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Promising results have been reported for adult patients with high-risk hematologic malignancies undergoing haploidentical bone marrow transplant (haploBMT) with post-transplantation cyclophosphamide (PTCy). We report results from the first multicenter trial for pediatric and young adult patients with high-risk acute leukemias and myelodysplastic syndrome (MDS) in the US and Canada in the Pediatric Transplantation and Cellular Therapy Consortium (PTCTC). Nine centers transplanted 32 patients with acute leukemias or MDS with myeloablative conditioning (MAC), haploBMT with PTCy, mycophenolate mofetil, and tacrolimus. The median age was 12y (range 1-23y). Diagnoses included acute myeloid leukemia (n=15), acute lymphoid leukemia (n=11), mixed lineage leukemia (n=1), and MDS (n=5). Transplant-related mortality (TRM) at 180 days, our primary objective, was 0%. The cumulative incidence (CuI) of acute graft-versus-host disease (aGVHD) grade II at Day 100 was 13%. No patients developed aGVHD grades III-IV. The CuI of moderate-severe chronic GVHD (cGVHD) at 1 year was 4%. Donor engraftment occurred in 27/32 (84%). Primary graft failures included three patients that received suboptimal bone marrow grafts, all successfully engrafted after second transplants. The CuI of relapse at 1y was 32%, with more relapse in pre-BMT MRD+ versus MRD- patients. Overall survival at 1y and 2y is 77% and 73%, and event-free survival at 1y and 2y is 68% and 64%, respectively. We demonstrate no TRM or severe aGVHD, low cGVHD, and favorable relapse and survival rates. This successful pilot has led to a phase III trial comparing MAC haploBMT versus HLA-matched unrelated donors, now open in the Children's Oncology Group.

Severe aplastic anemia (SAA) is a marrow failure disorder with high morbidity and mortality. It is treated with bone marrow transplantation (BMT) for those with fully matched donors or immunosuppressive therapy (IST) for those who lack such a donor, which is often the case for underrepresented minorities. We conducted a prospective phase II trial of reduced-intensity conditioning HLA-haplo BMT and post-transplantation cyclophosphamide (PTCy)-based graft-versus-host (GVHD) prophylaxis as initial therapy for patients with SAA. The median age was 25 (range 3-63) years and the median follow-up was 40.9 months (95% CI: 29.4, 55.7 mos). Over 35% of enrollment was from underrepresented racial/ethnic groups. The cumulative incidence of grade II-IV aGVHD at day 100 is 7% (95% CI: NA, 17%) and chronic GVHD at 2 years is 4% (95% CI: NA, 11%). The overall survival for 27 patients is 92% (95% CI: 83,100%) at one, two, and three years. The first 7 patients received lower dose total body irradiation (200 versus 400 cGY), but these patients were more likely to have graft failure, 3 of 7, compared to 0 out of 20 patients in the higher dose group (p=0.01, Fisher exact). HLA-haploidentical BMT with PTCy using 400cGY total body irradiation resulted in 100% overall survival with minimal GVHD in 20 consecutive patients. Not only does this approach avoid the ramifications of IST and its low failure-free survival, but also the use of haploidentical donors expands access to BMT across all populations. Clinical trial: NCT02833805

Promising results have been reported for patients with high-risk hematologic malignancies undergoing HLA-haploidentical bone marrow transplantation (haploBMT) with posttransplantation cyclophosphamide (PTCy), but there are few data on outcomes with myeloablative conditioning in this context. We report the results of a single-institution, prospective phase 2 trial of myeloablative haploBMT using busulfan-based or total body irradiation–based conditioning in 96 children or adults (median age, 42 years; range, 1-65 years) with high-risk hematologic malignancies. Recovery of neutrophils and platelets occurred at a median of 24 and 29 days. Engraftment of donor cells with chimerism >95% was achieved in 91%. The cumulative incidence of acute graft-versus-host disease (GVHD) grades II to IV and grades III to IV at day 100 was 11% and 4%, and of chronic GVHD at 6 and 12 months was 4% and 15%, with 6% moderate to severe. The cumulative incidence of nonrelapse mortality was 6% at 100 days and 11% at 1 year (19% in those aged >55 years). The cumulative incidence of relapse at 1 year was 35%; at 3 years, it was 43%. In multivariable analysis, relapse was associated with increased age (P = .02 for age 20-55 years and P = .02 for age >55 years) and with minimal residual disease before transplantation (P = .05). The overall survival at 1 and 3 years is 73% and 54%, and event-free survival at 1 and 3 years is 57% and 49%. We show that haploBMT with PTCy after myeloablative conditioning is safe and efficacious for adult and pediatric patients with hematologic malignancies. Careful consideration must be given to using myeloablative conditioning in patients age >55 years. This trial was registered at www.clinicaltrials.gov as #NCT00796562.

Severe aplastic anemia (SAA) is a stem cell disorder often treated with bone marrow transplantation (BMT) to reconstitute hematopoiesis. Outcomes of related HLA-haploidentical (haplo) donors after reduced-intensity conditioning with intensive graft-versus-host disease (GVHD) prophylaxis including posttransplantation cyclophosphamide are presented here from 37 SAA, 20 relapsed/refractory (R/R), and 17 treatment-naïve (TN) SAA patients. Median follow-up is 32 months (90% confidence interval [CI], 29-44). The median age was 25 (range, 4-69) years. The median time to neutrophil recovery was 17 days (range, 15-88). Four of 37 patients (11%) experienced graft failure (GF). There was 1 primary GF of 20 patients in the R/R group and 3 of 17 in the TN group at 200 cGy (1 primary, 2 secondary), but none in the 10 patients who received 400 cGy total body irradiation. Two patients with GF succumbed to infection and 2 were rescued with second haplo BMT. The overall survival for all patients is 94% (90% CI, 88-100) at 1 and 2 years. The cumulative incidence of grade II-IV acute GVHD at day 100 is 11%. The cumulative index of chronic GVHD at 2 years is 8%. Similar results were seen in 10 SAA patients who received the identical nonmyeloablative regimen with posttransplant cyclophosphamide but matched donor transplants. Haplo BMT with posttransplant cyclophosphamide represents a potential cure in SAA, with all 20 R/R currently alive, disease-free, and with no evidence of active GVHD. Extending this approach to TN patients was associated with higher GF rates, but an increase in total body irradiation dose to 400 cGy was associated with durable engraftment without greater early toxicity. Nonmyeloablative haplo BMT in TN SAA could lead to a paradigm shift, such that essentially all patients can proceed quickly to safe, curative BMT. These trials were registered at www.cincialtrials.gov as #NCT02224872) and #NCT02833805.

The key immunologic signatures associated with clinical outcomes after posttransplant cyclophosphamide (PTCy)-based HLA-haploidentical (haplo) and HLA-matched bone marrow transplantation (BMT) are largely unknown. To address this gap in knowledge, we used machine learning to decipher clinically relevant signatures from immunophenotypic, proteomic, and clinical data and then examined transcriptome changes in the lymphocyte subsets that predicted major posttransplant outcomes. Kinetics of immune subset reconstitution after day 28 were similar for 70 patients undergoing haplo and 75 patients undergoing HLA-matched BMT. Machine learning based on 35 candidate factors (10 clinical, 18 cellular, and 7 proteomic) revealed that combined elevations in effector CD4+ conventional T cells (Tconv) and CXCL9 at day 28 predicted acute graft-versus-host disease (aGVHD). Furthermore, higher NK cell counts predicted improved overall survival (OS) due to a reduction in both nonrelapse mortality and relapse. Transcriptional and flow-cytometric analyses of recovering lymphocytes in patients with aGVHD identified preserved hallmarks of functional CD4+ regulatory T cells (Tregs) while highlighting a Tconv-driven inflammatory and metabolic axis distinct from that seen with conventional GVHD prophylaxis. Patients developing early relapse displayed a loss of inflammatory gene signatures in NK cells and a transcriptional exhaustion phenotype in CD8+ T cells. Using a multimodality approach, we highlight the utility of systems biology in BMT biomarker discovery and offer a novel understanding of how PTCy influences alloimmune responses. Our work charts future directions for novel therapeutic interventions after these increasingly used GVHD prophylaxis platforms. Specimens collected on NCT0079656226 and NCT0080927627 https://clinicaltrials.gov/.

Long-term outcomes after allogeneic hematopoietic cell transplantation (HCT) for therapy-related myeloid neoplasms (tMNs) are dismal. There are few multicenter studies defining prognostic factors in pediatric patients with tMNs. We have accumulated the largest cohort of pediatric patients who have undergone HCT for a tMN to perform a multivariate analysis defining factors predictive of long-term survival. Sixty-eight percent of the 401 patients underwent HCT using a myeloablative conditioning (MAC) regimen, but there were no statistically significant differences in the overall survival (OS), event-free survival (EFS), or cumulative incidence of relapse and non-relapse mortality based on the conditioning intensity. Among the recipients of MAC regimens, 38.4% of deaths were from treatment-related causes, especially acute graft versus host disease (GVHD) and end organ failure, as compared to only 20.9% of deaths in the reduced intensity conditioning (RIC) cohort. Exposure to total body irradiation (TBI) during conditioning and experiencing grade III/IV acute GVHD were associated with worse OS. In addition, a diagnosis of therapy related myelodysplastic syndrome and having a structurally complex karyotype at tMN diagnosis were associated with worse EFS. Reduced-toxicity (but not reduced-intensity) regimens might help to decrease relapse while limiting mortality associated with TBI-based HCT conditioning in pediatric patients with tMNs.

Relapse is the most common cause of treatment failure following allogeneic blood or marrow transplantation (alloBMT) for AML or MDS. Post-transplant maintenance therapies may prevent relapse. We conducted a phase II trial combining azacitidine (AZA) with GM-CSF in non-relapsed, post-transplant patients with AML or MDS. Patients received escalating doses of AZA to a maximum of 75 mg/m2 for 5 days per cycle for up to 12 cycles. GM-CSF was given on days 1-10 of each cycle. Eighteen patients were treated following non-myeloablative (17) and myeloablative (1) alloBMT for AML (61.1%), MDS (27.7%), or therapy-related myeloid neoplasm (11.1%). The majority of patients (72%) received their graft from an HLA-haploidentical donor. The treatment was well-tolerated with rare grade 3-4 hematologic toxicities. One patient suffered an exacerbation of GVHD. The 24-month relapse-free and overall survivals were 47 and 57%, respectively, with a median of 18.6 and 29 months.

Increasingly, adolescent, young adult, and adult children are relied upon as donors for their parents undergoing blood and marrow stem cell transplant. How family functioning impacts donors' decision making and whether haploidentical donor children have unique supportive care needs is unknown. In this qualitative research study, we conducted 15 semistructured telephone interviews among individuals who underwent blood or marrow stem cell donation for their parent. Interviews explored donors' perspectives of the transplant experience across the trajectory from screening through early post-transplant follow-up and elicited unmet needs. Major themes included: (1) perception of choice, (2) act of giving back, (3) burdens of donation, (4) anticipated health benefit to parent, and (5) impact of donation on parent/child relationship. The majority of participants described high family functioning, but strain was also evident. Family functioning rarely was reported as affecting the decision to donate, with all donors expressing a sense of obligation. Participants were overwhelmingly satisfied with their decision and the ability to give back to their parent. Suggestions for the health care team to improve the donation experience focused on increased education about potential delays in screening, better description of possible complications for recipients, and provision of emotional support following donation.

Purpose Allogeneic bone marrow transplantation (alloBMT) is the only cure for many primary immune deficiency disorders (PIDD), primary immune regulatory disorders (PIRD), and inherited bone marrow failure syndromes (IBMFS). Methods We report the results of 25 patients who underwent alloBMT using reduced intensity conditioning (RIC), alternative donors, and post-transplantation cyclophosphamide (PTCy). In an attempt to reduce regimen-related toxicities, we removed low-dose TBI from the prep and added mycophenolate mofetil and tacrolimus for graft-versus-host disease (GVHD) prophylaxis for all donor types in the latter 14 patients. Donors were haploidentical related (n = 14), matched unrelated (n = 9), or mismatched unrelated (n = 2). The median age was 9 years (range 5 months–21 years). Results With a median follow-up of 26 months (range 7 months–9 years), the 2-year overall survival is 92%. There were two deaths, one from infection, and one from complications after a second myeloablative BMT. Three patients developed secondary graft failure, one at 2 years and two at >3 years, successfully treated with CD34 cell boost in one or second BMT in two. The remaining 20 patients have full or stable mixed donor chimerism and are disease-free. The incidence of mixed chimerism is increased since removing TBI from the prep. The 6-month cumulative incidence of grade II acute GVHD is 17%, with no grade III–IV. The 1-year cumulative incidence of chronic GVHD is 14%, with severe of 5%. Conclusion This alloBMT platform using alternative donors, RIC, and PTCy is associated with excellent rates of engraftment and low rates of GVHD and non-relapse mortality, and offers a curative option for patients with PIDD, PIRD, and IBMFS. Trial registration ClinicalTrials.gov Identifier: NCT04232085

With post-transplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis, nonmyeloablative HLA-haploidentical (NMA haplo) and HLA-matched blood or marrow transplantation (BMT) have comparable outcomes. Early discontinuation of immunosuppression may reduce the risk of relapse and improve immune reconstitution, but may increase the risk of GVHD. We conducted a prospective trial of NMA haplo BMT for patients with hematologic malignancies (median age, 61 years), evaluating the safety of early discontinuation of tacrolimus. All patients received T cell-replete bone marrow followed by high-dose PTCy, mycophenolate mofetil, and tacrolimus. Tacrolimus was prespecified to stop without taper at day +90, +60, or +120, contingent on having ≥5% donor T cells, no relapse, and no grade II-IV acute or significant chronic GVHD. Safety stopping rules were based on ≥5% graft failure, ≥10% nonrelapse mortality (NRM), or a ≥20% combined incidence of severe acute and chronic GVHD from the tacrolimus stop date through day +180. Of the 47 patients in the day +90 arm, 23 (49%) stopped tacrolimus as planned. Of the 55 patients in the day +60 arm, 38 (69%) stopped as planned. Safety stopping criteria were not met. In both arms, at day +180, the probability of grade II-IV acute GVHD was

Large alternative donor pools provide the potential for selecting a different donor for a second allogeneic (allo) bone or marrow transplant (BMT). As HLA disparity may contribute to the graft-versus-tumor effect, utilizing new mismatched haplotype donors may potentially improve the antitumor activity for relapsed hematologic malignancies despite a previous alloBMT. Data from patients who received a second alloBMT for relapsed hematologic malignancies at Johns Hopkins were analyzed. Outcomes were compared between patients who received a second allograft with the same MHC composition and those who received an allograft with a new mismatched haplotype. Loss of heterozygosity analysis was performed for patients with acute myeloid leukemia (AML) whose first allograft was haploidentical. Between 2005 and 2015, 40 patients received a second BMT for a relapsed hematologic malignancy. The median follow-up is 750 (range, 26 to 2950) days. The median overall survival (OS) in the cohort is 928 days (95% confidence interval [CI], 602 to not reached [NR]); median event-free survival (EFS) for the cohort is 500 days (95% CI, 355 to NR). The 4-year OS is 40% (95% CI, 25% to 64%), and the 4-year EFS is 36% (95% CI, 24% to 55%). The cumulative incidence of nonrelapsed mortality by 2 years was 27% (95% CI, 13% to 42%). The cumulative incidence of grade 3 to 4 acute graft-versus-host disease (GVHD) at 100 days was 15% (95% CI, 4% to 26%); the cumulative incidence of extensive chronic GVHD at 2 years was 22% (95% CI, 9% to 36%). The median survival was 552 days (95% CI, 376 to 2950+) in the group who underwent transplantation with a second allograft that did not harbor a new mismatched haplotype, while it was not reached in the group whose allograft contained a new mismatched haplotype (hazard ratio [HR], .36; 95% CI, .14 to .9; P = .02). EFS was also longer in the group who received an allograft containing a new mismatched haplotype, (NR versus 401 days; HR, .50; 95% CI, .22 to 1.14; P = .09). Although the allograft for this patient's second BMT contained a new mismatched haplotype, AML nevertheless relapsed a second time. Second BMTs are feasible and provide a reasonable chance of long-term survival. An allograft with a new mismatched haplotype may improve outcomes after second BMTs for relapsed hematologic malignancies.

Post-transplantation cyclophosphamide (PTCy) can be used for graft-versus-host disease (GVHD) prophylaxis alone or in combination with other agents and is associated with excellent rates of engraftment and acute and chronic GVHD, as well as absence of post-transplantation lymphoproliferative disease. No study has previously evaluated the risk for developing donor-derived malignancy (DDM) in patients who receive PTCy. Giving chemotherapy in the immediate post-transplantation period carries with it a theoretic risk of disturbing the graft at a time of increased hematopoietic stress and causing or accelerating the development of malignancy. From 2000 to 2011, 789 patients underwent allogeneic transplantation and received PTCy at the Johns Hopkins Hospital. There were 4 cases of DDM identified among this large population, which is similar to or below the rate of DDM published in the literature. We found that the estimated cumulative incidence by competing risk analysis of DDM is 1.4% (SE, 1.02%). The use of PTCy does not appear to increase the risk of DDM.

Severe aplastic anemia (SAA) is a life-threatening hematopoietic stem cell disorder that is treated with bone marrow transplantation (BMT) or immunosuppressive therapy (IST). The management of patients with refractory SAA after IST is a major challenge. Alternative donor BMT is the best chance for cure in refractory SAA, but morbidity and mortality from graft failure and complications of graft-versus-host disease (GVHD) have limited enthusiasm for this approach. Here, we employed post-transplantation high-dose cyclophosphamide in an effort to safely expand the donor pool in 16 consecutive patients with refractory SAA who did not have a matched sibling donor. Between July 2011 and August 2016, 16 patients underwent allogeneic (allo) BMT for refractory SAA from 13 haploidentical donors and 3 unrelated donors. The nonmyeloablative conditioning regimen consisted of antithymocyte globulin, fludarabine, low-dose cyclophosphamide, and total body irradiation. Post-transplantation cyclophosphamide 50 mg/kg/day i.v. on days +3 and +4 was administered for GVHD prophylaxis. Additionally, patients received mycophenolate mofetil on days +5 through 35 and tacrolimus from day +5 through 1 year. The median age of the patients at the time of transplantation was 30 (range, 11 to 69) years. The median time to neutrophil recovery over 1000 × 103/mm3 for 3 consecutive days was 19 (range, 16 to 27) days, to red cell engraftment was 25 (range, 2 to 58) days, and to last platelet transfusion to keep platelets counts over 50 × 103/mm3 was 27.5 (range, 22 to 108) days. Graft failure, primary or secondary, was not seen in any of the patients. All 16 patients are alive, transfusion independent, and without evidence of clonality. The median follow-up is 21 (range, 3 to 64) months. Two patients had grade 1 or 2 skin-only acute GVHD. These same 2 also had mild chronic GVHD of the skin/mouth requiring systemic steroids. One of these GVHD patients was able to come off all IST by 15 months and the other by 17 months. All other patients stopped IST at 1 year. Nonmyeloablative alloBMT using post-transplantation cyclophosphamide allowed for safe expansion of the donor pool to include HLA-haploidentical donors. This approach appears promising in refractory SAA patients. Importantly, engraftment was 100%, pre-existing clonal disease was eradicated, and the risk of GVHD was low.

Background We previously demonstrated comparable immune reconstitution after HLA-matched sibling (MSD), HLA-matched unrelated (MUD), and HLA-haploidentical (haplo) bone marrow transplantation (BMT) with posttransplant cyclophosphamide (PTCy). Here, we use machine learning algorithms to identify predictive immunologic variables, providing insight for future translational interventions. Methods We assessed 11 pre-transplant factors, 22 immune subsets, and 7 serum markers at day 28 and day 56 post-BMT in 70 patients who engrafted after myeloablative conditioned (MAC) haplo BMT with PTCy (50mg/kg on days +3 and +4), mycophenolate mofetil (days +5-35), and tacrolimus (days +5-180) and 74 patients who engrafted after MAC HLA-matched BMT with PTCy (50mg/kg on days +3 and +4). Classification and regression tree machine based learning with nodal selection was applied to detect risk groups for four outcomes: overall survival (OS), progression-free survival (PFS), acute graft-versus-host disease (aGVHD), and chronic graft-versus-host disease (cGVHD). Results When compared with cytomegalovirus (CMV) seronegative recipients, CMV seropositive recipients had higher CD3+ T cells, effector memory (EM) CD4+ T cells, T effector memory expressing RA (TEMRA) CD4+ T cells, CD8+ T cells, EM CD8+ T cells, and TEMRA CD8+ T cells at early time points after both BMT platforms (not shown). Pre-BMT disease status and natural killer (NK) cell count at day 28 emerged as predictive variables for survival. Two-year OS and PFS for patients in complete remission (CR) with NK cells >54 cells/µL were 98% and 89%, in CR with NK cells 55 cells/µL, the CuI of aGVHD was 18% in those with CXCL-9 Conclusion Machine learning using immune cellular and soluble markers can be successfully applied to identify risk factors for BMT outcomes. High CD4+ counts and CXCL-9 levels at day 28 predicted aGVHD and high reg3α at day 56 predicted cGVHD. Both CXCL-9 and reg3α represent potential therapeutic targets. Finally, disease status and NK cell counts at day 28 predicted OS and PFS. These data support research to determine what influences NK cell recovery as well as to investigate NK cell therapy for recipients with active disease or for those with poor early NK cell reconstitution.

Summary Background Although severe haemoglobinopathies can be cured with allogeneic blood or bone marrow transplantation, availability of matched donors and toxic effects can be problematic. We previously found that non-myeloablative haploidentical related bone marrow transplantation with post-transplantation cyclophosphamide expanded the donor pool while limiting graft-versus-host disease (GVHD). However, graft failure—albeit with full host haemopoietic recovery—occurred in 50% of patients. In this study, we investigated whether increasing total body irradiation from 200 cGy to 400 cGy would improve engraftment while maintaining the safety profile. Methods This study was done at Johns Hopkins Hospital (Baltimore, MD, USA). Patients aged 2–70 years receiving their first bone marrow transplant were eligible for inclusion in the study. Patients received rabbit-derived intravenous anti-thymocyte globulin 0·5 mg/kg on day −9 and 2 mg/kg on days −8 and −7, intravenous fludarabine 30 mg/m2 on days −6 to −2, intravenous cyclophosphamide 14·5 mg/kg on days −6 and −5, and total body irradiation 400 cGy administered as a single fraction on day −1. We collected unmanipulated bone marrow and infused on day 0. GVHD prophylaxis comprised intravenous cyclophosphamide 50 mg/kg per day on days 3 and 4 after transplantation, oral mycophenolate mofetil 15 mg/kg per dose (maximum 1 g) every 8 h on days 5 to 35, and oral sirolimus to maintain a level of 5–15 ng/dL for at least 1 year starting on day 5. The original planned primary objectives of this phase 2 clinical trial were transplant-related mortality and progression-free survival. However, the coverage decision by the Centers for Medicare and Medicaid Services to only provide payment for allogeneic bone marrow transplantation for patients with sickle cell disease on a clinical trial that had a comparison arm with patients not receiving bone marrow transplantation prompted the closure of this trial to accrual in 2017. Therefore, as we were unable to perform our planned statistical analysis, the primary objective was modified to evaluate engraftment, assessed by chimerism. This trial is registered with ClinicalTrials.gov , number NCT00489281 . The study is closed to new participants and this is the primary analysis. Findings Between Sept 24, 2014, and Aug 1, 2017, we enrolled 17 consecutive patients: 12 (71%) with sickle cell disease and 5 (29%) with β-thalassaemia major. The median patient age was 16 years (range 6–31, IQR 7·7–27·5). One (6%) of 17 patients had primary graft failure with recovery of host haemopoiesis. 13 (76%) of 17 patients achieved full donor chimerism and three (18%) had mixed donor-host chimerism. Five (29%) of 17 patients developed grade 2–4 acute GVHD, including four (24%) with maximal grade 2 GVHD and one (6%) with grade 3 GVHD. Chronic GVHD developed in three (18%) patients. As of their last follow-up visit, GVHD had resolved in all patients and no patients were receiving systemic GVHD therapy. All patients remained alive as of Aug 4, 2018, and the median follow-up duration was 705 days (range 355–1294; IQR 398–943). Only one (6%) of the 16 engrafted patients remained transfusion dependent, and 14 (88%) discontinued immunosuppression. Interpretation Increasing total body irradiation to 400 cGy substantially reduced graft failure while maintaining the safety of haploidentical bone marrow transplantation with post-transplantation cyclophosphamide. These results suggest that engraftment after haploidentical bone marrow transplantation for haemoglobinopathies is possible, and primary graft failure—the main problem previously reported—might be addressed by this strategy. Therefore, this curative approach should no longer be restricted to patients with HLA-matched donors. Funding Maryland Stem Cell Research Fund and US National Institutes of Health.

Composite endpoints that not only encompass mortality and relapse, but other critical post-transplant events such as graft-versus-host disease, are being increasingly utilized to quantify survival without significant morbidity after allogeneic blood or marrow transplantation. High-dose, post-transplantation cyclophosphamide reduces severe graft-versus-host disease with allogeneic marrow transplantation, making composite endpoints after this management particularly interesting. We retrospectively analyzed 684 adults with hematologic malignancies who received T-cell-replete bone marrow grafts and cyclophosphamide after myeloablative HLA-matched related (n=192) or unrelated (n=120), or non-myeloablative HLA-haploidentical (n=372) donor transplantation. The median follow up was 4 (range, 0.02-11.4) years. Graft-versus-host disease-free, relapse-free survival was defined as the time after transplantation without grade III-IV acute graft-versus-host disease, chronic graft-versus-host disease requiring systemic treatment, relapse, or death. Chronic graft-versus-host disease-free, relapse-free survival was defined as the time after transplantation without moderate or severe chronic graft-versus-host disease, relapse, or death. One-year graft-versus-host disease-free, relapse-free survival and chronic graft-versus-host disease-free, relapse-free survival estimates were, respectively, 47% (95% CI: 41-55%) and 53% (95% CI: 46-61%) after myeloablative HLA-matched related, 42% (95% CI: 34-52%) and 52% (95% CI: 44-62%) after myeloablative HLA-matched unrelated, and 45% (95% CI: 40-50%) and 50% (95% CI: 45-55%) after non-myeloablative HLA-haploidentical donor transplantation. In multivariable models, there were no differences in graft-versus-host disease-free, or chronic graft-versus-host disease-free, relapse-free survival after either myeloablative HLA-matched unrelated or non-myeloablative HLA-haploidentical, compared with myeloablative HLA-matched related donor transplantation. Although limited by inclusion of dissimilar cohorts, we found that post-transplantation cyclophosphamide-based platforms yield comparable composite endpoints across conditioning intensity, donor type, and HLA match.

Allogeneic (allo-) hematopoietic stem cell transplant (HSCT) is curative for many nonmalignant pediatric disorders, including hemoglobinopathies, bone marrow failure syndromes, and immunodeficiencies. There is great success using HLA-matched related donors for these patients; however, the use of alternative donors has been associated with increased graft failure, graft versus host disease (GVHD), and transplant-related mortality (TRM). HSCT using alternative donors with post-transplantation cyclophosphamide (PT/Cy) for GVHD prophylaxis has been performed for hematologic malignancies with engraftment, GVHD, and TRM comparable to that seen with HLA-matched related donors. There are limited reports of HSCT in nonmalignant pediatric disorders other than hemoglobinopathies using alternative donors and PT/Cy. We transplanted eleven pediatric patients with life-threatening nonmalignant conditions using reduced intensity conditioning (RIC), alternative donors, and PT/Cy alone or in combination with tacrolimus and mycophenolate mofetil. We observed limited GVHD, no TRM, and successful engraftment sufficient to eliminate manifestations of disease in all patients. Allo-HSCT using alternative donors and PT/Cy shows promise for curing nonmalignant disorders; development of prospective clinical trials to confirm these observations is warranted.

There are few therapeutic options for patients with T-cell acute lymphoblastic leukemia (T-ALL) who have recurrent disease after initial matched sibling hematopoietic stem cell transplantation. While a second hematopoietic stem cell transplant (HSCT) from a haploidentical donor offers the conceptual possibility of greater graft versus leukemia effect, there is minimal literature to describe the efficacy of this approach in recurrent pediatric T-ALL. We present the case of a now 9-year-old female in whom second haploidentical HSCT, followed by successive donor lymphocyte infusions in response to minimal residual disease reemergence, has led to 3+ years of ongoing disease control without graft versus host disease and excellent quality of life.

Noninfectious fevers are common early after T cell–replete HLA haploidentical (haplo) peripheral blood transplants and have been associated with cytokine release syndrome and overall mortality. However, less is known regarding the incidence and associations of early fever after bone marrow transplantation (BMT) with post-transplant cyclophosphamide (PTCy). We hypothesized that early fever would be associated with myeloablative conditioning (MAC), because of its relative increase in tissue damage augmenting antigen presentation and class II HLA-mismatching because of recognition of antigen-presenting cells by CD4(+) T cells. In 672 recipients of MAC HLA-matched related donor (MRD) (n = 183), MAC HLA-matched unrelated donor (MUD) (n = 115), MAC haplo (n = 79), or nonmyeloablative (NMA) haplo (n = 295) T cell–replete BMT with PTCy, we retrospectively analyzed early noninfectious fever defined as temperature of ≥38.3°C once or ≥38.0°C twice or more on days 1 to 6. Fever occurred in 13% after MAC MRD, 23% after MAC MUD, 44% after NMA haplo, and 84% after MAC haplo BMT (P < .0001). Survival outcomes did not differ between patients with and without early fever. In NMA haplo BMT, mismatch in the graft-versus-host direction at HLA-DRB1 or-DPB1 (but not HLA -A, -B, -Cw, or -DQB1) was associated with early fever compared with no mismatches at these loci (P < .0001 and P =.02, respectively). In multivariable modeling, -DRB1 or -DPB1 mismatch and higher CD3(+) graft cell dose were significantly associated with early fever. Early fever is more common after haplo compared with HLA-matched BMT. Fever is associated with myeloablation, -DRB1 or -DPB1 mismatching, and higher CD3(+) graft cell dose but not survival.

Introduction Therapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/AML) are rare but well-recognized complications of cancer therapy. Allogeneic hematopoietic cell transplantation (HCT) with myeloablative conditioning (MAC) remains the mainstay of treatment but is associated with a high incidence of non-relapse mortality (NRM). Reduced intensity conditioning (RIC) may reduce NRM in these heavily pre-treated patients. The primary objective of this study was to compare outcomes following RIC and MAC regimens in patients receiving an allogeneic HCT. Methods Retrospective chart review of patients Results One hundred and forty-seven patients were included with 29 (19.7%) receiving RIC and 115 (78.2%) MAC (Table 1). The median follow-up of entire cohort was 13.4 (0-246) months. OS and EFS of the entire cohort was 44.7% (95% CI: 37.1-53.9) and 40.2% (95% CI: 32.8-49.3) at 3 years, respectively, and there was no significant difference between MAC and RIC cohorts (Fig A & B). Karnofsky performance status of the patients (>=90) was the only factor that was found to be statistically associated with improved EFS (HR 0.49, p=0.01). NRM was noted in 61% of patients after MAC compared to 28% after RIC, however disease relapse was a major cause of death after RIC (Fig C & D). The majority of transplants were performed after 2005 (81.6%) and outcomes seem to be slightly better in contemporary era due to improved supportive care and decreased NRM. Conclusion This is one of the largest reported cohorts of pediatric patients receiving allogeneic transplantation for t-MDS/AML. Outcomes are poor relative to de novo MDS/AML due to high rate of NRM with MAC and high rate of disease related death after RIC. Novel strategies that lead to a reduction in transplant-related mortality in these heavily pre-treated patients while providing sufficient disease control are needed to improve survival in t-MDS/AML patients receiving HCT.

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.

Background Allogeneic Bone Marrow Transplantation (alloBMT) is the only cure for many primary immune deficiencies (PID) and inherited bone marrow failure syndromes (IBMFS). There has been great success using HLA-matched related donors; however, use of alternative donors has been associated with increased graft failure, graft versus host disease (GVHD), and transplant related mortality (TRM). BMT using reduced intensity conditioning (RIC), alternative donors, and post-transplantation cyclophosphamide (PT/Cy) has been previously reported by our institution with no TRM, and low rates of graft failure and GVHD. Here, we present outcomes on an additional 8 patients treated, along with updated results of the previously reported 11 patients. Design We transplanted 19 patients (CGD n = 8; DKC n = 2; DBA n = 2; CVID n = 1; CTLA4 def n = 1; Glanzmann's n = 1; HLH n = 1; HyperIgM n = 1; IPEX n = 1; XIAP n = 1) using an alemtuzamab/fludarabine/melphalan-based preparative regimen (Figure 1), with or without total body irradiation. GVHD prophylaxis was PT/Cy alone (n = 4), or PT/Cy with mycophenolate mofetil and tacrolimus or sirolimus (n = 15). Donors were HLA-haploidentical related (n = 11), 10/10 HLA-identical unrelated (n = 6), and 9/10 (n = 1) or 5/8 (n = 1) HLA-mismatched unrelated. Results Of 18 evaluable patients, 17 (95%) achieved 100% donor chimerism by day 30 in peripheral blood, and 15 (83%) maintained 100% donor chimerism at day 60. At 1-year post-transplant, 14 (78%) remained >92% donor chimerism. Two patients developed late (>3 years) secondary graft failure, both were re-transplanted and are alive and 100% donor at one and four years post their second BMTs. All evaluable patients have had sufficient sustained donor chimerism to eliminate manifestations of their underlying diseases. Grade 1 or 2 acute GVHD developed in 5 patients, all treated successfully with steroids and a CNI. One patient developed skin-only chronic GVHD, successfully treated with immune suppression and UV light therapy. One patient developed concurrent adenovirus and cytomegalovirus infections early after BMT, which ultimately led to multi-organ failure and death. Two patients developed veno-occlusive disease, successfully treated with defibrotide. With median follow-up of surviving patients of 2 years, ranging 1 to 8 years, overall survival is 95%, disease-free survival (alive without manifestations of underlying disease) is 95%, and event free survival (time from BMT to death or graft loss/re-transplantation) is 72% (Figure 2). Conclusion We have observed high rates of engraftment, limited GVHD, and low TRM in 19 patients with PID and IBMFS using alternative donors, RIC, and PT/Cy. RIC BMT with PT/Cy shows promise for curing these pediatric disorders. Development of a prospective clinical trial is currently underway to confirm these observations and to further study the kinetics of immune reconstitution in these patients.

Related HLA-haploidentical blood or marrow transplantation (BMT) with high-dose posttransplantation cyclophosphamide (PTCy) is being increasingly used because of its acceptable safety profile. To better define outcomes of nonmyeloablative (NMA) HLA-haploidentical BMT with PTCy, 372 consecutive adult hematologic malignancy patients who underwent this procedure were retrospectively studied. Risk-stratified outcomes were evaluated using the refined Disease Risk Index (DRI), developed to stratify disease risk across histologies and allogeneic BMT regimens. Patients received uniform conditioning, T-cell–replete allografting, then PTCy, mycophenolate mofetil, and tacrolimus. Six-month probabilities of nonrelapse mortality and severe acute graft-versus-host disease were 8% and 4%. With 4.1-year median follow-up, 3-year probabilities of relapse, progression-free survival (PFS), and overall survival (OS) were 46%, 40%, and 50%, respectively. By refined DRI group, low (n = 71), intermediate (n = 241), and high/very high (n = 60) risk groups had 3-year PFS estimates of 65%, 37%, and 22% (P < .0001), with corresponding 3-year OS estimates of 71%, 48%, and 35% (P = .0001). On multivariable analyses, the DRI was statistically significantly associated with relapse, PFS, and OS (each P < .001). This analysis demonstrates that the DRI effectively risk stratifies recipients of NMA HLA-haploidentical BMT with PTCy and also suggests that this transplantation platform yields similar survivals to those seen with HLA-matched BMT.

OBJECTIVE The objective of this study was to evaluate pretransplant sinus computed tomography (CT) as predictor of post-hematopoietic stem cell transplant sinusitis. METHODS We evaluated pretransplant and posttransplant CT findings in 100 children using the Lund-Mackay system and "common-practice" radiology reporting and correlated these with the presence of acute sinusitis. RESULTS Fourteen percent of patients with normal screening CT developed posttransplant sinusitis, compared with 23% with radiographic abnormalities and 22% with clinical sinusitis alone, not statistically significant. Sensitivity of CT findings for clinical sinusitis ranged between 19% and 56%. Except for mucosal thickening (71% specificity), other findings had high specificity between 92% and 97%, particularly when combined. Lund-Mackay score change of 10 or greater from baseline was associated with a 2.8-fold increased likelihood of having sinusitis (P < 0.001). CONCLUSIONS Screening CT can serve as a baseline, with a Lund-Mackay score change of 10 or greater constituting a significant threshold. The strongest correlation with the presence of acute sinusitis was seen with combined CT findings.

High-risk, recurrent, or refractory solid tumors in pediatric, adolescent, and young adult (AYA) patients have an extremely poor prognosis despite current intensive treatment regimens. We piloted an allogeneic bone marrow transplant platform using reduced-intensity conditioning (RIC) and partially HLA-mismatched (haploidentical) related donors for this population of pediatric and AYA solid tumor patients. Sixteen patients received fludarabine, cyclophosphamide, melphalan, and low-dose total body irradiation RIC haploidentical BMT (haploBMT) followed by post-transplantation cyclophosphamide (PTCy), mycophenolate mofetil, and sirolimus. All assessable patients were full donor chimeras on day 30 with a median neutrophil recovery of 19 days and platelet recovery of 21 days. One patient (7%) exhibited secondary graft failure associated with concomitant infection. The median follow-up time was 15 months. Overall survival was 88%, 56%, and 21% at 6, 12, and 24 months, respectively. Median survival from transplant date was 14 months with a median progression-free survival 7 months. We observed limited graft-versus-host disease in 3 patients and nonrelapse mortality in 1 patient. We demonstrated that RIC haploBMT with PTCy is feasible and has acceptable toxicities in patients with incurable pediatric and AYA solid tumors; thus, this approach serves as a platform for post-transplant strategies to prevent relapse and optimize progression-free survival.

Importance Early palliative care integration for cancer patients is now touted as the optimal care model, yet significant barriers often prevent its implementation. A perceived barrier, especially for pediatric oncology patients, is the notion that patients and their families may not need or want palliative care involvement early in the disease trajectory. Objective To determine the perception of symptom burden early in treatment and assess attitudes toward early integration of palliative care in pediatric oncology patient-parent pairs. Design, Setting, and Participants Novel but pretested survey tools were administered to 129 patient-parent dyads of hospital-based pediatric oncology ambulatory clinics and inpatient units between September 2011 and January 2015. All patient participants were aged between 10 and 17 years and were diagnosed as having an oncologic condition 1 month to 1 year before enrollment. Both the patient and the parent in the dyad spoke English, and all participating parents provided written informed consent. A convenience sample was used for selection, with participants screened when otherwise presenting at a participating site. A total of 280 eligible participants were approached for study inclusion, 258 of whom were enrolled in the study (92.1% positive response-rate). Main Outcomes and Measures Degree of perceived suffering from early symptom-related causes, attitudes toward early palliative care integration, and patient-parent concordance. Statistical analysis included descriptive statistics, calculation of concordance, McNemar test results, and Cochran-Armitage trend test results. Results Of the 129 patients in the dyads, 68 were boys, and 61 girls; of the 129 parents, 15 were men, and 114 women. Patients reported the following symptoms in the first month of cancer therapy: nausea (n = 109; 84.5%), loss of appetite (n = 97; 75.2%), pain (n = 96; 74.4%), anxiety (n = 77; 59.7%), constipation (n = 69; 53.5%), depression (n = 64; 49.6%), and diarrhea (n = 52; 40.3%). A large proportion of those reporting suffering indicated substantial suffering severity from specific symptoms (ie, a great deal or a lot) including nausea, 52.3% (57 of 109), loss of appetite, 50.5% (49 of 97), constipation 30.4% (21 of 69), pain 30.2% (29 of 96), anxiety 28.6% (22 of 77), depression 28.1% (18 of 64), and diarrhea 23.1% (12 of 52). Few children and parents expressed opposition to early palliative care involvement (2 [1.6%] and 8 [6.2%]) or perceived any detrimental effects on their relationship with their oncologist (6 [4.7%] and 5 [3.9%]), loss of hope (3 [2.3%] and 10 [7.8%]), or therapy interference (3 [2.3%] and 2 [1.6%], respectively). Intradyad concordance was low overall: 26% to 29% for exact concordance and 40% to 69% for agreement within 1 response category. Significant differences in patient-parent attitudes toward aspects of early palliative care included child participants being more likely than their parents (40.3% [n = 52] vs 17.8% [n = 23]) to indicate that palliative care would have been helpful for treating their symptoms ( P Conclusions and Relevance Pediatric oncology patients experience a high degree of symptom-related suffering early in cancer therapy, and very few patients or parents in this study expressed negative attitudes toward early palliative care. Our findings suggest that pediatric oncology patients and families might benefit from, and are not a barrier to, early palliative care integration in oncology.

The inaugural meeting of ‘New Frontiers in Pediatric Allogeneic Stem Cell Transplantation’ organized by the Pediatric Blood and Transplant Consortium (PBMTC) was held at the American Society of Pediatric Hematology and Oncology Annual Meeting. This meeting provided an international platform for physicians and investigators active in the research and utilization of pediatric Allo-SCT in children and adolescents with malignant and non-malignant disease (NMD), to share information and develop future collaborative strategies. The primary objectives of the conference included: (1) to present advances in Allo-SCT in pediatric ALL and novel pre and post-transplant immunotherapy; (2) to highlight new strategies in alternative allogeneic stem cell donor sources for children and adolescents with non-malignant hematological disorders; (3) to discuss timing of immune reconstitution after Allo-SCT and methods of facilitating more rapid recovery of immunity; (4) to identify strategies of utilizing Allo-SCT in pediatric myeloproliferative disorders; (5) to develop diagnostic and therapeutic approaches to hematological complications post pediatric Allo-SCT; (6) to enhance the understanding of new novel cellular therapeutic approaches to pediatric malignant and non-malignant hematological disorders; and (7) to discuss optimizing drug therapy in pediatric recipients of Allo-SCT. This paper will provide a brief overview of the conference.

Promising results have been reported for patients with high-risk hematologic malignancies undergoing T-cell-replete myeloablative bone marrow transplant (BMT) from HLA-haploidentical donors with post-transplantation cyclophosphamide (PT/Cy). Here, we report results from the first prospective multicenter pilot trial in the Pediatric Blood and Marrow Transplant Consortium (PBMTC) for pediatric, adolescent, and young adult patients with high risk acute leukemias and myelodysplastic syndrome (MDS) in the US and Canada. Nine centers transplanted 32 patients with acute leukemias or MDS in complete remission (CR) who received myeloablative conditioning consisting of IV Busulfan (pharmacokinetically adjusted) and Cyclophosphamide (Cy, 50 mg/kg/day) days –2 and –1 except for patients with acute lymphocytic leukemia who received Cy (50 mg/kg/day x 2) and total body irradiation (1200cGy). T-cell-replete bone marrow from haploidentical related donors was used for all patients. Postgrafting immunosuppression consisted of Cy (50 mg/kg/day) days 3 and 4, followed by mycophenolate mofetil for 30 days and tacrolimus for 90-180 days. Median age of patients was 12y (range, 1-23) and donors was 35y (range, 4-53). Diagnoses included AML (CR1 = 7, CR2 = 6), ALL (CR1 = 8, CR2 = 5), mixed lineage leukemia (1), and MDS (5). One patient had received a prior BMT. Donor engraftment occurred in 27/32 (84%). Primary graft failures included 3 patients with MDS and 2 with AML (CR1 = 1, CR2 = 1); three of these patients had received suboptimal bone marrow grafts (TNC/kg ≤2e8) and all successfully engrafted after second transplants. Median time to neutrophils >500/μL was 22 days and platelets >20,000/μL was 21 days. Transplant related mortality (TRM) at 180 days, our primary objective, was 0%. Cumulative incidence of acute GVHD grades II-IV at Day 100 was 13%. No patients developed severe acute GVHD grades III-IV. The cumulative incidence of mod-severe chronic GVHD at 1 year was 4%. The cumulative incidence of relapse at 1y was 32%. With a median follow-up of surviving patients of 477 days (range, 180-1127), actuarial overall survival is 77% at 1y. With a median follow-up of event-free patients of 451 days (180-1127), actuarial event-free survival is 68% at 1y. For this first reported multicenter pediatric myeloablative HLA-haploidentical HSCT for high-risk leukemias and MDS with T-cell replete bone marrow and PT/Cy, we have demonstrated a 0% TRM, low cumulative incidences of acute and chronic GVHD, and favorable rates of relapse and survival. Further investigation as to potential reasons for graft failure and consideration of any changes needed to ensure engraftment for certain disease groups are underway. A larger trial comparing haploidentical BMT with other alternative donor sources is in development.

The role of allogeneic blood or marrow transplantation (alloBMT) for peripheral T cell lymphoma (PTCL) remains to be defined. There is growing interest in reduced-intensity conditioning (RIC) regimens and/or utilization of human leukocyte antigen haploidentical (haplo) grafts given concerns about treatment-associated toxicities and donor availability. We reviewed the outcomes of 44 consecutive, related donor alloBMTs for PTCL performed at Johns Hopkins Hospital from 1994 to 2011, including 18 RIC/haplo alloBMTs. Patients receiving RIC (n = 24) were older, with median age of 59 years (range, 24 to 70), than patients receiving myeloablative conditioning (MAC, n = 20), with median age of 46 years (range, 18 to 64), P = .01. The median age at RIC/haplo alloBMT was 60 years. The estimated 2-year progression-free survival (PFS) was 40% (95% confidence interval [CI], 26% to 55%) and overall survival (OS) was 43% (95% CI, 28% to 59%). In older patients (≥60, n = 14), the estimated 2-year PFS and OS were 38% (95% CI, 18% to 79%) and 45% (95% CI, 24% to 86%), respectively. On unadjusted analysis, there was a tendency toward superior outcomes for alloBMT in first remission versus beyond first remission, with an estimated 2-year PFS of 53% (95% CI, 33% to 77%) versus 29% (95% CI, 9% to 45%), P = .08. On competing risk analysis, the 1-year cumulative incidence of relapse was 38% for MAC/HLA-identical alloBMTs and 34% for RIC/haplo alloBMTs. Estimated 1-year nonrelapse mortality was 10% for MAC and 8% for RIC (11% for RIC/haplo alloBMT). On unadjusted landmark analysis, patients with acute grade II-IV or chronic graft-versus-host disease (GVHD) had a 17% probability of relapse (95% CI, 0% to 39%), compared with 66% (95% CI, 48% to 84%) in patients without GVHD, P = .04. Utilization of RIC and alternative donors expands treatment options in PTCL to those who are older and unable to tolerate high-dose conditioning, with outcomes comparable with approaches using myeloablative regimens and HLA-matched donors. AlloBMT may be appropriate in first remission in select high-risk cases.

Lower-intensity conditioning regimens for haploidentical blood or marrow transplantation (BMT) are safe and efficacious for adult patients with hematologic malignancies. We report data for pediatric/young adult patients with high-risk hematologic malignancies (n = 40) treated with nonmyeloablative haploidentical BMT with post-transplantation cyclophosphamide from 2003 to 2015. Patients received a preparative regimen of fludarabine, cyclophosphamide, and total body irradiation. Post-transplantation immunosuppression consisted of cyclophosphamide, mycophenolate mofetil, and tacrolimus. Donor engraftment occurred in 29 of 32 (91%), with median time to engraftment of neutrophils >500/µL of 16 days (range, 13 to 22) and for platelets >20,000/µL without transfusion of 18 days (range, 12 to 62). Cumulative incidences of acute graft-versus-host disease (GVHD) grades II to IV and grades III and IV at day 100 were 33% and 5%, respectively. The cumulative incidence of chronic GVHD was 23%, with 7% moderate-to-severe chronic GVHD, according to National Institutes of Health consensus criteria. Transplantation-related mortality (TRM) at 1 year was 13%. The cumulative incidence of relapse at 2 years was 52%. With a median follow-up of 20 months (range, 3 to 148), 1-year actuarial overall and event-free survival were 56% and 43%, respectively. Thus, we demonstrate excellent rates of engraftment, GVHD, and TRM in pediatric/young adult patients treated with this regimen. This approach is a widely available, safe, and feasible option for pediatric and young adult patients with high-risk hematologic malignancies, including those with a prior history of myeloablative BMT and/or those with comorbidities or organ dysfunction that preclude eligibility for myeloablative BMT.

OBJECTIVE Use of high-dose cyclophosphamide without hematopoietic stem cell transplant to treat severe aplastic anemia (SAA) has been controversial due to concern for increased infectious toxicity as compared with antithymocyte globulin and cyclosporine A. As children often tolerate dose-intensive therapy better than adults, we sought to perform a detailed retrospective analysis of both treatment response and toxicity in 28 patients younger than 22 years of age treated with 29 courses of high-dose cyclophosphamide as the sole form of immunosuppression. STUDY DESIGN Children and adolescents with SAA who lacked an human leukocyte antigen-matched sibling donor were treated with cyclophosphamide 50 mg/kg/d for 4 consecutive days then received daily granulocyte colony stimulating factor until neutrophil recovery, transfusion support, and antimicrobial prophylaxis. RESULTS Overall survival was 85%, with hematologic response of 79% and complete response of 66%. Cumulative incidences of bacterial infection (86%) and fungal infection (62%) were high but deaths due to infection were rare, as were clonal evolution (1/28), clinically relevant paroxysmal nocturnal (1/28), and relapse (2/28). CONCLUSIONS Response rates and survival following high-dose cyclophosphamide in pediatric patients with SAA exceed those seen in adults and compare favorably to antithymocyte globulin/cyclosporine A with manageable infectious toxicity.

Recent studies have suggested that plasma-derived proteins may be potential biomarkers relevant for graft-versus-host disease and/or non-relapse mortality occurring after allogeneic blood or marrow transplantation. However, none of these putative biomarkers have been assessed in patients treated either with human leukocyte antigen-haploidentical blood or marrow transplantation or with post-transplantation cyclophosphamide, which has been repeatedly associated with low rates of severe acute graft-versus-host disease, chronic graft-versus-host disease, and non-relapse mortality. We explored whether seven of these plasma-derived proteins, as measured by enzyme-linked immunosorbent assays, were predictive of clinical outcomes in post-transplantation cyclophosphamide-treated patients using plasma samples collected at serial predetermined timepoints from patients treated on prospective clinical studies of human leukocyte antigen-haploidentical (n=58; clinicaltrials.gov Identifier: 00796562) or human leukocyte antigen-matched-related or -unrelated (n=100; clinicaltrials.gov Identifiers: 00134017 and 00809276) T-cell-replete bone marrow transplantation. Day 30 levels of interleukin-2 receptor α, tumor necrosis factor receptor 1, serum STimulation-2 (IL1RL1 gene product), and regenerating islet-derived 3-α all had high areas under the curve of 0.74-0.97 for predicting non-relapse mortality occurrence by 3 months post-transplant in both the human leukocyte antigen-matched and human leukocyte antigen-haploidentical cohorts. In both cohorts, all four of these proteins were also predictive of subsequent non-relapse mortality occurring by 6, 9, or 12 months post-transplant and were significantly associated with non-relapse mortality in univariable analyses. Furthermore, day 30 elevations of interleukin-2 receptor α were associated with grade II-IV and III-IV acute graft-versus-host disease occurring after day 30 in both cohorts. These data confirm that plasma-derived proteins previously assessed in other transplantation platforms appear to retain prognostic and predictive utility in patients treated with post-transplantation cyclophosphamide.

Since typical inflammatory responses may be diminished in children following bone marrow transplant (BMT), computed tomography (CT) imaging of the sinuses has been increasingly ordered to diagnose sinusitis in this group. The objective of this study was to determine the association between clinical sinusitis symptoms and sinus opacification on CT scans in post BMT versus immunocompetent children. Our sample was comprised of 64 post BMT and 86 immunocompetent children with sinus CT scans. CT sinus opacification was scored using the modified Lund–Mackay staging system. The relationship between clinical sinusitis symptoms (rhinorrhea, nasal congestion, cough, headache, and facial pain) and opacification was compared for the two groups. The severity of sinus opacification in the BMT group was significantly higher compared to the immunocompetent group. In combined patient groups the odds ratio (OR) for moderate/severe sinusitis was significantly elevated for rhinorrhea (OR = 3.00; 95% confidence interval [CI], 1.27–7.12), cough (OR = 2.80; 95% CI, 1.22–6.42), and having either rhinorrhea, nasal congestion, or cough (OR = 4.76; 95% CI, 1.71–13.24). While the immunocompetent group had a greater number of sinusitis symptoms compared to the post BMT group, both groups had a significant increase in the severity on CT with increasing number of symptoms. Conclusion: In post BMT patients, our data demonstrated higher odds of moderate/severe sinusitis on CT scans associated with rhinorrhea, cough or nasal congestion. These finding suggest that in post BMT children, detailed sinus history may still play a vital role in the diagnosis of sinusitis.

Hematopoietic cell transplantation is the only potentially curative option for a variety of pediatric malignant and nonmalignant disorders. Despite advances in transplantation biology and immunology as well as in posttransplant management that have contributed to improved survival and decreased transplant-related mortality, hematopoietic cell transplantation does not come without significant risk of complications. When patients who have undergone hematopoietic cell transplantation present to the emergency department, it is important to consider a variety of therapy-related complications to optimize management and outcome. In this article, we use clinical cases to highlight some of the more common emergent complications after hematopoietic cell transplantation.

Natural killer (NK) cell alloreactivity, which may contribute to the graft-versus-leukemia effect of allogeneic hematopoietic stem cell transplantation (HSCT), is influenced by the interaction of killer-cell immunoglobulin-like receptors (KIRs) on donor NK cells and their ligands, human leukocyte antigen (HLA) Class I molecules on recipient antigen-presenting cells. Distinct models to predict NK cell alloreactivity differ in their incorporation of information from typing of recipient and donor KIR and HLA gene loci, which exist on different autosomes and are inherited independently as haplotypes. Individuals may differ in the inheritance of the two KIR haplotypes, A and B, or in the expression of individual KIR genes. Here, we examined the effect of KIR and HLA genotype, in both the recipient and donor, on the outcome of 86 patients with advanced hematologic malignancies who received nonmyeloablative, HLA-haploidentical HSCT with high-dose, post-transplantation cyclophosphamide (Cy). Compared to recipients of marrow from donors with identical KIR gene content, recipients of inhibitory KIR (iKIR) gene-mismatched marrow had an improved overall survival (HR=0.37; CI: 0.21- 0.63; p=0.0003), event-free survival (HR=0.51; CI: 0.31- 0.84; p=0.01), and relapse rate (cause specific hazard ratio, SDHR=0.53; CI: 0.31-0.93; p=0.025). Patients homozygous for the KIR “A” haplotype, which encodes only one activating KIR, had an improved overall survival (HR=0.30; CI: 0.13-10.69; p=.004), event-free survival (HR=0.47; CI: 0.22-1.00; p=.05) and non-relapse mortality (NRM; cause specific HR=0.13; CI: 0.017-0.968; p=0.046) if their donor expressed at least one KIR B haplotype, which encodes several activating KIRs. Models that incorporated information from recipient HLA typing, with or without donor HLA typing, were not predictive of outcome in this patient cohort. Thus, nonmyeloablative conditioning and T cell-replete, HLA-haploidentical HSCTs involving iKIR gene mismatches between donor and recipient, or KIR haplotype AA recipients of marrow from KIR Bx donors, were associated with lower relapse and NRM and improved overall and event-free survival. These findings suggest that selection of donors based upon inhibitory KIR gene or haplotype incompatibility may be warranted.

Hematopoietic SCT from a partially HLA-mismatched (HLA-haploidentical) first-degree relative offers the benefits of rapid and near universal donor availability but also the risks that result from traversing the HLA barrier; namely, graft failure, severe GVHD and prolonged immunodeficiency. Improvements over the last 10 years in conditioning regimens, graft engineering and pharmacological immuno-prophylaxis of GVHD have substantially reduced the morbidity and mortality of HLA-haploidentical SCT. Highly immunosuppressive but nonmyeloablative conditioning extends the availability of HLA-haploidentical SCT to elderly hematologic malignancy patients lacking HLA-matched donors and permits recovery of autologous hematopoiesis in the event of graft failure. Current regimens for HLA-haploidentical SCT are associated with a 2-year non-relapse mortality of 20 ± 5%, relapse of 35 ± 15% and overall survival of 50 ± 20%. Major developmental areas include harnessing natural killer cell alloreactivity to reduce the risk of disease relapse and improving immune reconstitution by delayed infusions of lymphocytes selectively depleted of alloreactive cells. Hematologic malignancy patients who lack suitably matched related or unrelated donors can now be treated with HLA-haploidentical related donor or unrelated umbilical cord blood SCT. Future clinical trials will assess the relative risks and benefits of these two graft sources.

We evaluated the safety and efficacy of high-dose, posttransplantation cyclophosphamide (Cy) to prevent graft rejection and graft-versus-host disease (GVHD) after outpatient nonmyeloablative conditioning and T cell-replete bone marrow transplantation from partially HLA-mismatched (haploidentical) related donors. Patients with advanced hematologic malignancies (n = 67) or paroxysmal nocturnal hemoglobinuria (n = 1) received Cy 50 mg/kg i.v. on day 3 (n = 28) or on days 3 and 4 (n = 40) after transplantation. The median times to neutrophil (>500/μL) and platelet recovery (>20,000/μL) were 15 and 24 days, respectively. Graft failure occurred in 9 of 66 (13%) evaluable patients, and was fatal in 1. The cumulative incidences of grades II-IV and grades III-IV acute (aGVHD) by day 200 were 34% and 6%, respectively. There was a trend toward a lower risk of extensive chronic GVHD (cGVHD) among recipients of 2 versus 1 dose of posttransplantation Cy (P = .05), the only difference between these groups. The cumulative incidences of nonrelapse mortality (NRM) and relapse at 1 year were 15% and 51%, respectively. Actuarial overall survival (OS) and event-free survival (EFS) at 2 years after transplantation were 36% and 26%, respectively. Patients with lymphoid malignancies had an improved EFS compared to those with myelogenous malignancies (P = .02). Nonmyeloablative HLA-haploidentical BMT with posttransplantation Cy is associated with acceptable rates of fatal graft failure and severe aGVHD or cGVHD. © 2008 American Society for Blood and Marrow Transplantation.

The "allogeneic effect" refers to the induction of host B cell antibody synthesis or host T cell cytotoxicity, including tumoricidal activity, by an infusion of allogeneic lymphocytes. We show that treatment of mice with cyclophosphamide (Cy) followed by CD8(+) T cell-depleted allogeneic donor lymphocyte infusion (Cy + CD8(-) DLI) induces regression of established tumors with minimal toxicity in models of both hematologic and solid cancers, even though the donor cells are eventually rejected by the host immune system. The optimal antitumor effect of Cy + CD8(-) DLI required the presence of donor CD4(+) T cells, host CD8(+) T cells, and alloantigen expression by normal host but not tumor tissue. The results support a model in which a donor CD4(+) T cell-mediated graft-versus-host (GVH) reaction effectively awakens antitumor immunity among Cy-resistant host CD8(+) T cells. These events provide the cellular mechanism of the "allogeneic effect" in antitumor immunity. Cy + CD8(-) DLI may be an effective and minimally toxic strategy for awakening the host immune response to advanced cancers.

High-dose cyclophosphamide given after HLA-matched related and unrelated allogeneic bone marrow transplantation (BMT) for patients with hematologic malignancies is effective single-agent graft-versus-host disease (GVHD) prophylaxis in adults. Data describing outcomes for pediatric and young adult patients have not been reported. Between the years 2007 and 2013, 29 pediatric and young adult patients ages ≤21 years of age treated at our institution for high-risk hematologic malignancies underwent myeloablative HLA-matched related T cell–replete BMT. Eleven patients received post-transplantation cyclophosphamide (PTCy) as single-agent GVHD prophylaxis and were followed prospectively. Eighteen patients received calcineurin inhibitor (CNI)–based standard GVHD prophylaxis and were studied retrospectively as a control group. No acute GVHD (aGVHD) developed in patients receiving PTCy, whereas patients receiving CNI-based GVHD prophylaxis had cumulative incidences of grades II to IV and grades III and IV aGVHD of 27% and 5%, respectively. No patients receiving PTCy developed chronic GHVD, compared to 1 in the control group. Two-year overall survival was similar between the 2 groups (54% PTCy versus 58% CNI-based prophylaxis), as was event-free survival (42% PTCy versus 47% CNI-based). The 5-year cumulative incidence of relapse was 58% for PTCy and 42% for CNI-based GVHD prophylaxis (P = .45). These results suggest that PTCy is a safe and efficacious method of GVHD prophylaxis after an HLA-matched related BMT in the pediatric and young adult population that affords patients to be off all post-transplantation immunosuppression on day +5.

Hematopoietic SCT is currently the only curative therapy for a range of benign inherited and acquired primary hematologic disorders in children, including BM failure syndromes and hemoglobinopathies. The preferred HLA-matched sibling donor is available for only about 25% of such children. However, there has been substantial progress over the last four decades in the use of alternative donors for those without a matched sibling—including HLA-matched unrelated donors, HLA-haploidentical related donors and unrelated-donor umbilical cord blood—so that it is now possible to find a donor for almost every child requiring an allograft. Below, we summarize the relative merits and limitations of the different alternative donors for benign hematologic conditions, first generally, and then in relation to specific disorders, and suggest recommendations for selecting such an alternative donor.