An international learning collaborative phase 2 trial for haploidentical bone marrow transplant in sickle cell disease.

ABSTRACT: In the setting of a learning collaborative, we conducted an international multicenter phase 2 clinical trial testing the hypothesis that nonmyeloablative-related haploidentical bone marrow transplant (BMT) with thiotepa and posttransplant cyclophosphamide (PTCy) will result in 2-year event-free survival (no graft failure or death) of at least 80%. A total of 70 participants were evaluable based on the conditioning protocol. Graft failure occurred in 8 of 70 (11.4%) and only in participants aged <18 years; all had autologous reconstitution. After a median follow-up of 2.4 years, the 2-year Kaplan-Meier-based probability of event-free survival was 82.6%. The 2-year overall survival was 94.1%, with no difference between children and adult participants. After excluding participants with graft failure (n = 8), participants with engraftment had median whole blood donor chimerism values at days +180 and +365 after transplant of 100% (n = 58), respectively, and 96.6% (57/59) were off immunosuppression 1 year after transplant. The 1-year grade 3 to 4 acute graft-versus-host disease (GVHD) rate was 10%, and the 2-year moderate-severe chronic GVHD rate was 10%. Five participants (7.1%) died from infectious complications. We demonstrate that nonmyeloablative haploidentical BMT with thiotepa and PTCy is a readily available curative therapy for most adults, even those with organ damage, compared to the more expensive myeloablative gene therapy and gene editing. Additional strategies are required for children to decrease graft failure rates. The trial was registered at www.clinicaltrials.gov as #NCT01850108.

A randomized controlled trial of everolimus for neurocognitive symptoms in PTEN hamartoma tumor syndrome.

PTEN hamartoma tumor syndrome (PHTS) is a complex neurodevelopmental disorder characterized by mechanistic target of rapamycin (mTOR) overactivity. Limited data suggest that mTOR inhibitors may be therapeutic. No placebo-controlled studies have examined mTOR inhibition on cognition and behavior in humans with PHTS with/without autism. We conducted a 6-month phase II, randomized, double-blinded, placebo-controlled trial to examine the safety profile and efficacy of everolimus (4.5 mg/m2) in individuals (5-45 years) with PHTS. We measured several cognitive and behavioral outcomes, and electroencephalography (EEG) biomarkers. The primary endpoint was a neurocognitive composite derived from Stanford Binet-5 (SB-5) nonverbal working memory score, SB-5 verbal working memory, Conners' Continuous Performance Test hit reaction time and Purdue Pegboard Test score. Forty-six participants underwent 1:1 randomization: n = 24 (everolimus) and n = 22 (placebo). Gastrointestinal adverse events were more common in the everolimus group (P < 0.001). Changes in the primary endpoint between groups from baseline to Month 6 were not apparent (Cohen's d = -0.10, P = 0.518). However, several measures were associated with modest effect sizes (≥0.2) in the direction of improvement, including measures of nonverbal IQ, verbal learning, autism symptoms, motor skills, adaptive behavior and global improvement. There was a significant difference in EEG central alpha power (P = 0.049) and central beta power (P = 0.039) 6 months after everolimus treatment. Everolimus is well tolerated in PHTS; adverse events were similar to previous reports. The primary efficacy endpoint did not reveal improvement. Several secondary efficacy endpoints moved in the direction of improvement. EEG measurements indicate target engagement following 6 months of daily oral everolimus. Trial Registration Information: ClinicalTrials.gov NCT02991807 Classification of Evidence: I.

Omidubicel vs standard myeloablative umbilical cord blood transplantation: results of a phase 3 randomized study.

Omidubicel is an ex vivo expanded hematopoietic progenitor cell and nonexpanded myeloid and lymphoid cell product derived from a single umbilical cord blood unit. We report results of a phase 3 trial to evaluate the efficacy of omidubicel compared with standard umbilical cord blood transplantation (UCBT). Between January 2017 and January 2020, 125 patients age 13 to 65 years with hematologic malignancies were randomly assigned to omidubicel vs standard UCBT. Patients received myeloablative conditioning and prophylaxis with a calcineurin inhibitor and mycophenolate mofetil for graft-versus-host disease (GVHD). The primary end point was time to neutrophil engraftment. The treatment arms were well balanced and racially diverse. Median time to neutrophil engraftment was 12 days (95% confidence interval [CI], 10-14 days) for the omidubicel arm and 22 days (95% CI, 19-25 days) for the control arm (P < .001). The cumulative incidence of neutrophil engraftment was 96% for patients receiving omidubicel and 89% for patients receiving control transplants. The omidubicel arm had faster platelet recovery (55% vs 35% recovery by 42 days; P = .028), had a lower incidence of first grade 2 to 3 bacterial or invasive fungal infection (37% vs 57%; P = .027), and spent more time out of hospital during the first 100 days after transplant (median, 61 vs 48 days; P = .005) than controls. Differences in GVHD and survival between the 2 arms were not statistically significant. Transplantation with omidubicel results in faster hematopoietic recovery and reduces early transplant-related complications compared with standard UCBT. The results suggest that omidubicel may be considered as a new standard of care for adult patients eligible for UCBT. The trial was registered at www.clinicaltrials.gov as #NCT02730299.

Pediatric Aggressive Mature B-Cell Lymphomas, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology.

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Pediatric Aggressive Mature B-Cell Lymphomas include recommendations for the diagnosis and management of pediatric patients with primary mediastinal large B-cell lymphoma (PMBL) and sporadic variants of Burkitt lymphoma and diffuse large B-cell lymphoma. PMBL is now considered as a distinct entity arising from mature thymic B-cells accounting for 2% of mature B-cell lymphomas in children and adolescents. This discussion section includes the recommendations outlined in the NCCN Guidelines for the diagnosis and management of pediatric patients with PMBL.

Use of Thrombopoietin Receptor Agonists in Prolonged Thrombocytopenia after Hematopoietic Stem Cell Transplantation.

Prolonged thrombocytopenia after hematopoietic stem cell transplantation (HSCT) is a strong risk factor for transplantation-related morbidity and mortality, and no standard treatment guideline exists. Thrombopoietin receptor agonists (TPO-RAs), eltrombopag and romiplostim, increases the platelet production, and are being increasingly used in various conditions with thrombocytopenia. In this review, we present an overview of these TPO-RAs and review their efficacy and safety in prolonged post-HSCT thrombocytopenia. Through a systematic literature search, we identified 25 reports describing their use for this indication. Thirteen reports (8 case series and 5 case reports) described the use of eltrombopag in 78 patients with prolonged isolated thrombocytopenia (PIT) and 43 patients with secondary failure of platelet recovery (SFPR). A consistent and durable response with a rise in platelet counts >50 × 10 9/L for 7 consecutive days without platelet transfusion was seen in 85 of 121 patients (overall response rate [ORR], 70%). The responders included 56 patients with PIT (ORR for PIT, 72%) and 29 patients with SFPR (ORR for SFPR, 67%). No serious grade 3 or 4 adverse effects were reported. Similarly, 12 reports (6 case series and 6 case reports) described the use of romiplostim in prolonged post-HSCT thrombocytopenia (in 17 patients with PIT and 32 patients with SFPR). Response with the increment of platelet count was described in 40 out of 49 patients (ORR, 82%). Among the responders, 10 patients had PIT (ORR for PIT, 59%) and 30 patients had SFPR (ORR for SFPR, 94%). Our data show that TPO-RAs have an overall favorable response rate for both PIT and SFPR with a reasonable safety profile. However, given the lack of control groups, study heterogeneity, and the potential publication bias, these results should be interpreted with caution.

Quality-of-Life Trajectories in Adolescent and Young Adult versus Older Adult Allogeneic Hematopoietic Cell Transplantation Recipients.

Hematopoietic cell transplantation (HCT) is physically and psychologically challenging, potentially exposing patients to quality-of-life (QoL) impairments. Adolescent and young adults (AYAs, aged 15 to 39 years) are a vulnerable cohort facing multiple hurdles due to dynamic changes in several aspects of their lives. The AYA population may be particularly prone to QoL issues during HCT. We hypothesized that due to the unique psychosocial challenges faced by AYAs, they would have an inferior quality of life. We studied QoL differences between AYA (aged 15 to 39 years) and older adult (aged 40 to 60 years) allogeneic HCT recipients before and after HCT. Additionally, we determined if pre-HCT QoL for AYA transplant recipients changed over time. QoL data were collected prospectively before and after transplant on 431 recipients aged 15 to 60 years from June 2003 through December 2017 using the Functional Assessment of Cancer Therapy-Bone Marrow Transplantation (FACT-BMT) questionnaire. Repeated-measures analysis of variance was used to assess differences among age groups. Pearson correlation (r) was used to determine if baseline QoL had improved after HCT from June 2003 through December 2017 in the AYA cohort. QoL did not differ among younger AYAs, older AYAs, or older adults at any time in the first year after allogeneic HCT. At 1 year post-HCT, total FACT-BMT score and all FACT-BMT domains except physical well-being improved from pre-HCT in all age groups. From 2003 to 2017, AYA allogeneic recipients experienced modest improvement in additional concerns (r = 0.26, P = .003), trial outcome index (r = 0.23, P = .008), and total FACT-BMT score (r = 0.19, P = .031), although no improvements were seen in physical, social, emotional, or functional well-being. Contrary to our hypothesis, we found that QoL in the AYA population is similar to that of older adults before and after HCT. Improvements in QoL of AYA allogeneic patients since 2003 were driven by the additional concerns domain, which addresses multiple psychosocial aspects such as vocation, hobbies, and acceptance of illness. Continued efforts to tailor treatment and support for AYA HCT recipients is critical to improving QoL outcomes.

Risk Factors for Graft-versus-Host Disease in Haploidentical Hematopoietic Cell Transplantation Using Post-Transplant Cyclophosphamide.

Post-transplant cyclophosphamide (PTCy) has significantly increased the successful use of haploidentical donors with a relatively low incidence of graft-versus-host disease (GVHD). Given its increasing use, we sought to determine risk factors for GVHD after haploidentical hematopoietic cell transplantation (haplo-HCT) using PTCy. Data from the Center for International Blood and Marrow Transplant Research on adult patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, or chronic myeloid leukemia who underwent PTCy-based haplo-HCT (2013 to 2016) were analyzed and categorized into 4 groups based on myeloablative (MA) or reduced-intensity conditioning (RIC) and bone marrow (BM) or peripheral blood (PB) graft source. In total, 646 patients were identified (MA-BM = 79, MA-PB = 183, RIC-BM = 192, RIC-PB = 192). The incidence of grade 2 to 4 acute GVHD at 6 months was highest in MA-PB (44%), followed by RIC-PB (36%), MA-BM (36%), and RIC-BM (30%) (P = .002). The incidence of chronic GVHD at 1 year was 40%, 34%, 24%, and 20%, respectively (P < .001). In multivariable analysis, there was no impact of stem cell source or conditioning regimen on grade 2 to 4 acute GVHD; however, older donor age (30 to 49 versus <29 years) was significantly associated with higher rates of grade 2 to 4 acute GVHD (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.11 to 2.12; P = .01). In contrast, PB compared to BM as a stem cell source was a significant risk factor for the development of chronic GVHD (HR, 1.70; 95% CI, 1.11 to 2.62; P = .01) in the RIC setting. There were no differences in relapse or overall survival between groups. Donor age and graft source are risk factors for acute and chronic GVHD, respectively, after PTCy-based haplo-HCT. Our results indicate that in RIC haplo-HCT, the risk of chronic GVHD is higher with PB stem cells, without any difference in relapse or overall survival.

Distance to treatment center is associated with survival in children and young adults with acute lymphoblastic leukemia.

BACKGROUND: Socioeconomic and demographic categories such as income, race, insurance status, and treatment center type are associated with outcomes in acute leukemia. This study was aimed at determining whether the distance to treatment center affects overall survival for children and young adults with acute leukemia. METHODS: The National Cancer Database was queried for patients 39 years old or younger who were diagnosed with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). A backward elimination procedure was used to select final multivariate Cox models. RESULTS: In total, 12,301 patients with AML and 22,683 patients with ALL were analyzed. The ALL model included distance to treatment center, Charlson-Deyo score, age, race, insurance status, and community income level. US census definitions of urban and rural were not statistically significant, and no interaction was significant for included variables. Compared with distances > 50 miles, all other distances were associated with improved survival (hazard ratio [HR] for ≤10 miles, 0.91; P = .04; HR for >10 to ≤20 miles, 0.86; P = .004; HR for >20 to ≤50 miles, 0.87; P = .005). The final model for AML included the same variables as the ALL model except for distance to treatment center, which was not statistically significant. CONCLUSIONS: For children and young adults with ALL, distances > 50 miles are associated with inferior overall survival; however, no difference is seen for AML. Although it is unknown whether differences in survival for patients with ALL based on distance are driven by relapse or treatment-related mortality, increased attention to adherence, supportive care, and logistics for patients traveling long distances is warranted. LAY SUMMARY: For children and young adults with acute lymphoblastic leukemia, living more than 50 miles from the treatment center is associated with worse outcomes.

Paediatric haematologists' attitudes regarding haematopoietic cell transplantation as treatment for sickle cell disease.

Beginning early in childhood, patients with sickle cell disease [SCD; a group of genetic haemoglobin disorders characterized by the sickle or HbS mutation (HBB E7V)] are at risk of life-threatening and debilitating health events. Despite the high morbidity and mortality of this disease, haematopoietic cell transplantation (HCT), a curative therapy for SCD, remains underutilized. A variety of factors, including the limited availability of suitable donors, play a role in this trend, but do not fully explain the low frequency with which this therapy is employed. The objective of this study was to identify paediatric haematologists' attitudes about HCT as a treatment option for SCD, and to describe the impact of these attitudes on their practices of discussing HCT with families of children affected by this disease. A nationwide survey of paediatric haematologists in the United States was conducted between February and May 2016. Two hundred and eighty-seven surveys were included in the final analysis (response rate 20%). On average, respondents reported informing 42% of families about HCT as a treatment option (N = 248, 95% confidence interval: 38-46). Clinician attitudes about the cost and safety of HCT were associated with practices of discussing this therapy with families. These findings suggest that clinician attitudes and referral practices may play a role in the underutilization of this therapy in the SCD population.

Reduced-intensity conditioning for hematopoietic cell transplant for HLH and primary immune deficiencies.

Allogeneic hematopoietic cell transplantation (HCT) with myeloablative conditioning for disorders associated with excessive inflammation such as hemophagocytic lymphohistiocytosis (HLH) is associated with early mortality. A multicenter prospective phase 2 trial of reduced-intensity conditioning with melphalan, fludarabine, and intermediate-timing alemtuzumab was conducted for HLA matched or single HLA locus mismatched related or unrelated donor HCT in a largely pediatric cohort. Graft-versus-host disease (GVHD) prophylaxis was cyclosporine with methylprednisolone. The primary end point was 1-year overall survival (OS). Thirty-four patients with HLH and 12 with other primary immune deficiencies were transplanted. With a median follow-up of 20 months, the 1-year OS for transplanted patients was 80.4% (90% confidence interval [CI], 68.6%-88.2%). Five additional deaths by 16 months yielded an 18-month OS probability of 66.7% (90% CI, 52.9%-77.3%). Two patients experienced primary graft failure, and 18 patients either experienced a secondary graft failure or required a second intervention (mostly donor lymphocyte infusion [DLI]). At 1 year, the proportion of patients alive with sustained engraftment without DLI or second HCT was 39.1% (95% CI, 25.2%-54.6%), and that of being alive and engrafted (with or without DLI) was 60.9% (95% CI, 45.4 %-74.9%). The day 100 incidence of grade II to IV acute GVHD was 17.4% (95% CI, 8.1%-29.7%), and 1-year incidence of chronic GVHD was 26.7% (95% CI, 14.6%-40.4%). Although the trial demonstrated low early mortality, the majority of surviving patients required DLI or second HCT. These results demonstrate a need for future approaches that maintain low early mortality with improved sustained engraftment. The trial was registered at Clinical Trials.gov (NCT 01998633).

Pediatric Aggressive Mature B-Cell Lymphomas, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology.

Pediatric aggressive mature B-cell lymphomas are the most common types of non-Hodgkin lymphoma in children, and they include Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL). These diseases are highly aggressive but curable, the treatment is complex, and patients may have many complicated supportive care issues. The NCCN Guidelines for Pediatric Aggressive Mature B-Cell Lymphomas provide guidance regarding pathology and diagnosis, staging, initial treatment, disease reassessment, surveillance, therapy for relapsed/refractory disease, and supportive care for clinicians who treat sporadic pediatric BL and DLBCL.

Defining Moments: Making Time for Virtual Visits and Catalyzing Better Cancer Care.

Time is quite possibly a physician's most valuable asset, yet the tendency of almost all physicians is to be overly committed. How do we slowdown and make a meaningful difference? Virtual visits provide a new way to share and care without sacrificing the important nuances of face-to-face communication. When the Cleveland Clinic expanded our Distance Health capabilities in 2017 using virtual visits, we began a successful journey which provides cancer patients and their caregivers a new type of expert, unrushed cancer care access. This essay describes our current process for providing virtual visit access, preparing prior to the visit, keeping the visit as informative a possible, and closing the visit with a "distance health encounter" in the electronic medical record coupled with a summary and additional information via email.

Conditional Long-Term Survival after Autologous Hematopoietic Cell Transplantation for Diffuse Large B Cell Lymphoma.

Autologous hematopoietic cell transplantation (AHCT) is standard therapy for patients with chemosensitive, relapsed, diffuse large B cell lymphoma (DLBCL). We performed a retrospective cohort study to delineate subsequent (conditional) and relative survival in 371 adult patients with DLBCL who underwent AHCT between 2000 and 2014 and had survived for 1, 2, 3, or 5 years after transplant. The probability of overall survival at 10 years after AHCT was 62%, 71%, 77%, and 86%, respectively, for the 4 cohorts, whereas that of progression-free survival (PFS) was 55%, 65%, 72%, and 81%, respectively. The respective cumulative incidence of nonrelapse mortality (NRM) at 10 years after transplantation was 13%, 12%, 11%, and 8%, respectively. In multivariable analysis, older age was associated with greater mortality risk among all but 5-year survivors; relapse within the landmark time was associated with greater mortality risk in all groups. Older age and relapse within the landmark time were associated with worse PFS in all groups. Standardized mortality ratio (SMR) was significantly higher than an age-, gender-, and race-matched general population, with the magnitude of SMR decreasing as the landmark time increased (4.0 for 1-year, 3.0 for 2-year, 2.4 for 3-year, and 1.8 for 5-year survivors). Our study provides information on long-term survival and prognosis that will assist in counseling patients with DLBCL who have received AHCT. Survival improves with longer time in remission post-transplant, although patients continue to remain at risk for NRM, underscoring the need for continued vigilance and prevention of late complications.

Impact of germline CTC1 alterations on telomere length in acquired bone marrow failure.

Compound heterozygous germline mutations in CTC1 gene have been found in patients with atypical dyskeratosis congenita (DC), whereas heterozygous carriers are unaffected. Through screening of a large cohort of adult patients with acquired bone marrow failure syndromes, in addition to a DC case, we have also found extremely rare or novel heterozygous deleterious germline variants of CTC1 in patients with aplastic anaemia (AA; n = 5), paroxysmal nocturnal haemoglobinuria (PNH; n = 3) and myelodysplastic syndrome (MDS; n = 2). A compound heterozygous case of AA showed clonal evolution. Our results suggest that some of the inherited CTC1 variants may represent predisposition factors for acquired bone marrow failure.

Immunosuppressive therapy for pediatric aplastic anemia: a North American Pediatric Aplastic Anemia Consortium study.

Quality of response to immunosuppressive therapy and long-term outcomes for pediatric severe aplastic anemia remain incompletely characterized. Contemporary evidence to inform treatment of relapsed or refractory severe aplastic anemia for pediatric patients is also limited. The clinical features and outcomes for 314 children treated from 2002 to 2014 with immunosuppressive therapy for acquired severe aplastic anemia were analyzed retrospectively from 25 institutions in the North American Pediatric Aplastic Anemia Consortium. The majority of subjects (n=264) received horse anti-thymocyte globulin (hATG) plus cyclosporine (CyA) with a median 61 months follow up. Following hATG/CyA, 71.2% (95%CI: 65.3,76.6) achieved an objective response. In contrast to adult studies, the quality of response achieved in pediatric patients was high, with 59.8% (95%CI: 53.7,65.8) complete response and 68.2% (95%CI: 62.2,73.8) achieving at least a very good partial response with a platelet count ≥50×109L. At five years post-hATG/CyA, overall survival was 93% (95%CI: 89,96), but event-free survival without subsequent treatment was only 64% (95%CI: 57,69) without a plateau. Twelve of 171 evaluable patients (7%) acquired clonal abnormalities after diagnosis after a median 25.2 months (range: 4.3-71 months) post treatment. Myelodysplastic syndrome or leukemia developed in 6 of 314 (1.9%). For relapsed/refractory disease, treatment with a hematopoietic stem cell transplant had a superior event-free survival compared to second immunosuppressive therapy treatment in a multivariate analysis (HR=0.19, 95%CI: 0.08,0.47; P=0.0003). This study highlights the need for improved therapies to achieve sustained high-quality remission for children with severe aplastic anemia.

Safety of allogeneic hematopoietic stem cell transplantation in beta-thalassemia patients with chronic hepatitis C infections treated at a pediatric center.

The outcome of allogeneic HCT in patients previously infected with HCV is a widely debated topic and rarely reported in the pediatric and young adult age group given the small population of affected patients. New medications directly targeting HCV have induced virologic cures for over 90% of patients, and their use in the pretransplant setting may improve outcomes for patients infected with HCV. We describe two patients with transfusion-dependent beta-thalassemia major who underwent matched sibling donor bone marrow transplantation, one with a myeloablative regimen and one with a reduced-intensity conditioning regimen. Allogeneic HCT appears feasible in patients with HCV infection that clear viremia prior to conditioning therapy and with a reduced-intensity conditioning regimen. Further investigation is warranted to better define transplant risks in this population.

Parent and Guardian Knowledge of Hematopoietic Cell Transplantation as a Treatment Option for Sickle Cell Disease.

Beginning early in childhood, patients with sickle cell disease (SCD) are at risk of life-threatening and debilitating health events. Despite the high morbidity and mortality of this disease, hematopoietic cell transplantation (HCT), a curative treatment for SCD, remains underutilized. In the literature there is a paucity of data concerning medical decision maker (MDM) awareness of HCT as a treatment option for SCD. The objective of this study was to estimate the proportion of parents/guardians of children with SCD who are aware of HCT as a treatment option, and to identify the demographic factors associated with knowledge of this therapy's curative potential. Between November 2015 and December 2016, 327 parents/guardians were surveyed across 4 clinical sites in 3 Midwestern US cities. Although 82% of parents/guardians had heard of HCT in the past and 78% were aware of the therapy's curative potential, nearly half indicated that they did not know whether HCT could specifically cure their child of the disease. Respondents who had discussed HCT with their child's physician had 5 times higher odds of being aware of HCT's curative potential than those who had not. These findings suggest that additional efforts to enhance MDM knowledge of HCT as well as shared decision making in the use of this therapy, is warranted.

Prognostic Factors for Mortality among Day +100 Survivors after Allogeneic Hematopoietic Cell Transplantation.

Although day +100 survival among allogeneic hematopoietic cell transplantation (HCT) recipients has improved over time, longer-term survival remains a challenge. The aim of this study was to identify prognostic factors for survival among patients surviving longer than 100 days using baseline characteristics and factors identified within the first 100 days after transplantation. Of 413 patients undergoing a first allogeneic HCT between 2006 and 2014, 335 survived >100 days post-transplantation. The majority underwent a myeloablative transplantation (75%) with a bone marrow (BM) (52%) graft source. One-year all-cause mortality (ACM) was 29%, with 16% relapse mortality (RM) and 12% nonrelapse mortality. In multivariable analysis, high-risk disease (hazard ratio [HR], 1.55; P = .003), non-cytomegalovirus infection (HR, 1.79; P = .003), more days hospitalized (HR, 1.16; P < .001), and relapse (HR, 4.38; P < .001) within the first 100 days were associated with increased risk of ACM. Patients with higher income (HR, .89; P = .024) and those who received BM (HR, .52; P < .001) or umbilical cord blood (HR, .40; P = .002) relative to peripheral blood stem cells had lower risk of ACM. Our study identifies risk factors for adverse long-term survival in 100-day survivors, a time point when patients frequently are discharged from transplantation centers. In addition to disease- and transplantation-related factors, low socioeconomic status was associated with worse long-term survival, highlighting the need for focused efforts to improve outcomes in vulnerable patient populations.

Treosulfan, Fludarabine, and Low-Dose Total Body Irradiation for Children and Young Adults with Acute Myeloid Leukemia or Myelodysplastic Syndrome Undergoing Allogeneic Hematopoietic Cell Transplantation: Prospective Phase II Trial of the Pediatric Blood and Marrow Transplant Consortium.

This multicenter study evaluated a treosulfan-based regimen in children and young adults with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic cell transplant (HCT). Forty patients with median age 11 years (range, 1 to 19) underwent allogeneic HCT for AML in first (n = 18), second (n = 11), and third or greater remission (n = 3) or MDS (n = 8) using bone marrow (n = 25), peripheral blood stem cells (n = 5), or cord blood (n = 9). The regimen consisted of body surface area (BSA)-based treosulfan 10 g/m2/day (BSA ≤ .5 m2), 12 g/m2/day (BSA > .5 to 1.0 m2), or 14 g/m2/day (BSA > 1.0 m2) on days -6 to -4; fludarabine 30 mg/m2/day on days -6 to -2; and a single fraction of 200 cGy total body irradiation on day -1. Graft-versus-host disease (GVHD) prophylaxis included tacrolimus and methotrexate for marrow and peripheral blood stem cell and cyclosporine/mycophenolate mofetil for cord blood. One-year overall survival, disease-free survival, and nonrelapse mortality were 80%, 73%, and 3%, respectively. One-year relapse was 38% for AML and 13% for MDS. No serious organ toxicities were observed. All 37 assessable patients engrafted. Cumulative incidences of grades II to IV acute GVHD and chronic GVHD were 22% and 40%, respectively. BSA-based treosulfan dosing resulted in predictable area under the curve and maximum concentration, which is required for dosing without measuring individual pharmacokinetic parameters. Observed differences in pharmacokinetics did not impact disease control or regimen toxicity. This BSA-based treosulfan regimen resulted in excellent engraftment and disease-free survival and minimal toxicity and transplant-related mortality (3%) in children and young adults with AML and MDS.

Comparative Effectiveness of Busulfan and Fludarabine versus Fludarabine and 400 cGy Total Body Irradiation Conditioning Regimens for Acute Myeloid Leukemia/Myelodysplastic Syndrome.

Allogeneic hematopoietic cell transplantation conditioning regimen intensity has varied for patients with acute myeloid leukemia and myelodysplastic syndrome. A comparative effectiveness analysis was performed to assess outcomes of busulfan and fludarabine (BuFlu) versus those of fludarabine and 400 cGy total body irradiation (FluTBI) conditioning. Thirty-three subjects received BuFlu and 38 received FluTBI. The BuFlu group received more red blood cell transfusions (P = .02) and had a longer time to platelet recovery (P = .004). There were no differences between the regimens regarding incidence of acute or chronic graft-versus-host disease (GVHD), quality of life, or 2-year outcome estimates for relapse (48; 95% confidence interval [CI], 30 to 64 and 50; 95% CI, 33 to 65), nonrelapse mortality (29; 95% CI, 14 to 45 and 29; 95% CI, 15 to 44), relapse-free survival (27; 95% CI, 13 to 43 and 29; 95% CI, 16 to 44), and overall survival (35; 95% CI, 19 to 51; and 37; 95% CI, 22 to 52), respectively. These comparable outcomes have implications for health care resource utilization. Future prospective investigation comparing these regimens with larger patient cohorts and additional strategies to prevent relapse and limit toxicities as well as cost-effectiveness analyses are warranted.