Modeling unrelated blood stem cell donor recruitment using simulated registrant cohorts: Assessment of human leukocyte antigen matching across ethnicity groups.

BACKGROUND: Human leukocyte antigen (HLA)-matched unrelated donors are not available for some patients considered for allogeneic hematopoietic cell transplantation, particularly among certain ethnic groups. Simulated recruitment modeling can inform efforts to find new matches for more patients. METHODS: Simulated recruits were generated by assigning a pair of donor HLA haplotypes from historical data files and matched against HLA data of patient searches in the Canadian Blood Services Stem Cell Registry. Recruitment cohorts reflected the proportion of five specific ethnic groups in the 2016 Canadian census data. RESULTS: Novel 8/8 HLA matches between simulated recruits and patients increased linearly with larger recruitment cohorts. The proportion of novel 8/8 HLA matches from Caucasian, Hispanic, and Native American/First Nations recruits was equal to or greater than their relative proportion in the recruited cohort (match to: recruit ratio (MRR) ≥ 1). In contrast, African American and Asian & Pacific Islander recruits represented a smaller proportion of novel matches relative to their percentage of the recruited cohort (MRR <1). The proportion of novel 7/8 HLA-matches from each ethnic group was approximately the same as their proportion in the recruited cohort (MRR ~ 1) and high rates of 7/8 HLA-matching already exist within the Canadian Blood Services registry for all ethnic groups. CONCLUSION: Continued large recruitment cohorts are needed to add new 8/8 HLA matches to registry inventories. Likelihoods of novel HLA matches varied across ethnic groups, reflecting varied HLA haplotype frequencies across groups. Simulated cohort modeling can inform recruitment strategies that will generate new donor options for patients.

HLA-haplotype redundancy and rareness in Canadian Blood Services' Stem Cell Registry and Cord Blood Bank: Novel metrics for optimizing utility.

BACKGROUND: The utility of unrelated donor registries that support allogeneic hematopoietic cell transplantation could be optimized through greater understanding of redundancy and rareness of HLA phenotypes. METHODS: HLA phenotype rareness was determined using known HLA haplotype frequencies. Donor redundancy was determined through pairwise comparison of donor HLA profiles within an inventory. RESULTS: Among 61,730 registrants in the Canadian Blood Services (CBS) Stem Cell Registry (SCR) with high resolution HLA typing at 5 loci, 6.6% of HLA phenotypes were redundant with variation across ethnic groups (8.3% of Caucasian phenotypes; 8% of Native American/First Nations, 4.4% of Asia-Pacific Islanders (API), 2.1% of Hispanic, 0.7% of African-American (AFA), and 4.5% of other ethnicities). A total of 18.5% of registrants had redundant HLA phenotypes with variation across ethnic groups. All 3716 cord blood units in the CBS's cord blood bank (CBB) had high resolution HLA typing at 5 loci and 202 units were redundant (5.4%) comprising 78 HLA phenotypes, with varying rareness. Repeated HLA phenotypes were from Caucasian donors (77%), multiple ethnicity (13%), API (9%), and AFA (1%). Registrants and CBUs with AFA ethnicity had the rarest phenotypes while Caucasian ethnicity was associated with the most common HLA phenotypes. CONCLUSIONS: Redundancy was greater in the SCR compared to the CBB and was most common with CAU ethnicity. Recruiting non-Caucasian registrants and continued cord blood banking should reduce redundancy. A sub-inventory of redundant donors and cord blood units could support new uses for donor-supported cellular therapies that do not require HLA matching.

Hematopoietic Cell Transplantation in the Treatment of Adult Acute Lymphoblastic Leukemia: Updated 2019 Evidence-Based Review from the American Society for Transplantation and Cellular Therapy.

The role of hematopoietic cell transplantation (HCT) in adults with acute lymphoblastic leukemia (ALL) is reviewed and critically evaluated in this systematic evidence-based review. Specific criteria were used for searching the published literature and for grading the quality and strength of the evidence and the strength of the recommendations. A panel of ALL experts developed consensus on the treatment recommendations based on the evidence. Allogeneic HCT offers a survival benefit in selected patients with ALL, and this review summarizes the standard indications as well as the areas of controversy. There is now greater experience with pediatric-inspired chemotherapy regimens that has transformed upfront therapy for adult ALL, resulting in higher remission rates and overall survival. This in turn has increased the equipoise around decision making for ALL in first complete remission (CR1) when there is no measurable residual disease (MRD) at the end of induction and/or consolidation. Randomized studies are needed for adults with ALL to compare allogeneic HCT in CR1 with pediatric-inspired chemotherapy alone. Indications for transplantation in the evolving landscape of MRD assessments and novel targeted and immune therapeutics remain important areas of investigation.

Choosing Wisely BMT: American Society for Blood and Marrow Transplantation and Canadian Blood and Marrow Transplant Group's List of 5 Tests and Treatments to Question in Blood and Marrow Transplantation.

Choosing Wisely encourages dialogue about reducing unnecessary procedures, tests, or treatments in healthcare. The American Society for Blood and Marrow Transplantation (ASBMT) and Canadian Blood and Marrow Transplant Group (CBMTG) established a Choosing Wisely BMT Task Force whose objective was to create a list of top 5 practices in blood and marrow transplantation to be questioned. The Task Force consisted of representatives from ASBMT's Quality Outcomes, Education, and Practice Guidelines committees; ASBMT's Pharmacy Special Interest Group; CBMTG Program Directors; and Center for International Blood and Marrow Transplant Research (CIBMTR). Suggestions for current transplantation practices to question were elicited from the CBMTG Program Directors; members of ASBMT's Quality Outcomes, Practice Guidelines, and Education committees; and chairs of the CIBMTR scientific working committees. We received 119 unique suggestions that were ranked based on their potential impact on harm reduction, cost reduction, necessity of the test or practice, and the strength of available evidence. Through a modified Delphi process, suggestions were narrowed down to 6, which were then subjected to systematic reviews. The final 5 recommendations focus on graft source for patients with aplastic anemia, corticosteroid dose for initial treatment of graft-versus-host-disease, optimal number of umbilical cord blood units for transplantation, graft source in matched unrelated donor transplantation, and use of prophylactic intravenous immunoglobulin in transplant recipients. These Choosing Wisely BMT recommendations are relevant to the current clinical practice of blood and marrow transplantation and focus on tests, treatments, or procedures that may be harmful, wasteful, or for which there is no apparent clinical benefit.

Intravenous Busulfan Compared with Total Body Irradiation Pretransplant Conditioning for Adults with Acute Lymphoblastic Leukemia.

Total body irradiation (TBI) has been included in standard conditioning for acute lymphoblastic leukemia (ALL) before hematopoietic cell transplantation (HCT). Non-TBI regimens have incorporated busulfan (Bu) to decrease toxicity. This retrospective study analyzed TBI and Bu on outcomes of ALL patients 18-60 years old, in first or second complete remission (CR), undergoing HLA-compatible sibling, related, or unrelated donor HCT, who reported to the Center for International Blood and Marrow Transplant Research from 2005 to 2014. TBI plus etoposide (25%) or cyclophosphamide (75%) was used in 819 patients, and intravenous Bu plus fludarabine (41%), clofarabine (30%), cyclophosphamide (15%), or melphalan (13%) was used in 299 patients. Bu-containing regimens were analyzed together, since no significant differences for patient outcomes were noted between them. Bu patients were older, with better performance status; took longer to achieve first CR and receive HCT; were treated more recently; and were more likely to receive peripheral blood grafts, antithymocyte globulin, or tyrosine kinase inhibitors. With median follow-up of 3.6 years for Bu and 5.3 years for TBI, adjusted 3-year outcomes showed treatment-related mortality Bu 19% versus TBI 25% (P = .04); relapse Bu 37% versus TBI 28% (P = .007); disease-free survival (DFS) Bu 45% versus TBI 48% (P = .35); and overall survival (OS) Bu 57% versus TBI 53% (P = .35). In multivariate analysis, Bu patients had higher risk of relapse (relative risk, 1.46; 95% confidence interval, 1.15 to 1.85; P = .002) compared with TBI patients. Despite the higher relapse, Bu-containing conditioning led to similar OS and DFS following HCT for ALL.

The use of prophylactic anticoagulation during induction and consolidation chemotherapy in adults with acute lymphoblastic leukemia.

Treatment for acute lymphoblastic leukemia (ALL) in adults confers a high risk of venous thromboembolic (VTE) complications. We describe the implementation and results of prophylactic anticoagulation guidelines in adults (18-50 years) treated on a Dana-Farber Cancer Institute ALL pediatric inspired consortium protocol from 2007 to 2013. A high rate of asparaginase related toxicity events, including thrombosis, resulted in a protocol amendment adding guidelines for prophylactic anticoagulation and a modified asparaginase dose and schedule. After excluding patients with Philadelphia positive ALL, a cohort of 36 patients were treated after the protocol amendment with prophylactic anticoagulation and compared to 49 patients who received no prophylactic anticoagulation. Bleeding complications were not significantly different in those treated with prophylactic anticoagulation compared with those enrolled prior to the amendment (p = 0.26). No patients on prophylactic anticoagulation had grade ≥ 3 bleeding. Prior to the amendment, the 2 year cumulative incidence of VTE post-induction was 41% compared to 28% while on prophylactic anticoagulation (p = 0.32). The 2 year cumulative incidence pulmonary embolus pre-amendment was 16% compared with 8% post-amendment (p = 0.34). Prophylactic anticoagulation can be safely administered to adults with ALL without increasing the number or severity of bleeding events and, in addition to modifications in the asparaginase regimen, resulted in a reduction in the cumulative incidence of VTE.

Myeloablative versus Reduced-Intensity Conditioning in Patients with Myeloid Malignancies: A Propensity Score-Matched Analysis.

Reduced-intensity conditioning (RIC) has been shown to have similar overall survival (OS) but higher relapse rates compared with myeloablative (MAC) regimens in patients with myeloid malignancies undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Using propensity score matching (PSM) analysis, well-balanced pairs of different variables can be compared effectively. We retrospectively compared allo-HSCT recipients with acute myeloid leukemia or myelodysplasia receiving a RIC regimen (FBT200; fludarabine 30 mg/m2/day for 4 days, busulfan 3.2 mg/kg/day for 2 days, and total body irradiation [TBI] 200 cGy) or MAC regimen (FBT400; fludarabine 50 mg/m2/day for 4 days, busulfan 3.2 mg/kg/day for 4 days, and TBI 400 cGy). A total of 248 patients (121 in the RIC group and 127 in the MAC group) were included in the analysis. No statistically significant difference was observed in 2-year OS (RIC group, 45.2 ± 5.0%; MAC group, 51.7 ± 5.2%; P = .541), nonrelapse mortality (NRM; RIC group, 28.7 ± 2.8% MAC group, 34.7 ± 4.6%; P = .368), and acute graft-versus-host disease (GVHD) (P = .171) or chronic GVHD (P = .605) at 1 year. The cumulative incidence of relapse (CIR) at 2 years was statistically significantly different between the 2 groups, however (RIC, 26.1 ± 2.6%; MAC, 14.2 ± 3.5%; P = .033). When PSM was applied to the study population, 42 case-control pairs were evenly matched. PSM analysis confirmed no statistically significant difference in 2-year OS (RIC, 49.0 ± 9.1%; MAC, 54.9 ± 7.7%; P = .718), NRM (RIC, 22.2 ± 2.3%; MAC, 33.3 ± 2.8%; P = .238), or CIR (RIC, 25.7 ± 2.6%; MAC, 9.5 ± 1.1%; P = .315) in the PSM pairs. Our findings demonstrate that after applying PSM, FBT 200 RIC conditioning has comparable OS, NRM, and CIR to FBT 400 MAC conditioning before allo-HSCT.

Significant Improvements in the Practice Patterns of Adult Related Donor Care in US Transplantation Centers.

Recent investigations have found a higher incidence of adverse events associated with hematopoietic cell donation in related donors (RDs) who have morbidities that if present in an unrelated donor (UD) would preclude donation. In the UD setting, regulatory standards ensure independent assessment of donors, one of several crucial measures to safeguard donor health and safety. A survey conducted by the Center for International Blood and Marrow Transplant Research (CIBMTR) Donor Health and Safety Working Committee in 2007 reported a potential conflict of interest in >70% of US centers, where physicians had simultaneous responsibility for RDs and their recipients. Consequently, several international organizations have endeavored to improve practice through regulations and consensus recommendations. We hypothesized that the changes in the 2012 Foundation for the Accreditation of Cellular Therapy and the Joint Accreditation Committee-International Society for Cellular Therapy and European Society for Blood and Marrow Transplantation standards resulting from the CIBMTR study would have significantly impacted practice. Accordingly, we conducted a follow-up survey of US transplantation centers to assess practice changes since 2007, and to investigate additional areas where RD care was predicted to differ from UD care. A total of 73 centers (53%), performing 79% of RD transplantations in the United States, responded. Significant improvements were observed since the earlier survey; 62% centers now ensure separation of RD and recipient care (P < .0001). This study identifies several areas where RD management does not meet international donor care standards, however. Particular concerns include counseling and assessment of donors before HLA typing, with 61% centers first disclosing donor HLA results to an individual other than the donor, the use of unlicensed mobilization agents, and the absence of long-term donor follow-up. Recommendations for improvement are made.

Extracorporeal photopheresis in solid organ transplant-associated acute graft-versus-host disease.

BACKGROUND: Extracorporeal photopheresis (ECP) culls pathogenic T lymphocytes, be these the clones of cutaneous T-cell lymphoma, or mediators of chronic graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT-GVHD). Whether or not ECP may have an effect in the rarer instances of solid organ transplantation-associated GVHD (SOT-GVHD) is unclear. Mortality rates in SOT-GVHD rival those of transfusion-associated GVHD, with fatalities preceded by pancytopenia and peripheral blood chimerism (PBC) levels exceeding 20%. ECP has been described in two SOT-GVHD cases to date, with one surviving. STUDY DESIGN AND METHODS: Clinicolaboratory features (including HLA relationships) in a case of multivisceral transplantation were reviewed from the time of surgery to the onset and progression of SOT-GVHD. ECP, which was introduced as a less immunosuppressive and more selective intervention, was assessed for its effect on serial PBC (as measured by short-tandem-repeat analysis) and clinical outcome. RESULTS: Multivisceral SOT-GVHD manifested with erythroderma, neutropenic sepsis, and PBC increasing from 6% on Posttransplant Day (PTD) 38 to 78% by PTD 60 (at a doubling time of 6 days despite corticosteroids). ECP was administered on PTDs 62 and 67 and was associated with the first evidence of PBC decay to 67% on PTD 69. Death nevertheless ensued on the last day of salvage antithymocyte globulin (PTDs 69-73) despite further PBC reduction to 41%. CONCLUSION: Further study is needed to determine if the sooner or more frequent application of ECP might attenuate the high case fatality rates of SOT-GVHD.

Pediatric-inspired therapy compared to allografting for Philadelphia chromosome-negative adult ALL in first complete remission.

For adults with Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukemia (ALL) in first complete remission (CR1), allogeneic hematopoietic cell transplantation (HCT) is an established curative strategy. However, pediatric-inspired chemotherapy may also offer durable leukemia-free survival in the absence of HCT. We compared 422 HCT recipients aged 18-50 years with Ph-ALL in CR1 reported to the CIBMTR with an age-matched concurrent cohort of 108 Ph- ALL CR1 patients who received a Dana-Farber Consortium pediatric-inspired non-HCT regimen. At 4 years of follow-up, incidence of relapse after HCT was 24% (95% CI 19-28) versus 23% (95% CI 15-32) for the non-HCT (chemo) cohort (P=0.97). Treatment-related mortality (TRM) was higher in the HCT cohort [HCT 37% (95% CI 31-42) versus chemo 6% (95% CI 3-12), P<0.0001]. DFS in the HCT cohort was 40% (95% CI 35-45) versus 71% (95% CI 60-79) for chemo, P<0.0001. Similarly, OS favored chemo [HCT 45% (95% CI 40-50)] versus chemo 73% [(95% CI 63-81), P<0.0001]. In multivariable analysis, the sole factor predictive of shorter OS was the administration of HCT [hazard ratio 3.12 (1.99-4.90), P<0.0001]. For younger adults with Ph- ALL, pediatric-inspired chemotherapy had lower TRM, no increase in relapse, and superior overall survival compared to HCT. Am. J. Hematol. 91:322-329, 2016. © 2015 Wiley Periodicals, Inc.

Outcomes of human leukocyte antigen-matched sibling donor hematopoietic cell transplantation in chronic lymphocytic leukemia: myeloablative versus reduced-intensity conditioning regimens.

Allogeneic hematopoietic cell transplantation (HCT) can cure some chronic lymphocytic leukemia (CLL) subjects. This study compared outcomes of myeloablative (MA) and reduced-intensity conditioning (RIC) transplants from HLA-matched sibling donors (MSD) for CLL. From 1995 to 2007, information regarding 297 CLL subjects was reported to the Center of International Blood and Marrow Transplant Research; of these, 163 underwent MA and 134 underwent RIC MSD HCT. The MA subjects underwent transplantation less often after 2000 and less commonly received antithymocyte globulin (4% versus 13%, P = .004) or prior antibody therapy (14% versus 53%; P < .001). RIC was associated with a greater likelihood of platelet recovery and less grade 2 to 4 acute graft-versus-host disease compared with MA conditioning. One- and 5-year treatment-related mortality (TRM) were 24% (95% confidence intervals [CI], 16% to 33%) versus 37% (95% CI, 30% to 45%; P = .023), and 40% (95% CI, 29% to 51%) versus 54% (95% CI, 46% to 62%; P = .036), respectively, and the relapse/progression rates at 1 and 5 years were 21% (95% CI, 14% to 29%) versus 10% (95% CI, 6% to 15%; P = .020), and 35% (95% CI, 26% to 46%) versus 17% (95% CI, 12% to 24%; P = .003), respectively. MA conditioning was associated with better progression-free (PFS) (relative risk, .60; 95% CI, .37 to .97; P = .038) and 3-year survival in transplantations before 2001, but for subsequent years, RIC was associated with better PFS and survival (relative risk, 1.49 [95% CI, .92 to 2.42]; P = .10; and relative risk, 1.86 [95% CI, 1.11 to 3.13]; P = .019). Pretransplantation disease status was the most important predictor of relapse (P = .003) and PFS (P = .0007) for both forms of transplantation conditioning. MA and RIC MSD transplantations are effective for CLL. Future strategies to decrease TRM and reduce relapses are warranted.

Acute promyelocytic leukaemia is characterized by stable incidence and improved survival that is restricted to patients managed in leukaemia referral centres: a pan-Canadian epidemiological study.

Timely diagnosis and care are major determinants of the outcome in acute promyelocytic leukaemia (APL), a malignancy whose incidence may be increasing. The Canadian Cancer Registry (CCR) and health system represent valuable settings to study APL epidemiology. We analysed the CCR, which contains data on all Canadians with APL. To provide clinical information lacking in the CCR, we obtained data from five leukaemia referral centres during a similar time period. Between 1993 and 2007, there were 399 APL in Canada. Age-standardized incidence was 0·083/100,000 and was stable over time. The early death (ED) rate was 21·8% (10·6% in patients <50 years old and 35·5% for those aged >50 years), with no improvement over time. Five-year overall survival (OS) was 54·6% (73·3% in patients <50 years; 29·1% older patients). In the referral cohort, 131 patients were diagnosed between 1999 and 2010. ED was 14·6% and 2-year OS was 76·5%. Within this cohort, ED and OS improved over time, although advanced patient age remained an adverse determinant of OS. In Canada, APL incidence is unexpectedly low and temporally stable. ED was higher than reported in clinical trials, but similar to reports from other registries. In contrast, ED was lower in referral centres and improved with time.

Early lymphocyte recovery at 28 d post-transplant is predictive of reduced risk of relapse in patients with acute myeloid leukemia transplanted with peripheral blood stem cell grafts.

Allogeneic hematopoietic cell transplantation (HCT) is potentially curative for acute myeloid leukemia (AML). Impact of lymphocyte recovery on post-transplant outcomes has been suggested but reports are conflicting. We evaluated the impact of lymphocyte recovery at 28 d post-HCT in 191 AML patients using peripheral blood stem cells as graft. Patients were divided into those with absolute lymphocyte count (ALC) ≥ 0.5 × 10(9) /L (n = 111, 58%; high ALC group) and those with ALC < 0.5 × 10(9) /L (n = 80, 42%; low ALC group), at day 28 post-transplant. With a median follow-up of 49 months, overall survival (OS) was significantly improved in the high ALC group (59% at 3 yr) vs. patients with low ALC (40% at 3 yr, P = 0.03). Cumulative incidence of relapse (CIR) was significantly lower in the high ALC group (16% at 3 yr) vs. low ALC group (36% at 3 yr, P = 0.001). Multivariable analysis for CIR demonstrated high ALC group as an independent factor decreasing relapse risk (P = 0.03, HR = 0.49, 95% CI = 0.26-0.92). Multivariable analysis for OS and non-relapse mortality did not demonstrate ALC ≥ 0.5 × 10(9) /L at 28 d post-transplant to be predictive. We conclude that lymphocyte recovery with ALC ≥ 0.5 × 10(9) /L at day 28 post-transplant is associated with less relapse in AML patients undergoing allogeneic peripheral blood HCT, but without survival benefit.

Optimizing Access to Unrelated Donors in Canada: Re-Examining the Importance of Donor Factors on Outcomes Following Hematopoietic Cell Transplantation.

HLA-matched allogeneic hematopoietic cell transplantation (HCT) is a curative therapy for many patients. Unrelated HLA-matched donors are the most frequently used donor for HCT. When more than one donor transplant option is available, transplant centers can select donors based on non-HLA factors. With improved ability to prevent and treat immune complications, such as graft-versus-host disease and infections, it may be possible to proceed more often using HLA-mismatched donors, allowing greater consideration of non-HLA factors, such as donor age, CMV serostatus, and ABO blood group matching, which have demonstrated important impacts on transplant outcomes. Additional factors to consider are donor availability rates and the usage of domestic donors to optimize outcomes. A review of non-HLA factors and considerations on the selection of optimal unrelated donors for HCT are provided within this updated current context.