Post-transplant cyclophosphamide (PTCy) at 80 mg/kg with low dose post-engraftment anti-thymocyte globulin (ATG) in haploidentical transplantation (Haplo-HCT) with myeloablative conditioning (MAC).

A retrospective study analyzed the efficacy and safety of PTCy 80 mg/kg (day [d] +4 and +5) combined with tacrolimus (0.05 mg/kg/d from d +5 onward) and post-engraftment ATG (Sanofi; dose 2.5 mg/kg 48–72 hours after neutrophil engraftment) as graft-versus-host disease (GvHD) prophylaxis in 46 patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS)  aged more than 55 years or with cardiac antecedents (not specified), or hematopoietic cell transplantation-specific comorbidity index (HCT-CI) score >2 undergoing Haplo-HCT with MAC (the intensity of the conditioning regimen was classified according to Transplant Conditioning Intensity [https://doi.org/10.1038/s41409-020-0803-y]). The cumulative incidence of grade III-IV acute GvHD at d +100 and moderate to severe chronic GvHD at 1 year was 4.8% ± 3.4% and 19.9% ± 7.0%, respectively. When compared with patients receiving the reference regimen (PTCy 100mg/kg), patients from the PTCy 80 mg/kg group had a similar incidence of GvHD and survival as their younger counterparts. Two patients in each group died from PTCy-associated toxicity. Thus, PTCy 80 mg/kg seems to be feasible for patients treated with MAC regimens in Haplo-HCT.

Younger unrelated donors may be preferable over HLA match in the post-transplant cyclophosphamide (PTCy) era: a study from the ALWP of the EBMT. 

A retrospective study analyzed the characteristics of 10/10 matched unrelated (UD) donors (MUDs) and 9/10 mismatched UDs (MMUDs) that may affect hematopoietic stem cell transplantation (HSCT)  outcomes in patients with acute myeloid leukemia (AML) in first or second complete remission (CR1 or CR2). The primary end point was leukemia-free survival (LFS). Overall, 1011 patients were included with a median age of 54 years (range, 18-77). Donors had a median age of 29 years (range, 18-64); 304 (30%) were females, of which half were donors to male recipients, and 621 (61%) were MUDs; 522 (52%) had negative cytomegalovirus (CMV-neg) serostatus, of which 189/1011 (19%) were used for CMV-neg recipients. Donor age older than 30 years had a negative impact on relapse (hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.06-1.8), LFS (HR, 1.4; 95% CI, 1.12-1.74), overall survival (HR, 1.45; 95% CI, 1.14-1.85) and graft-versus-host disease-free, relapse-free survival (HR, 1.29; 95% CI, 1.07-1.56). In addition, CMV-neg donors for CMV-neg recipients were associated with improved LFS (HR, 0.74; 95% CI, 0.55-0.99). One allele mismatch did not influence UD transplant outcomes using PTCy. For patients undergoing HSCT from a UD with PTCy for AML, donor age <30 years significantly improves survival. 

Harmonizing definitions for hematopoietic recovery, graft rejection, graft failure, poor graft function, and donor chimerism in allogeneic hematopoietic cell transplantation.

The EBMT, ASTCT, CIBMTR, and APBMT convened a steering committee to address challenging issues in allogeneic hematopoietic cell transplantation for which definitions vary or are unclear. Based on the definitions of the original publication by Kharfan-Dabaja et al. on behalf of the ASTCT, expert panel members used a modified Delphi method to facilitate the achievement of a consensus. Panel members voted on all consensus definitions in the ASTCT paper except on definitions for delayed engraftment and primary graft failure after granulocyte colony stimulating factor (G-CSF) stimulated bone marrow, as these statements did not achieve consensus in the original publication. For all applicable statements, the expert panel members agreed to use the international system terminology (i.e., 0.5 x 109/L for neutrophils and 20 x109/L for platelets instead of ≥500/μL and 20,000/μL, respectively). With few minor exceptions, there was consensus to endorse ASTCT definitions. 

•    Neutrophil recovery: Both panels endorsed the existing definition of neutrophil recovery as the first of 3 successive days with an absolute neutrophil count (ANC) of ≥500/μL after post-transplantation nadir.
•    Platelet recovery: Both panels endorsed the definition of platelet recovery as the first of 3 consecutive days with a platelet count of 20,000/μL or higher in the absence of platelet transfusion for 7 consecutive days.
•    Graft rejection versus graft failure: Both panels defined graft rejection as an immune-mediated process, whereas graft failure represents a wider array of possibilities, including cell dosing, disease, infection, drugs, and an immune-mediated event.
•    Graft failure (primary): Donor chimerism testing is also done to confirm the suspicion of graft failure.
o    Peripheral blood cells: Both panels defined graft failure as lack of achievement of an ANC ≥0.5 x 109/L /μL by day +30 with associated pancytopenia.
o    Unstimulated bone marrow: Both panels defined graft failure as lack of achievement of an ANC ≥0.5 x 109/L μL by day +30 with associated pancytopenia.
o    Umbilical cord blood: Both panels defined graft failure as lack of achievement of an ANC ≥0.5 x 109/L /μL by day +42 with associated pancytopenia.
•    Poor graft function: Both panels defined poor graft function as frequent dependence on blood and/or platelet transfusions and/or growth factor support in the absence of other explanations, such as disease relapse, drugs, or infections.  This assumes that donor myeloid and lymphoid chimerism are within a desirable target level.
•    Secondary graft failure: Both panels defined secondary graft failure as a decline in hematopoietic function (may involve hemoglobin and/or platelets and/or neutrophils) necessitating blood products or growth factor support, after having met the standard definition of hematopoietic (neutrophils and platelets) recovery. Donor chimerism testing is also done to confirm the suspicion of graft failure.
•    Donor chimerism:
o    Full: Both panels endorsed the existing definition of full donor chimerism as >95% for both myeloid and lymphoid lineages.
o    Mixed or partial: Both panels endorsed the existing definition of mixed donor chimerism as 5%–95% for both myeloid and lymphoid lineages. New endorsed statement: Mixed donor chimerism as 5%–95% for either one or both myeloid and lymphoid lineages.
o    Absent: Both panels endorsed the existing definition of absence of donor chimerism as <5% for both myeloid and lymphoid lineages.

How I diagnose and treat organizing pneumonia in hematopoietic cell transplant recipients.

Organizing pneumonia (OP) is a known non-infectious pulmonary complication following allogeneic hematopoietic cell transplantation (HCT) and represents a significant risk factor for non-relapse mortality in HCT recipients. Unlike bronchiolitis obliterans syndrome, it is not universally acknowledged as a distinctive pulmonary manifestation of chronic graft-versus-host disease (cGVHD) and therefore, its diagnostic criteria and management approach is lacking. Given it shares similar clinical features, radiological and histological findings to OP in the non-HCT population, the diagnostic approach and treatment strategy for OP in HCT recipients is largely adapted from the non-HCT population.

If the clinical history (dyspnea, a non-productive cough, pleuritic chest pain with deep inspiration and low-grade fevers, and that it often occurs temporally with new onset or an exacerbation of extrapulmonary GVHD), functional test (a decline in diffusion capacity for carbon monoxide with a restrictive spirometry pattern), and radiographic history (classic atoll sign and/or combination of non-specific unilateral or bilateral ground glass opacities, consolidation in peri-bronchovascular or subpleural distribution, with or without architectural distortion of the lung resulting from fibrosis) are highly suggestive of HCT-OP and infectious work up is unrevealing, treatment for HCT-OP should be initiated.  Lung biopsy is reserved for highly selective cases, instances where (a) the diagnosis remains elusive despite comprehensive assessment; (b) the patient has not improved clinically despite treatment with corticosteroids; or (c) if malignancy or invasive fungal disease remain high on the differential.

Systemic corticosteroids remain the primary treatment at the time of diagnosis. Typically, we start prednisone at 1 mg/kg/day. For a patient who is not hypoxemic, prednisone at 0.5 mg/kg/day may be sufficient (for a critically ill patient who requires mechanical ventilatory support or is severely hypoxemic and needing intensive care unit  admission, they recommend methylprednisolone pulse at 1-2 mg/kg/day, with tapering at the physician’s discretion depending on clinical stability until the patient can be tapered to prednisone of 1 mg/kg/day). Response to corticosteroids should be apparent after 1-2 weeks of initiation. Once clinical improvement is observed, try to taper the prednisone dose. A repeat computed tomography scan of the chest is performed to ensure radiographic improvement and to monitor for possible opportunistic infections related to immunosuppression.  Relapse of HCT-OP is common, occurring in 30-50% of cases, and may be associated with tapering of immunosuppression, at the onset of new manifestations or during an exacerbation of cGVHD. At present there are no evidence-based standards for the use of medications as steroid-sparing agents in HCT-OP. Because there are no consensus guidelines or research on the optimal treatment approach, there is wide variability in clinical practice.

Yttrium-90 Anti-CD25-BEAM-Conditioning for Autologous Hematopoietic Cell Transplantation (AHCT) in Peripheral T Cell Lymphoma (PTCL).  

About 10-15% of non-Hodgkin lymphomas are PCLT, and due to their low incidence, large randomized studies are challenging to conduct. CD25 (Tac) is frequently expressed at a high level in PTCL. Radioimmunotherapy (RIT) with antibodies labeled with radioactive conjugates enables the delivery of radiotherapy to tumors. Recently, an attractive therapy for this difficult-to-treat disease is combining Yttrium-90 (90Y) labeled basiliximab (aTac) with high-dose chemotherapy as part of conditioning regimens before AHCT. A single-center, phase I study evaluated 20 patients with PTCL, 90Y-aTac with BEAM [BCNU (carmustine), etoposide, cytarabine, melphalan] between July 2015, and June 2020. Anaplastic lymphoma kinase (ALK)+ anaplastic large cell lymphomas and cutaneous T cell lymphomas were not included. To block circulating soluble CD25 antigen, unlabeled basiliximab (5 mg) was administered intravenously 21 days before AHCT (day -21). 90Y-aTac dose was administered on day -14. Three dose levels were tested: 0.4, 0.5, and 0.6 mCi/kg (maximum 90Y dose was: 40 mCi, 50 mCi, and 60 mCi, respectively). The conditioning regimen was administered as follows: BCNU on days -7 and -6, 150 mg/m² IV per adjusted ideal body weight (aIBW); cytarabine and etoposide twice daily on days -5, -4, -3, and -2, each dose 100 mg/m2per aIBW; melphalan 140 mg/m2 on day -1. Dose-limiting toxicities (DLTs) were assessed from day -21 through day +30. The primary endpoint was the safety and feasibility of 90Y-aTac in combination with BEAM as part of conditioning for AHCT. At the end of the observation period, 14 patients were alive, and 12 remained progression-free. No DLTs were observed at any dose level, and grade 2 mucositis accounted for 80% of the side effects. Six (30%) of the treated patients died; five from progressing illness, and one from multiple organ failure. The 2-year progression-free and overall survival were 59% (95% CI: 34-77%) and 68% (95% CI: 42-84%), respectively. A 0.6 mCi/kg dose was recommended to continue phase 2 studies. In summary, targeted routes such as RIT might be more beneficial for PTCL patients than merely boosting classical chemotherapy regimens.

Vedolizumab for the prevention of intestinal acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT): a randomized phase 3 trial.

Grade 2–4 aGVHD develops in ~40–50% of well-matched allo-HSCT recipients and is the main risk factor for chronic GVHD. Gut aGVHD remains a major cause of morbidity. Directed therapy to α4β7 integrin leukocyte receptor in combination with standard prophylaxis led to promising results in a previous phase Ib trial. Recently, a multicenter, randomized, double-blind, placebo-controlled phase 3 trial published in the journal Nature Medicine tested the efficacy and safety of vedolizumab (a humanized monoclonal antibody that binds to the α4β7 integrin) for the prevention of gastrointestinal aGVHD. 343 patients (pts) were randomly assigned 1:1 to receive vedolizumab (174 pts) or placebo (169 pts). In a per-protocol analysis, 333 pts received allo-HSCT. They were included for efficacy study endpoints (vedolizumab 300 mg [168 pts] or placebo [165 pts]  intravenously on day −1 and days +13, +41, +69, +97, +125, and +153 after allo-HSCT in addition to standard GVHD prophylaxis (calcineurin inhibitor [CNI] plus methotrexate or mycophenolate mofetil). The primary endpoint was lower-GI aGVHD-free survival by day +180 after allo-HSCT. Unfortunately, the COVID-19 pandemic reduced the planned sample to 60% of enrollment. Baseline characteristics were balanced. The most frequent underlying malignancies were acute myeloid leukemia, myelodysplastic syndrome, and acute lymphoid leukemia. By day +180, the vedolizumab group's Kaplan–Meier estimate for lower-GI aGVHD-free survival was 85.5% (95% confidence interval [CI] 79.2–90.1), while the placebo group's estimate was 70.9% (95% CI 63.2–77.2). Vedolizumab reduced the risk of a lower-GI aGVHD event or death by day +180 after allo-HSCT compared to placebo (hazard ratio [HR]  0.45, 95% CI 0.27–0.73; p < 0.001). By day +180 following allo-HSCT, there was no significant difference in the overall incidence of upper-GI aGVHD, cutaneous aGVHD, or liver aGVHD between treatment groups. For safety endpoints, statistical analyses were not adequately powered for comparisons between treatment groups. However, no new safety signals were observed (including Clostridioides colitis and cytomegalovirus colitis). To date, this is the largest trial of vedolizumab for the prevention of gut GVHD. 

Evaluation of European LeukemiaNet (ELN) 2022 risk classification in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT) for acute myeloid leukemia (AML): Identification of a very poor prognosis genetic group.  

Based on pretreatment cytogenetic abnormalities and gene alterations, patients with AML are categorized into three risk groups by the ELN. The ELN 2022 states that when the likelihood of recurrence without allo-HCT surpasses 35%–40%, allo-HCT should be considered. The predictive value of this risk classification in the population that achieves a complete remission before allo-HCT has not been thoroughly investigated. In a single-center study, investigators evaluated the predictive power of ELN 2022 classification to predict overall survival (OS) and disease remission in a retrospective cohort with AML who underwent allo-HCT (primary endpoint). Secondary endpoints were leukemia-free survival (LFS), cumulative incidence of relapse (CIR), non-relapse mortality (NRM), and graft-versus-host disease-free and relapse-free survival (GRFS). 120 patients were analyzed (22 categorized as favorable risk, 42 as intermediate risk, and 56 as adverse risk). Mutational analysis for allocation to an ELN 2022 risk category included standard polymerase chain reaction-based analysis of recurrent abnormalities (NPM1, FLT3-ITD, FLT3-TKD, IDH1, and IDH2) and targeted next-generation sequencing. Patients in the adverse risk group had lower five-year OS and LFS rates (OS: 42% vs. 68% vs. 81% in the adverse, intermediate, and favorable risk groups, respectively; p=0.003, LFS: 39% vs. 66% vs. 62%, respectively; p=0.02). The adverse risk group also had the worst 2-year GRFS rates (21% vs. 45% vs. 46% in adverse, intermediate, and favorable groups, respectively, p=0.03) and 2-year CIR (39 vs. 20 vs. 18% in adverse, intermediate, and favorable groups, respectively, p=0.04). The NRM at the same point did not differ between these categories. Patients in the ELN 2022 genetic adverse-risk category had a shorter OS hazard ratio (HR: 2.00 [95% confidence interval [CI]: 1.04–3.8], p=0.038) and LFS (HR: 2.07  [95% CI: 1.1–3.87], p=0.023) compared to the remaining genetic risk groups. Furthermore, the authors refined the ELN risk classification within the adverse-risk group and defined a subgroup with a dismal prognosis: complex karyotype, inv(3)/t(3;3) with MECOM(EVI1) rearrangement and loss of 17p region, and/or TP53 mutated. This group showed worse OS (HR: 3.66 [95% CI: 1.77–6.6], p<0.001) and LFS (HR: 3.69  [95% CI: 1.8–7.53], p<0.001).

Prognostic factors impacting post-transplant outcomes in adult T-cell acute lymphoblastic leukemia (T-ALL): a registry-based study by the EBMT acute leukemia working party

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the standard therapy for patients with high-risk T-ALL in first complete remission (CR1) or relapsed T-ALL. There exists limited information about the prognostic factors and outcomes in this population. A retrospective registry-based analysis from the European Society for Blood and Marrow Transplantation (EBMT) evaluated the prognostic factors and main outcomes in adults with T-ALL after their first allo-HSCT in CR1. 1907 adult T-ALL patients (70% male) who underwent allo-HSCT from matched sibling donors (MSD; 45%), unrelated donors (UD; 43%), or haploidentical donors (HD; 12%) between January 2010 and December 2021 were included. The main outcomes were overall survival (OS), leukemia-free survival (LFS), relapse incidence (RI), non-relapse mortality (NRM), and graft-versus-host disease (GHVD)-free and relapse-free survival (GRFS), acute GVHD (aGVHD) grades II-IV and III-IV, chronic GVHD (cGVHD), and extensive cGVHD. The median follow-up was 2.9 years. The 2-year OS was 69.4%, and LFS was 62.1%. In multivariate analysis, advanced age at transplant was associated with poorer outcomes in terms of OS (or each 10-year increment, hazard ratio [HR] = 1.12, p= 0.002), LFS (HR= 1.11, p= 0.004), GRFS (HR= 1.06, p= 0.04), and NRM (HR= 1.23, p< 0.001). Another adverse prognostic factor was female-to-male transplant combination that reduced OS (HR  1.23, p= 0.048) and GRFS (HR= 1.21, p= 0.02). In comparison, improved outcomes were related to the increment in the year period of allo-HSCT in terms of OS (for each 3-year increment, HR= 0.9, p= 0.02), GFRS (HR= 0.89, p< 0.001), and decreased NRM (HR= 0.82, p= 0.008). Total body irradiation body (TBI) and in vivo T-cell depletion improved GFRS (HR= 0.83, p= 0.04, and HR= 0.74, p< 0.001, respectively). Also, TBI improved LFS (HR= 0.79, p= 0.02) and RI (HR= 0.65, p< 0.001). In conclusion, in this large registry of patients with T-ALL after their first allo-HSCT in CR1, advanced age, and donor type (female donor to male recipient) had a negative impact on outcomes of allo-HSCT although with notable improvement over the years due to the therapy advances in this scenario (e.g., myeloablative conditioning with TBI-based regimens).

Anti-thymocyte globulin (ATG) or post-transplant cyclophosphamide to prevent graft-versus-host disease (GVHD) in matched unrelated donor (MUD) allogeneic hematopoietic stem cell transplantation (allo-HSCT)?

It was believed that the use of posttransplant cyclophosphamide (PTCy), which is more frequently utilized in the context of antigen-MUD and matched sibling donor (MSD), would lower the rates of GVHD, particularly in chronic GVHD (cGVHD). However, in Europe, the standard of care in transplantations from MUD is rabbit ATG (rATG). Controversy exists about the comparative efficacy between rATG vs. PTCy for the prevention of GVHD in MUD allo-HSCT. For this reason, Penack, et al investigated the outcomes of rATG and PTCy in a retrospective multicenter analysis using the data set of the EBMT registry. Study endpoints were overall survival (OS), progression-free survival (PFS), non-relapse mortality (NRM), relapse incidence (RI), GVHD-free/relapse-free survival (GRFS), and incidence and severity of acute and cGVHD. The Kaplan-Meier method was used to calculate the probabilities of OS, PFS, and GRFS. NRM, RI, and acute and cGVHD were all estimated using cumulative incidence. The provided p-values and hazard ratios (HR) are derived from a multivariate analysis. Patients in the PTCy group (interquartile range [IQR] 38.6, 62.3 years) were younger than those in the rATG group (p< 0.01), with a median age of 58.6 years (IQR 48.1, 65.4). Also, rATG patients had a significantly lower use of TBI (14.5% vs. 24.7%, p< 0.01) and a lower use of myeloablative conditioning (52% vs. 62.3%, p< 0.01). In transplantations of MUD allo-HSCT, the PTCy prophylaxis vs. rATG prophylaxis was associated with improved NRM (2-year incidence: 12.4% vs. 16.1%; HR: 0.72 [95% confidence interval, CI: 0.55–0.94], p= 0.016) and OS (2 year-incidence: 73.9% vs. 65.1%; HR: 0.82 [95% CI 0.72–0.92], p= 0.001). PFS showed a statistically significant benefit for the PTCy arm (2-year-incidence: 64.9% vs. 57.2%; HR: 0.83 [95% CI 0.74–0.93], p < 0.001). RI was lower with PTCy compared to rATG (2-year-incidence: 22.8% vs. 26.6%; HR: 0.87 [95% CI 0.75–1.00], p= 0.046). Although the overall cGHVD was lower with PTCy vs. rATG (2-year-incidence: PTCy 28.4% vs. rATG 31.4%; HR: 0.77 [95% CI 0.63–0.95], p= 0.012), the difference for acute GHVD was not statistically significant (100-day incidence: 24.1% vs. 26.5%; HR: 0.85 [95% CI 0.69–1.04], p= 0.11). In conclusion, PTCy is a reasonable option for the prevention of cGVHD in this population, with improved OS, PFS, and NRM. These data open the gates to future improvements in prevention strategies for GHVD after MUD allo-HSCT, including the combination of rATG and PTCy.

Neurologic Complications of the Central Nervous System after Allogeneic Stem Cell Transplantation (AlloSCT): The Role of Transplantation-Associated Thrombotic Microangiopathy as a Potential Underreported Cause.

Central nervous system (CNS) neurologic complications (NC) after AlloSCT remain an important source of morbidity and transplant-related mortality (TRM). The use of calcineurin inhibitors (CNIs) are frequently used as part of post-transplant graft-versus-host disease (GvHD) prophylaxis and can lead to NC through direct toxicity or through increased risk of infection.

The authors assessed the rate of CNS-NC in a retrospective cohort of 739 consecutive adult patients undergoing Allo-SCT for a hematological malignancy at a single institution over a 20-year period (1999-2019) who received cyclosporin-A (CsA) or tacrolimus (TAC) as GvHD prophylaxis. The development of NC was classified by the investigators as non-CNI related (infectious, cerebrovascular, metabolic, secondary CNS malignancy), and CNI-related, which included CNI intolerance (headache, confusion, or tremor with otherwise neuroimaging), seizures, posterior reversible encephalopathy syndrome (PRES), or transplant-associated thrombotic microangiopathy (TA-TMA) with neurological involvement. Patients without NC were used as controls.  129 patients (17%) had at least one NC, and 152 CNS-NC events were identified, 42% of which were CNI-related. Infections were the most common non-CNI-NC in 46/88 (56%) of events. Among the CNI-related events, TA-TMA with CNS involvement was seen in 25 events, representing 16% of all CNS-NC and 39% of CNI-related complications. Of note, when updated TA-TMA criteria (including proteinuria and complement activation) was used, the incidence of TA-TMA increased from 3.1% to 13%. The presence of CNS-NC adversely impacted overall survival (OS) (HR 4.6, p < 0.001) in a univariable model and remained significant for all subgroups of CNS-NC except for CNI intolerance. CNI-related CNS-NC remained associated with worse OS (HR 5.4; p < .001) in the multivariable model, along with male sex, higher hematopoietic stem cell transplantation-specific comorbidity index (HCT-CI), higher EBMT risk score, preexisting CNS conditions, previous autologous-SCT, acute and chronic GvHD, and bone marrow as the stem cell source. The use of TAC and ATG was associated with improved OS and TRM. The use of TAC, total body irradiation, and the presence of GvHD were associated with higher rates of CNS-NC in the multivariable model.

The authors conclude that CNS-NC are relatively common after AlloSCT and represent an important source of morbidity and mortality, with higher rates in patients receiving TAC versus CsA. TA-TMA with neurological involvement is an important cause of CNS-NC.

Racial/ethnic disparities in availability of volunteer unrelated donors for allogeneic stem cell transplantation (AlloSCT).  

AlloSCT relies on the availability of a suitable donor. In many cases, no related donors are available, requiring the identification of unrelated donors (URD) through large URD registries that have traditionally prioritized the human leukocyte antigen (HLA)-matching rather than donor availability. Additionally, there may be disparities in access to a suitable URD for underserved racial/ethnic subgroups.

The authors evaluated available URD request from January 2020 to December 2022 for 455 consecutive patients with a diagnosis of myeloid neoplasm who had a formal URD request, and at least 1 URD who was requested for confirmatory-HLA typing (CT) or CT-simultaneous workup. All patients were prioritized for an 8/8 HLA-matched URD, followed by HLA-disparate grafts, double unit cord blood, or haploidentical grafts. A URD search was carried out before proceeding for all patients who received cord blood or haploidentical grafts. Patient ancestry was recorded by the transplant team based on kinship history including patient ancestor’s country of origin, self-identification as black or Hispanic for each patient. 455 patients were included, 55% had acute leukemia as their indication for AlloSCT, and 26% had non-European ancestry.  A total of 3843 URD were requested for CT (including 314 for simultaneous CT-workup), of which 2140 (56%) were domestic. A median of 7 URD were requested for CT for the cohort, with >70% of patients requesting at least 5 URD. Although the cohort had a median of 4 URD available for CT, nearly 2/3 of URD were not available. More non-European patients (n = 120) than Europeans (n = 335) had >10 URDs requested but had <5 available. Of workup requests (after CT or CT-workup), <70% (604/889 [68%]) were available. More non-Europeans had <2 URDs available. URD availability for CT was markedly worse for non-Europeans, with availabilities for African, non-Black Hispanic, and Asian patients being 150/458 (33%), 120/258 (47%), and 119/270 (44%), respectively, with further decrements in URD workup availability. Among 339 who had at least one 5-8/8 URD planned for collection, 23% and 12% (77 and 39 patients) had no URD that could be collected <7 or <14 days from the first proposed date, respectively. 

The authors conclude that the pool of available URDs is effectively much smaller than initially considered, especially for those patients of underrepresented ancestry subgroups. Considering patient ancestry and URD Donor Readiness scores, centers and registries should be aware of the individual likelihood of URD availability to allow for broader CT or workup or they should consider alternative sources for those with a low chance of finding a URD.

Autologous stem cell boost improves persistent immune effector cell associated hematotoxicity following BCMA directed chimeric antigen receptor (CAR) T-cell therapy in multiple myeloma (MM).

CAR T-cell therapies targeting BCMA is a highly effective therapy against relapsed/ refractory MM, with an overall response rate >80%. However, the presence of cytopenias beyond 30 days (late immune effector cell associated hematotoxicity – ICAHT) after CAR T-cell infusion is a topic of growing interest as it often leads to increased transfusion and the number of outpatient and hospital visits, in addition to the increased risk of infectious complications.

The authors report the outcomes of 108 patients who received BCMA CAR T-cells for MM at two academic institutions in the US, and describe the rate of ICAHT, defined as the presence of any of the following: absolute neutrophil count <1000 cel/uL, platelet count <50,000, or hemoglobin <9 gr/dL, at day +21, 3 and 6 months. In this cohort, ICAHT was frequent at day +21, with 41/101 (60%) having at least 1 cytopenia, neutropenia being the most common, and the authors identified the use of previous autologous stem cell transplant (ASCT), number of ASCTs, and more previous lines of therapy as characteristics associated with ICAHT development at day +21. Importantly, the authors report their experience using autologous stem cell boost to manage ICAHT. 59/61 (97%) of patients who experienced ICAHT had available stem cells in storage, and 16/59 (28%) received a stem cell boost to manage ICAHT. The median time to stem cell boost was 116 days (range 29-270), and the median dose of stem cells infused was 3.84 (range 1.05-9) x10⁶/kg. Patients who received a stem cell boost had higher rates of cytopenias, with a lower platelet count (24 vs. 48 x10⁹/L, p= 0.002) and hemoglobin (8.45 vs. 9 gr/dL, p= 0.001). Patients who received a stem cell boost had significantly improved cytopenias that persisted at 3 and 6 months. However, patients who did not receive a stem cell boost also had improvement in ICAHT, although more modest than those who did receive one. Off note, there were no changes in clinical outcomes with the use of stem cell boost in this cohort.

The authors conclude that stem cell boost significantly improved cytopenias at 3 and 6 months after BCMA CAR T-cell therapy without any adverse effect on progression-free survival and overall survival, highlighting the safety of this procedure.

Myeloablative vs nonmyeloablative consolidation for primary central nervous system lymphoma (PCNSL): results of Alliance 51101.

PCNSL is associated with inferior outcomes when compared to systemic large B-cell lymphoma and is refractory to CHOP. The Alliance 51101 was a phase II, open label, randomized controlled trial conducted in 27 centers in the United States. Patients with newly diagnosed PCNSL aged 18-75 years with a Karnofsky performance status (KPS) >30 for those aged <69 years and >50 for those aged 70-75 years were enrolled. Human immunodeficiency virus infection and history of organ transplant were exclusion criteria. All patients received induction with high-dose methotrexate, temozolomide, rituximab and intravenous (IV) cytarabine for a total of 5 cycles (for full details on induction regimen please access the article). Patients were randomized to consolidation with a myeloablative or a non-myeloablative regimen using a dynamic allocation stratified by a composite of age and KPS (age <51 years vs age ≥51 years and KPS ≥70 vs age ≥51 years and KPS < 70). Patients enrolled on the myeloablative arm underwent mobilization and harvest of stem cells using granulocyte colony stimulating factor (G-CSF) followed by IV carmustine and thiotepa, followed by stem cell infusion on day 0 with G-CSF until absolute neutrophil count was >1500/uL. Patients in the nonmyeloablative arm received IV cytarabine and etoposide.  The primary outcome of the study was progression-free survival (PFS), while secondary outcomes included event-free survival (EFS), overall survival (OS), adverse events and tolerability, and neurocognitive changes as assed by the mini-mental state examination (MMSE). A total of 113 patients were randomized, and 108 (54 in each arm) were evaluable. More patients in the nonmyeloablative arm experienced progressive disease or death during induction (28% vs. 11%; p= 0.05). Thirty-six patients received autologous stem cell transplants, and 34 received nonmyeloablative consolidation. The estimated 2-year PFS was higher in the myeloablative vs. nonmyeloablative arm (73% vs. 51%; p= 0.02). However, a planned secondary analysis, landmarked at start of the consolidation, revealed that the estimated 2-year PFS in those who completed consolidation therapy was not significantly different between the arms (86% vs. 71%; p= 0.21). Of note, after 4.1 years of follow up and 26 deaths in 108 evaluable patients, median OS has not been reached in this cohort but there were no differences across groups (hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.27-1.31; p= 0.1). Outcome was not correlated with age, KPS, lactate dehydrogenase, deep brain involvement, or central system fluid involvement. However, MMSE appears as an independent predictor of OS, with patients with a MMSE <27 having worse outcomes (HR 3.25, 95% CI, 1.36-7.76, p= 0.008). The authors conclude both regimens appear effective and safe in this population, with overall similar toxicity profile. Additionally, they highlight the fact this is the first trial to enroll patients with primary PCNSL without any of the arms involving whole brain radiation and support the use of carmustine/thiotepa as a consolidation regimen in PCNSL, including in elderly patients (age 69-75) which is in line to the previously reported MARITA trial.

Graft Failure (GF) Incidence, Risk Factors, and Outcomes in Patients Undergoing Non-Myeloablative Allogeneic Hematopoietic Cell Transplantation (AlloSCT) Using Post-Transplant Cyclophosphamide (PTCy).

GF is a major complication following AlloSCT and is associated with high morbidity and mortality. The authors present the incidence, clinical features, risk factors, and outcomes for patients with primary and secondary GF in a retrospective cohort of 958 patients at a single institution who received non-myeloablative AlloSCT with PTCy-based graft-versus-host disease (GVHD) prophylaxis.

The authors defined primary GF (PGF) as failure to achieve an absolute neutrophil count >500cell/m³ by day +30 without residual disease. Secondary GF (SGF) was defined as complete loss of chimerism after initial engraftment.  Patients received a conditioning regimen consisting of fludarabine 30mg/m2 on days -6 through -2, cyclophosphamide 14.5mg/kg on day -6 and -5, and total body irradiation as a single fraction of 200 or 400 cGy on day -1. GVHD prophylaxis consisted of PTCy 50mg/kg on day +3 and +4, mycophenolate mofetil from day +5 to +35, and tacrolimus or sirolimus from day +5 to +180. The incidences of PGF and SGF were 3.8% (n = 37) and 1.8% (n = 17), respectively. Neither PGF nor SGF were associated with human leucocyte antigen (HLA) disparity. In a multivariate analysis, risk factors for PGF in this cohort included age ≥ 65 years (odds ratio ([OR] 2.4, 95% CI 1.2 to 4.8, P = 0.0120), an underlying diagnosis of MDS, MPN, or MDS/MPN overlap (OR 2.8, 95% CI 1.4 to 5.7, p = 0.0050), post-transplant viremia with HHV-6 (OR 2.9, 95% CI 1.5 to 5.7, p = .0030), and low CD34+ dose (OR 0.7, 95% CI 0.5 to 0.9, P =0.0080). SGF was associated with the use of a bone marrow graft and a diagnosis of Hodgkin lymphoma. Patients with PGF had poor overall survival, driven primarily by a high rate of non-relapse mortality (59% at 36 months), whereas patients with SGF had good clinical outcomes, with only 1/17 patients experiencing disease relapse.

The authors conclude that the incidence of PGF and SGF in patients receiving NMA conditioning and PTCy is low and is not impacted by HLA disparities between donors and recipients, which is contrary to previous reports. PGF is more common in recipients with age ≥ 65 years, a diagnosis of MDS, MPN, or MDS/MPN-overlap, post-transplant HHV-6 viremia, and low CD34+ cell dose. Low total nucleated cell dose is also a risk factor for PGF in patients receiving a bone marrow graft.