How I prevent GVHD in high-risk patients: posttransplant cyclophosphamide and beyond.

Advances in conditioning, graft-versus-host disease (GVHD) prophylaxis and antimicrobial prophylaxis have improved the safety of allogeneic hematopoietic cell transplantation (HCT), leading to a substantial increase in the number of patients transplanted each year. This influx of patients along with progress in remission-inducing and posttransplant maintenance strategies for hematologic malignancies has led to new GVHD risk factors and high-risk groups: HLA-mismatched related (haplo) and unrelated (MMUD) donors; older recipient age; posttransplant maintenance; prior checkpoint inhibitor and autologous HCT exposure; and patients with benign hematologic disorders. Along with the changing transplant population, the field of HCT has dramatically shifted in the past decade because of the widespread adoption of posttransplantation cyclophosphamide (PTCy), which has increased the use of HLA-mismatched related donors to levels comparable to HLA-matched related donors. Its success has led investigators to explore PTCy's utility for HLA-matched HCT, where we predict it will be embraced as well. Additionally, combinations of promising new agents for GVHD prophylaxis such as abatacept and JAK inhibitors with PTCy inspire hope for an even safer transplant platform. Using 3 illustrative cases, we review our current approach to transplantation of patients at high risk of GVHD using our modern armamentarium.

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/.

HLA informs risk predictions after haploidentical stem cell transplantation with posttransplantation cyclophosphamide.

Hematopoietic cell transplantation from HLA-haploidentical related donors is increasingly used to treat hematologic cancers; however, characteristics of the optimal haploidentical donor have not been established. We studied the role of donor HLA mismatching in graft-versus-host disease (GVHD), disease recurrence, and survival after haploidentical donor transplantation with posttransplantation cyclophosphamide (PTCy) for 1434 acute leukemia or myelodysplastic syndrome patients reported to the Center for International Blood and Marrow Transplant Research. The impact of mismatching in the graft-versus-host vector for HLA-A, -B, -C, -DRB1, and -DQB1 alleles, the HLA-B leader, and HLA-DPB1 T-cell epitope (TCE) were studied using multivariable regression methods. Outcome was associated with HLA (mis)matches at individual loci rather than the total number of HLA mismatches. HLA-DRB1 mismatches were associated with lower risk of disease recurrence. HLA-DRB1 mismatching with HLA-DQB1 matching correlated with improved disease-free survival. HLA-B leader matching and HLA-DPB1 TCE-nonpermissive mismatching were each associated with improved overall survival. HLA-C matching lowered chronic GVHD risk, and the level of HLA-C expression correlated with transplant-related mortality. Matching status at the HLA-B leader and HLA-DRB1, -DQB1, and -DPB1 predicted disease-free survival, as did patient and donor cytomegalovirus serostatus, patient age, and comorbidity index. A web-based tool was developed to facilitate selection of the best haploidentical-related donor by calculating disease-free survival based on these characteristics. In conclusion, HLA factors influence the success of haploidentical transplantation with PTCy. HLA-DRB1 and -DPB1 mismatching and HLA-C, -B leader, and -DQB1 matching are favorable. Consideration of HLA factors may help to optimize the selection of haploidentical related donors.

Age barriers in allogeneic hematopoietic cell transplantation: Raising the silver curtain.

Allogeneic hematopoietic cell transplantation (HCT) is no longer exclusively for the young. With an aging population, development of non-intensive remission-inducing strategies for hematologic malignancies, and novel graft-versus-host disease-prevention platforms, an older population of patients is pursuing HCT. The evolving population of HCT recipients requires an overhaul in the way we risk-stratify and optimize patients prior to HCT. Here, we review the history and current state of HCT for older adults and propose an assessment and intervention flow to bridge the gaps in today's clinical guidelines.

Haploidentical donor hematopoietic cell transplantation for myelodysplastic/myeloproliferative overlap neoplasms: results from a North American collaboration.

Haploidentical donors offer a potentially readily available donor, especially for non-White patients, for hematopoietic cell transplantation (HCT). In this North American collaboration, we retrospectively analyzed outcomes of first HCT using haploidentical donor and post-transplantation cyclophosphamide (PTCy) in myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap neoplasms (MDS/MPN). We included 120 consecutive patients who underwent HCT using a haploidentical donor for MDS/MPN across 15 centers. Median age was 62.5 years and 38% were of non-White/Caucasian ethnicity. The median follow-up was 2.4 years. Graft failure was reported in seven of 120 (6%) patients. At 3 years, nonrelapse mortality (NRM) was 25% (95% confidence interval [CI]: 17-34), relapse 27% (95% CI: 18-36), grade 3-4 acute graftversus- host disease 12% (95% CI: 6-18), chronic graft-versus-host disease requiring systemic immunosuppression 14% (95% CI: 7-20), progression-free survival (PFS) 48% (95% CI: 39-59), and overall survival (OS) 56% (95% CI: 47-67). On multivariable analysis, NRM was statistically significantly associated with advancing age at HCT (per decade increment, subdistribution hazard ratio [sdHR] =3.28; 95% CI: 1.30-8.25); relapse with the presence of mutation in EZH2/RUNX1/SETBP1 (sdHR=2.61; 95% CI: 1.06-6.44); PFS with advancing age at HCT (per decade increment, HR=1.98, 95% CI: 1.13-3.45); and OS with advancing age at HCT (per decade increment, HR=2.01; 95% CI: 1.11-3.63) and splenomegaly at HCT/prior splenectomy (HR=2.20; 95% CI: 1.04-4.65). Haploidentical donors are a viable option for HCT in MDS/MPN, especially for those disproportionately represented in the unrelated donor registry. Hence, donor mismatch should not preclude HCT for patients with MDS/MPN, an otherwise incurable malignancy. In addition to patient age, disease-related factors including splenomegaly and high-risk mutations dominate outcomes following HCT.

Real-world effectiveness of intensive chemotherapy with 7&3 versus venetoclax and hypomethylating agent in acute myeloid leukemia.

Intensive chemotherapy with cytarabine and anthracycline (7&3) remains the standard therapy for patients medically fit for induction, but the assessment of fitness remains controversial. Venetoclax and hypomethylating agent (ven/HMA) combination therapy has improved outcomes in unfit patients but no prospective study has assessed ven/HMA versus 7&3 as initial therapy in older, fit patients. Given no studies and expectation of ven/HMA use in patients outside of trial criteria, we evaluated retrospective outcomes among newly diagnosed patients. A nationwide electronic health record (EHR)-derived database and the University of Pennsylvania EHR identified 312 patients receiving 7&3 and 488 receiving ven/HMA who were 60-75 years old without history of organ failure. Ven/HMA patients were older and more likely to have secondary AML, adverse cytogenetics, and adverse mutations. Median overall survival (OS) for patients receiving intensive chemotherapy was 22 versus 10 months for ven/HMA (HR 0.53, 95% CI 0.40-0.60). Controlling for measured baseline characteristic imbalances reduced survival advantage by half (HR 0.71, 95% CI 0.53-0.94). A sub-group of patients with equipoise, likelihood at least 30%-70% of receiving either treatment, had similar OS outcomes (HR 1.10, 95% CI 0.75-1.6). Regarding safety outcomes, 60-day mortality was higher for ven/HMA (15% vs. 6% at 60 days) despite higher documented infections and febrile neutropenia for 7&3. In this multicenter real-word dataset, patients selected for intensive chemotherapy had superior OS but a large group had similar outcomes with ven/HMA. Prospective randomized studies, controlling for both measured and unmeasured confounders, must confirm this outcome.

Central line-associated Rhizobium radiobacter bloodstream infection in two allogeneic hematopoietic cell transplant recipients.

INTRODUCTION: Rhizobium radiobacter is a gram-negative, opportunistic phytopathogen that rarely causes human infections. We report two cases of Rhizobium radiobacter central line-associated bloodstream infection (CLABSI) in allogeneic hematopoietic cell transplantation (alloHCT) recipients. We review previous reports and common microbiological characteristics associated with this organism. CASE REPORTS: Two adult males developed R. radiobacter CLABSIs at day +81 and day +77 post-alloHCT. Patient one was asymptomatic on presentation while patient two was febrile. One patient had a polymicrobial infection, which has not been previously described. The presence of high-level ceftazidime resistance in both patients suggests third-generation cephalosporin resistance may be more common than previously recognized. MANAGEMENT AND OUTCOME: For both patients, microbiologic clearance was achieved through peripherally inserted central catheter removal and initiation of intravenous cefepime. Antibiotic therapy was narrowed to oral levofloxacin for a total 14-day course from the time of first negative blood culture. There has been no subsequent recurrence of R. radiobacter infection at 12 and 5 months of follow-up for patients one and two, respectively. DISCUSSION: These two cases add to the scant literature characterizing R. radiobacter infection following alloHCT. Immunosuppressive agents for graft-versus-host disease prophylaxis may have predisposed these patients to R. radiobacter infection. Our reports, and previously reported cases, suggest R. radiobacter exhibits low virulence, mild symptom burden, and does not confer a high mortality risk. In the alloHCT setting, further accumulation of cases is needed to aid in understanding clinical features and characteristics of R. radiobacter infection.

Pentosan polysulfate for the treatment of hemorrhagic cystitis after allogeneic hematopoietic cell transplant.

INTRODUCTION: Hemorrhagic cystitis can commonly occur following an allogeneic hematopoietic cell transplant and treatment options are currently limited. Pentosan polysulfate, a heparin-like, sulfated polysaccharide, is used to relieve bladder pain and discomfort associated with interstitial cystitis. Initial reports in patients with hemorrhagic cystitis demonstrate that pentosan polysulfate may hasten hemorrhagic cystitis resolution and control symptoms. METHODS AND RESULTS: This report includes a retrospective case series of six patients who received pentosan polysulfate for the treatment of hemorrhagic cystitis following an allogeneic hematopoietic cell transplant. Pentosan polysulfate was initiated at a median of 4.5 days (range: 3-18) following hemorrhagic cystitis onset and continued for a median duration of 17.5 days (range: 7-64). Four patients were tested for BK virus and all were found to have BK viremia and viruria around the time of pentosan polysulfate initiation. The median number of red blood cell transfusions seemed to decrease in the patients initiated on pentosan polysulfate. All patients received a multi-agent treatment regimen, which included pentosan polysulfate, and half the patients had symptom resolution. The median time to symptom resolution from pentosan polysulfate initiation was 9 days (range: 7-10). CONCLUSION: Pentosan polysulfate was well-tolerated and seemed to assist with symptom resolution. Future studies are needed to confirm the impact of pentosan polysulfate on the treatment of hemorrhagic cystitis.

Day 4 vs. day 12 G-CSF administration following reduced intensity peripheral blood allogeneic stem cell transplant.

INTRODUCTION: Granulocyte colony-stimulating factor (G-CSF) hastens neutrophil engraftment and reduces infections after allogeneic hematopoietic cell transplant (alloHCT), yet the optimal start date is unknown. Additionally, concurrent G-CSF and methotrexate for graft-vs-host disease (GVHD) prophylaxis may potentiate myelosuppression, and prolonged G-CSF is costly. Our institution changed from day + 4 to day + 12 G-CSF initiation following reduced intensity (RIC) alloHCT with methotrexate GVHD prophylaxis. METHODS: We retrospectively compared day + 4 and day + 12 G-CSF initiation after RIC alloHCT from 2017-2021. The primary endpoint was the time to neutrophil engraftment. Secondary endpoints included length of stay (LOS) and the time to platelet engraftment as well as the incidence of infectious events, acute GVHD (aGVHD), and mucositis. RESULTS: Thirty-two patients were included in each group with similar baseline characteristics. We observed faster neutrophil engraftment (median 12 vs. 15 days, p = 0.01) and platelet engraftment (median 13 vs. 15 days, p = 0.026) with day + 4 vs. day + 12 G-CSF initiation. Median LOS was 23 days (range, 19-32) with day + 4 initiation vs. 24 days (21-30) with day + 12 (p = 0.046). The incidence of culture-negative febrile neutropenia (p = 0.12), any grade aGVHD (p = 0.58), and grade 2-4 mucositis (p = 0.8) were similar between groups. CONCLUSION: Compared to day + 4, day + 12 G-CSF initiation following RIC alloHCT had a longer time to neutrophil and platelet engraftment. Day + 12 initiation also resulted in longer LOS, which while statistically significant, was potentially of limited clinical significance. These findings are hypothesis generating.

How we perform haploidentical stem cell transplantation with posttransplant cyclophosphamide.

HLA-haploidentical hematopoietic stem cell transplantation is now one of the most commonly employed alternative donor techniques, with most centers applying T-cell-replete strategies such as that developed by the Baltimore group using high-dose posttransplant cyclophosphamide. HLA-haploidentical hematopoietic stem cell transplantation using posttransplant cyclophosphamide is associated with low rates of severe graft-versus-host disease and nonrelapse mortality and does not require graft manipulation or storage, which results in a low graft acquisition cost. Its remarkable safety when used with reduced-intensity conditioning has been demonstrated in patients up to 75 years old with outcomes similar to those of patients in their 50s. Several large, registry-based retrospective studies have confirmed the efficacy of HLA-haploidentical hematopoietic stem cell transplantation with posttransplant cyclophosphamide, achieving results comparable to those of HLA-matched hematopoietic stem cell transplantation. In this article, we describe our approach to this rapidly available and clinically simple platform and address some of the key clinical questions associated with its use.

Dose intensity for induction in acute myeloid leukemia: what, when, and for whom?

Intensive chemotherapy has been the backbone of the treatment of acute myeloid leukemia (AML) for decades. However, an increase in novel targeted agents, which has been brought about in part by a deeper understanding of the genetic makeup of AML, has led to remission-inducing regimens that do not require traditional cytotoxic agents. Combinations of a hypomethylating agent (HMA) and venetoclax have doubled the chance of remission for patients considered unfit for induction chemotherapy who would have traditionally been offered singleagent HMA. In fact, this regimen may rival the complete remission rate achieved with induction chemotherapy for certain populations such as the very elderly and those with secondary AML, but equivalency has yet to be established. Further advances include the addition of gemtuzumab ozogamicin and FLT3 inhibitors to induction chemotherapy, which improves survival for patients with core-binding factor and FLT3-mutated AML, respectively. Still, much work is needed to improve the outcomes of the highest-risk subgroups: frail patients and those with high-risk cytogenetics and/or TP53 mutations. Promisingly, the landscape of AML therapy is shifting dramatically and no longer is intensity, when feasible, always the best answer for AML.

Tacrolimus induced pseudogout following allogeneic hematopoietic cell transplant.

INTRODUCTION: Crystalline arthritis (CA), characterized by acute joint pain and erythema secondary to calcium pyrophosphate deposition (CPPD, or pseudogout) or monosodium urate crystals (gout), is a potentially underreported complication following allogeneic hematopoietic cell transplant (alloHCT). Graft-versus-host disease prophylaxis with calcineurin inhibitors (CNIs) causes hypomagnesemia and hyperuricemia, resulting in CA. CA related to tacrolimus has yet to be characterized following alloHCT. CASE REPORT: We retrospectively reviewed records of 450 consecutive patients undergoing alloHCT and identified 15 (3.3% incidence) who developed CA on tacrolimus. Large joints were involved in 10 (66.7%) patients, all patients had recent hypomagnesemia, and no patient had hyperuricemia, suggesting CPPD was the most likely etiology.Management and outcome: Eleven (73.3%) patients received systemic corticosteroids; 6 as initial therapy and 5 added to or substituted for colchicine in the setting of slow or inadequate response. The median duration of corticosteroid therapy was 6 days, however 2 patients (13.3%) required prolonged maintenance due to recurrence. Eleven (73.3%) patients received colchicine; 9 as initial therapy and 2 added to or substituted for corticosteroids in the setting of slow or inadequate response. The median duration of colchicine therapy was 18 days. The median time to symptom resolution was 21 days. DISCUSSION: Patients on tacrolimus following alloHCT presenting with acute joint pain and erythema should be evaluated for CPPD. Hypomagnesemia secondary to CNIs is likely the precipitating factor for CPPD in this population. Patients can effectively be managed with systemic corticosteroids and/or colchicine, however prolonged duration of treatment and even maintenance may be necessary. Based on the Naranjo Algorithm, CPPD secondary to tacrolimus induced hypomagnesemia is a possible adverse drug event, with a score of 3-4.

Risk of invasive fungal infections in patients with high-risk MDS and AML receiving hypomethylating agents.

Invasive fungal infections (IFI) are a significant source of morbidity and mortality for patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Given the heterogeneity of the population receiving hypomethylating agents (HMA), it is difficult for clinicians to accurately assess their patients' risk of infection. Literature on the incidence of IFI following HMA is limited to several studies of azacitidine. The primary objective of this retrospective study was to establish the incidence of IFI in HMA treated AML/MDS patients at a large U.S. comprehensive cancer center. Secondary objectives included comparing incidence of IFI among pre-specified subgroups to identify potential risk factors for IFI. Two hundred three patients with AML, intermediate to very high risk MDS or chronic myelomonocytic leukemia who received at least two cycles of HMA were included. The incidence of IFI, as defined by the European Organization for Research and Treatment of Cancer / Invasive Fungal Infections Cooperative Group criteria, was 9.6%, with 20 IFI diagnosed following HMA (three proven, four probable, 13 possible). Among the proven cases of IFI, molds included Scedosporium and Fusarium spp. Eleven patients who developed IFIs were neutropenic upon initiating HMA. The majority (17/20) of infections occurred during the first four cycles. Given this incidence, mold-active prophylaxis can be considered in patients who are neutropenic at the start of therapy.

Development of Grade II Acute Graft-versus-Host Disease Is Associated with Improved Survival after Myeloablative HLA-Matched Bone Marrow Transplantation using Single-Agent Post-Transplant Cyclophosphamide.

Post-transplant cyclophosphamide (PTCy) can be used as the sole immunosuppression after myeloablative conditioning (MAC) for HLA-matched bone marrow transplantation (BMT). However, the effects of graft-versus-host disease (GVHD) with this platform are undefined. We retrospectively analyzed 298 consecutive adult patients with hematologic malignancies who engrafted after MAC HLA-matched sibling donor (MSD; n = 187) or HLA-matched unrelated donor (MUD; n = 111) T-cell-replete BMT with PTCy 50 mg/kg on days +3 and +4. After MSD and MUD BMT, 35% and 57% of patients, respectively, developed grade II acute GVHD (aGVHD) by 100 days, 11% and 14% grade III to IV aGVHD by 100 days, and 9% and 16% chronic GVHD (cGVHD) by 1 year. In landmark analyses at 100 days after HLA-matched BMT, 4-year overall survival (OS) and progression-free survival (PFS) were 57% (95% confidence interval [CI], .49 to .67) and 40% (95% CI, .31 to .51) in patients without grades II to IV aGVHD, and 68% (95% CI, .59 to .78) and 54% (95% CI, .44 to .65) in patients with grade II aGVHD. In adjusted time-dependent multivariable analyses, grade II aGVHD was associated with improved OS (hazard ratio, .58; 95% CI, .37 to .89; P = .01) and PFS (hazard ratio, .50; 95% CI, .34 to .74; P < .001) after HLA-matched BMT with PTCy. The ability of PTCy to limit grades III to IV aGVHD and cGVHD while maintaining grade II aGVHD may contribute to its effectiveness, and further attempts to reduce aGVHD may be detrimental.

Grade II Acute Graft-versus-Host Disease and Higher Nucleated Cell Graft Dose Improve Progression-Free Survival after HLA-Haploidentical Transplant with Post-Transplant Cyclophosphamide.

Compared with standard graft-versus-host disease (GVHD) prophylaxis platforms, post-transplantation cyclophosphamide (PTCy) after T cell-replete HLA-haploidentical (haplo) bone marrow transplantation (BMT) reduces the risk of grades III to IV acute (a) and chronic (c) GVHD, but maintains similar rates of grade II aGVHD. Given that mild GVHD has been associated with reduced treatment failure in HLA-matched BMT, we evaluated the risk factors for and effects of GVHD on survival in 340 adults with hematologic malignancies who engrafted after nonmyeloablative haplo-BMT with PTCy, mycophenolate mofetil, and tacrolimus. The cumulative incidence at 100 days of grade II and grades III to IV aGVHD were 30% (95% confidence interval [CI], 25% to 35%) and 2% (95% CI, 1% to 4%), respectively. The 1-year cumulative incidence of cGVHD was 10% (95% CI, 7% to 13%). In landmark analyses at 100 days, the 4-year probabilities of overall survival (OS) and progression-free survival (PFS) were, 48% (95% CI, 41% to 56%) and 39% (95% CI, 32% to 47%) for patients without grades II to IV aGVHD, compared with 63% (95% CI, 53% to 73%) and 59% (95% CI, 50% to 71%) for patients with grade II aGVHD (P = .05 and P = .009). In multivariable modeling, when compared with patients who never experienced GVHD, the hazard ratio (HR) for OS and PFS in patients with grade II aGVHD was .78 (95% CI, .54 to 1.13; P = .19) and .69 (95% CI, .48 to .98; P = .04). Higher nucleated cell graft dose was also associated with improved OS (HR, .88; 95% CI, .78 to 1.00; P = .05) and PFS (HR, .89; 95% CI, .79 to 1.0; P = .05) and decreased risk of grades III to IV aGVHD (subdistribution HR, .66; 95% CI, .46 to .96; P = .03). PTCy reduces grades III to IV aGVHD and cGVHD, but retains similar incidence of grade II aGVHD, the development of which improves PFS. Higher nucleated cell graft dose goals may also improve survival after nonmyeloablative haplo-BMT with PTCy.

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.

Haploidentical Bone Marrow Transplantation with Post-Transplant Cyclophosphamide Using Non-First-Degree Related Donors.

Outcomes of nonmyeloablative (NMA) haploidentical (haplo) blood or marrow transplant (BMT) with post-transplantation cyclophosphamide (PTCy) using non-first-degree relatives are unknown. We evaluated 33 consecutive adult patients (median age, 56 years) with hematologic malignancies who underwent NMA haplo T cell-replete BMT with PTCy at Johns Hopkins using second- or third-degree related donors. Donors consisted of 10 nieces (30%), 9 nephews (27%), 7 first cousins (21%), 5 grandchildren (15%), and 2 uncles (6%). Thirty-one patients (94%) reached full donor chimerism by day 60. The estimated cumulative incidence (CuI) of grades II to IV acute graft-versus-host disease (aGVHD) at day 180 was 24% (90% confidence interval [CI], 9% to 38%). Only 1 patient experienced grades III to IV aGVHD. At 1 year the CuI of chronic GVHD was 10% (90% CI, 0% to 21%). The CuI of nonrelapse mortality at 1 year was 5% (90% CI, 0% to 14%). At 1 year the probability of relapse was 31% (90% CI, 12% to 49%), progression-free survival 64% (90% CI, 48% to 86%), and overall survival 95% (90% CI, 87% to 100%). The 1-year probability of GVHD-free, relapse-free survival was 57% (90% CI, 41% to 79%). NMA haplo BMT with PTCy from non-first-degree relatives is an acceptably safe and effective alternative donor platform, with results similar to those seen with first-degree relatives.

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.

Risk-stratified outcomes of nonmyeloablative HLA-haploidentical BMT with high-dose posttransplantation cyclophosphamide.

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.