Unmanipulated Haploidentical Hematopoietic Stem Cell Transplantation Research Articles

SMART101 Donor T-Lymphoid Progenitors to Accelerate Immune Reconstitution Post-Haploidentical Peripheral Blood Stem Cell Transplantation with Post-Transplant Cyclophosphamide: SI101-02 First-in-Human Phase I/II

Background and Significance Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment option for many patients with hematological malignancies, but an HLA-matched donor may not be available, e.g., for ethnic populations under-represented in donor registries. In the absence of an HLA-matched donor, the use of post-transplant cyclophosphamide in unmanipulated haploidentical HSCT (haplo PTCy HSCT) is the favored strategy. However, in vivo T-cell depletion by PTCy significantly impairs immune reconstitution up to 2 years post-transplant, resulting in higher infection-related mortality and relapse rate. SMART101 is a cell therapy using allogeneic CD7+ T-lymphoid progenitors (TLP) produced in culture from mobilized peripheral blood CD34+ cells from an HSCT donor via Smart Immune's GMP manufacturing process. This ex vivo lymphoid niche culture system uses the Notch ligand Delta-like 4 coupled to IgG2 Fc fragment (DLL4-Fc) and RetroNectin® and a specific combination of cytokines, mimicking the initial steps of bone marrow lymphoid and T-cell differentiation. Characterization studies of these allogeneic CD7+ TLPs using single cell RNA sequencing analysis, suggested their high lymphoid commitment and thymic homing potentials. Preclinical in vivo experiments in irradiated adult and non-conditioned neonatal NSG mice demonstrate the capacity of these cells to migrate to the thymus, induce the generation of medullary thymic epithelial cells (TEC) and accelerate the generation of a polyclonal human T cell repertoire. Fig 1 shows the kinetic of cell engraftment and T-cell differentiation for CD34+ cells or CD7+ TLPs. Aims The SI101-02 clinical study (EudraCT 2022-002530-14) seeks to provide proof of concept that SMART101 cells can rapidly complete their differentiation within patient's thymus into naïve T-cells, accelerating the production of polyclonal donor T-cells without GvHD-inducing potential, and reduce the non-relapse and disease relapse mortality post haplo PTCy HSCT. Study Design and Methods This first-in-human, open-label, dose-escalation, two-cohort, multicenter phase I/II study will evaluate the safety and activity of SMART101 infusion (D6) in adult patients with AML, ALL or high-risk MDS eligible for an haplo PTCy HSCT (D0) as standard of care. The study is comprised of two segments. The first is a phase I dose escalation with three dose-levels of SMART101 (1.5 x 10 6, 4.5 x 10 6 and 9.0 x 10 6 CD7+ cells/kg of body weight) to define the recommended dose. The second is a phase II segment that will be comprised of 2 cohorts according to the type of conditioning regimen (myeloablative vs. reduced intensity conditioning). Patients will be enrolled in two consecutive stages following a Simon's 2 stage design, with 9 patients in stage 1 and 8 new patients in stage 2. Each cohort will be analyzed separately. The primary endpoints are the occurrence of unexpected unacceptable toxicity within 14 days after the infusion of SMART101 for the dose escalation segment, with a co-primary endpoint evaluating the activity of SMART101 in term of immune reconstitution (naïve CD4+ T cells ≥ 50/μL by D100) for the phase II segment. Secondary endpoints include the overall safety profile, especially the occurrence of GvHD and graft failure, the incidence of non-relapse/relapse mortality, and a detailed evaluation of the immune reconstitution. The SI101-02 study was initiated in H1-2023 in France and Italy. The study design, major inclusion and exclusion criteria, study treatment specificities, statistical methods and details of the ProTcell platform will be presented. Conclusion SMART101 is the first-generation of allogeneic TLP cell therapy obtained from Smart Immune's proprietary GMP manufacturing platform. The duration and the depth of T cell immunodeficiency post haplo PTCy HSCT is expected to be significantly reduced by the infusion of SMART101 thereby decreasing the non-relapse mortality and morbidity rates and thus improving the overall clinical outcome of this therapy.

P574: CPX-351 COMBINED WITH HEMATOPOIETIC CELL TRANSPLANTATION WITH REGULATORY AND CONVENTIONAL T CELL IMMUNOTHERAPY FOR HIGH-RISK ACUTE MYELOID LEUKEMIA

Background: Patients with newly diagnosed acute myeloid leukemia with myelodysplasia-related changes (MRC-AML) or therapy-related AML (t-AML) have an extremely poor prognosis. CPX-351, a dual-drug liposomal encapsulation of cytarabine and daunorubicin, improved significantly rates of remission and overall survival (Lancet JE et al, JCO 2018). Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative strategy for such patients, but incidence of post-transplant relapse is still unacceptably high. We developed a novel HSCT strategy that combines an age-adapted myeloablative irradiation-based conditioning regimen with regulatory and conventional T-cell adoptive immunotherapy (Treg/Tcon HSCT). HLA-haploidentical Treg/Tcon HSCT ensured low relapse rate (4%) and resulted in an unprecedented chronic graft versus host disease/relapse free survival (CRFS, 75%) in AML patients (Pierini et al., Blood Adv. 2021). Aims: We report preliminary outcomes of the combination therapy with CPX-351 and Treg/Tcon HSCT for MRC-AML and t-AML at our center. Methods: We included in the study all patients with MRC-AML or t-AML who were referred at our center from September 2019 to January 2022 and could be treated with CPX-351. Treg/Tcon HSCT consisted of a myeloablative conditioning regimen with total marrow/lymphoid irradiation, thiotepa, fludarabine and cyclophosphamide followed by an infusion of 2x106/Kg donor Tregs on day -4, 1x106/Kg Tcons on day -1 and a megadose (>6x106/Kg) of purified CD34+ hematopoietic progenitor cells on day 0. No pharmacological GvHD prophylaxis was given post-transplant (clinicaltrials.gov: #NCT03977103). Results: Seventeen patients with a median age of 57.5 years (46-72) were treated with CPX-351: 13 with newly diagnosed AML (11 MRC-AML and 2 t-AML) and 4 patients who relapsed after a previous HSCT and who acquired novel cytogenetic abnormalities (2 complex karyotypes, CK). 9/13 patients with newly diagnosed AML had karyotype abnormalities: 4 monosomy 7, 1 CK, 1 t(3;3), 1 isolated del(20q) and 2 (both t-AML) t(11;20) which resulted in NUP98-TOP1 fusion. Nine patients achieved complete remission (CR), 2 partial response (PR) and 2 had persistent disease. No patient experienced grade>3 extrahematologic toxicity. Ten/13 patients underwent a first HSCT (8 in CR, 2 in PR). Eight underwent Treg/Tcon HSCT (3 from HLA-matched, 5 from HLA-haploidentical donor), while 2 unmanipulated haploidentical HSCT followed by post-transplant cyclophosphamide (PT-Cy). All patients achieved full-donor engraftment. No patients experienced non-relapse mortality (NRM). Three/10 patients had a grade ≥ III acute GvHD; all of them are alive and off immunosuppressive therapy. At a median follow up of 16.2 months (range 9-29 months), 9/10 patients are alive and in CR with no chronic GvHD. No relapse occurred in the 8 patients who underwent Treg/Tcon HSCT, while one patient who underwent HSCT followed by PT-CY relapsed. The 4 patients who were treated after one previous HSCT received one single induction cycle with CPX-351, achieved CR and experienced no grade>3 extra-hematologic toxicity. All of them could undergo a second HSCT. NRM occurred in 1 patient (septic shock), while 3 patients are alive to date. Summary/Conclusion: CPX-351 allowed most of MRC-AML and t-AML patients to reach HSCT in CR despite high risk genetics and even when used in patients who relapsed after a 1st HSCT. Combination of CPX-351 with Treg-Tcon HSCT is safe and exert powerful antileukemic activity. Thus, it appears to be a promising strategy to ensure high rate of CRFS in very high-risk AML.

Transjugular Intrahepatic Portosystemic Shunt for Very Severe Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) after Unmanipulated Haploidentical Hematopoietic Stem Cell Transplantation with Post-transplantation Cyclophosphamide.

Hepatic veno-occlusive disease or sinusoidal obstruction syndrome (VOD/SOS) is a threatening complication after both autologous and allogeneic hematopoietic stem cell transplantation (HSCT), with high mortality rates despite early medical treatment, including the use of defibrotide (DF). We retrospectively analyzed 185 unmanipulated haploidentical (haplo-) HSCT with post-transplantation cyclophosphamide as graft-versus-host disease prophylaxis performed consecutively between 2011 and June 2019 in a single center. Seventeen patients (9.2%) were diagnosed with VOD/SOS. Based on revised European Society for Blood and Marrow Transplantation severity criteria, the VOD/SOS cases were classified as mild in 2 patients (11.7%), moderate in 2 (11.7%), severe in 2 (11.7%), and very severe in 11 (64.9%). Thirteen patients (76%) were treated with DF, including all patients with severe or very severe VOD/SOS, except 1 patient with CNS hemorrhage. Sixteen patients (94%) were alive at day +100 after HSCT. Seven patients (41%) with very severe VOD/SOS were treated with transjugular intrahepatic portosystemic shunt (TIPS) owing to rapid clinical or analytical deterioration or refractory hepatorenal syndrome despite medical treatment, including DF. TIPS insertion was performed at a median time since VOD/SOS diagnosis of 4 days (range, 1 to 28 days) without technical complications in any case. The median hepatic venous pressure gradient before and after TIPS treatment was 24 mmHg (range, 14 to 29 mmHg) and 7 mmHg (range, 2 to 11 mmHg), respectively, with a median drop of 16 mmHg (range, 9 to 19 mmHg). Following TIPS insertion, all patients showed clinical improvement with hepatomegaly, ascites, and renal failure resolution, and all showed analytical improvement with reduced alanine aminotransferase (ALT), creatinine, and international normalized ratio values, except for patient 2, whose indication for TIPS was refractory hepatorenal syndrome with a normal ALT level. The 6 patients who had initiated DF before TIPS insertion completed 21 days of treatment. All patients met the criteria for complete remission (CR) at a median of 8 days after TIPS insertion (range, 2 to 82 days). The 100-day overall survival was 100%. For patients with rapid progressive VOD/SOS, early TIPS insertion allowed completion of DF therapy. The use of TIPS together with DF resulted in CR and no associated complications with no VOD/SOS-associated mortality despite high severity. In our experience, timely and individualized use of TIPS significantly improves outcomes of very severe VOD/SOS after haplo-HSCT. Therefore, TIPS should be promptly considered in rapidly progressive cases.

Unmanipulated haploidentical hematopoietic stem cell transplantation using very low-dose antithymocyte globulin and methylprednisolone in adults with relapsed/refractory acute leukemia

Allogeneic hematopoietic stem cell transplantation (HSCT) could be the only curative therapy for patients with relapsed/refractory acute leukemia (RRAL). Many reports have described unmanipulated haploidentical HSCT (HID-HSCT) using high-dose antithymocyte globulin (ATG). However, the transplant outcomes of HID-HSCT using very low-dose ATG (thymoglobulin, 2-2.5mg/kg) and methylprednisolone (mPSL, 1mg/kg) for patients with RRAL have not been reported. We compared the outcomes of 46 patients with RRAL who underwent HID-HSCT using very low-dose ATG (thymoglobulin) and mPSL with the outcomes of 72 patients who underwent non-HID-HSCT. Patient characteristics differed regarding conditioning intensity (myeloablative; 19.6% in HID-HSCT vs. 61.1% in non-HID-HSCT, P < 0.001) and having undergone multiple HSCT (26.1% vs. 11.1%, P = 0.045). However, we found no significant differences in the 1-year overall survival (OS, 31.7% vs. 29.1%; P = 0.25), disease-free survival (DFS, 20.5% vs. 23.7%; P = 0.23), cumulative incidence of relapse (CIR, 40.0% vs. 42.8%; P = 0.92), non-relapse mortality (NRM, 39.5% vs. 33.5%; P = 0.22), or 100-day grade II-IV acute graft-versus-host disease (32.6% vs. 34.7%; P = 0.64) following HID-HSCT vs. non-HID-HSCT, respectively. Subgroup analysis stratified by disease and intensity of conditioning regimen demonstrated the same results between HID-HSCT and non-HID-HSCT. Furthermore, multivariate analysis showed that HID-HSCT was not an independent prognostic factor for OS (hazard ratio (HR) = 0.95 [95% confidence interval (CI), 0.58-1.58]), DFS (HR = 1.05 [95%CI, 0.67-1.68]), CIR (HR = 0.84 [95%CI, 0.48-1.47]), or NRM (HR = 1.28 [95%CI, 0.66-2.46]). In summary, transplant outcomes for RRAL were comparable in the HID-HSCT and non-HID-HSCT groups. HID-HSCT using very low-dose ATG and mPSL for RRAL may be a viable alternative to non-HID-HSCT.

Unmanipulated Haploidentical Hematopoietic Stem Cell Transplantation in First Complete Remission Can Abrogate the Poor Outcomes of Children with Acute Myeloid Leukemia Resistant to the First Course of Induction Chemotherapy

Allogeneic hematopoietic stem cell transplantation (HSCT) is an important therapy option for children with acute myeloid leukemia (AML) resistant to the first course of induction chemotherapy (IC1st). We aimed to identify the efficacy of unmanipulated haploidentical HSCT (haplo-HSCT) in children with AML in the first complete remission and whether children resistant (IC1st-resistant; n = 38) or sensitive (IC1st-sensitive; n = 59) to the IC1st can achieve comparable outcomes. The cumulative incidence of grades III to IV acute graft-versus-host disease (GVHD) and severe chronic GVHD was .0% versus 20.1% (P = .038) and 21.7% versus 13.2% (P = .238), respectively, for the IC1st-resistant and IC1st-sensitive groups. The 3-year cumulative incidence of relapse and nonrelapse mortality was 22.2% versus 7.6% (P = .061) and 5.3% versus 10.8% (P = .364), respectively, for the IC1st-resistant and IC1st-sensitive groups. The 3-year probability of overall survival and disease-free survival was 76.3% versus 83.0% (P = .657) and 72.5% versus 81.6% (P = .396), respectively, for the IC1st-resistant and IC1st-sensitive groups. Multivariate analysis failed to show significant differences in survival rates between the groups. Thus, our results show that unmanipulated haplo-HSCT may overcome the poor prognostic significance of IC1st-resistance in children with AML, and it is valid as a postremission treatment for children with IC1st-resistant AML lacking an HLA-matched donor.

Unmanipulated Haploidentical Hematopoietic Stem Cell Transplantation Might Overcome the Adverse Effect of Minimal Residue Disease Pretransplant in Patients with Standard-Risk Acute Myeloid Leukemia

▪BackgroundsIn patients with acute myeloid leukemia (AML), detection of minimal residual disease (MRD) before allogeneic hematopoietic stem cell transplantation (HSCT) is correlated to the risk of relapse. Persistent intensive chemotherapy might further reduce the load of leukemia pretransplant, but it also brings the risk of treatment mortality. Unmanipulated haploidentical HSCT which was established by Peking University Institute of Hematology would induce a stronger graft-versus-leukemia (GVL) effect in compared with sibling transplantation. Moreover, our previous studies have demonstrated that the prophylactic use of modified donor lymphocyte infusion (DLI) would significantly increase the survival of patients with progressive acute leukemia. However, for those patients with standard-risk AML who has the detectable MRD before transplant, whether they would benefit from further chemotherapy to reduce MRD, or should receive active intervention strategy towards leukemia relapse is still unknown.MethodsThe MRD level was measured immediately before and after transplant in 86 standard-risk AML patients who received unmanipulated haploidentical HSCT at the Peking University Institute of Hematology from January, 2011 to May, 2012. All patients were selected from the clinical trial which was registered at http://www.chictr.org as No. ChiCTR-TRC-11001761 if the following criteria were met: having standard-risk AML, defined as first or second complete remission without t(9;22)(q34; q11), t(15;17), inv(16)(p13q22), t(16;16)(p13; q22) or t(8;21)(q22; q22) cytogenetic abnormalities. The duration of follow-up after HSCT was 980 days (range, 55-1277). MRD were examined by 8-color flow cytometry and real-time quantitative polymerase chain reaction (RQ-PCR). WT1+ was defined as a transcript >0.60% and FCM+ was defined as >0.01% of cells with leukemia-associated aberrant immune phenotypes (LAIPs). Patients had at least one of FCM+/WT1+ before transplant were termed as MRD+. The combinative criteria for positive MRD (MRDco+) were defined as 2 consecutive FCM+ or WT1+ results or both FCM+ and WT1+ in a single sample within 1 year after transplantation.ResultsAmong these 86 AML patients, there were 42 and 44 cases in the 6mg/kg ATG and 10mg/kg ATG group, respectively. The proportion of patients with or without detectable MRD before transplantation was comparable in those two groups with different dose of ATG. During the follow-up, 9 patients underwent hematological relapse at a median time of 157 days (range, 30-726). Finally 18 patients died and 7 patients died of relapse. The number of FCM+/WT1+ patients pretransplant was 8 and 16, respectively. There were 18 patients met the criteria of MRD+ before HSCT. None of the FCM+, WT1+ and MRD+ pretransplant but the FCM+ (P=0.001), WT1+ (P=0.013) and MRDco+ (P<0.001) posttransplant was significantly correlated to relapse during univariate analysis. A multivariate Cox regression analysis that included age, sex, relationship and matched status of blood type between donor and recipient, GVHD and MRD status before and after transplantation was performed. It showed that only MRDco+ posttransplant was an independent risk factor of leukemia relapse (P=0.022, HR=4.653, 95%CI:1.249-17.334). Through Kaplan-Meier analysis, a significant difference in cumulative incidence of relapse between patients with or without posttransplant MRDco+ would be observed (P=0.012). However, it seemed that MRD status before transplant might not affect leukemia relapse after haploidentical HSCT.Conclusion Although detectable MRD before HSCT is a strong prognostic factor, its adverse impact could be diminished and overcome in patients with standard-risk AML receiving our unmanipulated haploidentical HSCT. These kinds of patients might not need to receive further intensive chemotherapy or active intervention around HSCT. DisclosuresNo relevant conflicts of interest to declare.

Haploidentical vs identical-sibling transplant for AML in remission: a multicenter, prospective study

AbstractThe effects of HLA-identical sibling donor (ISD) hematopoietic stem cell transplantation (HSCT) on adults with intermediate- or high-risk acute myeloid leukemia (AML) in the first complete remission (CR1) are well established. Previous single-center studies have demonstrated similar survival after unmanipulated haploidentical donor (HID) vs ISD HSCT for hematologic malignancies. To test the hypothesis that haploidentical HSCT would be a valid option as postremission therapy for AML patients in CR1 lacking a matched donor, we designed a disease-specific, prospective, multicenter study. Between July 2010 and November 2013, 450 patients were assigned to undergo HID (231 patients) or ISD HSCT (219 patients) according to donor availability. Among HID and ISD recipients, the 3-year disease-free survival rate was 74% and 78% (P = .34), respectively; the overall survival rate was 79% and 82% (P = .36), respectively; cumulative incidences of relapse were 15% and 15% (P = .98); and those of the nonrelapse-mortality were 13% and 8% (P = .13), respectively. In conclusion, unmanipulated haploidentical HSCT achieves outcomes similar to those of ISD HSCT for AML patients in CR1. Such transplantation was demonstrated to be a valid alternative as postremission treatment of intermediate- or high-risk AML patients in CR1 lacking an identical donor. This trial was registered at www.chictr.org as #ChiCTR-OCH-10000940.