Enteral nutrition optimization program for children undergoing blood & marrow transplantation: A quality improvement project.

BACKGROUND: Malnutrition in children and young adults undergoing blood and marrow transplantation (BMT) increases morbidity and mortality. Addressing this via optimization of enteral nutrition can potentially improve outcomes. METHODS: This Quality Improvement project utilized pre-post-intervention design and post-intervention survey to evaluate a novel program optimizing enteral nutrition support in children undergoing BMT. All patients aged 0-18 who were admitted during the 16-week implementation period followed the Enteral Nutrition Optimization Program from pre-BMT through discharge. Data on biometric indicators, complications, and post-transplant milestone time markers were evaluated via Mann-Whitney U, Fisher's exact, and Chi-square tests as indicated using SPSS™ Version 27. A separate sample of clinical providers completed a post-intervention survey to evaluate the feasibility and acceptance of the intervention. FINDINGS: Six patients received the intervention, with 12 patients evaluated. There were no statistical differences between groups on measured evaluations of weight loss (0.15 kg vs +0.4 kg, p = 0.39), malnutrition (2 vs 3, p = 0.545), graft-versus-host-disease (2 vs 2, p = 1), time to engraftment (platelets day 22 vs 20.5, p = 0.589), infections (p = 0.368), and length of stay (32.5 days vs 31 days, p = 1). The provider sample of 45 participants showed overall feasibility and acceptance of the intervention (88.9% agreed or strongly agreed). DISCUSSION: Feasibility and acceptance were high, resulting in increased use of nasogastric and gastrostomy tubes. Though no clinical significance, interpretation is limited due to the small sample size. PRACTICE IMPLICATIONS: Implementing a novel nutritional support program resulted in a culture shift towards enteral nutrition optimization. Further studies are needed to determine clinical impacts.

Prospective PTCTC trial of myeloablative haplo-BMT with posttransplant cyclophosphamide for pediatric acute leukemias.

Promising results have been reported for adult patients with high-risk hematologic malignancies undergoing haploidentical bone marrow transplant (haploBMT) with posttransplant cyclophosphamide (PTCy). To our knowledge, 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 Pediatric Transplantation and Cellular Therapy Consortium. Nine centers performed transplants in 32 patients having acute leukemias or MDS, with myeloablative conditioning (MAC), haploBMT with PTCy, mycophenolate mofetil, and tacrolimus. The median patient age was 12 years. Diagnoses included AML (15), ALL (11), mixed-lineage leukemia (1), and MDS (5). Transplant-related mortality (TRM) at 180 days was 0%. The cumulative incidence (CuI) of grade 2 acute graft-versus-host disease (aGVHD) on day 100 was 13%. No patients developed grades 3-4 aGVHD. The CuI of moderate-to-severe chronic GVHD (cGVHD) at 1 year was 4%. Donor engraftment occurred in 27 patients (84%). Primary graft failures included 3 patients who received suboptimal bone marrow grafts; all successfully engrafted after second transplants. The CuI of relapse at 1 year was 32%, with more relapse among patients MRD positive pre-BMT vs MRD negative. Overall survival rates at 1 and 2 years were 77% and 73%, and event-free survival rate at 1 and 2 years were 68% and 64%. There was no TRM or severe aGVHD, low cGVHD, and favorable relapse and survival rates. This successful pilot trial has led to a phase 3 trial comparing MAC haploBMT vs HLA-matched unrelated donor BMT in the Children's Oncology Group. This trial was registered at www.clinicaltrials.gov as #NCT02120157.

Alternative donor BMT with posttransplant cyclophosphamide as initial therapy for acquired severe aplastic anemia.

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 2 trial of reduced-intensity conditioning HLA-haploidentical BMT and posttransplantation cyclophosphamide (PTCy)-based graft-versus-host (GVHD) prophylaxis as initial therapy for patients with SAA. The median patient age was 25 years (range, 3-63 years), and the median follow-up time was 40.9 months (95% confidence interval [CI], 29.4-55.7). More than 35% of enrollment was from underrepresented racial/ethnic groups. The cumulative incidence of grade 2 or 4 acute GVHD on day 100 was 7% (95% CI, not applicable [NA]-17), and chronic GVHD at 2 years was 4% (95% CI, NA-11). The overall survival of 27 patients was 92% (95% CI, 83-100) at 1, 2, and 3 years. The first 7 patients received lower dose total body irradiation (200 vs 400 cGy), but these patients were more likely to have graft failure (3 of 7) compared with 0 of 20 patients in the higher dose group (P = .01; Fisher exact test). HLA-haploidentical BMT with PTCy using 400 cGy total body irradiation resulted in 100% overall survival with minimal GVHD in 20 consecutive patients. Not only does this approach avoid any adverse ramifications of IST and its low failure-free survival, but the use of haploidentical donors also expands access to BMT across all populations. This trial was registered at www.clinicaltrials.gov as NCT02833805.

Signatures of GVHD and relapse after posttransplant cyclophosphamide revealed by immune profiling and machine learning.

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/.

Outcomes of pediatric patients with therapy-related myeloid neoplasms.

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 was 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.

Reduced Intensity Bone Marrow Transplantation with Post-Transplant Cyclophosphamide for Pediatric Inherited Immune Deficiencies and Bone Marrow Failure Syndromes.

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.

Myeloablative haploidentical BMT with posttransplant cyclophosphamide for hematologic malignancies in children and adults.

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.

Haploidentical BMT for severe aplastic anemia with intensive GVHD prophylaxis including posttransplant cyclophosphamide.

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.

Effect of increased dose of total body irradiation on graft failure associated with HLA-haploidentical transplantation in patients with severe haemoglobinopathies: a prospective clinical trial.

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 ß-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, 2019, 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.

Early Fever after Haploidentical Bone Marrow Transplantation Correlates with Class II HLA-Mismatching and Myeloablation but Not Outcomes.

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.

Shortened-Duration Tacrolimus after Nonmyeloablative, HLA-Haploidentical Bone Marrow Transplantation.

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 <40%, that of grade III-IV acute GVHD was <8%, and that of NRM was <5%. The 1-year probabilities of chronic GVHD and NRM were <15% and <10%, respectively, in both arms. The 1-year GVHD-free relapse-free survival was higher in the day 60 arm. Thus, stopping tacrolimus as early as day +60 is feasible and carries acceptable risks after NMA haplo BMT with PTCy. This approach may facilitate post-transplantation strategies for relapse reduction.

Reduced-Intensity Haploidentical Bone Marrow Transplantation with Post-Transplant Cyclophosphamide for Solid Tumors in Pediatric and Young Adult Patients.

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.

Patients' and Parents' Needs, Attitudes, and Perceptions About Early Palliative Care Integration in Pediatric Oncology.

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 < .001). 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.

Plasma-derived proteomic biomarkers in human leukocyte antigen-haploidentical or human leukocyte antigen-matched bone marrow transplantation using post-transplantation cyclophosphamide.

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.

Post-Transplantation Cyclophosphamide after Bone Marrow Transplantation Is Not Associated with an Increased Risk of Donor-Derived Malignancy.

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.

Comparable composite endpoints after HLA-matched and HLA-haploidentical transplantation with post-transplantation cyclophosphamide.

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.

Nonmyeloablative Haploidentical Bone Marrow Transplantation with Post-Transplantation Cyclophosphamide for Pediatric and Young Adult Patients with High-Risk Hematologic Malignancies.

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.

Tolerance and effectiveness of nivolumab after pediatric T-cell replete, haploidentical, bone marrow transplantation: A case report.

To date, there has been a lack of pediatric experience regarding the efficacy and tolerability of immune checkpoint inhibitors after haploidentical hematopoietic stem cell transplant (HSCT). We present the case of a 22-year-old female with multiple-relapsed Hodgkin lymphoma (HL) who presented with a new relapse after haploidentical (post-haplo) HSCT. Anti-PD-1 therapy with nivolumab resulted in significant objective disease response and clinical improvement without notable side effects, including the absence of a graft-versus-host disease (GVHD). This case report suggests that immune checkpoint inhibition may be safely tolerated even in the setting of haploidentical HSCT, without triggering overt GVHD.

High-dose Cyclophosphamide is Effective Therapy for Pediatric Severe Aplastic Anemia.

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.

Persistent Multiyear Control of Relapsed T-Cell Acute Lymphoblastic Leukemia With Successive Donor Lymphocyte Infusions: A Case Report.

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.