMT; (2) examine the relationships among caregiver demographics, relationship quality, preparedness, ABMT recipient function, predictability of caregiving, caregiver role strain and rewards of caregiving; and (3) examine the relative contribution of caregiver age, preparedness, relationship quality, and ABMT recipient function on caregiver role strain, and rewards of caregiving. Fifty-two family caregivers of ABMT recipients completed questionnaires about caregiving at hospital discharge, and again 2, 6, and 12 weeks following discharge. The amount of caregiving activities performed, and caregiver role strain, declined steadily from 2 weeks to 12 weeks of recovery. The caregiving situation was relatively predictable during recovery, and caregivers reported that caregiving was consistently rewarding. The caregiving activities rated as most difficult were those related to supporting recipients' emotional well-being. Strain from caregiving, although low, was explained by disruption in recipients' emotional and physical functioning, while caregiving rewards were explained by caregivers' preparedness for caregiving. Relationship quality, a significant predictor of strain in other samples, did not influence caregiving strain or rewards in this population. Caregiving processes delineated in studies of caregivers of persons with chronic illness are quite different from those described in this study. The acuity of the recipients' illness, the life threatening nature of the treatment, and the younger age of caregivers, and recipients, may underlie these differences.

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.

The autologous blood and marrow transplant long-term follow-up clinic: a model of care for following and treating survivors of autotransplant.

The number of long-term survivors of autologous blood and marrow transplantation (ABMT) is increasing, but little is known about the models of care used to follow these patients. Such information would help in comparison of different methods of follow-up and allow other centers to create programs to follow their survivors. Here we describe a multidisciplinary long-term follow-up clinic for survivors of ABMT and report patient satisfaction with the clinic and economic analysis 1.5 years after its inception. In its first 1.5 years of operation, 83 new patients were seen in the clinic. Patients were evaluated a median of 4.0 years after ABMT (range 4.9 months to 12 years) and were a median of 48.5 years (range 22.5-69.0 years) old. Patients received their ABMT for non-Hodgkin's lymphoma ( n=26), Hodgkin's disease ( n=18), acute myeloid leukemia ( n=18), multiple myeloma ( n=15), breast cancer ( n=5), or desmoplastic round-cell tumor ( n=1). Patient satisfaction was assessed 1.5 years after the establishment of the long-term follow-up clinic by means of a self-report questionnaire. Seventy-five percent of patients returned the survey. Waiting times in the clinic were short, with 70% of patients seen within 30 minutes of arrival. Overall, patients were very satisfied with the new clinic model, with 85% patients reporting that the clinic met their expectations. An economic analysis indicated that the estimated annual cost of operating the clinic was approximately $53,000, which translates into $440 per patient visit, $962 per new patient or $172 per patient visit with the clinic operating at peak capacity. In conclusion, we present an inexpensive model of care for ABMT survivors that can be extended to adult survivors of malignancy not treated by ABMT.

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.

Respiratory syncytial virus infections in autologous blood and marrow transplant recipients with breast cancer: combination therapy with aerosolized ribavirin and parenteral immunoglobulins.

Scant data are available concerning the impact and response to therapy of respiratory syncytial virus (RSV) infections in patients undergoing autologous blood and marrow transplantation (BMT) for breast cancer. During eight winter seasons from 1992-1993 to 1999-2000, nine (4%) of 249 such patients were hospitalized with RSV infections. Six patients, including all five patients who were early post transplant in the pre-engraftment period, developed pneumonia and were treated with a combination of aerosolized ribavirin and IVIG. Among five patients with pneumonia in whom therapy was initiated prior to respiratory failure, one (20%) died. The sixth patient, in whom therapy was initiated after respiratory failure developed, also died. In total, two (1%) patients, both of whom were in the pre-engraftment period, died of progressive pneumonia. In conclusion, RSV is a significant cause of life-threatening pneumonia in autologous BMT recipients with breast cancer during the early post-transplant period, and accounted for a substantial portion of the overall transplant-related mortality, which in recent years has been minimal.

Autologous blood and marrow transplantation in patients 60 years and older

Although many hematologic malignancies are more common in older patients, autologous blood and marrow transplantation (ABMT) has traditionally been restricted to patients younger than 60 years because of concerns that older patients would be either unable to provide a graft or unable to tolerate the therapy. From June 1995 to May 1998, 30 patients > or = 60 years underwent ABMT at our institution for low-grade lymphoma (4 patients), relapsed intermediate-grade lymphoma (17 patients), or multiple myeloma (9 patients). The median patient age was 62.5 years (range 60-73). Pretransplantation conditioning regimens were CBV (cyclophosphamide, BCNU [carmustine], etoposide) or BEAM (carmustine, etoposide, cytarabine, melphalan) for intermediate-grade lymphoma patients and melphalan 140 mg/m2 + etoposide 60 mg/kg + total body irradiation 500 cGy for the others. The rescue product was bone marrow (BM; 4 patients), peripheral blood stem cells (PBSC; 23 patients), or BM+PBSC (3 patients). The median number of CD34+ cells/kg infused was 3.60 x 10(6) (range 0.53-31.0), by the International Society for Hematotherapy and Graft Engineering method. The treatment-related mortality at day 100 and at 6 months was 10% and 16.7%, respectively. The median days to neutrophil > 0.5 x 10(9)/L was 11 (range 9-25) and platelets > 20 x 10(9)/L was 16 (range 6-70). Three patients died of infection (days 26, 27, and 38), and 1 died of an intracranial hemorrhage related to persistent thrombocytopenia (day 130). Bearman regimen-related toxicity was moderate, with most toxicities < or = grade 2. Seven patients developed significant gut toxicity: 4 patients with Clostridium difficile colitis and 3 patients with neutropenic enterocolitis. Depressive symptoms and signs were noted in 4 patients. Three male patients developed decreased gonadal function after transplantation. These transplantations accounted for 997 patient days, of which 266 days (27%) were in the outpatient BMT program--a smaller percentage than in patients < 60 years (56%, P = .002). Twenty patients are alive 153 to > or = 1224 days after transplantation. ABMT in patients > or = 60 years of age is feasible. Further studies addressing supportive care particular to older patients and comparisons of ABMT with traditional approaches to multiple myeloma and relapsed non-Hodgkin's lymphoma in older patients are needed. Further work to identify elderly patients most likely to benefit from this approach is also required. Biol Blood Marrow Transplant 2000;6(2A):204-10.

Salvage chemotherapy with mini-BEAM for relapsed or refractory non-Hodgkin's lymphoma prior to autologous bone marrow transplantation

The role of intensive chemotherapy with autologous blood and marrow transplantation (ABMT) for patients with relapsed or refractory intermediate grade non-Hodgkin's lymphoma has recently been established. However, conventional dose salvage chemotherapy is frequently used to determine chemotherapy sensitivity and reduce tumor bulk prior to intensive therapy. Different salvage regimens have been proposed but none appears significantly superior. The purpose of this study was to determine the efficacy of mini-BEAM salvage chemotherapy in patients referred for AMBT and to define prognostic factors of response. One hundred four patients referred for consideration of AMBT after failure of primary anthracycline-based chemotherapy received BCNU 60 mg/m2 day 1, etoposide 75 mg/m2 day 2-5, ara-C 100 mg/m2 q12 h day 2-5, melphalan 30 mg/m2 day 6 (mini-BEAM) until maximum tumor reduction. Median age was 52 (range 18-65), 57% had failed to achieve a complete response (CR) to doxorubicin-based chemotherapy at diagnosis and only 13% had a previous CR lasting > 12 months. Seventy-six received mini-BEAM as first salvage chemotherapy. The overall response rate (RR) was 37% (95% confidence interval (CI) 28-46%) with 12 patients achieving CR and 25 achieving PR. The response rate among patients treated as first salvage was 43% compared to 20% for patients who had failed to respond to a previous salvage regimen. Only 15% of patients who failed to respond to mini-BEAM responded to another conventional dose salvage regimen. Thirty-eight of 104 patients ultimately demonstrated sufficient response to proceed to ABMT. Actuarial survival at four years is 22% for all 104 patients, and 36% for those who went on to AMBT. For those who were not transplanted, four-year survival was 18%. B symptoms and tumor burden at relapse were significant predictors of response to mini-BEAM in multivariate analysis, and identified a poor prognosis group of patients unlikely to be cured by the approach. Mini-BEAM does not appear to be a superior salvage regimen in this high-risk group of relapsed or refractory NHL patients for whom ABMT was the ultimate treatment intention. Only one-third of patients referred for ABMT ultimately proceed to transplant; alternative treatment strategies should be developed for those with a low likelihood of cure by this approach.