Peripheral Blood Stem Cell Grafts Research Articles

Long Term Outcomes of Patients with Chronic Myeloid Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation in the Era of Oral Tyrosine Kinase Inhibitors

Introduction. Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm (MPN) that without therapy is a uniformly lethal disease. Historically allogenic stem cell transplant (HCT) was the only curative therapy. In 2001 imatinib was the first CML specific oral tyrosine kinase inhibitor (TKI) approved and since then the treatment of CML has dramatically improved. Subsequently, 2nd and 3rd generation TKIs were developed and have been shown to be superior to imatinib either as initial therapy in certain high-risk patients and in other patients that fail imatinib. However, despite the advances in therapy, patients still die of CML, in fact, in 2020 it is estimated that 8,450 patients will be diagnosed with CML and 1,130 patients will die of CML. HCT remains a curative option for patients with CML. As the safety and availability of HCT improve, we aimed to describe the role of transplant in the modern era of CML therapy. Methods. We performed a retrospective chart review of patients who underwent their first HCT between June 28, 2006 and December 31, 2021 for CML in either chronic or accelerated phase at the time of transplant. Results. A total of 122 patients were identified. Patient and HCT characteristics are shown in Table 1. The median age at time of transplant was 45 (8-67), 72 (59%) are male. Fifty-four (44.3%) of patients received their transplant between 2006-2012 and 68 (55.7%) of patients received their transplants between 2013-2021. Fourteen (11.5%) patients were in accelerated phase CML at the time of HCT and the rest were in chronic phase. The median time from diagnosis to transplant was 23 months (1.8-307). Ninety-seven patients (79.5%) received ablative conditioning regimens. A total of 46 patients (37.7%) had matched related donors, 54 patients (44.3%) had matched unrelated donors, 14 patients (11.5%) had haploidentical donors, and 8 patients (6.7%) had a cord blood graft. 102 patients (83.6%) received peripheral blood stem cell grafts. GVHD prophylaxis always included a calcineurin inhibitor with the addition of methotrexate in 36 (29.5%) of patients, sirolimus in 60 (49.2%), Mycophenolate in 7 (5.7%), and post-transplant cyclophosphamide in 19 (15.6%) patients. Sixty-one patients (50%) had grade 2 or higher acute GVHD, and 19 (15.6%) had grade 3-4 acute GVHD. Extensive chronic GVHD was present in 81 (66.4%) of patients. Median follow-up of surviving patients was 59.3 months (3.3, 183.8) and overall the median follow-up was 30 months (0.55, 183.8). The estimated 12, 36, and 60-month Overall Survival (OS) of the cohort was 76.9% (95%CI 69.7-85), 66.1% (95% CI 57.7-75.6), and 58.4% (95% CI 49.4-69). Progression free survival (PFS) of the cohort at 12, 36, and 60 months was 71% (95% CI 63.2-79.7), 62% (95% CI 53.6-71.7) and 54.1% (45.1-65%) respectively. The median OS and PFS was not reached (Figure 1a,b). Fifty-two patients in the cohort died, 31 (59.6%) died of complications of treatment, 12 (23.1%) died of progression of disease, and 9 (17.3%) died of unknown causes. The day 100 cumulative incidence of non-relapse mortality (NRM) was 4.1% (1.7-9.7%) and the 1-year NRM was 17.2% (11.5-25.7%). Conclusion. This study shows excellent long term survival in patients who received an allo HCT for CML. And while, the modern treatment of CML largely relies on oral TKIs, in those patients who do not tolerate TKIs or fail available TKIs, allogeneic transplant remains an active, potentially curable therapy and should be considered. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Autologous Stem Cell Transplantation (ASCT) for Refractory Juvenile-Onset Systemic Sclerosis (jSSc) Is Safe and Well Tolerated and Improves Clinical and Patient-Reported Outcomes

Introduction: jSSc is a rare autoimmune disease that leads to inflammation, fibrosis, and dysfunction of multiple organ systems which can cause skin sclerosis, interstitial lung disease (ILD), myositis, fasciitis, gastrointestinal and vascular disease. Severe SSc is often refractory to immunomodulatory medications including newer targeted agents. ASCT has demonstrated success in adults with SSc, but experience and data in pediatric patients is limited. Methods: We report our first four consecutive adolescent and young adult ASCT patients. All patients were referred to our scleroderma center at UPMC Children's Hospital of Pittsburgh where they were evaluated by our multidisciplinary team. Baseline patient characteristics are summarized in Table 1. Patients met criteria for ASCT by severity of lung or skin disease, or both. The first 3 patients had severe ILD or musculoskeletal chest wall weakness resulting in pulmonary function tests (PFTs) below traditional cut offs for adult SSc ASCT trials. All four patients had refractory disease and had previously received 3-8 immunomodulatory medications. Autologous stem cells were mobilized with cyclophosphamide and filgrastim and collected via pheresis. Following this, conditioning chemoradiation was administered per an IRB-approved individual treatment plan (Patients 1-3) or on our clinical trial NCT03630211 (Patient 4) with rituximab, anti-thymocyte globulin (ATG), TBI 600 cGy with lung and kidney shielding, and cyclophosphamide or thiotepa +/- alemtuzumab. A CD34+ selected cryopreserved autologous peripheral blood stem cell graft was infused on day 0. Antimicrobial prophylaxis was given per institutional standard and PCRs for EBV, CMV and adenovirus were closely monitored. Steroids were weaned off by 5 weeks post-ASCT. Results: The median cell dose was 5.9 e6 CD34/kg. All patients engrafted, with median neutrophil engraftment on day 11 (range 11-15), and median platelet engraftment (>50K) on day 18.5 (range 16-20). There were infusion-related side effects with equine ATG, but none with rabbit ATG. There were no cases of sinusoidal obstructive syndrome, thrombotic microangiopathy or clinically significant bleeding. No patients required a PCA for pain and received minimal (median=3) doses of narcotics. Patients were discharged from the hospital a median of 19 days after transplant (range 17-21). Only one patient was readmitted, and had a negative 48 hour infectious rule out. Two patients acquired COVID-19 infections at 5 and 19.5 months post-ASCT; both remained outpatient with quick improvement after treatment with best available therapy. There were no viral reactivations, bacterial or fungal infections. There has been no evidence of organ toxicity and there are objective improvements in clinical parameters as well as patient reported outcomes (PROs) over the follow-up visits (Table 2). All patients demonstrated an improvement in their skin involvement, as measured by the modified Rodnan Skin Score (mRSS). There was an improvement in clinical symptoms and exam findings of Raynaud's. The lower esophageal sphincter became less hypotensive; objective measures and symptoms of gastroesophageal reflux were much improved. Despite severely reduced values of forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLCO) prior to ASCT, all subjects regained pre-ASCT values. All patients demonstrated an improvement in their PROs and report improvement in fatigue, pain, and the ability to participate in activities of daily living. All patients are off immunomodulatory medications. Tandem serial skin biopsies of the forearm support decreased collagen burden and disappearance of a myofibroblasts population with single cell RNA sequencing (n=3, timepoints 0, 6, 12 mos; data not shown), which correlates with an improvement in the skin score. Conclusions: In refractory jSSc patients, ASCT is well tolerated, even in patients with severe disease who would otherwise not be eligible for clinical trials based on exclusion criteria that were developed for adults with SSc. ASCT can serve as a hard reset to the immune system for patients with this refractory autoimmune disease, with improvements in clinical parameters that reflect disease modification involving the skin, musculoskeletal, vascular, and gastrointestinal systems. Further clinical research treating patients with this rare disease is of great need. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Haploidentical Stem Cell Transplantation Had a Lower Incidence of Bronchiolitis Obliterans Syndrome Compared with HLA-Matched Sibling Transplantation for Patients with Hematologic Malignancies: Benefit from ATG?

Background: Haploidenticalstem cell transplantation(HID-SCT) based on antithymocyte globulin (ATG) GVHD prophylaxis had achieved similar incidence of cGVHD with HLA-matched sibling transplantation (MSD-SCT). However, bronchiolitis obliterans syndrome (BOS) serve as pulmonary cGVDH, was rarely compared between HID and MSD transplantation. Methods: One thousand four hundred and five patients with hematologic malignancies underwent SCT were enrolled in this retrospective study. Based on donor type, we divided the patients into three groups: HID, MSD and MUD (match unrelated donor) groups. All patients in HID and MUD group received ATG for GVHD prophylaxis, and the minority of patients in MSD group because of clinical trials. The vast majority of HID-SCT recipients transplanted with mixed grafts (bone marrow plus peripheral blood stem cell), whereas most MSD-SCT and all MUD-SCT recipients received PBSC (peripheral blood stem cell) grafts. The cumulative incidences and risk factors of BOS were analyzed. Results: The 5-year cumulative incidence of BOS was 7.2% in the whole population. HID transplantation had lower 5-year cumulative incidence of BOS than MSD transplantation (4.1% vs 10.0%; p<0.001), and the similar incidence with MUD transplantation (4.1% vs 6.2%; p=0.224). The 5-year cumulative incidence of BOS was lower in ATG group than that in non-ATG group in the whole and MSD population both (4.6% vs 11.2%; p<0.001; and 4.1% vs 11.2%; p=0.042, respectively). The 5-year incidence of BOS in mixed grafts group was also lower than that in PBSC group (4.2% vs 9.1; p=0.001). Multivariate analysis showed that HID, ATG and mixed grafts were protective factors for BOS (OR 0.3; 95%CI, 0.2 to 0.6; p<0.001; OR 0.3; 95%CI, 0.2 to 0.7; p=0.001; OR 0.3; 95%CI, 0.1 to 0.8; p=0.013), and aGVHD and cGVHD were independent risk factors for BOS (OR 2.1; 95%, 1.1 to 4.3; p= 0.035; OR 10.1; 95%CI, 4.0 to 25.0; p<0.001). Conclusions: HID transplantation had a lower incidence of BOS than MSD transplantation, which might be associated with ATG and mixed grafts. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Allogeneic Peripheral Blood Stem Cell Transplantation for Bone Marrow Failure Syndromes Using CD34+-Selected Progenitor Cells Co-Infused with a Reduced Number of Non-Mobilized T-Cells

Background Severe aplastic anemia (SAA) patients who fail immunosuppressive therapy (IST) may be candidates for curative allogeneic hematopoietic stem cell transplantation (HCT). Patients with SAA are often heavily transfused with underlying immune-mediated disease, which increases their risk for graft rejection when bone marrow (BM) is used as a graft source. Peripheral Blood Stem Cell (PBSC) grafts have been associated with better engraftment but at a cost of a higher incidence of graft-versus-host disease (GVHD). We developed a novel protocol combining high numbers of GCSF-mobilized CD34+ peripheral blood stem cells with a BM transplant-equivalent dose of T-cells (collected from donors before GCSF administration) to improve engraftment and decrease the risk of GVHD associated with a conventional, unmanipulated PBSC HCT. Methods In this phase II trial, eligible patients included those age 4-80 years with a diagnosis of SAA or other bone marrow failure (BMF) syndromes with ≥ 9/10 HLA-matched related (sibling/family) donors (MRD) or 10/10 matched unrelated donors (MUD). All patients received conditioning with cyclophosphamide (day -7 to -6), anti-thymocyte globulin (day -5 to -2), and fludarabine (day -5 to -1). For MUD patients, low dose total body irradiation (200 cGy) was added to the regimen on day -1. GVHD prophylaxis included cyclosporin (day -4 until at least day +30) and methotrexate (5 mg/m2 , day +1, +3 and +6). The primary outcome of the study was chronic GVHD at 1 year. Secondary outcomes included mortality, engraftment and chimerism, acute and chronic GVHD, immune reconstitution, and comparisons of MRD vs. MUD patients. Results Thirty-five patients (27 with MRD and 8 with MUD) were transplanted between February 2011 and December 2021. Patients had a median age of 30 (range 6-70) years, 46% were males and 54% were females, including 31 having SAA, 3 with SAA transformed to myelodysplastic syndrome (MDS), and one with MDS; 11 patients also had PNH clone pre-transplant. The median numbers of transplanted CD34+ and CD3+ T-cells were 8 ´ 106 cells/kg and 2 ´ 107 cells/kg, respectively. After HCT transplants, all patients had neutrophil recovery with a median 14 (10-32) days. Except for 2/35 (6%) patients having late graft failure, all other 33 (94%) patients achieved sustained engraftment. Platelet recovery was reached in 29 (83%) patients at a median 19 (13-321) days. A total of 97% of patients achieved >95% donor myeloid chimerism (median 14 days), and 94% of patients achieved >95% donor T-cell chimerism (median 30 days). Reactivation of CMV occurred in 21/29 (72%) patients at risk with none developing CMV disease. Full immune reconstitution occurred for most patients by 1-year post-transplant. With a median follow-up of 5 years, the estimated 200-day survival and overall survival were 89% and 85%, respectively. The cumulative incidence of acute grade II-IV GVHD was 23%, and 1-year chronic GVHD rate was 11%, which was significantly lower than our hypothesis that this regimen would lower the chronic GVHD rate to 50% (P < .001). The subgroups of patients with MRD and MUD were compared (Table 1): patients with MUD showed a slower time to achieve neutrophil recovery (P = .001) and platelet recovery (P = .03), and a slightly high graft failure incidence (2 cases), but most other outcomes were similar, compared to patients with MRD. Conclusion For patients with SAA and other BMF syndromes, transplanting high doses of mobilized CD34+ selected cells from MRD and MUD donors combined with a bone marrow transplant equivalent of non-mobilized donor T-cells (a partially T-cell depleted PBSC transplant) achieves rapid and durable donor engraftment and excellent survival. The cumulative incidence of both acute and chronic GVHD with this regimen was significantly lower than that historically reported with conventional PBSC transplants. Notably, low acute and chronic GVHD rates were also achieved in SAA patients with disease refractory to conventional IST who received a graft from a 10/10 HLA-matched MUD donor, although hematopoietic recovery was slightly delayed compared to recipients of a partially T-cell depleted graft from a MRD donor. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Regulatory T Cell Depletion during Stem Cell Mobilization Enhances Anti-Myeloma Immunity after Experimental Autologous Stem Cell Transplantation

Autologous stem cell transplantation (ASCT) with G-CSF/plerixafor mobilized peripheral blood stem cells (PBSC) remains the standard of care for newly diagnosed eligible multiple myeloma (MM) patients and prolongs progression-free survival. However, most patients eventually progress and require additional therapy. We have previously demonstrated that experimental ASCT can enhance myeloma-specific immunity and limits disease progression characterized by immunological escape. Here we explored the ability of stem cell mobilization (SCM) to mobilize putative myeloma-specific T cells from the bone marrow (BM) and concurrent effects of regulatory T cell depletion (Treg), hypothesizing that this may represent an opportunity to optimize myeloma-specific immunity prior to ASCT. In myeloma patients we noted increased proportions of subsets of effector memory CD8 T cells, including a CX3CR1/granzyme B (GzmB)+ subset in PBSC grafts relative to BM (P<0.01). TIGIT+ Treg were also significantly expanded in PBSC (P <0.01). To study the relevance of these effects, we transferred congenically marked BM T cells into syngeneic mice. We noted that BM-derived effector (CD44+) CD8 cells preferentially homed back to BM (vs. spleen/blood), consistent with T cell residency at this site. SCM subsequently promoted the migration of these resident effector CD8 T cells from BM (4-fold reduction, P <0.001) to blood (5-fold expansion, P <0.001), confirming that PBSC contain BM resident T cells. BM Foxp3+ Treg were also reduced in BM and increased in blood after SCM. Mobilized Treg were characterized by an immunosuppressive phenotype with high levels of CD73, Nrp-1, CTLA4 and TIGIT, and this represents a possible suppressive pathway invoked by SCM. We thus examined the role of BM Treg in limiting myeloma-specific immunity during SCM with Foxp3-GFP-DTR mice. Depletion of Treg with diphtheria toxin (DT) during SCM promoted the expansion of antigen experienced CD8 T cells that secreted IFNg, TNF and GzmB. We next hypothesized that expansion of these polyfunctional cells would enhance myeloma-specific immunity after ASCT. To test this, we treated Vk*MYC bearing Foxp3-GFP-DTR donor mice with DT (vs. saline) 1 week after tumor injection followed by SCM. CD8 T cells from mobilized grafts were transplanted with BM and CD4 T cells from naïve B6 into lethally irradiated Vk*MYC bearing recipients (Figure 1A). Recipients transplanted with CD8 T cells from Treg depleted donors had dramatically improved tumor control (Figure 1B) after ASCT compared to recipients of cells from Treg intact donors (survival 100 days post-ASCT; 100% for DT group vs 13% for saline group, P <0.0001). Rechallenge of mice surviving over 100 days after ASCT confirmed MM clone-specific immunity with complete elimination of the MM seen at initial ASCT, but not an unrelated clone. We next studied clinically relevant approaches to mimic this scenario. Administration of TIGIT, CTLA4, CD25 or LAG3 antibodies resulted in inadequate Treg depletion in BM to recapitulate this effect. In contrast, a synthetic IL-2/IL-15 mimetic NL-201 that selectively binds the beta and gamma chains of IL-2 receptor but not the high affinity IL-2Ra (CD25) reduced BM Treg (45.9% vs 18.6%, P <0.05) and expanded polyfunctional effector cells expressing IFNg+TNF+GzmB+ in SCM grafts. MM-bearing mice transplanted with NL-201 mobilized CD8 T cells were also protected against relapse after ASCT (survival 100 days post-ASCT; 87.5% for NL-201 group vs 25% for saline group, P <0.05). This protection was characterized by expansion of antigen experienced (CD38+) and cytokine secreting (TNF, IFNg) memory (CD44+) CD8 T cells in the BM 3 weeks after ASCT. BM CD8 T cells and Treg are efficiently mobilized after G-CSF/plerixafor. Depletion of Treg in donors during SCM dramatically increases myeloma specific T cells in stem cell grafts and enhances myeloma-specific immunity after ASCT. Stem cell mobilization in the presence of the synthetic IL-2/15 mimetic NL-201 is a promising clinically tractable approach to recapitulate these effects. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abatacept for the Prevention of Gvhd in Pediatric and Adult Patients Receiving 7/8 HLA-Mismatched Unrelated Transplant for Hematologic Malignancies: A Real-World Analysis

Background: Recipients of HLA mismatched unrelated donor (MMURD) hematopoietic cell transplant (HCT) are at increased risk for severe acute graft versus host disease (aGVHD) and treatment related mortality (TRM). Abatacept, CTLA4-Ig was granted FDA approval for the prevention of aGVHD in patients receiving unrelated donor HCT in part based on results of ABA2, a phase II trial evaluating abatacept in addition to standard immunoprophylaxis (calcineurin inhibitor (CNI)/ methotrexate (MTX) for GVHD prevention in either 8/8 MUD or 7/8 MMURD HCT (Watkins et al., 2021). The 7/8 MMURD cohort from ABA2 showed a significant reduction in grade III-IV aGVHD compared with a matched cohort from the CIBMTR receiving CNI/MTX alone (2.3% vs 30.2%, P<0.001). The lower rates of severe aGVHD translated into significant improvements in TRM and overall survival (OS) at 2 years for patients receiving abatacept. While ABA2 included pediatric and adult patients in the analysis, outcomes were not reported separately. Furthermore, there may be selection bias associated with study eligibility and participation that could result in benefits that may not translate into everyday clinical practice. Objectives: To determine the real-world impact of abatacept combined with CNI/MTX on the development of acute and chronic GVHD, survival, and relapse in pediatric and adult patients with hematologic malignancies receiving of 7/8 MMURD HCT as standard of care (off-study). Methods: We conducted a multi-center retrospective analysis of outcomes for pediatric and adult patients receiving a 7/8 MMUD HCT (bone marrow (BM) or peripheral blood stem cells (PBSC)) for hematologic malignancies and received GVHD prophylaxis with abatacept (4 doses on days -1, +5, +14, and +28) combined with CNI/MTX between January 2015 and December 2021. Patients were excluded if they were on ABA2, not in remission at time of HCT, received a prior HCT, or required additional GVHD prophylaxis. The analysis included consecutive adult patients transplanted at Emory University and pediatric patients transplanted at Children's Healthcare of Atlanta and Boston Children's Hospital. Data were analyzed for all patients and for pediatric and adult patients as separate cohorts. Results: A total of 50 consecutive patients (27 pediatric patients and 23 adult patients) met inclusion criteria. Median follow up was 759 days. Twenty-five of 27 pediatric patients received BM grafts while 20 out of 23 adult patients received PBSC. Grade II-IV aGVHD at day 180 was 40%, 48% and 28% for all patients, pediatric patients and adult patients, respectively. Grade III-IV aGVHD at day 180 was 10%, 5% and 15% for all, pediatric and adult patients respectively. Moderate-severe chronic GVHD (cGVHD) at 1 year was 49%, 56% and 42% for all, pediatric and adult patients respectively. TRM at day 180 was 8%, 7% and 9% for all, pediatric and adult patients respectively. OS at 1 year was 82%, 85% and 78% for all, pediatric and adult patients respectively. Relapse at 1 year was 16%, 15% and 17% for all, pediatric and adult patients respectively Disease-free survival (DFS) at 1 year was 73%, 77% and 70% for all, pediatric and adult patients respectively. Grade III-IV aGVHD free, severe cGVHD free, relapse free survival at day 180 was 74%, 70% and 78% for all, pediatric and adult patients respectively. Conclusion: Our real-world results using abatacept prophylaxis for 7/8 MMUD HCT compared favorably with ABA2 results with low incidence of grade III-IV aGVHD and TRM and encouraging DFS. These results are promising given that our off-study patients had more advanced disease compared to the patients on ABA2 (27% vs 13%). This was especially true in our adult patients where 50% had advanced disease and almost all received PBSC grafts. This study was the first to analyze and report outcomes separately for pediatric and adult patients receiving abatacept for GVHD prophylaxis. Our results indicate that both pediatric and adult patients had favorable outcomes with abatacept. Similar to results from ABA2, cGVHD rates were not reduced with the 4 dose abatacept regimen and further studies are needed to evaluate the efficacy of extended dosing abatacept to mitigate this risk. Our real-world results mirrored the results from ABA2 and suggest that the addition of abatacept to standard immunoprophylaxis for our highest risk patients can be effective at substantially improving aGVHD related transplant outcomes in MMUD recipients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Minimal residual disease detected by droplet digital PCR in peripheral blood stem cell grafts has a prognostic impact on high-risk neuroblastoma patients

sMore than half of high-risk neuroblastoma (NB) patients have experienced relapse due to the activation of chemoresistant minimal residual disease (MRD) even though they are treated by high-dose chemotherapy with autologous peripheral blood stem cell (PBSC) transplantation. Although MRD in high-risk NB patients can be evaluated by quantitative PCR with several sets of neuroblastoma-associated mRNAs (NB-mRNAs), the prognostic significance of MRD in PBSC grafts (PBSC-MRD) is unclear. In the present study, we collected 20 PBSC grafts from 20 high-risk NB patients and evaluated PBSC-MRD detected by droplet digital PCR (ddPCR) with 7NB-mRNAs (CRMP1, DBH, DDC, GAP43, ISL1, PHOX2B, and TH mRNA). PBSC-MRD in 11 relapsed patients was significantly higher than that in 9 non-relapsed patients. Patients with a higher PBSC-MRD had a lower 3-year event-free survival (P = 0.0148). The present study suggests that PBSC-MRD detected by ddPCR with 7NB-mRNAs has a prognostic impact on high-risk NB patients.

ATG in HLA-Matched, Peripheral Blood, Hematopoietic Cell Transplantation in Acute Myeloid Leukemia and Myelodysplastic Syndrome: A Secondary Analysis of a CIBMTR Database

w?>Peripheral blood stem cells (PBSC) are the preferred grafts for hematopoietic cell transplantation (HCT), according to the CIBMTR. Donor recovery is faster with PBSC harvest, but PBSC is associated with higher chronic graft-versus-host disease (GVHD) and poorer quality of life. Anti-T-cell globulin (ATG) is polyclonal IgG from rabbits or horses immunized with human thymocytes or a human T-cell line, which may reduce GVHD in HCT and improve outcomes. The objective of this study was to analyze the impact of ATG in HLA-matched related (MRD) and matched (HLA 8/8) unrelated donor (MUD) HCT. We used a freely available CIBMTR database published online for secondary analyses. The database included patients ≥ 40 years old who have undergone their first PBSC MRD or MUD HCT for acute myeloid leukemia or myelodysplastic syndrome with or without ATG between 2008 and 2017. Patients who received posttransplant cyclophosphamide or alemtuzumab were excluded. Overall survival was not different with ATG (hazard ratio [HR] = 1.09; 95% confidence interval [CI], 1.00-1.19; P = .06) compared with no ATG. Relapse rate was higher with ATG (HR = 1.29; 95% CI, 1.17-1.43; P < .001) and non-relapse mortality was lower with ATG (HR = 0.84; 95% CI, 0.72-0.98; P = .03). Grades II-IV acute GVHD was significantly lower with ATG (HR = 0.77; 95% CI, 0.69-0.87; P < .001) but not grades III-IV acute GVHD (HR = 0.85; 95% CI, 0.69-1.04; P = .11). Both chronic GVHD (HR = 0.54; 95% CI, 0.48-0.60; P < .001) and moderate/severe chronic GVHD (HR = 0.45; 95% CI, 0.38-0.52; P < .001) were lower with ATG. There was an interaction between ATG and conditioning regimen for relapse rate and overall survival. Relapse rate was higher in those who received reduced-intensity (RIC) or non-myeloablative (NMA) conditioning regimens and ATG, compared with MAC ± ATG or RIC without ATG (interaction test, P = .003). Overall survival was also poorer with ATG and RIC or NMA conditioning regimens (interaction test, P = .03). Our results show that ATG can mitigate the more severe forms of chronic GVHD without impairing overall survival in HLA-matched HCT with PBSC grafts and myeloablative conditioning regimen. ATG should be standard in this population.© 2023 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Effect of Cryopreservation in Unrelated Bone Marrow and Peripheral Blood Stem Cell Transplantation in the Era of the COVID-19 Pandemic: An Update from the Japan Marrow Donor Program

During the COVID-19 pandemic, donor grafts are frequently cryopreserved to ensure that a graft is available before starting a conditioning regimen. However, there have been conflicting reports on the effect of cryopreservation on transplantation outcomes. Also, the impact of cryopreservation may differ in bone marrow (BM) transplantation (BMT) and peripheral blood stem cell (PBSC) transplantation (PBSCT). In this retrospective study, we analyzed the clinical data of both cryopreserved unrelated BMTs (n = 235) and PBSCTs (n = 118) and compared these with data from a large control cohort without cryopreservation including 4133 BMTs and 720 PBSCTs. Among the patients with cryopreserved grafts, 10 BMT recipients (4.3%) and 3 PBSCT recipients (2.5%) did not achieve neutrophil engraftment after transplantation, including 4 of the former and all 3 of the latter who died early before engraftment. In a multivariate analysis, cryopreservation was not associated with neutrophil engraftment in BMT but significantly delayed neutrophil engraftment in PBSCT (hazard ratio [HR], .82; 95% confidence interval [CI], .69 to .97; P = .023). There was an interaction with borderline significance between cryopreservation and the stem cell source (P = .067). Platelet engraftment was delayed by cryopreservation after both BMT and PBSCT. Only 2 cryopreserved grafts (<1%) were unused during the study period. The cryopreservation of unrelated donor BM and PBSC grafts is associated with a slight delay in neutrophil and platelet engraftment but an acceptable rate of graft failure. PBSC grafts may be more sensitive to cryopreservation than BM grafts. Cryopreservation is a reasonable option during COVID-19 pandemic, provided that the apheresis and transplantation centers are adept at cryopreservation.© 2022 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

The Outcome of Allogeneic Hematopoietic Stem Cell Transplantation From Different Donors in Recipients With Mucopolysaccharidosis.

There is limited information regarding hematopoietic stem cell transplantation (HSCT) for mucopolysaccharidosis (MPS) IV and VI. This study examined the full donor chimerism, specific lysosomal enzyme levels, and the survival of different MPS children after HSCT from various donor sources and compared the prognosis. A total of 42 children with MPS underwent HSCT, 9 cases were type I, 14 were type II, 15 were type IV, and 4 were type VI. A total of 24 patients received peripheral blood stem cells (PBSC) and 18 patients received umbilical cord blood (UCB). Patients who received PBSC were conditioned with intravenous (IV) busulfan every 6 h for a total of 16 doses, IV cyclophosphamide (CY, 200 mg/kg), and antihuman thymocyte globulin (ATG, 10 mg/kg). While conditioning regimen of patients who received UCB was adjusted to ATG (preposed, pre-) + busulfan + fludarabine + Cy, which includes IV ATG (pre-, 6 mg/kg), IV busulfan every 6 h for a total of 16 doses, IV fludarabine (200 mg/m2) and CY (200 mg/kg). Also, 95.2% (40 of 42) of patients achieved full donor chimerism, and all patients’ specific lysosomal enzyme levels reached normal. The estimated overall survival (OS) at 1 year was 92.9%. There was no significant difference in 1-year OS between patients who received PBSC transplantation and those who received UCB grafts (87.5% vs. 100%, p = 0.0247). The incidence of acute and chronic GVHD did not differ between them. The incidences of pneumonia in PBSC recipients and UCB recipients were 45.8 and 33.3%, respectively, but there few patients suffering from respiratory failure (4.2 and 5.6%, respectively) due to pneumonia. The incidence of cytomegaloviremia was also high in both groups, 58.3 and 44.4% respectively, However, no patient developed CMV disease. All deaths (3 of 42) occurred in patients receiving PBSC grafts, and there was no death in patients receiving UCB grafts. There was no death after transplantation in patients with MPS IV and VI. In addition, respiratory and nervous system functions were improved, whereas valvular heart disease was improved in some patients but progressed in more patients after transplantation. In summary, HSCT is a good therapeutic option for MPS, not only for patients with MPS I or II but also for those with MPS IV or VI. The specific lysosomal enzyme levels can be completely restored to normal, which is the basis for patients to resolve a broad range of clinical outcomes. Moreover, UCB with suitable HLA (HLA-match above 7/10 and 4/6) is a suitable donor source for MPS. Patients who underwent UCB transplantation using the conditioning regimen ATG (pre-) + busulfan + fludarabine + Cy can achieve a higher proportion of full donor chimerism and survival with less severe complications. HSCT can improve organs function in patients with MPS, but it is still worth exploring.

The Viability of Hematopoietic Progenitor Cell Grafts after Cryopreservation Does Not Predict Delayed Engraftment in Allogeneic Hematopoietic Stem Cell Transplantation.

Due to the COVID-19 pandemic, more peripheral blood stem cell (PBSC) allogeneic grafts are being frozen and infused thawed. Our objective was to study the influence of graft viability on engraftment outcome in patients treated with PBSCs. Using trypan blue stain, we compared total nucleated cell (TNC) viability of both fresh and thawed grafts in allogeneic PBSCs. The viability of thawed PBSC grafts median was 74%, and fresh was 99.0%. The median number of CD34 + cells/kg infused thawed was 6.3 × 106/kg and median time to neutrophil and platelet engraftment was 17.5 and 20 days. Median number of CD34 + cells/kg infused fresh was 5.1 × 106/kg and median time to neutrophil and platelet engraftment was 18 and 19 days. There were no statistically significant differences in the time to engraftment between the 2 groups. A low TNC viability of thawed PBSC grafts does not have an effect on time to neutrophil and platelet engraftment when more than 2.85 × 106 CD34 + cells/kg are infused.

Impact of donor kinship on non-T-cell depleted haploidentical stem cell transplantation with post transplantation cyclophosphamide for acute leukemia: From the ALWP of the EBMT.

Non-T-cell depleted haploidentical hematopoietic cell transplantation (Haplo-HCT) is a unique transplantation setting in which several donors are available. We assessed the impact of donor kinship on outcome of Haplo-HCT with post-transplantation cyclophosphamide in a cohort of 717 acute leukemia patients. We compared sibling with parent donors in patients ≤45 years, and child with sibling donors in patients >45 years. Donor kinship was not associated with worse outcomes in multivariate analysis. For patients ≤45 years, the hazard ratio (HR) for leukemia-free survival (LFS), overall survival (OS), relapse incidence (RI), and chronic graft-versus-host disease (cGVHD) was 0.87 (p = 0.75), 1.19 (p = 0.7), 0.52 (p = 0.19), and 0.99 (p = 0.97) for parents versus siblings, respectively, and for patients >45 years the HR was 0.93 (p = 0.8), 0.98 (p = 0.94), 1.3 (p = 0.53), and 0.98 (p = 0.95) for children versus siblings, respectively. Univariate incidence of acute GVHD grade II-IV was significantly higher in patients transplanted from siblings versus children (p = 0.002). Factors associated with inferior outcome were advanced disease and earlier transplant. In patients ≤45 years, acute lymphocytic leukemia and peripheral blood stem cell graft were additional prognostic factors for OS. We did not find a significant impact of donor kinship on transplantation outcome when analyzing by age group (≤45 and >45 years).

Endothelial Activation and Stress Index-Measured Pretransplantation Predicts Transplantation-Related Mortality in Patients with Thalassemia Major Undergoing Transplantation with Thiotepa, Treosulfan, and Fludarabine Conditioning

The use of thiotepa-treosulfan-fludarabine conditioning regimen and peripheral blood stem cell grafts is associated with improved outcomes of hematopoietic stem cell transplantation (HCT) in patients with high-risk thalassemia major. However, there remains a need to identify predictors of poor outcomes in this cohort to further optimize outcomes. The Endothelial Activation and Stress Index (EASIX) is a biomarker shown to predict survival in various settings, including graft-versus-host disease, veno-occlusive disease, and nonrelapse mortality following allogeneic HCT. In this retrospective analysis, we evaluated the role of EASIX-PreTx (measured before conditioning therapy) as a biomarker in predicting day +100 transplantation-related mortality (TRM+100) in 281 patients with thalassemia major who underwent HCT with a uniform conditioning regimen using thiotepa-treosulfan-fludarabine at our center between January 2012 and December 2019. The median patient age was 9 years (range, 1 to 25 years), and 109 (38.8%) were females. According to the Pesaro classification (with Vellore modification), 3 patients (1.1%) were class I, 34 (12.1%) were class II, 134 (47.7%) were class III low risk, and 110 (39.1%) were class III high risk. Stem cell donors were matched sibling (n=218; 77.6%), matched related nonsibling (n=23; 8.2%), or matched unrelated (n=40; 14.2%). Five patients (1.8%) received a bone marrow graft, and the others received a peripheral blood stem cell graft. Thirty-eight patients (13.5%) had TRM+100. EASIX-PreTx was available for 184 patients (65.5%). The median EASIX-PreTx was significantly higher in patients with TRM+100 compared with those without TRM+100 (1.09 versus .75; P=.008). An EASIX-PreTx cutoff of .85 had 70.4% sensitivity and 62% specificity for predicting TRM+100. The TRM+100 for patients with EASIX-PreTx >.85 was significantly higher than those with EASIX <.85 (24.4% versus 7.5%; P=.003). In a uniform subgroup of class III patients undergoing allogeneic HCT (n=156), EASIX-PreTx was an independent predictor of TRM+100.

CD34+ -selected hematopoietic stem cell transplant conditioned with a myeloablative regimen in patients with advanced myelofibrosis.

Allogeneic hematopoietic stem cell transplantation (Allo-HCT) remains the only curative treatment for myelofibrosis (MF). Transplantation in patients with MF is mostly done using a reduced intensity conditioning regimen with calcineurin inhibitors for graft versus host disease (GVHD) prophylaxis. Here we sought to evaluate outcomes of patients who underwent an ex vivo CD34+ -selected allo-HCT using myeloablative conditioning (MAC). Twenty-seven patients were included in this retrospective analysis. All patients were conditioned with busulfan, melphalan and fludarabine and antithymocyte globulin to prevent graft rejection. G-CSF mobilized peripheral blood stem cell grafts were depleted of T-cells using immunomagnetic CD34+ selection by CliniMACS device. Median follow-up among survivors was 50.6 months. The estimated 3-year overall survival, relapse free survival and the combined endpoint of GVHD/relapse free survival were 88% (95% CI, 75-100%), 80% (95% CI, 66-98%) and 74% (95% CI, 59-93%), respectively. The cumulative incidence of grade II-IV acute GVHD at day 100 was 33.3% (95% CI 16.4-51.3%), and two patients suffered chronic GVHD. There were no cases of primary graft failure. However, delayed graft failure occurred in two patients. We conclude that CD34+ selected allo-HCT with a MAC resulted in high survival rates in this cohort of patients with MF.

Myeloproliferative neoplasms – a global view

Myeloproliferative neoplasms – a global view

Updated Trends in Hematopoietic Cell Transplantation in the United States with an Additional Focus on Adolescent and Young Adult Transplantation Activity and Outcomes

Hematopoietic cell transplantation (HCT) has been successfully used to treat many malignant and nonmalignant conditions. As supportive care, donor selection, and treatment modalities evolve, documenting HCT trends and outcomes is critical. This report from the Center for International Blood and Marrow Transplant Research (CIBMTR) provides an update on current transplantation activity and survival rates in the United States. Additional data on the use and outcomes of HCT in the adolescent and young adult (AYA) population are included. AYA patients more frequently receive peripheral blood stem cell grafts than pediatric patients, which may reflect differences in practice in pediatric versus adult treatment centers. The proportions of donor types also differ those in adult and pediatric populations. Outcomes for patients in the AYA age range are similar to those of pediatric patients for acute myelogenous leukemia but worse for acute lymphoblastic leukemia. Outcomes for both leukemias are better in AYA patients compared with older adults. Comparing the time periods 2000 to 2009 and 2010 to 2019 revealed significant improvement in overall survival across the age spectrum, but the greatest improvement in the AYA age group.

Targeting the Retinoid X Receptor Pathway Prevents and Ameliorates Murine Chronic Graft-Versus-Host Disease.

Most allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients receive peripheral blood stem cell grafts resulting in a 30%–70% incidence of chronic graft-versus-host disease (cGVHD), a major cause of mortality and morbidity in long-term survivors. While systemic steroids remain the standard of care for first-line therapy, patients may require long-term administration, and those with steroid-resistant or refractory cGVHD have a worse prognosis. Although durable and deep responses with second-line therapies can be achieved in some patients, there remains an urgent need for new therapies. In this study, we evaluated the efficacy of IRX4204, a novel agonist that activates RXRs and is in clinical trials for cancer treatment to prevent and treat cGVHD in two complementary murine models. In a major histocompatibility complex mismatched, non-sclerodermatous multiorgan system model with bronchiolitis obliterans, IRX4204 prevented and reversed cGVHD including associated pulmonary dysfunction with restoration of germinal center T-follicular helper: T-follicular regulatory cell balance. In a minor histocompatibility antigen disparate sclerodermatous model, IRX4204 treatment significantly prevented and ameliorated skin cGVHD by reducing Th1 and Th17 differentiation due to anti-inflammatory properties. Together, these results indicate that IRX4204 is a promising therapeutic option to treat cGVHD with bronchiolitis obliterans or sclerodermatous manifestations.

Impact of Donor-to-Recipient ABO Mismatch on Outcomes of Antithymocyte Globulin-Based Peripheral Blood Stem Cell-Derived Myeloablative Conditioning Haploidentical Stem Cell Transplantation

ABO incompatibility is common in hematopoietic stem cell transplantation (HSCT); however, the impact of donor-recipient ABO compatibility on transplantation outcomes in different HSCT settings is controversial. Moreover, haploidentical stem cell transplantation (haplo-SCT) with peripheral blood stem cell (PBSC)-derived grafts has not been well investigated. The present study aimed to investigate the impact of ABO incompatibility on post-transplantation outcomes, engraftment kinetics, blood product requirements, transfusion independence, and the incidence of poor graft function (PGF) in antithymocyte globulin (ATG)-based haplo-SCT with PBSC grafts during long-term follow-up. We prospectively evaluated 510 patients with hematologic malignancies who underwent haplo-SCT after myeloablative conditioning (MAC). The primary endpoint was overall survival (OS), and secondary endpoints were nonrelapse mortality (NRM), graft-versus-host disease (GVHD), relapse, neutrophil and platelet engraftment, blood transfusion requirements, transfusion independence, and the incidence of PGF. There was no significant association between ABO matching and OS, disease-free survival (DFS), relapse, NRM, grade II-IV acute GVHD, grade III-IV acute GVHD, and moderate and severe chronic GVHD. There were also no significant differences in neutrophil and platelet engraftment, blood transfusion independence, and transfusion requirements at 30, 60, 90, 180, and 365 days post-transplantation among patients with ABO matching and those with minor, major, or bidirectional ABO incompatibility. Donor-recipient ABO matching did not differ significantly according to graft function (good versus poor). ABO incompatibility status has no major impact on patient outcomes in patients with hematologic malignancies undergoing ATG-based MAC haplo-SCT with PBSC-derived grafts.

The impact of transportation time on apoptosis in allogeneic stem cell grafts and the clinical outcome in malignant patients with unrelated donors

BackgroundThe quality of cells in peripheral blood stem cell (PBSC) grafts is important for allogeneic stem cell transplantation outcome. The viability of PBSC grafts may decrease during transportation time between donor and transplant center. We hypothesize that the graft viability based on apoptosis and necrosis in the graft may better reflect graft quality and clinical outcome. MethodsPBSC graft viability from unrelated donors was analyzed in 91 patients. Viable cells were defined as 7-aminoactinomycin D– and Annexin V–negative. The clinical outcome, including survival, transplant-related mortality and graft-versus-host disease (GvHD), was correlated to graft viability. ResultsGrafts transported for 1 day had a median viability of 86.4% (range 63.8 to 98.9%), and grafts transported for 2 days had median viability of 83.2% (range 52.8% to 96.2%) (P = .003). Grafts were divided into two groups based on the median graft viability of 85.1%. Patients who received low viability grafts had lower 1-year survival of 63.7% compared with 88.9% for those who received high viability grafts (P = .007). In the multivariate analysis, transplant-related mortality (TRM) was higher in the low viability group (P = .03), whereas overall survival was not significantly associated with graft viability. The incidence of acute GvHD grade II to IV, chronic GvHD and relapse risk remained comparable between the groups. ConclusionLow graft viability was an independent predictor of 1-year survival and TRM after adjusting for multiple confounders. Better graft quality markers are important for the detection of clinically important variations in the stem cell graft.

Addition of a Single Low Dose of Anti T-Lymphocyte Globulin to Post-Transplant Cyclophosphamide after Allogeneic Hematopoietic Stem Cell Transplant: A Pilot Study.

Correlation between risk of graft-versus-host disease (GvHD) and CD3+ counts within the peripheral blood stem cell graft has recently been reported in the setting of post-transplant cyclophosphamide (PT-Cy). We aimed to investigate the benefit of the addition of a single dose of anti-T lymphocyte globulin (ATLG 5 mg/kg) to PT-Cy in this setting. Starting in 2019, all patients receiving PBSC transplant containing CD3+ counts above 300 × 106/kg (study group) received a post-transplant dose of ATLG in addition to standard PT-Cy. The study was designed as a real-life analysis and included all consecutive Hematopoietic Stem Cell Transplantation (HSCT) recipients according to the above-mentioned inclusion criterion (n = 21), excluding cord blood and bone marrow donors. Using a 1:2 matched-pair analysis, we compared the outcomes with a historical population who received PT-Cy only (control group). We found a delayed platelet engraftment (29% vs. 45% at 30 days, p = 0.03) and a non-significant trend toward higher risk of poor graft function (29% vs. 19%, p = 0.52). The addition of ATLG impacted long-term immune reconstitution on the CD4+ subsets, but this did not translate into higher rate of relapse or viral infection. Acute GvHD was not significantly impacted, but 1-year cumulative incidence of chronic GvHD was significantly lower in the study group (15% vs. 41%, p = 0.04). Survival outcomes were comparable. In conclusion PT-Cy and ATLG was overall safe and translated into a low rate of chronic GvHD incidence.