Allogeneic Blood And Marrow Transplantation Research Articles

Demographics, Motivations, and Experiences of Participants in Transplantation or Cellular Therapy Fellowships

Recent American Society for Transplantation and Cellular Therapy guidelines have sought to establish clinical and research expectations for participants in blood and marrow transplantation (BMT) and cellular therapy (CT) fellowships. However, little is known about participants in BMT/CT fellowships and the value they find from this additional training. We wanted to characterize the demographics, motivations, and experiences of recent participants in BMT/CT fellowships. We developed a 27-item online survey addressing backgrounds, application processes, training experiences, and perceived benefits among physicians who had started a clinical U.S.-based BMT/CT fellowship between 2012 to 2021. Anonymous responses were solicited through program director outreach, society website postings, targeted emails, and social media. Of 105 respondents (44% pediatric trainees), 4% were URMs and 39% were non-U.S. IMGs. The most important motivations for applying were comfort with allogeneic BMT, improved career prospects, and opportunities for research and publication. Almost all respondents (92%) attended donor selection meetings, whereas smaller proportions visited cell processing facilities (65%), HLA laboratories (57%), or good manufacturing practice facilities (22%). Most respondents reported ≥1 publication (26% reported 4+) based on research or experiences during their fellowship. Respondents reported improved post-fellowship comfort with all queried BMT/CT-related competencies. Seventy percent of respondents stated that they would recommend their fellowship highly to others; this corresponded to a Net Promoter Score of +65%, consistent with a strongly positive experience. Most respondents reported currently being in clinical practice (89% at academic centers), with a median of 70% of time currently spent caring for BMT/CT recipients. Although limited by recruitment methods and recall bias, our study demonstrated that BMT/CT fellowships are effective at increasing comfort with BMT/CT management and that most participants would highly recommend this BMT/CT training to others. Nevertheless, our study identified substantial heterogeneity in clinical responsibilities and BMT/CT-related laboratory exposure. The high representation of non-U.S. IMGs underscores the distinct role of BMT/CT fellowships for this group, whereas improved URM recruitment remains an important future direction for the field. Whether advanced fellowships will ever become required for the future BMT/CT workforce, analogous to the additional training required for solid organ transplantation in other medical and pediatric subspecialties, remains uncertain.

Reducing Central Line Associated Bloodstream Infections in Allogeneic Hematopoietic Stem Cell Transplant Patients

Background: The blood and marrow transplant (BMT) unit at Cleveland Clinic had an increased rate of central line associated bloodstream infections (CLABSIs) in 2020 for allogeneic transplant admissions from an expected average of 1 per month to 4 in August of 2020. We aimed to reduce the number of CLABSIs in allogeneic BMT patients during their transplant admission to an average of 1 per month.Patientsand Methods: We formed a multidisciplinary team with nursing, advanced practice providers (APPs), infection prevention, fellows, residents, BMT staff, and Taussig quality improvement staff. We underwent training through the SolVE (Solutions for Value Enhancement) program, with biweekly meetings for training and coaching sessions to help design and support the quality improvement project.Results: We performed an initial data review of CLABSIs from January 2020 until September 2020 with a total of 13 cases identified. 53% of cases were female, 76% of patients were neutropenic, 53% of patients had mucositis, 61% of patients had diarrhea and 7% of patients had graft versus host disease. Patients had the following underlying diagnoses: myelodysplastic syndrome (4), acute myeloid leukemia (3), acute lymphoblastic leukemia (4) and diffuse large B-cell lymphoma (1). Central line data revealed that all lines were placed at Cleveland Clinic. 76% of lines were removed after identification of infection, 46% of lines had signs of infection or malfunction. Microbiologic data culture revealed that 7 cases were Pseudomonas aeruginosa, 3 Staphylococcus epidermidis, 1 vancomycin-resistant Enterococcus faecalis, 1 Streptococcus mitis and 1 Stenotrophomonas maltophilia.To build our process map we performed a Gemba walk where we observed central line use and access on the BMT unit. We conducted a root cause analysis and identified the following factors as drivers of the rise in CLABSIs: severe immunocompromised state, pre-existing infections, long duration of line present, frequent access, excessive line manipulation, and poor hand hygiene.The changes that were implemented on the unit included: retraining of all nurses on central line care, central line care being added as a topic to the annual competency review, site and tubing checks were to be performed at the time of bedside handoff at shift change, increasing Shine Audits to 40 per week from 10 on average and deep clean of nursing unit by EVS following outbreak of pseudomonas.Following the above interventions, we decided to form a CLABSI review meeting to review each CLABSI in real time and to be able to have a longitudinal comprehensive data collection of factors contributing to each case. These meetings involve nursing, infection prevention, APPs, and physicians directly involved with the patient's care. Data is stored in Redcap and includes patient factors (admission date, conditioning regimen, type of transplant, disease data), line factors (placement date, location, infection date, line removal date), microbiologic data (organism, reason for culture collection), personnel factors, maintenance/environmental factors and space for other comments. Data is presented at regular quality meetings with the section chair to develop further quality improvement projects.Initially the reduction of CLABSI rates did not reach our objective: we had 5 CLABSIs from January to February 2021. However, in the following months (March to June, 2021) we were able to reach our objective of 0-1 CLABSI's per month.ConclusionWe continue to work as a team to reduce the number of infections in the BMT unit. Next steps include continuing CLABSI review meetings, discussions with ICU to better understand indications and process of blood culture collections, discussion with infectious disease for input on other strategies for CLABSI reduction and examining central line processes in other institutions. DisclosuresSobecks: CareDX: Membership on an entity's Board of Directors or advisory committees.

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.

Augmenting Non-Myeloablative BMT with Ptcy Using Thiotepa or 400 Cgy TBI Improves Engraftment in Patients with Transfusion Dependent Thalassemia: Results of a Haploidentical Transplant Consortium for Hemoglobinopathies (ICHH)

Introduction Post-transplant cyclophosphamide (PTCy) enables blood and marrow transplantation (BMT) across the HLA barrier. BMT for transfusion dependent thalassemia (TDT) is restricted due to limited donor availability, graft rejection, and regimen-related toxicity. We explored the use of non-myeloablative (NMA) allogeneic BMT using best available donor with PTCy in the setting of a collaborative consortium to improve donor engraftment and estimate transplant-related mortality (TRM) and event-free survival. Methods A multicenter collaboration (3 centers in U.S. and U.K.) used common NMA conditioning with ATG, fludarabine, cyclophosphamide, and TBI and GvHD prophylaxis with PTCy, MMF, and sirolimus developed by the John Hopkins group (Bola–os-Meade, Blood 2012; Figure 1). Twenty-seven patients with TDT were transplanted. Local IRB approvals were obtained. 4 initial patients received established conditioning, 50% (2/4) had primary graft failure with autologous reconstitution, and 2 achieved neutrophil engraftment on D+29 and +38 with mixed chimerism. To improve donor engraftment rates: i, group A received pre-conditioning with hydroxyurea (HU) plus 400 cGy TBI, ii. group B were pre-conditioned with HU +/- azathioprine and hypertransfusion plus thiotepa. Twenty-one patients received haplo-BMT, 5 MRD and 1 MMUD transplant. Stem cells were G-primed BM for group B and unmanipulated BM for group A. Results Median follow-up was 16 months. In Group A, all patients engrafted with 100% OS and TFS; 18% (2/11) had grade-II aGvHD, but no cGVHD. In Group B, there was 1 case of graft failure, 2 deaths from idiopathic pulmonary syndrome and macrophage activation syndrome, 3 cases each of grades II-III aGvHD and limited cGvHD, with an 83% OS and TFS. No statistical differences were found between groups for neutrophil or platelet engraftment, age, TNC, or CD34+ cell dose. Engrafted patients remain transfusion independent, Figure 2. Conclusion NMA-BMT with PTCy augmented with either 400 cGy TBI or thiotepa, and at least HU preconditioning appears feasible in patients with TDT. A phase II study will help determine the optimal regimen with least toxicity and improved thalassaemia free survival.

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.

CMV Viremia and African-American Ethnicity Are Risk Factors for Post-Engraftment Blood Stream Infections in Pediatric Allogeneic Blood and Marrow Transplantation

Background: Blood stream infections (BSI) are a major source of morbidity and mortality after allogeneic blood and marrow transplantation (BMT). In studies of risk for BSI various factors have been identified. The impact of cytomegalovirus (CMV) viremia, however, on risk has not been assessed. This is important since both CMV infection and ganciclovir (GCV), the mainstay of pre-emptive therapy, have myelosuppressive and immunosuppressive effects. We conducted a retrospective analysis to test the hypothesis that CMV viremia predisposes allogeneic BMT patients to BSI.Methods: We retrospectively analyzed 278 allogeneic BMTs performed at Children's Healthcare of Atlanta between January 1st 2005 and December 31st 2014 that met eligibility criteria. The primary outcome was the first episode of BSI occurring between day +30 and +100 seen in engrafted patients following allogeneic BMT. We compared clinical characteristics between patients with and without BSI. This analysis was based on a time dependent competing risk model. Risk events including acute GVHD and CMV viremia were counted only when they preceded the BSI. We performed a multivariate analysis to estimate the effect of CMV viremia on risk for BSI in the post-engraftment period (days +30-100).Results: The median age was 9 years (range 0-22 years). 44.6% of the patients were Caucasian, while 38.5% were African-American. 59.7% received an unrelated marrow, unrelated cord or the alternative donor transplant. 60.8% were transplanted for a hematologic malignancy. The cumulative incidence of BSI between day +30 and+100 was 21.9% (95% confidence interval (CI), 17.5-27.3%). The median day of BSI development was 54 (range 30-99). The leading cause of BSI was Staphylococcus epidermidis. Gram-positive cocci were responsible for 71.4% of all BSIs. In the multivariate analysis, three factors were significant: grade III/IV aGVHD (hazard ratio (HR)=3.490, 95% CI 1.530-7.980, P=0.003), CMV viremia (HR=3.410, 95% CI 1.410-8.250, P=0.007), and African-American ethnicity (HR=2.520, 95% CI 1.130-5.600, P=0.024). Form of insurance (Medicaid/no insurance vs. other), employed as a surrogate for income level, had no influence on risk. In the 57 patients with CMV viremia, the frequency of neutropenia (<500/mm3) after the development of CMV viremia until day +100 was 26.3% (15/57), significantly higher than that observed in patients without CMV viremia (5.4% (12/221), P<0.001).Conclusion:Our analysis of risk for post-engraftment BSI in children yielded three factors. One, aGVHD, is well established. The other two, CMV viremia and African-American ethnicity, have not been previously recognized. That CMV viremia would predispose to subsequent BSI is highly plausible. Our results suggest that the risk of CMV viremia may be mediated in part by neutropenia stemming from CMV or its treatment with ganciclovir. That African-American ethnicity has not previously been recognized as a risk factor may simply reflect the ethnic make up of previous studies. Our findings are consistent with those of studies performed in other settings, showing patients of African descent to be at increased risk for bacteremia and sepsis. An increased risk for BSI among patients of African descent could partly explain the concerning excess risk for transplant related mortality previously observed among these patients. DisclosuresNo relevant conflicts of interest to declare.

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.

African American Race Is a Newly Identified Risk Factor for Postengraftment Blood Stream Infections in Pediatric Allogeneic Blood and Marrow Transplantation

Blood stream infections (BSI) are a major source of morbidity and mortality both in allogeneic blood and marrow transplant (BMT) recipients. Various risk factors for BSI in BMT have been identified. The impact of race and cytomegalovirus (CMV) viremia, a common complication after engraftment, however, has not been rigorously assessed. This is important because both CMV infection and ganciclovir, the mainstay of pre-emptive therapy, have myelosuppressive and immunosuppressive effects. We conducted a retrospective analysis to test the hypothesis that race and CMV viremia predispose allogeneic BMT patients to postengraftment BSI. We analyzed 278 allogeneic BMT performed at Children's Healthcare of Atlanta between January 1, 2005 and December 31, 2014 that met eligibility criteria. We performed a multivariate analysis to estimate the effect of CMV viremia on risk for BSI in the postengraftment period (days +30 to 100). Risk for BSI was associated with CMV viremia (hazard ratio [HR], 3.34; 95% confidence interval [CI], 1.51 to 7.36; P = .003); grade III and IV acute graft-versus-host disease (HR, 3.28; 95% CI, 1.55 to 6.92; P = .002), and African American race (HR, 2.22; 95% CI, 1.09 to 4.51; P = .027). The results of our study highlight the importance of a novel risk factor for postengraftment BSI, not previously considered—African American race.

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.

Long-term follow-up of imatinib in pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia: Children's Oncology Group Study AALL0031

We previously reported preliminary findings that post induction imatinib mesylate (340 mg/m(2)/day), in combination with intensive chemotherapy, resulted in outcomes similar to blood and marrow transplant (BMT) for pediatric patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). We now report 5-year outcomes of imatinib plus intensive chemotherapy in 91 children (1-21 years) with and without allogeneic BMT (N=91). We explore the impacts of additional chromosomal abnormalities and minimal residual disease (MRD) by flow cytometry on outcomes. The 5-year disease-free survival was similar for Cohort 5 patients, treated with chemotherapy plus imatinib (70%±12%, n=28), sibling donor BMT patients (65%±11%, n=21) and unrelated donor BMT patients (59±15%; P=0.60, n=13). Patients with additional cytogenetic abnormalities had worse outcomes (P=0.05). End induction (pre-imatinib) MRD was not prognostic for Cohort 5 or allogeneic BMT patients, although limited by small numbers. The re-induction rate following relapse was similar to other higher-risk ALL groups. Longer-term follow-up confirms our initial observation of substantially good outcomes for children and adolescents with Ph+ ALL treated with imatinib plus intensive chemotherapy with no advantage for allogeneic BMT.

HLA Mismatch Allogeneic Blood and Marrow Transplantation

A full haplotype mismatch or mismatched unrelated donor transplantation nowadays are well being focused on, as main alternative donor tools for acute leukemia patients in desperate need of allogeneic blood and marrow transplantation (BMT), the ability to overcome various posttransplant complications by adopting the T-cell replete technique in reality. Increasing numbers of allogeneic BMT in good clinical status are largely because it`s the best post-remission therapy especially for many patients with acute leukemias. Due to the problems of unavailable donors at appropriate clinical condition and the process of long duration of donor searching step with relatively much higher cost, some of physicians have indulged in haploidentical BMT rather than mismatched unrelated BMT. Both myeloablative and reduced intensity conditioning regimens for mismatched BMT with T-cell replete or T-cell depletion method have been exploited worldwide. Most of all, Asian countries have experienced lower rates of severe acute and chronic GvHD, graft failure, and impressively low transplant-related mortality with longer follow-up duration. Also, we need many future trials to compare outcomes between these two transplant modalities with cord blood transplant in various diseased patient populations. (Korean J Med 2014;86:1-13)

Graft-versus-Host Disease Impairs Vaccine Responses through Decreased CD4+ and CD8+ T Cell Proliferation and Increased Perforin-Mediated CD8+ T Cell Apoptosis

Tumor-targeted vaccines represent a strategy to enhance the graft-versus-leukemia effect after allogeneic blood and marrow transplantation (BMT). We have previously shown that graft-versus-host disease (GVHD) can negatively impact quantitative responses to vaccines. Using a minor histocompatibility Ag-mismatched BMT (B6 → B6 × C3H.SW) followed by adoptive transfer of HY-specific T cells and HY-expressing dendritic cells, we assessed whether GVHD induced by donor lymphocyte infusion (DLI) affects the persistence, proliferation, and survival of vaccine-responding, nonalloantigen reactive T cells. Both CD8(+) and CD4(+) HY-specific T cells undergo less vaccine-driven proliferation in allogeneic recipients with GVHD. Although vaccine-responding CD8(+) T cells show decreased IFN-γ and CD107a production, CD4(+) T cells exhibit increased programmed death 1 and T cell Ig mucin-like domain 3 expression. In addition, the degree of apoptosis in vaccine-responding CD8(+) T cells was higher in the presence of GVHD, but there was no difference in CD4(+) T cell apoptosis. Using Fas ligand-deficient or TRAIL-deficient DLI had no impact on apoptosis of HY-specific T cells. However, perforin-deficient alloreactive DLI induced significantly less apoptosis of vaccine-responding CD8(+) T cells and resulted in enhanced tumor protection. Thus, diminished vaccine responses during GVHD result from impaired proliferation of CD8(+) and CD4(+) T cells responding to vaccination, with an additional contribution from perforin-mediated CD8(+) T cell apoptosis. These results provide important insights toward optimizing vaccine responses after allogeneic BMT.

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.

Pharmacotherapeutic advances in the treatment of acute lymphoblastic leukaemia in adults.

Acute lymphoblastic leukaemia (ALL) in adults is a challenging malignancy in that many patients will show evidence of initial chemotherapy responsiveness but will subsequently relapse. The disease is heterogeneous and outcomes vary dramatically depending on the prognostic factors present in an individual patient. An important determinant of outcome is the age of the patient. The stunning success of therapy in paediatric ALL has led to the use of intensive paediatric regimens in adolescents and young adults with what appear to be improved outcomes. For patients who relapse or have high-risk features, blood and marrow transplantation (BMT) continues to play an important role in the therapeutic armamentarium. The use of reduced-intensity conditioning regimens for allogeneic BMT suggests that outcomes may be improved by this approach. Monoclonal antibodies are showing benefit as single agents in the relapsed setting or in combination with chemotherapy in newly diagnosed patients. In recent years, several new chemotherapeutic agents have shown promise as single agents and are being incorporated into multi-agent chemotherapy. The development of tyrosine kinase inhibitors for Philadelphia chromosome-positive leukaemias has significantly improved outcomes. The molecular revolution has led to the identification of new aberrant molecular pathways in the pathogenesis of ALL, and drugs targeting these aberrancies are in various stages of development preclinically and clinically. These developments bring the hope that therapeutic outcomes in adult ALL can begin to approach those seen in the paediatric setting.

5-Azacytidine as Salvage Treatment in Relapsed Myeloid Tumors after Allogeneic Bone Marrow Transplantation

Relapse after allogeneic blood or marrow transplantation carries a very poor prognosis. Current strategies for management that include donor lymphocyte infusions (DLIs) and salvage chemotherapies are usually toxic and ineffective. Here we report the outcome of 10 patients with myeloid malignancies that received 5-azacytidine after a failed allogeneic bone marrow transplant. Of the 10 patients, 6 achieved a complete remission, 1 had stable disease, and 3 progressed after a median of 6 cycles administered. Only 1 patient has died (of disease progression), and no flares of graft-versus-host disease (GVHD) were observed with 5-azacytidine. As of latest follow-up, the median overall survival (OS) for the group was 422.5 days (127-1411). These results further suggest that 5-azacytidine is an active agent after failing an allogeneic bone marrow transplant, and prospective studies are warranted.

Anti-CD13 Abs in children with extensive chronic GVHD and their relation to soluble CD13 after allogeneic blood and marrow transplantation from a Children's Oncology Groups Study, ASCT0031

Our group previous demonstrated a strong association between elevated plasma soluble CD13 enzyme activity and newly diagnosed extensive chronic graft-versus-host disease (cGVHD) in children. Since cytotoxic anti-CD13 antibodies have been documented after blood and marrow transplant in association with cytomegalovirus infection and cGVHD, we hypothesized soluble CD13 contributes to cGVHD pathogenesis by induction of CD13 reactive antibodies and that anti-CD13 antibodies could be additional biomarkers for newly diagnosed pediatric extensive cGVHD. Using prospectively collected plasma samples from pediatric allogeneic blood and marrow transplant subjects with cGVHD and controls without cGVHD enrolled in a large multi-institution Children's Oncology Group cGVHD therapeutic trial we evaluated whether soluble CD13 correlates with induction of anti-CD13 antibodies. We found that CD13 reactive antibodies are present in a proportion of patients after allogeneic BMT, but did not appear to correlate with the presence of soluble CD13. Anti-CD13 antibodies also did not meet our criteria as a diagnostic biomarker for cGVHD. These data are not able to confirm that induction of CD13 reactive antibodies is a mechanism for cGVHD in children nor are part of the pathogenesis of cGVHD associated with elevated soluble CD13. The exact role of CD13 in cGVHD remains to be determined.

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.

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.

Secondary Chromosomal Abnormalities Appear to Be Less Prognostic for Children with Philadelphia Chromosome Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) Treated with Intensified Imatinib and Chemotherapy: Results of the Children's Oncology Group (COG) Study AALL0031.

Abstract 2606Poster Board II-582 Background:Secondary chromosomal aberrations at diagnosis occur frequently in both pediatric and adult patients with Ph+ ALL. Several studies have shown that the presence of additional cytogenetic abnormalities is a major negative prognostic factor among children and adults with Ph+ ALL. A Japanese study in adults with Ph+ ALL indicated that the adverse prognostic significance of secondary rearrangements was seen even in patients treated with imatinib-combined chemotherapy including consolidation with blood and marrow transplantation (BMT) (Haematologica 92:287, 2008). Two-year EFS in that study was 48.5±5.7%, and the 50 patients with secondary chromosomal abnormalities had a 35% - 40% lower EFS than those with t(9;22) only (p=0.003). COG AALL0031 treated children with imatinib in combination with intensive chemotherapy. This study had an overall 3 year EFS of 80±11% for those receiving chemotherapy only, an outcome similar to those receiving allogeneic BMT. We evaluated the impact of secondary chromosomal abnormalities in children and adolescents receiving this regimen. Methods:Children and adolescents (age 1–21 years) with Ph+ ALL enrolled on AALL0031 after completing 3- or 4-drug induction therapy. Imatinib was given at 340mg/m2/day for an increasing number of days in combination with an intense chemotherapy backbone. Cohort 4 received imatinib for 126 (N=12) and cohort 5 for 280 continuous days (N=50) prior to maintenance therapy. The first two cycles of the intensive chemotherapy included ifosfamide and etoposide (cycle 1) and high dose (HD) methotrexate and HD cytarabine (cycle 2). Patients were non-randomly assigned to an HLA-identical related donor BMT, if a donor was available, or to an intensive chemotherapy regimen that continued for approximately 2.2 years. Unrelated donor BMT was not allowed; these patients were taken off protocol but included in survival evaluation by an intent-to-treat evaluation. Results:Satisfactory cytogenetic results were available for 71 (76%) of 93 enrolled children. Secondary aberrations were present in 46 (65%) patients. The most frequent secondary aberrations were +der(22) (N=21), =50 chromosomes (N=14), −7/del(7p) (N=11), abnormal (9p) (N=7), and +8 (N=5). The overall 3 year CCR was 79±6% for patients in cohorts 4/5, including those with non evaluable cytogenetics (N=55). When outcome analyses were limited to Ph+ ALL patients in cohorts 4/5 (N=43), three-year CCR for patients with Ph+ alone (N=14) was 86±10% versus 71±9% for those with Ph+ and secondary abnormalities (N=29) (p=0.19). Conclusions:In this study, the lower 3 year CCR seen in patients with Ph+ ALL with secondary chromosomal abnormalities was not significantly different than for children with Ph+ alone possibly reflecting small patient numbers. The lower 3 year CCR for Ph+ ALL with secondary chromosomal abnormalities in those treated on AALL0031 (∼15% lower) appeared to be less than that seen in the previous adult trial (∼35%). This may be the result of the addition of imatinib to intensified chemotherapy reducing the poor prognostic significance of additional chromosome abnormalities seen in previous studies. Larger patient numbers and longer follow-up will be necessary to answer this question. Disclosures:Schultz:DOR Biopharma: Membership on an entity's Board of Directors or advisory committees; Genzyme Canada: Membership on an entity's Board of Directors or advisory committees.