The history of haploidentical stem cell transplantation: a trip from the bench to the bedside.

Allogeneic bone marrow transplantation is a curative intervention for both neoplastic and non-malignant conditions. However, not all patients have an HLA-matched donor. Therefore, the development of an approach that expand the donor pool was of paramount relevance. The development of post-transplantation cyclophosphamide as graft versus host disease prophylaxis allows the safe use of haploidentical donors, solving the donor availability problem to the vast majority of patients in need. The present paper reviews the history of the development of haploidentical transplantation at Johns Hopkins University, from the bench to the bedside.

Post-Transplantation Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis.

BACKGROUND: In patients undergoing allogeneic hematopoietic stem-cell transplantation (HSCT), a calcineurin inhibitor plus methotrexate has been a standard prophylaxis against graft-versus-host disease (GVHD). A phase 2 study indicated the potential superiority of a post-transplantation regimen of cyclophosphamide, tacrolimus, and mycophenolate mofetil. METHODS: In a phase 3 trial, we randomly assigned adults with hematologic cancers in a 1:1 ratio to receive cyclophosphamide-tacrolimus-mycophenolate mofetil (experimental prophylaxis) or tacrolimus-methotrexate (standard prophylaxis). The patients underwent HSCT from an HLA-matched related donor or a matched or 7/8 mismatched (i.e., mismatched at only one of the HLA-A, HLA-B, HLA-C, and HLA-DRB1 loci) unrelated donor, after reduced-intensity conditioning. The primary end point was GVHD-free, relapse-free survival at 1 year, assessed in a time-to-event analysis, with events defined as grade III or IV acute GVHD, chronic GVHD warranting systemic immunosuppression, disease relapse or progression, and death from any cause. RESULTS: In a multivariate Cox regression analysis, GVHD-free, relapse-free survival was significantly more common among the 214 patients in the experimental-prophylaxis group than among the 217 patients in the standard-prophylaxis group (hazard ratio for grade III or IV acute GVHD, chronic GVHD, disease relapse or progression, or death, 0.64; 95% confidence interval [CI], 0.49 to 0.83; P = 0.001). At 1 year, the adjusted GVHD-free, relapse-free survival was 52.7% (95% CI, 45.8 to 59.2) with experimental prophylaxis and 34.9% (95% CI, 28.6 to 41.3) with standard prophylaxis. Patients in the experimental-prophylaxis group appeared to have less severe acute or chronic GVHD and a higher incidence of immunosuppression-free survival at 1 year. Overall and disease-free survival, relapse, transplantation-related death, and engraftment did not differ substantially between the groups. CONCLUSIONS: Among patients undergoing allogeneic HLA-matched HSCT with reduced-intensity conditioning, GVHD-free, relapse-free survival at 1 year was significantly more common among those who received cyclophosphamide-tacrolimus-mycophenolate mofetil than among those who received tacrolimus-methotrexate. (Funded by the National Heart, Lung, and Blood Institute and others; BMT CTN 1703 ClinicalTrials.gov number, NCT03959241.).

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.

NCCN Guidelines® Insights: Hematopoietic Cell Transplantation, Version 3.2022.

The NCCN Guidelines for Hematopoietic Cell Transplantation (HCT) provide an evidence- and consensus-based approach for the use of autologous and allogeneic HCT in the management of malignant diseases in adult patients. HCT is a potentially curative treatment option for patients with certain types of malignancies; however, recurrent malignancy and transplant-related complications often limit the long-term survival of HCT recipients. The purpose of these guidelines is to provide guidance regarding aspects of HCT, including pretransplant recipient evaluation, hematopoietic cell mobilization, and treatment of graft-versus-host disease-a major complication of allogeneic HCT-to enable the patient and clinician to assess management options in the context of an individual patient's condition. These NCCN Guidelines Insights provide a summary of the important recent updates to the NCCN Guidelines for HCT, including the incorporation of a newly developed section on the Principles of Conditioning for HCT.

Allogeneic Blood or Marrow Transplantation with High-Dose Post-Transplantation Cyclophosphamide for Acute Lymphoblastic Leukemia in Patients Age ≥55 Years.

Patients age ≥55 years with acute lymphoblastic leukemia (ALL) fare poorly with conventional chemotherapy, with a 5-year overall survival (OS) of ∼20%. Tyrosine kinase inhibitors and novel B cell-targeted therapies can improve outcomes, but rates of relapse and death in remission remain high. Allogeneic blood or marrow transplantation (alloBMT) provides an alternative consolidation strategy, and post-transplantation cyclophosphamide (PTCy) facilitates HLA-mismatched transplantations with low rates of nonrelapse mortality (NRM) and graft-versus-host disease (GVHD). The transplantation database at Johns Hopkins was queried for patients age ≥55 years who underwent alloBMT for ALL using PTCy. The database included 77 such patients. Most received reduced-intensity conditioning (RIC) (88.3%), were in first complete remission (CR1) (85.7%), and had B-lineage disease (90.9%). For the entire cohort, 5-year relapse-free survival (RFS) and overall survival (OS) were 46% (95% confidence interval [CI], 34% to 57%) and 49% (95% CI, 37% to 60%), respectively. Grade III-IV acute GVHD occurred in only 3% of patients, and chronic GVHD occurred in 13%. In multivariable analysis, myeloablative conditioning led to worse RFS (hazard ratio [HR], 4.65; P = .001), whereas transplantation in CR1 (HR, .30; P = .004) and transplantation for Philadelphia chromosome-positive (Ph+) ALL versus T-ALL (HR, .29; P = .03) were associated with improved RFS. Of the 54 patients who underwent RIC alloBMT in CR1 for B-ALL, the 5-year RFS and OS were 62% (95% CI, 47% to 74%) and 65% (95% CI, 51% to 77%), respectively, with a 5-year relapse incidence of 16% (95% CI, 7% to 27%) and an NRM of 24% (95% CI, 13% to 36%). RIC alloBMT with PTCy in CR1 represents a promising consolidation strategy for B-ALL patients age ≥55 years.

Allogeneic Blood or Marrow Transplantation with Post-Transplantation Cyclophosphamide for Peripheral T Cell Lymphoma: The Importance of Graft Source.

The use of post-transplantation cyclophosphamide (PTCy) for graft-versus host-disease (GVHD) prophylaxis has revolutionized allogeneic blood or marrow transplantation (alloBMT), but there is limited published experience in peripheral T cell lymphoma (PTCL). We sought to assess outcomes in patients with PTCL who underwent alloBMT with PTCy. We reviewed the charts of all adult patients age ≥18 years who underwent alloBMT with nonmyeloablative conditioning and PTCy-based GVHD prophylaxis at the Sidney Kimmel Comprehensive Cancer Center between January 2004 and December 2020. Sixty-five patients were identified. The median age was 59 years (range, 24 to 75 years). Lymphoma histology included PTCL not otherwise specified (n = 24), anaplastic lymphoma kinase-negative anaplastic large cell lymphoma (n = 14), angioimmunoblastic T cell lymphoma (n = 7), enteropathy-associated T cell lymphoma (n = 6), hepatosplenic T cell lymphoma (n = 4), and others (n = 10). Eleven patients were in first complete remission (17%); the remaining patients were in first partial remission or underwent salvage therapy to at least PR prior to transplantation. Forty-eight patients underwent alloBMT from a haploidentical related donor (74%), 10 from a fully matched donor (15%), and 7 from a mismatched unrelated donor (11%). All patients received fludarabine, cyclophosphamide, and total body irradiation (TBI). The graft source was bone marrow (BM) in 46 patients (71%) and peripheral blood (PB) in 19 patients (29%); all patients in the BM cohort received 200 cGy TBI, and most patients in the PB cohort (15 of 19) received 400 cGy TBI. GVHD prophylaxis comprised PTCy, mycophenolate mofetil, and a calcineurin inhibitor or sirolimus. With a median follow-up of 2.8 years (range, 290 days to 14.2 years), the 2-year progression-free survival (PFS) for the entire cohort was 49% (95% confidence interval [CI], 38% to 64%), and the 2-year overall survival (OS) was 55% (95% CI, 44% to 69%). Outcomes were significantly improved in those receiving PB compared to those receiving BM, including a 2-year PFS of 79% (95% CI 63% to 100%) versus 39% (95% CI, 27% to 56%), 2-year OS of 84% (95% CI, 69% to 100%) versus 46% (95% CI, 33% to 63%), and 1-year cumulative incidence of relapse of 5% (95% CI, 0 to 16%) versus 33% (95% CI, 19% to 46%), with no difference in GVHD and nonrelapse mortality. AlloBMT with PTCy is safe and well-tolerated in patients with PTCL. Our data suggest that increasing the TBI dose to 400 cGy and using PB allografts may offer improved disease control and better survival outcomes, though additional studies are needed to confirm these findings.

Three-Year Outcomes in Recipients of Mismatched Unrelated Bone Marrow Donor Transplants Using Post-Transplantation Cyclophosphamide: Follow-Up from a National Marrow Donor Program-Sponsored Prospective Clinical Trial.

The use of post-transplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis has resulted in reductions in GVHD and improved outcomes in allogeneic hematopoietic cell transplantation (HCT) using HLA-mismatched related donors. We report the 3-year outcomes of the first multicenter prospective clinical trial using PTCy in the setting of mismatched unrelated donor (MMUD) bone marrow HCT. The study enrolled 80 patients, treated with either myeloablative conditioning (MAC; n = 40) or reduced-intensity conditioning (RIC; n = 40), with the primary endpoint of 1-year overall survival (OS). The median follow-up for this study was 34 months (range, 12 to 46 months) in the RIC group and 36 months (range, 18 to 49 months) in the MAC group. Three-year OS and nonrelapse mortality were 70% and 15%, respectively, in the RIC group and 62% and 10% in the MAC group. No GVHD was reported after 1 year. The incidence of relapse was 29% in the RIC group and 51% in the MAC group. OS did not differ based on HLA match grade (63% in the 7/8 strata and 71% in the 4 to 6/8 strata). These encouraging outcomes, which were sustained for 3 years post-HCT, support the continued exploration of MMUD HCT using a PTCy platform. Important future areas to address include relapse reduction and furthering our understanding of optimal donor selection based on HLA and non-HLA factors.

Hyperinflammatory syndrome resembling haemophagocytic lymphohistiocytosis following axicabtagene ciloleucel and brexucabtagene autoleucel.

Haemophagocytic lymphohistiocytosis-like toxicity following chimeric antigen receptor T cells (CAR-HLH) is being increasingly recognized, while published data are limited and criteria for recognition are elusive. We describe three patients who developed CAR-HLH after infusion of brexucabtagene autoleucel (n = 2) or axicabtagene ciloleucel (n = 1). All three patients presented following cytokine release syndrome, with fever, recurrent or worsening cytopenias, hyperferritinaemia, elevated soluble interleukin (IL)-2 receptor, hypofibrinogenaemia, hypertriglyceridaemia, elevated liver transaminases, and decreasing C-reactive protein and IL-6. Clinical improvement following treatment with anakinra (n = 2) and ruxolitinib (n = 1) was observed. Our report offers an opportunity for prompt recognition and initiation of potentially life-saving treatment for CAR-HLH.

Post-Transplantation Cyclophosphamide-Based Graft- versus-Host Disease Prophylaxis with Nonmyeloablative Conditioning for Blood or Marrow Transplantation for Myelofibrosis.

We describe outcomes after post-transplantation cyclophosphamide and nonmyeloablative conditioning-based allogeneic blood or marrow transplantation for myelofibrosis using matched or mismatched related or unrelated donors. The conditioning regimen consisted of fludarabine, cyclophosphamide, and total body irradiation. Forty-two patients were included, with a median age of 63 years, of whom 19% had Dynamic International Prognostic Scoring System (DIPSS)-plus intermediate-1 risk, 60% had intermediate-2 risk, and 21% had high-risk disease, and 60% had at least 1 high-risk somatic mutation. More than 90% of patients engrafted neutrophils, at a median of 19.5 days, and 7% experienced graft failure. At 1 year and 3 years, respectively, overall survival was 65% and 60%, relapse-free survival was 65% and 31%, relapse was 5% and 40%, and nonrelapse mortality was 30% and 30%. Acute graft-versus-host disease grade 3-4 was seen in 17% of patients at 1 year, and chronic graft-versus-host disease requiring systemic therapy in occurred in 12% patients. Spleen size ≥17 cm or prior splenectomy was associated with inferior relapse-free survival (hazard ratio [HR], 3.50; 95% confidence interval [CI], 1.18 to 10.37; P = .02) and higher relapse rate (subdistribution HR [SDHR] not calculable; P = .01). Age >60 years (SDHR, 0.26; 95% CI, 0.08 to 0.80, P = .02) and receipt of peripheral blood grafts (SDHR, 0.34; 95% CI, 0.11 to 0.99; P = .05) were associated with a lower risk of relapse. In our limited sample, the presence of a high-risk mutation was not statistically significantly associated with an inferior outcome, although ASXL1 was suggestive of inferior survival (SDHR, 2.36; 95% CI, 0.85 to 6.6; P = .09). Overall, this approach shows outcomes comparable those of to previously reported approaches and underscores the importance of spleen size in the evaluation of transplantation candidates.

Nonmyeloablative Allogeneic Transplantation With Post-Transplant Cyclophosphamide for Acute Myeloid Leukemia With IDH Mutations: A Single Center Experience.

INTRODUCTION: Mutations in the IDH1 or IDH2 genes are detected in approximately 20% of cases of acute myeloid leukemia (AML). Few studies have examined the impact of IDH mutations in AML on allogeneic bone marrow transplant (alloBMT) outcomes. PATIENTS AND METHODS: In this single center study, alloBMT outcomes for 61 patients with IDH-mutated (mIDH) AML were compared to those for 146 patients with IDH-wildtype (wtIDH) AML. RESULTS: Patients with mIDH AML had a 2-year overall survival (OS) of 85% (95% CI 76%-95%), 2-year relapse free survival (RFS) of 71% (95% CI 59%-85%), 1-year cumulative incidence of relapse (CIR) of 14% (95% CI 5%-23%) and a 1-year cumulative incidence of transplant related mortality (CITRM) of 3% (95% CI 0%-8%). Patients with wtIDH had a 2-year OS of 61% (95% CI 53%-70%), 2-year RFS of 58% (95% CI 50%-67%), 1-year CIR of 27% (95% CI 20%-35%), and a 1-year CITRM of 9% (95% CI 5%-14%). In a univariate analysis cox-proportional hazard model, mIDH was associated with significantly better OS (HR 0.52, 95% CI 0.29-0.96) and a trend toward better RFS (HR 0.60, 95% CI 0.35-1.01). After controlling for donor age, diagnosis, and ELN risk category, mIDH was associated with a nonsignificantly improved OS (HR 0.54, 95% CI 0.29-1.01) and RFS (HR 0.67, 95% CI 0.39-1.15). CONCLUSION: Among patients with mIDH AML, patients who received a peritransplant IDH inhibitor had improved OS (P = .03) compared to those who did not, but there was no detectable difference for RFS (P = .29).

American Society of Hematology 2021 guidelines for sickle cell disease: stem cell transplantation.

BACKGROUND: Sickle cell disease (SCD) is a life-limiting inherited hemoglobinopathy that results in significant complications and affects quality of life. Hematopoietic stem cell transplantation (HSCT) is currently the only curative intervention for SCD; however, guidelines are needed to inform how to apply HSCT in clinical practice. OBJECTIVE: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and health professionals in their decisions about HSCT for SCD. METHODS: The multidisciplinary guideline panel formed by ASH included 2 patient representatives and was balanced to minimize potential bias from conflicts of interest. The Mayo Evidence-Based Practice Research Program supported the guideline development process, including performing systematic evidence reviews (through 2019). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment. RESULTS: The panel agreed on 8 recommendations to help patients and providers assess how individuals with SCD should consider the timing and type of HSCT. CONCLUSIONS: The evidence review yielded no randomized controlled clinical trials for HSCT in SCD; therefore, all recommendations are based on very low certainty in the evidence. Key recommendations include considering HSCT for those with neurologic injury or recurrent acute chest syndrome at an early age and to improve nonmyeloablative regimens. Future research should include the development of a robust SCD registry to serve as a comparator for HSCT studies.

Nonmyeloablative, HLA-Mismatched Unrelated Peripheral Blood Transplantation with High-Dose Post-Transplantation Cyclophosphamide.

High-dose post-transplantation cyclophosphamide (PTCy) is an effective platform for prevention of severe graft-versus-host disease (GVHD) after allogeneic bone marrow (BM) transplantation with mismatched unrelated donors (mMUDs). Previous studies evaluating PTCy with mMUDs favored BM allografts over peripheral blood stem cell transplantation (PBSCT) due to concerns that PBSCT may be associated with an increased risk of acute and chronic GVHD. In addition, haploidentical PBSCT is associated with high rates of cytokine release syndrome (CRS), which is another concern with mMUD PBSCT. This study was conducted to determine the feasibility and safety of using mMUD PBSCT with PTCy as GVHD prophylaxis. Patients who received mMUD PBSCT using a PTCy-based GVHD prophylaxis at Johns Hopkins Hospital as part of a prospective clinical trial of mMUD and non-first-degree relative haploidentical transplantation with PTCy (ClinicalTrials.gov identifier NCT01203722) were included. All patients underwent T cell-replete PBSCT between November 2012 and August 2020. Statistical analyses were performed using the Kaplan-Meier method and proportional subdistribution hazard regression model for competing risks. The 29 patients in the study had a median age of 54 years, with 10 patients (34%) age ≥60 years. Nineteen grafts (66%) were matched for 9/10 HLA loci, 6 (21%) were match for 8/10, and 4 (14%) were matched for 7/10. No primary or secondary graft failure occurred. The median time to neutrophil recovery (≥500/µL) was 17 days, and that to platelet recovery (≥20,000/µL) was 28 days. Full donor chimerism was achieved in all patients by day +60. The cumulative incidence (CuI) of grade II-IV acute GVHD at 180 days was 15% (90% confidence interval [CI], 3% to 26%). There were no cases of severe chronic GVHD, 3 cases of mild chronic GVHD, and 1 case of moderate chronic GVHD. The CuI of nonrelapse mortality (NRM) was 7% (90% CI, NA to 18%) at 1 year. Eighteen patients (62%) experienced mild CRS (grade 1-2), and 1 patient (3%) experienced severe CRS (grade 3-5). At 1 year, the CuI of relapse was 29% (90% CI, 8% to 50%), overall survival was 93% (90% CI, 85% to 100%), progression-free survival was 64% (90% CI, 46% to 88%), GVHD-free relapse-free survival was 41% (90% CI, 23% to 73%), and chronic GVHD-free relapse-free survival was 64% (90% CI, 46% to 88%). Our data indicate that mMUD PBSCT using PTCy-based GVHD prophylaxis is safe and feasible. All patients engrafted, and rates of NRM (7%) and acute GVHD (15%) at 1 year were low. There was only 1 case (3%) of severe CRS. Compared with previously published outcomes, mMUD PBSCT using PTCy-based GVHD prophylaxis has a safety and efficacy profile that may not be different from that of PBSCT from matched donors. These results further solidify that all patients who require blood or BM transplantation should be able to find an acceptable donor.

Allogeneic Blood or Marrow Transplantation with Nonmyeloablative Conditioning and High-Dose Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis for Secondary Central Nervous System Lymphoma.

Secondary central nervous system (CNS) lymphoma is a rare and often fatal complication of non-Hodgkin lymphoma (NHL). Treatment options include radiation therapy, high-dose systemic chemotherapy, intrathecal chemotherapy, and high-dose chemotherapy with autologous stem cell rescue, but outcomes remain poor. Allogeneic blood or marrow transplantation (alloBMT) is widely used in patients with relapsed/refractory systemic NHL. We sought to understand whether a graft-versus-lymphoma effect could maintain remission in CNS disease. We reviewed outcomes in 20 consecutive patients with secondary CNS lymphoma who underwent alloBMT with nonmyeloablative conditioning using fludarabine, cyclophosphamide, and 200 cGy total body irradiation. For graft-versus-host disease prophylaxis, all patients received post-transplantation cyclophosphamide, mycophenolate mofetil, and a calcineurin inhibitor. With a median follow up of 4.1 years, the median overall survival for the entire cohort was not reached. Median progression-free survival was 3.8 years (95% confidence interval [CI], 5.3 months to not reached). The cumulative incidence of relapse was 25% (95% CI, 5% to 45%), and nonrelapse mortality was 30% (95% CI, 5% to 54%) at 4 years. Of the 5 patients who relapsed, 2 were CNS only, 1 was systemic only, and 2 were combined CNS/systemic. The use of alloBMT in CNS lymphoma merits further investigation.

National Marrow Donor Program-Sponsored Multicenter, Phase II Trial of HLA-Mismatched Unrelated Donor Bone Marrow Transplantation Using Post-Transplant Cyclophosphamide.

PURPOSE: Hematopoietic cell transplantation (HCT) is curative for hematologic disorders, but outcomes are historically inferior when using HLA-mismatched donors. Despite unrelated donor registries listing > 38 million volunteers, 25%-80% of US patients lack an HLA-matched unrelated donor, with significant disparity across ethnic groups. We hypothesized that HCT with a mismatched unrelated donor (MMUD) using post-transplant cyclophosphamide (PTCy), a novel strategy successful in overcoming genetic disparity using mismatched related donors, would be feasible and increase access to HCT. PATIENTS AND METHODS: We performed a prospective phase II study of MMUD bone marrow HCT with PTCy for patients with hematologic malignancies. The primary end point was 1-year overall survival (OS), hypothesized to be 65% or better. 80 patients enrolled at 11 US transplant centers (December 2016-March 2019). Following myeloablative or reduced-intensity conditioning-based HCT, patients received PTCy on days +3, +4, with sirolimus and mycophenolate mofetil starting on day +5. We compared outcomes to Center for International Blood and Marrow Transplant Research contemporary controls receiving PTCy. RESULTS: Notably, 48% of patients enrolled were ethnic minorities. 39% of pairs were matched for 4-6 out of 8 HLA alleles. The primary end point was met, with 1-year OS of 76% (90% CI, 67.3 to 83.3) in the entire cohort, and 72% and 79% in the myeloablative and reduced-intensity conditioning strata, respectively. Secondary end points related to engraftment and graft-versus-host-disease were reached. Multivariate analysis comparing the study group with other mismatched HCT controls found no significant differences in OS. CONCLUSION: Our prospective study demonstrates the feasibility and effectiveness of HCT with an MMUD in the setting of PTCy. Remarkably, nearly half of the study participants belonged to an ethnic minority population, suggesting this approach may significantly expand access to HCT.

Pain Experiences of Adults With Sickle Cell Disease and Hematopoietic Stem Cell Transplantation: A Qualitative Study.

OBJECTIVE: Despite increasing use of hematopoietic stem cell transplantation (HSCT) for adults with sickle cell disease (SCD), little is known about pain management experiences throughout this process. The objective of this study was to explore patients' experiences with pain and pain management during and after HSCT for SCD. METHODS: We conducted a qualitative interview study with 10 patients who underwent HSCT for SCD. We transcribed interviews verbatim and inductively identified codes. We used thematic analysis alongside a constant comparative method to develop and refine a codebook that aided in the identification of themes. RESULTS: Four key themes emerged. (1) The pain trajectory: patients described a fluctuating course of pain during HSCT, which often extended long afterwards and impacted all aspects of life, particularly affected by pre-HSCT experiences; (2) The role of opioids-a double-edged sword: patients described opioids as reducing pain but insufficiently to balance significant adverse effects and burden; (3) Patient-centered decision making in pain management: patients described insufficient agency in decisions about opioid use and weaning; and (4) Consequences of health-related stigma: patients described experiences with stigma, mainly related to opioid use and weaning, as similar to pre-HSCT. CONCLUSIONS: From the perspective of patients who have undergone HSCT for SCD, clinicians should use a patient-centered approach, integrating non-opioid approaches into pain management, particularly psychosocial support. As transplant for SCD becomes increasingly available, incorporating patient perspectives may improve health care delivery and overall patient experiences.

Acute GVHD Diagnosis and Adjudication in a Multicenter Trial: A Report From the BMT CTN 1202 Biorepository Study.

PURPOSE: Accurate and reproducible methods to diagnose, grade, and report acute graft-versus-host disease (GVHD) are critical for the evaluation of therapies and biomarkers. PATIENTS AND METHODS: The Blood and Marrow Transplant Clinical Trials Network 1202 study is an observational study of 1,709 allogeneic hematopoietic cell transplantation recipients that implemented weekly data reporting and near real-time data adjudication by an end point review committee (ERC), assigning a confidence level (confirmed, probable, possible, or negative) to the diagnosis of acute GVHD at onset. RESULTS: During the first 100 days, symptoms consistent with GVHD developed in 90% of cases but were often determined by centers to be due to causes other than GVHD. Indeed, GVHD was under consideration in only 23% of cases at symptom onset. Diagnostic biopsies were obtained in 40% of cases, but treatment often was incongruous with biopsy findings and 10.5% of biopsies were equivocal. Importantly, more than 40% of steroid courses were started for reasons other than GVHD. The ERC modified the determination of GVHD diagnosis and/or grade in 12.3% of onset cases. The cumulative incidence of acute GVHD as reported by the centers was 62%. When the ERC adjudicated GVHD onset to be present only if the confidence level was probable or confirmed, the incidence of GVHD declined to 49%. CONCLUSION: This study demonstrates that the incidence of GVHD may be overestimated at symptom onset, establishes a contemporary benchmark for acute GVHD, and suggests a structured framework for reporting and adjudication of GVHD that could be used in prospective trials.

Allogeneic transplantation for Ph+ acute lymphoblastic leukemia with posttransplantation cyclophosphamide.

Allogeneic blood or marrow transplantation (alloBMT) is standard of care for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in first complete remission (CR1). The routine pretransplant and posttransplant use of tyrosine kinase inhibitors (TKIs) has dramatically improved outcomes, but the optimal conditioning regimen, donor type, and TKI remain undefined. The bone marrow transplant database at Johns Hopkins was queried for adult patients with de novo Ph+ ALL who received alloBMT using posttransplantation cyclophosphamide (PTCy) as a component of graft-versus-host disease (GVHD) prophylaxis from 2008 to 2018. Among transplants for Ph+ ALL, 69 (85%) were performed in CR1, and 12 (15%) were performed in second or greater remission (CR2+). The majority of transplants (58%) were HLA haploidentical. Nearly all patients (91.4%) initiated TKI posttransplant. For patients in CR1, the 5-year relapse-free survival (RFS) was 66%. The use of nonmyeloablative conditioning, absence of measurable residual disease (MRD) according to flow cytometry at transplant, and the use of dasatinib vs imatinib at diagnosis were associated with improved overall survival (OS) and RFS. Neither donor type nor recipient age ≥60 years affected RFS. When analyzing all transplants, alloBMT in CR1 (vs CR2+) and the absence of pretransplant MRD were associated with improved RFS. Most relapses were associated with the emergence of kinase domain mutations. The cumulative incidence of grade 3 to 4 acute GVHD at 1 year was 9%, and moderate to severe chronic GVHD at 2 years was 8%. Nonmyeloablative alloBMT with PTCy for Ph+ ALL in an MRD-negative CR1 after initial treatment with dasatinib yields favorable outcomes.