Grade 2 acute GVHD is a factor of good prognosis in patients receiving peripheral blood stem cells haplo-transplant with post-transplant cyclophosphamide.

BACKGROUND: The impact of acute graft versus host disease (GVHD) on survivals for patients receiving a haploidentical allogeneic stem-cell transplant (Allo-SCT) with peripheral blood stem-cells (PBSC) complemented by post-transplant cyclophosphamide (PTCY) is ill-known. MATERIAL AND METHODS: This retrospective study included 131 patients who received a PBSC haplograft in order to precise the impact of acute GVHD on outcomes. There were 78 males and 53 females and the median age for the whole cohort was 59 years (range: 20-71). Thirty-five patients were allografted for a lymphoid disease and 96 for a myeloid malignancy, including 67 patients with acute myeloid leukemia (AML). RESULTS: The cumulative incidence (CI) of day 100 grade 2-4 and 3-4 acute GVHD was 43.4 + 4.6% and 16.7 + 3.4%, respectively. The 2-year CI of moderate/severe chronic GVHD was 10.1 + 2.8%. The only factor affecting the occurrence of GVHD was GVHD prophylaxis. Indeed, CI of day 100 grade 2-4 (but not grade 3-4) acute GVHD was significantly reduced when adding anti-thymoglobulin (ATG) to PTCY. However, in multivariate analysis, grade 2 acute GVHD was significantly associated with better disease-free (HR: 0.36; 95%CI: 0.19-0.69, p = .002) and overall (HR: 0.35; 95%CI: 0.1-0.70, p = .003) survivals. The same results were observed when considering only AML patients. CONCLUSION: Acute grade 2 GVHD is a factor of good prognosis after PBSC haplotransplant with PTCY. Further and larger studies are needed to clarify the complex question of GVHD prophylaxis in the setting of haplo-transplant, especially that of combining ATG and PTCY.

Unmanipulated haplo-identical donor transplantation compared with identical sibling donor had better anti-leukemia effect for refractory/relapsed acute myeloid leukemia not in remission status.

Prior studies have suggested that for leukemia patients with high-risk features, haplo-identical-hematopoietic stem cell transplantation (HID-HSCT) has a stronger anti-leukemia effect compared with HSCT using an identical sibling donor (ISD-HSCT). However, it is unclear whether an HID-HSC transplant also augments the graft-versus-leukemia (GVL) effect among refractory/relapsed (R/R) acute myeloid leukemia (AML) patients who are not in remission (NR). We conducted a retrospective analysis of 124 R/R AML patients with NR status who underwent HID-HSCT between April 2012 and December 2016 and compared these to 27 R/R AML patients who underwent an ISD-HSCT within the same timeframe. Among all of the patients, 68 (45.0%) had primary induction failure (PIF) and 83 (54.9%) were relapsed and had failed to respond to at least one cycle of salvage combination chemotherapy. Myeloablative conditioning regimens were administered to all patients. Here, we present a retrospective multivariate analysis of pre-transplantation risk factors and characteristics of all 151 patients and developed a predictive scoring system to predict patient survival. The median period of follow-up was 46 months for all patients. The HID cohort had a higher 5-year overall survival (OS) compared with the ISD cohort (48.6% ± 4.6% vs 25.9% ± 8.4, respectively; P = 0.017) and higher LFS (leukemia-free survival) (41.6% ± 7.5% vs 25.9% ± 8.4%, respectively; P = 0.019). There was no difference in the 5-year cumulative incidence of non-relapse mortality (NRM) (18.0% ± 3.8% and 34.9% ± 12.6%, respectively; P = 0.212) between the two group. However, the 5-year cumulative incidence of relapse (CIRs) was lower in the HID group compared with the ISD group (55.4% ± 8.9% vs 67.3% ± 9.9%, respectively; P = 0.021). Multivariate analysis showed three risk factors associated with OS and LFS: (1) ISD-HSCT, (2) use of a standardized conditioning regimen, and (3) less than 50% proportional reduction of blast cells in the bone marrow (BM). Based on these three risk factors, we developed a predictive scoring system for R/R AML patients undergoing HSCT. Patients who had a predictive score of 0 and 1 had a 66.6% ± 4.5% and 44.1% ± 3.6% OS rate at 5 years, respectively. Patients with a score ≥ 2 had only a 4.4 ± 0.2% OS rate at 5 years. An HID-HSCT had a better anti-leukemia effect among R/R AML patients with an NR status compared with an ISD-HSCT. We also identified pre-transplantation risk factors to delineate subgroups that could derive maximal benefit from HSCT.

A retrospective analysis on anti-CD20 antibody-treated Epstein-Barr virus-related posttransplantation lymphoproliferative disorder following ATG-based haploidentical T-replete hematopoietic stem cell transplantation.

Posttransplantation lymphoproliferation disorder (PTLD) is a life-threatening complication after hematopoietic stem cell transplantation (HSCT). Anti-CD20 antibody is the most widely used antibody to eliminate infected B cells. Few studies have focused on prognostic factors predicting the outcome of EBV (Epstein-Barr virus)-PTLD. We conducted a retrospective analysis of 2571 haplo-HSCTs performed between 2010 and 2017 at the Peking University Institute of Hematology; seventy patients who had been treated with rituximab for PTLD were enrolled. The overall EBV-related PTLD frequency was 3.1%. With a median follow-up time of 365 days (range, 54-2659), the overall survival rate was 51.43% (36/70). The cumulative incidence of EBV-PTLD complete remission with anti-CD20 antibody monotherapy was 68.57% (48/70). EBV-PTLD-related mortality was 11.43% (8/70), while the transplantation-related mortality was 38.57% (27/70). Multivariate analysis showed that a decrease in EBV viral load 1 week after therapy was associated with high response rate of EBV-PTLD (p = 0.007, 0.106 (0.021-0.549)), low PTLD-related mortality (p = 0.010, HR 0.058 (0.007-0.503)), and transplantation-related mortality (p = 0.051, HR 0.441 (0.194-1.003)). For EBV-PTLD patients after haplo-HSCT who received rituximab as first-line therapy, non-decreased EBV viral load 1 week after anti-CD20 therapy could be high risk factor for poor outcomes.

G-CSF-primed haplo-identical HSCT with intensive immunosuppressive and myelosuppressive treatments does not increase the risk of pre-engraftment bloodstream infection: a multicenter case-control study.

A multicenter retrospective study in 131 patients (44 females/87 males) with hematological disorders who underwent G-CSF-primed/haplo-identical (Haplo-ID) (n = 76) or HLA-identical (HLA-ID) HSCT (n = 55) from February 2013 to February 2016 was conducted to compare the incidence and risk factors for pre-engraftment bloodstream infection (PE-BSI). In the Haplo-ID group, 71/76 patients with high-risk (n = 28) or relapsed/refractory hematological malignancies (n = 43) received FA5-BUCY conditioning (NCT02328950). All received trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis. Blood cultures and catheter tip cultures were obtained to confirm the BSI. PE-BSI was detected in 24/131 HSCT patients (18/76 in Haplo-ID and 6/55 in HLA-ID) after 28 febrile neutropenic episodes. Among 28 isolates for the 24 patients, 21 (75%) were Gneg bacteria, 6 (21.4%) Gpos and 1 (3.6%) fungi. Bacteria sources were central venous line infection (7/29.2%), gastroenteritis (6/25%), lower respiratory tract infection (LRTI; 5/20.8%), perianal skin infection (4/16.7%), and unknown (2/8.3%). The duration of neutropenia (P = 0.046) and previous Gneg bacteremia (P = 0.037) were important risk factors by univariate analysis, while the type of HSCT was not. A trend of TMP-SMX-resistant BSI in both groups may be due to routine antibacterial prophylaxis strategies. Our data show that G-CSF-primed Haplo-ID HSCT did not increase the risk of PE-BSI, even with intensive immunosuppressive treatments.

Post transplant cyclophosphamide based haplo-identical transplant versus umbilical cord blood transplant; a meta-analysis.

OBJECTIVES: Both haplo-identical transplant (haplo) and umbilical cord transplant (UC) are valuable graft options for patients without available matched relative. Previous studies showed inconsistent outcomes comparing Post transplant Cyclophosphamide based haplo (PTCy-haplo) and UC; therefore, we attempt to compare the studies by mean of meta-analysis. METHODS: We searched for titles of articles in MEDLINE (PubMed), Cochrane library, EMBASE database and Google scholar that compared transplantation with PTCy-haplo versus UC. We conducted a random-effect meta-analysis of seven studies involving a total of 3434 participants and reported the pooled odd ratios (OR) of acute graft-versus-host disease (aGVHD), chronic graft-versus-host disease (cGVHD), relapse and overall survival (OS) between PTCy-haplo and UC groups. RESULTS: We found a significantly decreased risk of aGVHD and relapse in the PTCy-haplo group compared to the UC group with a pooled OR of 0.78, 95% Confidence Interval (CI) 0.67-0.92, I2=0%, and 0.74, 95% CI 0.57-0.97, I2=23.9% respectively. We also found a significantly increased rate of cGVHD and OS with a pooled OR of 1.41, 95% CI 1.02-1.95, I2=56.8%, and 1.77, 95% CI 1.1-2.87, I2=82.5%, respectively. CONCLUSION: Our meta-analysis of clinical trials demonstrated superior outcome from PTCy-haplo group compared to the UC group in terms of decreased rate of aGVHD and relapse as well as the increased rate of OS but inferior in terms of increased cGVHD risk compared to UC transplant.

Haplo-identical allografting with post-transplant cyclophosphamide in high-risk patients.

Haplo-identical transplants (Haplo-Tx) are an important alternative for patients with hematological malignancies who lack a HLA-identical donor. Seventy-one T-replete Haplo-Tx were performed in 70 high-risk patients at our center; 22/70 (31%) patients with refractory/relapsed leukemia received sequential salvage therapy (SeqTh) with high-dose chemotherapy followed by Haplo-Tx during the chemotherapy-induced neutropenia. Graft-versus-host disease (GVHD) prophylaxis consisted of post-transplant cyclophosphamide (days + 3 and + 4) with tacrolimus and mycophenolic acid. After a median follow-up of 29.2 months, 3-year overall survival (OS) and event-free survival (EFS) were 43.8 and 40.2%, while 3-year cumulative incidences (CIs) of non-relapse mortality (NRM) and relapse (RI) were 27 and 33%. Day 100 and day 400 CI of grade III-IV acute and moderate-severe chronic GVHD were 11 and 15%. Three-year RI was significantly lower in patients in complete remission (CR) versus those not in CR at the time of transplant (21.5 vs. 48%, p = 0.009) and in patients who received PBSC as compared to BM (22 vs. 45%, p = 0.009). In patients treated with SeqTh, 3-year OS was 19%, while 3-year RI and NRM were 52 and 28% at a median follow-up of 50 months. Overall, Haplo-Tx was feasible in heavily pretreated high-risk patients without a suitable HLA-identical donor.

[Cutaneous and systemic T-cell lymphoma treated with haploidentical bone marrow transplantation]. / Lymphome T cutané et systémique traité avec succès par greffe haplo-identique.

BACKGROUND: Herein, we report a case of systemic cutaneous T-cell lymphoma refractory to standard therapy, the course of which resulted in haplo-identical bone marrow grafting. PATIENTS AND METHODS: A 53-year-old woman consulted for facial erythema with infiltration, keratotic lesions on the trunk, and adenopathies measuring around 1cm on the axilla and inguinal folds. A diagnosis was made of Sézary syndrome (SS), a leukaemic form of epidermotropic cutaneous T-cell lymphoma. After three years of treatment with methotrexate, the patient developed transformed SS with visceral involvement. Given the high risk of relapse and the absence of an HLA-compatible donor, haploidentical bone marrow grafting was performed. The patient was still in complete remission two and a half years later. The disease course was nevertheless marked by the emergence one year after grafting of a Blaschko-distributed lichenoid eruption having histological features consistent with chronic graft-versus-host disease (GVHD); treatment with topical betamethasone proved efficacious. DISCUSSION: To our knowledge, this is the first reported case of haploidentical grafting for systemic and transformed cutaneous T-cell lymphoma. This approach could henceforth represent a therapeutic option for patients requiring an allograft in the absence of compatible donors. The Blaschko-distributed lichenoid lesions attributed to chronic GVHD could be the result of reduced immune tolerance to abnormal embryological clones leading to a T-lymphocyte-mediated inflammatory reaction.

Viral encephalitis after haplo-identical hematopoietic stem cell transplantation: Causative viral spectrum, characteristics, and risk factors.

OBJECTIVE: To retrospectively identify characteristics and risk factors of viral encephalitis (VE) in patients who underwent a haplo-identical hematopoietic stem cell transplant (HSCT). METHODS: A nested case-control study was designed. Cases with VE and controls were identified from a cohort composed of 1274 patients who underwent a haplo-identical HSCT from 2012 to 2015. RESULTS: VE was identified in 30 patients (2.4%). The median time from HSCT to diagnosis was 144.5 days. The viruses detected included RSV-B (43.3%), BKV (23.3%), more than one virus (10%), cytomegalovirus (CMV) (6.7%), RSV-A (6.7%), HSV (3.3%), HHV-6 (3.3%), and CVB3 (3.3%). Alterations of consciousness and seizures were the most frequently presented symptoms. Neuroimaging detected abnormalities in 19 (76%) patients. The cerebral spinal fluid cell count, protein, and glucose concentration were elevated in eight (26.7%), 18(60%), and nine (30%) patients, respectively. The treatment efficacy and prognoses varied considerably based on the different causative viruses. Multivariate analyses revealed that acute graft-versus-host disease (grade III-IV), CMV viremia, and engraftment syndrome were significantly and independently associated with VE. The cumulative mortality rate was significantly higher in patients suffering from VE than in the controls. CONCLUSION: Characteristics, such as onset time, response to treatment, and outcome, varied based on the different causative viruses.

Haploidentical T Cell-Replete Transplantation with Post-Transplantation Cyclophosphamide for Patients in or above the Sixth Decade of Age Compared with Allogeneic Hematopoietic Stem Cell Transplantation from an Human Leukocyte Antigen-Matched Related or Unrelated Donor.

It has recently been shown that a T cell-replete allogeneic (allo) hematopoietic stem cell transplantation (HSCT) from a haploidentical donor (haplo-ID) could be a valid treatment for hematological malignancies. However, little data exist concerning older populations. We provided transplantation to 31 patients over the age of 55 years from a haplo-ID and compared their outcomes with patients of the same ages who underwent transplantation from a matched related (MRD) or an unrelated donor (UD). All 3 groups were comparable, except for their conditioning. Patients in haplo-ID group received 2 days of post-transplantation high-dose cyclophosphamide followed by cyclosporine A and mycophenolate mofetil, whereas patients in other groups received pretransplantation antithymocyte globulin, cyclosporine A, and additional mycophenolate mofetil in case of 1-antigen mismatch. All patients but 1 in the haplo-ID group engrafted. The incidence of grades 2 to 4 acute graft-versus-host disease (GVHD) was not statistically different between recipients from haplo-ID (cumulative incidence, 23%) and MRD (cumulative incidence, 21%) transplantations but it was lower than after UD HSCT (cumulative incidence, 44%). No patient in the haplo-ID group developed severe chronic GVHD, compared with cumulative incidences of 16% and 14% after MRD (P = .02) and UD (P = .03) grafts, respectively. The cumulative incidences of relapse were similar in the 3 groups, whereas nonrelapse mortality after UD HSCT was 3-fold higher than after haplo-ID or MRD HSCT. Overall, 2-year overall survival (70%), progression-free survival (67%), and progression and severe chronic GVHD-free survival (67%) probabilities after haplo-ID did not statistically differ from MRD transplantation (78%, 64%, and 51%, respectively), although they were higher than after UD transplantation (51% [P = .08], 38% [P = .02], and 31% [P = .007]). We conclude that T cell-replete haplo-ID HSCT followed by post-transplantation high-dose- cyclophosphamide in patients over 55 years is associated with promising results, similar to MRD HSCT, and is deserving prospective evaluation.

Automation of cellular therapy product manufacturing: results of a split validation comparing CD34 selection of peripheral blood stem cell apheresis product with a semi-manual vs. an automatic procedure.

BACKGROUND: Automation of cell therapy manufacturing promises higher productivity of cell factories, more economical use of highly-trained (and costly) manufacturing staff, facilitation of processes requiring manufacturing steps at inconvenient hours, improved consistency of processing steps and other benefits. One of the most broadly disseminated engineered cell therapy products is immunomagnetically selected CD34+ hematopoietic "stem" cells (HSCs). METHODS: As the clinical GMP-compliant automat CliniMACS Prodigy is being programmed to perform ever more complex sequential manufacturing steps, we developed a CD34+ selection module for comparison with the standard semi-automatic CD34 "normal scale" selection process on CliniMACS Plus, applicable for 600 × 10(6) target cells out of 60 × 10(9) total cells. Three split-validation processings with healthy donor G-CSF-mobilized apheresis products were performed; feasibility, time consumption and product quality were assessed. RESULTS: All processes proceeded uneventfully. Prodigy runs took about 1 h longer than CliniMACS Plus runs, albeit with markedly less hands-on operator time and therefore also suitable for less experienced operators. Recovery of target cells was the same for both technologies. Although impurities, specifically T- and B-cells, were 5 ± 1.6-fold and 4 ± 0.4-fold higher in the Prodigy products (p = ns and p = 0.013 for T and B cell depletion, respectively), T cell contents per kg of a virtual recipient receiving 4 × 10(6) CD34+ cells/kg was below 10 × 10(3)/kg even in the worst Prodigy product and thus more than fivefold below the specification of CD34+ selected mismatched-donor stem cell products. The products' theoretical clinical usability is thus confirmed. CONCLUSIONS: This split validation exercise of a relatively short and simple process exemplifies the potential of automatic cell manufacturing. Automation will further gain in attractiveness when applied to more complex processes, requiring frequent interventions or handling at unfavourable working hours, such as re-targeting of T-cells.

A phase I/II trial of interleukin-15--stimulated natural killer cell infusion after haplo-identical stem cell transplantation for pediatric refractory solid tumors.

BACKGROUND AIMS: Preliminary data suggest that T-cell-depleted haplo-identical stem cell transplantation (haplo-SCT) has a clinically beneficial allograft-versus-tumor effect associated with natural killer (NK) cell immune reconstitution. METHODS: This phase I/II trial descriptively evaluates the feasibility of interleukin (IL)-15-stimulated NK cell infusion after haplo-SCT in pediatric patients with refractory solid tumors. RESULTS: Six patients received an IL-15-stimulated NK cell infusion at 30 days after haplo-SCT. The mean number of infused NK cells per product was 11.3 × 10(6)/kg (range, 3-27 × 10(6)/kg). The T-cell count was <1 × 10(3)/kg in all patients (range, 0-0.75 × 10(3)/kg). No toxic effects related to IL-15--stimulated NK cell infusion were observed. Four of the six patients showed a clinical response (one achieved very good partial remission, two achieved partial remission and one had stable disease). One patient had progressive disease, and the response was not evaluated in the remaining patient. After a median follow-up period of 310 days, all patients had died: four of cancer relapse, one of cancer-associated thrombotic micro-angiopathy and one of acute graft-versus-host disease. CONCLUSIONS: The adoptive transfer of allogeneic IL-15--stimulated NK cells might be feasible and safe in heavily pretreated pediatric patients with refractory solid tumors, though the advanced stage of disease and toxic effects of haplo-SCT may limit the efficacy of NK cell infusion in this population.

Automated CD34+ cell isolation of peripheral blood stem cell apheresis product.

BACKGROUND AIMS: Immunomagnetic enrichment of CD34+ hematopoietic "stem" cells (HSCs) using paramagnetic nanobead coupled CD34 antibody and immunomagnetic extraction with the CliniMACS plus system is the standard approach to generating T-cell-depleted stem cell grafts. Their clinical beneficence in selected indications is established. Even though CD34+ selected grafts are typically given in the context of a severely immunosuppressive conditioning with anti-thymocyte globulin or similar, the degree of T-cell depletion appears to affect clinical outcomes and thus in addition to CD34 cell recovery, the degree of T-cell depletion critically describes process quality. An automatic immunomagnetic cell processing system, CliniMACS Prodigy, including a protocol for fully automatic CD34+ cell selection from apheresis products, was recently developed. We performed a formal process validation to support submission of the protocol for CE release, a prerequisite for clinical use of Prodigy CD34+ products. METHODS: Granulocyte-colony stimulating factor-mobilized healthy-donor apheresis products were subjected to CD34+ cell selection using Prodigy with clinical reagents and consumables and advanced beta versions of the CD34 selection software. Target and non-target cells were enumerated using sensitive flow cytometry platforms. RESULTS: Nine successful clinical-scale CD34+ cell selections were performed. Beyond setup, no operator intervention was required. Prodigy recovered 74 ± 13% of target cells with a viability of 99.9 ± 0.05%. Per 5 × 10E6 CD34+ cells, which we consider a per-kilogram dose of HSCs, products contained 17 ± 3 × 10E3 T cells and 78 ± 22 × 10E3 B cells. CONCLUSIONS: The process for CD34 selection with Prodigy is robust and labor-saving but not time-saving. Compared with clinical CD34+ selected products concurrently generated with the predecessor technology, product properties, importantly including CD34+ cell recovery and T-cell contents, were not significantly different. The automatic system is suitable for routine clinical application.

Donor lymphocytes expressing the herpes simplex virus thymidine kinase suicide gene: detailed immunological function following add-back after haplo-identical transplantation.

BACKGROUND AIMS: Haplo-identical hematopoietic stem cell transplantation (HSCT) with add-back of donor lymphocytes expressing the herpes simplex virus thymidine kinase suicide gene (TK cells) is one of the most widely applied promising new gene therapy approaches. However, the immunological status of added-back TK cells after HSCT has yet to be well characterized. METHODS: We investigated TK cells through the use of flow cytometry, T-cell receptor (TCR) Vß repertoire spectratyping and linear amplification-mediated polymerase chain reaction followed by insertion site analysis in a patient enrolled in our clinical trial. RESULTS: A comparison of onset with remission of acute graft-versus-host disease confirmed that TK cells were predominantly eliminated and that proliferative CD8(+) non-TK cells were also depleted in response to ganciclovir administration. The TCR Vß-chain repertoire of both TK cells and non-TK cells markedly changed after administration of ganciclovir, and, whereas the TCR repertoire of non-TK cells returned to a normal spectratype long after transplantation, that of TK cells remained skewed. With the long-term prophylactic administration of acyclovir, TK cells oligoclonally expanded and the frequency of spliced variants of TK cells increased. Known cancer-associated genes were not evident near the oligoclonally expanded herpes simplex virus (HSV)-TK insertion sites. CONCLUSIONS: We demonstrate obvious differences in immunological status between TK cells and non-TK cells. In addition, we speculate that long-term prophylactic administration of acyclovir increases the risk of oligoclonal expansion of spliced forms of TK cells.

Improving Outcomes with Haploidentical Stem Cell Transplantation [HaploSCT] in Children Using Post-transplant Cyclophosphamide: a Single Center Experience.

Haplo-identical stem cell transplant using post-transplant cyclophosphamide is increasingly being used in children without a matched sibling donor. Between 2010 and June 2021, 127 children underwent 138 transplants with a median age of 7.1 years for malignant and non-malignant disorders. Conditioning regimens included both myeloablative and reduced intensity regimens with peripheral blood stem cells as the main graft source. Engraftment occurred in 113 [81.9%] at a median of 16 days [range: 10-32] with primary graft failure in 10.2%. Cumulative incidence of grade II-IV acute graft versus host disease (GVHD) was 49.5% and chronic GVHD in 40.7%. Majority [92.7%] had at least one infection with 31% incidence of bacterial infection, 76% incidence of viral and 16% incidence of fungal infection. The 2-year overall survival (OS) is 54.9 ± 4.6% with a lower survival among young children aged 0-5 years [28.2 ± 6.4%] compared to 5-10 years [71.3 ± 6.8%] and 11-15 years [55.7 ± 8.8%] [p = 0.032]. 2-year OS has gradually improved from 25.0 ± 2.1% for 2010-2013 to 47.5 ± 6.2% for 2014-2017 and 67.1 ± 6.6% for 2018-2021 [p = 0.049]. On multivariate analysis, bacterial infection [p = 0.017], invasive fungal disease [p = 0.002] and graft failure [p = 0.029] negatively impacted overall survival. Haplo-identical SCT with post-transplant cyclophosphamide is a reasonable option for children who do not have a matched sibling donor. Strategies to reduce graft failure, infection related mortality and GVHD needs to be explored.

Real-World Challenges of Haplo-Identical Hematopoietic Stem Cell Transplant in a Developing Country: A Single Center Experience.

Hematopoietic stem cell transplant (HSCT) is potentially, the sole curative option for many malignant and non-malignant hematological disorders. Finding a human leukocyte antigen (HLA) compatible donor remains one of the limiting factors, hampering the utilization of HSCT. However, the introduction of post-transplant cyclophosphamide (PTCy) has improved the outcomes of haploidentical transplants making it a suitable option for patients lacking HLA-compatible donors. We collected data from 44 patients who underwent haplo-identical allogeneic stem cell transplants at the Armed Forces Bone Marrow Transplant Center/National Institute of Blood and Marrow Transplant (AFBMTC/NIBMT) from the year 2015 to 2022. The diseases were divided into three categories, i.e., bone marrow failure (BMF) syndromes, hematological malignancies (HM) and miscellaneous (Misc) groups. Median age at transplant was 18 (01-39) years. Transplant indications included aplastic anemia (AA) in 21 (47.7%) cases, 15 (34.1%) HM, and eight (18.2%) cases falling in the Misc groups. A maximum number of graft failures occurred in the BMF group; primary graft failure in 07 (33.3%) cases and secondary graft failure in four (19%) cases, (p-value < 0.05). Acute graft versus host disease (aGVHD) grade II-IV occurred in nine (20.5%) cases while chronic graft versus host disease (cGVHD) occurred in 10 (22.7%) cases. Cytomegalovirus (CMV) reactivation was seen in 31 (70.5%) cases. Maximum CMV reactivation was seen in HM group 13 (86.6%) cases, (p-value < 0.05) as compared to BMF (71.4%) and Misc groups (37.5%). Post-transplant cyclophosphamide (PTCy) based regimens, early neutrophil engraftment, and patients with GVHD had better survival outcomes (p-value < 0.05) overall survival (OS), and relapse-free survival (RFS). and GVHD-free relapse-free survival (GFRS) were significantly better in cases with early neutrophil engraftment. OS of the study cohort was 50% while disease-free survival (DFS) and GFRS were 45.5% and 36.4%, respectively.

Haploidentical Transplant with Post-Transplant Cyclophosphamide for Acute Myeloid Leukaemia and Myelodysplastic Syndromes Patients: The Role of Previous Lines of Therapy.

Background: Allogeneic haematopoietic stem-cell transplant is an option, potentially curative, for high-risk acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) patients. Post-transplant cyclophosphamide administration allows for the selection of haploidentical donors in patients who are eligible for the procedure but do not have a fully matched donor since it can overcome the HLA barrier. There is still an active debate on whether intensifying the conditioning regimen is necessary with haploidentical donors when peripheral blood stem cells are used as the graft source. Herein, we report our decennial experience of haploidentical stem-cell transplant using peripheral blood stem cells (haplo-PBSC) at King's College Hospital. Objectives: The primary objective was to evaluate overall survival (OS) following haplo-PBSC. Secondary objectives were total OS for patients with less than two previous lines of therapy, OS according to cytomegalovirus (CMV) reactivation, incidence of transplant-related mortality (TRM), graft-versus-host disease (GVHD) and GVHD-relapse-free survival (GRFS). Results: One-year and three-year total OS were 62% and 43%, respectively, with a median OS of 22 months. One-year and three-year OS for patients with ≤2 and those with >2 previous lines of therapy were 72% and 55%, and 60% and 22%, respectively (p-value=0.04). The median OS in patients with >2 previous and ≤2 lines of therapy was 16 and 49 months, respectively. Cumulative incidence (CI) of relapse was 25% with a median time to relapse of 5 months (range 1 - 38 months). Conclusions: Haploidentical haematopoietic stem-cell transplant is potentially curative in chemosensitive AML and MDS and offers a high rate of prolonged remission. Our cohort further confirms the role of consolidative haploidentical transplant in patients in complete remission and highlights that patients with heavily pre-treated disease may not benefit from this strategy.

Haplo-cord transplant. Realizing the potential of umbilical cord blood grafts. - A review of techniques and analysis of outcomes.

The combination of cord blood transplant with progenitor cells from partially HLA-matched adult donors (haplo-cord transplant) has been used over the past two decades. In Europe and the US the adult donor graft is CD34 selected and provides early hematopoiesis, but durable engraftment derives from the cord blood graft (CD34 selected haplo-cord). Neutrophil recovery is prompt and rates of acute and chronic GVHD are low. Recent Chinese studies combine cord blood grafts with T-replete haplo-identical grafts (unmodified haplo-cord). The haplo graft usually establishes dominance and UCB chimerism is rarely detected. Comparison studies suggest considerably decreased rates of relapse and improved outcomes, compared with either haplo-identical transplant or CBU transplant, particularly in patients with advanced leukemia. A recent prospective randomized study confirms this. Haplo-cord mitigates the engraftment delay of UCB transplant. The unique biology of UCB grafts results in low GVHD and improved GVL especially beneficial in high-risk disease.

[Haploidentical Hematopoietic Stem Cell Transplantation with Co-Infusion of Mesenchymal Stromal Cells for Acquired Severe Aplastic Anemia: A Report of 127 Cases].

OBJECTIVE: To analyze the prognostic factors of haplo-HSCT combined with MSC in the treatment of SAA. METHODS: 127 SAA patients who had undergone haplo-HSCT with co-infusion of MSC in our center from January 2014 to August 2019 were analyzed retrospectively. Median age was 11 (1-37) years, and median follow-up time was 39.8 (1-74) months. RESULTS: The median time for neutrophil and platelet engraftment was 14 d and 18 d respectively. The cumulative incidences of grade III-IV aGVHD was 4.4%±1.9% at day +100. The 2-year cumulative incidence of extensive cGVHD was 8.3%± 2.7%. The estimated 3-year OS was 86.1%±3.1%. Univariate analysis showed that high-dose CD34+ cells (>6.69×106/kg) could promote the engraftment of neutrophil (97.9%±0.05% vs 88.6%±0.13% at day +21, P=0.0006) and platelet (81.2%±0.33% vs 70.8%±0.26% at day +28, P=0.002) and did not increase the incidence of aGVHD (10.4%±0.1% vs 18.9%±0.1% at day +100, P=0.18). More nucleated cells (>12.78×108/kg) caused a lower incidence of grade II-IV aGVHD (8.6%±0.13% vs 21.7%±0.25% at day+100, P=0.04) and a higher incidence of 3-year OS (91.3%±3.2% vs 78.1%±6.5%, P=0.03) than less nucleated cells (≤12.78×108/kg). Younger patients (age≤12 y) had faster neutrophil engraftment (94.9%±0.06% vs 87.5%±0.24% at day+21, P=0.02), higher 3-year OS (93.6%±2.8% vs 75.9%±6.4%, P=0.006) and higher 3-year FFS (93.6%±2.8% vs 68.3%±7.1%, P=0.000) than older patients (age>12 y). The shorter the time from diagnosis to HSCT (≤29.5 months), the higher the 3-year FFS of patients (88.8%±3.5% vs 74.2%±7.2%, P=0.028). Male patients with female donors had higher cumulative incidence of extensive cGVHD than others (20.0%±0.8% vs 4.6%±0.1%, P=0.01). CONCLUSION: In the haplo-HSCT of SAA, the prognosis of children patients is better than that of adults patients. More CD34+ cells and nucleated cells can promote engraftment, reduce the incidence of aGVHD and improve OS. HSCT should be performed as early as possible, and the occurrence of cGVHD should be reduced in male patients by avoiding female donors.

Mesenchymal stromal cells as prophylaxis for graft-versus-host disease in haplo-identical hematopoietic stem cell transplantation recipients with severe aplastic anemia?-a systematic review and meta-analysis.

BACKGROUND: Mesenchymal stromal cells (MSCs) are an emerging prophylaxis option for graft-versus-host disease (GVHD) in haplo-identical hematopoietic stem cell transplantation (haplo-HSCT) recipients with severe aplastic anemia (SAA), but studies have reported inconsistent results. This systematic review and meta-analysis evaluates the efficacy of MSCs as prophylaxis for GVHD in SAA patients with haplo-HSCT. METHODS: Studies were retrieved from PubMed, EMBASE, Cochrane, Web of Science, and http://clinicaltrials.gov from establishment to February 2020. Twenty-nine single-arm studies (n = 1456) were included, in which eight (n = 241) studies combined with MSCs and eleven (n = 1215) reports without MSCs in haplo-HSCT for SAA patients. The primary outcomes were the incidences of GVHD. Other outcomes included 2-year overall survival (OS) and the incidence of cytomegalovirus (CMV) infection. Odds ratios (ORs) were calculated to compare the results pooled through random or fixed effects models. RESULTS: Between MSCs and no MSCs groups, no significant differences were found in the pooled incidences of acute GVHD (56.0%, 95% CI 48.6-63.5% vs. 47.2%, 95% CI 29.0-65.4%; OR 1.43, 95% CI 0.91-2.25; p = 0.123), grade II-IV acute GVHD (29.8%, 95% CI 24.1-35.5% vs. 30.6%, 95% CI 26.6-34.6%; OR 0.97, 95% CI 0.70-1.32; p = 0.889), and chronic GVHD (25.4%, 95% CI 19.8-31.0% vs. 30.0%, 95% CI 23.3-36.6%; OR 0.79, 95% CI 0.56-1.11; p = 0.187). Furtherly, there was no obvious difference in 2-year OS (OR 0.98, 95% CI 0.60-1.61; p = 1.000) and incidence of CMV infection (OR 0.61, 95% CI 0.40-1.92; p = 0.018). CONCLUSIONS: Our meta-analysis indicates that the prophylactic use of MSC co-transplantation is not an effective option for SAA patients undergoing haplo-HSCT. Hence, the general co-transplantation of MSCs for SAA haplo-HSCT recipients may lack evidence-based practice.

CD3/CD19 Depletion for T-cell Reduction of Allogeneic Transplants: Mostly Efficient, but not Robust.

Aggressive T-cell depletion, in vitro or in vivo, is a prerequisite for survival of haplo-identical stem cell transplantation. The classical T-cell-depleted transplant, immunomagnetically enriched CD34+ cells, is very safe with respect to graft-versus-host reactivity, but associated with very high transplant-related and relapse mortality with an overall probability of survival of only 20%. Protocols for T- and B-cell depletion were therefore developed, reasoning that transplantation of the majority of Natural Killer (NK) cells and the substantial dose of residual T-cells might improve survival, which was, in principle, confirmed. Anecdotal reports of frequent failure to achieve adequate T-cell depletion prompted review of the aggregate data for transplant quality at our center. The first observation is the relative paucity of combined CD3/CD19 depletion processes as PTCy protocols have made inroads, 13 depletions in 8 years. Median T- and B-cell log-depletion were -3.89 and -1.92, respectively; instead of, CD34+ cell recovery was generally high (median 92%), as was NK-cell recovery (median 52%). However, the process failed to yield satisfactory T- and B-cell depletion in two out of 13 preparations, of which one product could be rescued by a second round of depletion, at the expense of CD34+ cell recovery. In our hands, the process is thus insufficiently robust for routine clinical use. Assuming similar observations in other centers, this may explain implementation of alternative protocols, such as TCRαß/CD19 depletion or transplantation of unmanipulated grafts with subsequent in vivo depletion.