Myeloablative Allogeneic Stem Cell Transplantation Research Articles

Successful Allogeneic Hematopoietic Stem Cell Transplantation for Nodal Epstein-Barr Virus-positive T/NK-cell Lymphoma.

Nodal Epstein-Barr virus-positive T/NK-cell lymphoma (EB-nTNKL) is an extremely rare disease characterized by an aggressive clinical course and poor prognosis, for which treatment strategies have not yet been established. We herein report a young man with EB-nTNKL. Although initial chemotherapies, including L-asparaginase, failed to produce a good response, subsequent myeloablative allogeneic hematopoietic stem cell transplantation (alloHSCT) resulted in favorable disease control and a long-term disease-free survival. The prompt performance of alloHSCT using an available donor source at that time, regardless of whether or not the initial chemotherapy was effective, could be critical to saving patients with this otherwise fatal disease.

Thiotepa/cyclophosphamide (TT/Cy) preparative regimen for patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic stem cell transplantation.

6556 Background: Total body irradiation (TBI)-based preparative regimens have been standard for patients with ALL undergoing allogeneic stem cell transplant (SCT). It is unclear if chemotherapy-only regimens are equally efficacious. Here, we present the largest reported experience with myeloablative TT/Cy in patients with ALL undergoing allogeneic SCT and compare outcomes with TBI-based regimens. Methods: Patients with ALL receiving myeloablative allogeneic SCT at Indiana University from 2007-2020 were included. TT/Cy consisted of TT 15 mg/kg and Cy 120 mg/kg. TBI/Cy consisted of 13.2 Gy in 8 fractions and Cy 3600 mg/m2 or etoposide 60 mg/kg. The primary endpoint was overall survival (OS). Secondary endpoints included relapse-free survival (RFS), engraftment, and toxicities within the first 100 days. Median follow up for surviving patients is 2,532 (range 599-4,762) days. Results: 80 patients with ALL of median age 40 (range 22-59 years) received conditioning with TT/Cy (n=25) versus TBI/Cy or TBI/etoposide (n=55). Baseline characteristics were similar. For patients receiving TT/Cy, the median OS was not reached, and the 4-year OS was 54.5% (95% confidence interval [CI], 34.3-74.7%), compared with a median OS of 1,491 days and a 4-year OS of 50.9% (95% CI, 37.8-64.2%) for those receiving TBI-based conditioning (p=.75). Similarly, for TT/Cy patients, the median RFS was 847 days and 4-year RFS was 43.2% (95% CI, 23.4-63%), not significantly different from median RFS of 1491 days and 4-year RFS 50.2% (95% CI 36.9-63.5; p=.232) for recipients of TBI regimens. On multivariable analysis, only a higher disease risk index was associated with significantly worse OS (p<.001), while conditioning regimen was not predictive of OS. Similarly, there was no significant difference in RFS between TT/Cy and TBI-based regimens on either univariable or multivariable analysis. Secondary endpoints are summarized in the table. As shown, TT/Cy was associated with significantly lower incidence of mucositis, TPN usage, bacterial infection, sinusoidal obstruction syndrome (SOS), and longer length of stay of primary transplant admission. Conclusions: While there was no significant difference in OS or RFS for patients receiving either TT/Cy or TBI-based conditioning, TBI was associated with greater toxicity. Our data suggests that TT/Cy is an acceptable alternative to TBI-based conditioning for ALL patients undergoing myeloablative allogeneic SCT. [Table: see text]

Improved survival for myeloid malignancy patients receiving thiotepa/cyclophosphamide (TT/Cy) versus total body irradiation/cyclophosphamide (TBI/Cy) conditioning and allogeneic stem cell transplantation.

6555 Background: TBI/Cy is a commonly used conditioning regimen prior to allogeneic stem cell transplant (SCT). Chemotherapy only regimens, mostly containing busulfan, have been shown to be effective and less toxic in patients with myeloid malignancies. Here, we present the largest reported experience with a non-busulfan myeloablative chemotherapy regimen of TT/Cy in myeloid malignancy patients undergoing allogeneic SCT and compare outcomes with TBI/Cy. Methods: Patients with myeloid malignancies receiving allogeneic SCT at Indiana University from 2007-2020 were included. TT/Cy consisted of TT 15 mg/kg and Cy 120 mg/kg. TBI/Cy consisted of 13.2 Gy in 8 fractions and Cy 3600 mg/m2. The primary endpoint was overall survival (OS). Secondary endpoints included relapse-free survival (RFS), engraftment, and toxicities within the first 100 days. Median follow up for surviving patients is 2,046 (range 816-5,572) days. Results: 225 patients with AML (n=160), CML (n=45), and MDS (n=30) of median age 44 (range 19-59 years) received conditioning with TT/Cy (n=159) or TBI/Cy (n=66). Baseline characteristics were similar. For TT/Cy patients, the median OS was not reached, and 4-year OS was 57.2% (95% confidence interval [CI], 49.2-65.2%), which was significantly better than with TBI/Cy, with median OS 373 days and 4-year OS 33.9% (95% CI, 22.3-45.5%; p<.001). Similarly, for TT/Cy patients, the median RFS was not reached and 4-year RFS was 59.2% (95% CI, 52-67.2%), significantly better than median RFS of 341 days and 4-year RFS 35.2% (95% CI, 23.7-46.9%; p<.001) for recipients of TBI/Cy. On multivariable analysis adjusting for age, sex, diagnosis, disease risk, comorbidity index (HCI), and degree of stem cell source, TT/Cy had significantly lower risk of death (HR 0.44, 95% CI, 0.30-0.65; p<.001) together with female sex (p=.03) and lower HCI (p=.046). As shown in the Table summarizing secondary endpoints, TBI/Cy was associated with significantly higher rates of mucositis, sinusoidal obstruction syndrome (SOS), TPN usage, multiorgan failure, and length of stay of primary admission. Conclusions: TT/Cy is an efficacious regimen for patients with myeloid malignancies undergoing myeloablative allogeneic SCT with less toxicity and improved RFS and OS compared with TBI/Cy. TT/Cy should be compared to other non-TBI containing busulfan-based regimens. [Table: see text]

Total body irradiation versus thiotepa/busulfan-based conditioning regimens for myeloablative allogeneic stem cell transplantation in adults with acute lymphoblastic leukemia.

Total body irradiation (TBI)-based conditioning regimens are generally recommended for allogeneic HSCT (allo-HSCT) in patients with acute lymphoblastic leukemia (ALL). Recent evidence suggests that modern chemotherapy-based regimens may be as effective. This multicenter retrospective study compared the clinical outcomes of myeloablative allo-HSCT with thiotepa, busulfan, and cyclophosphamide/fludarabine (TTB) to TBI-based conditioning. Between 2002 to 2018, 63 and 114 patients received TTB- and TBI-based conditioning regimens, respectively. The 5-year cumulative incidence of relapse was lower in the TBI cohort compared to the TTB cohort (30% [95% CI, 22-38] versus 47% [95% CI, 36-59]; P = 0.03). Multivariate analysis identified T-ALL, Ph-negative B-ALL, and measurable residual disease associated with a higher relapse risk. The 5-year cumulative incidence of non-relapsed mortality (NRM) was significantly lower with TTB (12% [95% CI, 5-20]) compared to TBI (25% [95% CI, 18-33]) (P = 0.001). Multivariate analysis found TBI conditioning, older age, and advanced stages of ALL at transplantation associated with a higher NRM. No statistical difference was seen in overall survival (49% [95% CI, 40-58] and 46% [95% CI, 35-60]) in the TBI and TTB groups, respectively; P = 0.9). The study suggests that TTB-based conditioning may be a promising option for ALL patients undergoing allo-HSCT, as it resulted in similar OS and lower NRM than TBI-based conditioning.

Development and Validation of a Novel LC-MS/MS Method for a TDM-Guided Personalization of HSCT Conditioning with High-Dose Busulfan in Children

Personalization of busulfan (Bu) exposure via therapeutic drug monitoring (TDM) is recommended for patients treated with high-dose conditioning regimens. Several laboratories' developed methods are available in the literature with a lack of standardization. The aim of this study is to develop a new standardized LC-MS/MS method and validate it according to the international ICH M10 (EMA) guidelines. Our method is based on rapid protein precipitation from 50 µL plasma followed by separation on a reversed-phase C-18 UHPLC column after the addition of deuterated internal standard and has been tested on real samples from pediatric patients treated with myeloablative conditioning regimens, including Bu, before autologous or allogeneic hematopoietic stem cell transplantation (HSCT). The validated LC-MS/MS method is linear over wide concentration ranges (125-2000 ng/mL), accurate, and reproducible in the absence of matrix effects, allowing for the specific and rapid quantification of Bu and allowing next-dose recommendations to be made in a timely fashion to answer clinicians' needs. Given the lack of data on the stability of Bu in real clinical samples, stability was assessed both on quality controls and on real samples to set up a robust protocol in real-life conditions. This novel LC-MS/MS method is suitable for application to the TDM-guided personalization of conditioning treatments with high-dose busulfan in pediatric patients undergoing HSCT.

Reduced-intensity conditioning versus myeloablative conditioning allogeneic stem cell transplantation for patients with myelofibrosis.

Allogeneic hematopoietic stem cell transplantation (alloSCT) is the sole curative option for myelofibrosis (MF). However, it is unknown as to which of the two, myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC), is a better preconditioning regimen. Twenty-five patients with MF were treated with alloSCT, 12 of whom underwent RIC. Baseline characteristics, response to alloSCT, adverse events, including graft-versus-host disease (GVHD), and survival outcomes were reviewed. There was no difference in the neutrophil engraftment rate and time to engraftment between MAC vs. RIC. The time to platelet engraftment was significantly longer in the MAC group (median, 112.8 vs. 28.8 days for MAC vs. RIC, respectively, P=0.049). RIC was more advantageous in terms of achieving complete chimerism (38.5% vs. 83.3%, P=0.041). The incidence of acute GVHD was 84.6% (11 of 13) and 58.3% (7 of 12) in the MAC and RIC groups, respectively. The cumulative incidence of grade III‒IV acute GVHD was significantly higher in the MAC group than in the RIC group (P=0.03). No significant differences were observed in progression-free and overall survival. The 17-month probability of progression-free survival was 38.4% [95% confidence interval (CI), 19.3‒76.5] vs. 47.6% (95% CI, 25.7‒88.2) (P=0.21), and that of overall survival was 53.8% (95% CI, 32.5‒89.1) vs. 48.6% (95% CI, 26.8‒88.3) (P=0.85) for MAC vs. RIC, respectively. RIC offers a significant advantage over MAC, even in younger patients with MF undergoing alloSCT, in terms of cell engraftment, rate of complete chimerism achievement, and incidence of acute GVHD.

Rapid Immune Reconstitution and Elevated Regulatory T Cell Frequencies in Patients Treated with Orca-T

BACKGROUND Immune reconstitution following myeloablative allogeneic hematopoietic stem cell transplant (MA-alloHSCT) is significantly delayed for T cell depleted allografts when compared to T-cell replete allografts, a feature that has been implicated in higher rates and grades of infection, less GVT, and worse overall survival. Orca-T is a high precision cell therapy currently being investigated for the treatment of certain hematological malignancies otherwise treated with MA-alloHSCT. The cellular drug products of Orca-T (HSPCs, Tregs, and Tcons) are administered at high purity, in controlled doses, and on an established schedule with the intent to reconstitute the blood and immune system while controlling GVHD. Here, we present data on the immune reconstitution in 100 adult patients who received Orca-T. METHODS In the context of an ongoing multicenter Phase Ib clinical trial of Orca-T in recipients with hematologic malignancies (NCT04013685), we performed longitudinal measurements (days -28, 28, 56, 100, 180, and 365 post-transplant) of immune reconstitution in the first 100 consecutive patients. With fresh whole blood, clinical 5-part leukocyte differentials were performed at clinical sites, and lymphocyte subset frequencies were measured by flow cytometry in a central lab. Principal component analysis (PCA) was performed to investigate potential associations with recipient sex (male vs. female) and donor relation (related vs. unrelated). RESULTS Longitudinal peripheral blood counts of platelets, WBCs, neutrophils, lymphocytes, monocytes, T cells, B cells, and NK cells are presented in Table 1. T cell and B cell counts were readily observed at days 28 and 56 respectively, and increased with each subsequent time point. Median NK cell levels were observed to be in the normal range at all post-transplant time points. CD4+ T cell and Treg cell counts exhibited similar post-transplant patterns with both being appreciably present at d28 and increasing with each subsequent time point. Strikingly, relative to the level measured in 75 corresponding PBSC donors, the Treg frequency among CD4+ T cells was significantly elevated at all time points post-transplant (Figure 1). Median CD8+ T cell counts increased for the first 6 months post-transplant and then plateaued in the normal range. Upon PCA, very few significant differences were observed in 2-group comparisons of recipient sex and donor relation. CONCLUSIONS Orca-T patients exhibit early immune reconstitution of each of the major leukocyte and lymphocyte subsets hypothesized to control relapse and infection. Concomitantly, elevated Treg frequencies were also observed. This feature of immune reconstitution profiles of Orca-T recipients may be correlated to the reduced occurrence and severity of acute and chronic GVHD in these patients (Meyer et al., EHA 2022, #S237). Similar immune reconstitution profiles were observed in patients of disparate sex and regardless of donor relation. Prospective comparisons of immune reconstitution between Orca-T and standard-of-care patients will be performed in our ongoing phase 3 clinical trial (NCT05316701). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CT-524 Orca-T, A Precision Engineered Allograft, Results in High GVHD-Free and Relapse-Free Survival Following Myeloablative Conditioning for Hematological Malignancies

Rates of graft-versus-host disease (GVHD) and non-relapse mortality (NRM) following myeloablative allogeneic hematopoietic stem cell transplant (MA-alloHSCT) remain unacceptably high. Orca-T is a high-precision, allogeneic investigational cell therapy product comprised of stem and immune cells that leverages highly purified, polyclonal donor regulatory T cells to control alloreactive immune responses, reducing the need for pharmacologic GVHD prophylaxis. Orca-T is produced in a central GMP facility and has been successfully scaled to clinical centers throughout the U.S. The aim of these studies was to evaluate the safety and efficacy of Orca-T in patients with hematologic malignancies. Data are reported for 138 patients with high-risk hematologic malignancies who received Orca-T in a single-center Phase 1/2 study (n=41) and a multicenter Phase 1b study (n=97) and had ≥ 100 days of follow-up as of 2/28/22. Orca-T was produced from G-CSF-mobilized peripheral blood (PB) from MRD (n=72), MUD (n=62), or MMUD (n=4). Median follow-up for recipients was 300 days (range: 27-1941). Median age was 49 years, and diagnoses included AML (43%), ALL (27%), MDS (10%), myelofibrosis (7%), and CML (6%). Patients received MAC (busulfan-based, n=109; TBI-based, n=27; BCNU, n=2) followed by GVHD prophylaxis with either single-agent tacrolimus (n=127), sirolimus (n=7), or tacrolimus plus mycophenolate (n=4, MMUD). A contemporaneous CIBMTR-based control arm was obtained that consisted of patients with similar diagnoses who received MA-alloHSCT from a PB source followed by tacrolimus/methotrexate prophylaxis. Orca-T was successfully manufactured, distributed, and infused for all patients. Overall time from donor centers to recipient centers was under 60 hours in all cases. Median time to neutrophil engraftment was 13 days. Rates of grade ≥ 3 acute GVHD in the first 180 days and moderate to severe chronic GVHD through 1 year were low at 4% and 5%, respectively. NRM was infrequent at 4% through 1 year. Orca-T exhibited GVHD-free relapse-free survival (GRFS) of 71% & OS of 90% at 1 year. No formal comparison to CIBMTR cohort was performed. Results from patients treated with Orca-T, a high-precision Treg-engineered donor product, suggest a reduction in cGVHD, improved GRFS, and low toxicity relative to historic data. A multicenter randomized-control phase 3 trial comparing Orca-T to SOC is enrolling.

S237: ORCA-T, AN ENGINEERED ALLOGRAFT, RESULTS IN HIGH GVHD-FREE AND RELAPSE-FREE SURVIVAL FOLLOWING MYELOABLATIVE CONDITIONING FOR HEMATOLOGICAL MALIGNANCIES

Background: Rates of graft versus host disease (GVHD) and non-relapse mortality (NRM) following myeloablative allogeneic hematopoietic stem cell transplant (MA-alloHSCT) remain unacceptably high. Strategies to reduce GVHD and NRM have been compromised by limited efficacy or increased risk of infection and relapse, emphasizing the need for new approaches that holistically improve outcomes. Orca-T is a high-precision, allogeneic investigational cell therapy product comprised of stem and immune cells that leverages highly purified, polyclonal donor regulatory T cells to control alloreactive immune responses, reducing the need for pharmacologic GVHD prophylaxis. Orca-T is produced in a central GMP facility and has been successfully scaled to clinical centers throughout the U.S. Aims: The aim of these studies was to evaluate the safety and efficacy of Orca-T in patients with hematologic malignancies. Methods: As of 28 February 2022, 138 patients with high-risk hematologic malignancies have received Orca-T in a single-center Phase 1-2 study (NCT01660607, n=41) and a multicenter Phase 1b study (NCT04013685, n=97) and have ≥ 100 days of follow-up. Informed consent was obtained from all transplant recipients and donors, and the studies received IRB approval from participating institutions. Orca-T was produced from G-CSF-mobilized peripheral blood (PB) from matched related donors (n=72), matched unrelated donors (n=62), or mismatched unrelated donors (MMUD, n=4). Median follow-up for recipients was 300 days (range: 27-1941). Median age was 49 years, and diagnoses included AML (43%), ALL (27%), MDS (10%), myelofibrosis (7%), and CML (6%). Patients received myeloablative conditioning (busulfan-based, n=109; TBI-based, n=27; BCNU, n=2) followed by GVHD prophylaxis with either single-agent tacrolimus (tac, n=127), sirolimus (n=7), or tac plus mycophenolate (n=4, MMUD). A contemporaneous CIBMTR-based control arm was obtained that consisted of patients with similar diagnoses who received myeloablative alloHSCT from a PB source followed by tac/methotrexate PPX. Results: Orca-T was successfully manufactured, distributed, and infused for all patients enrolled. Overall time from donor centers to recipient centers was under 60 hours in all cases. Median time to neutrophil engraftment was 13 days. The rates of grade ≥ 3 acute GVHD in the first 180 days and moderate to severe chronic GVHD through 1 year were low with Orca-T at 4% and 5%, respectively. NRM was infrequent at 4% through 1 year. Orca-T exhibited GRFS of 71% & OS of 90% at 1 year. No formal comparison to the CIBMTR cohort was performed, and a Phase 3 study has been initiated to confirm these findings. Longitudinal immune reconstitution data was collected and will be presented. Clinical data is summarized in Table 1. *MAGIC Criteria **NIH Consensus Grading Image:Summary/Conclusion: Results from patients treated with Orca-T, a high-precision Treg-engineered donor product, suggest a reduction in cGVHD, improved GRFS, and low toxicity relative to historic data. Orca-T manufacturing was accomplished with consistent and reliable cell manufacturing and distribution across a wide geographic area. A multicenter randomized-control trial phase 3 trial comparing Orca-T to SOC has been initiated.

Toward optimization of cyclosporine concentration target to prevent acute graft‐versus‐host disease following myeloablative allogeneic stem cell transplant

Despite the common use of cyclosporine (CsA) for acute graft-versus-host disease (aGVHD) prophylaxis following allogeneic stem cell transplant, the optimal CsA trough target remains unknown. Here, we report on outcomes of adult patients following myeloablative conditioning to identify an optimal CsA trough target and characterize the most relevant timeframe post-transplant for CsA trough targeting to minimize aGVHD. We retrospectively reviewed 399 consecutive patients who underwent first peripheral blood allogeneic stem cell transplant for hematological malignancies between January 2009 and December 2018. In the unadjusted and adjusted analyses, the incidence of grades 2-4 aGVHD was significantly higher among patients with an average CsA trough concentration <250mcg/L compared to patients with an average CsA trough concentration ≥250mcg/L during days 15-28 post-transplant (31.5% versus 18.8%, P = 0.037), with an odds ratio (OR) of 1.97 (95% confidence interval 1.04-3.71). In contrast, no correlations between CsA trough concentration and relapse, non-relapse mortality and overall survival was found. In conclusion, early post-transplant CsA trough concentrations are an important factor in the prophylaxis against aGVHD. Our findings suggest that CsA trough concentrations should be maximized between days 15-28 post-myeloablative transplant.

Kidney Disease Following Hematopoietic Stem Cell Transplantation.

Hematopoietic stem cell transplantation (SCT) provides a curative option for the treatment of several malignancies. Its growing use is associated with an increased burden of kidney disease. Acute kidney injury is usually seen within the first 100days of transplantation and has an incidence ranging between 12 and 73%, with the highest rate in myeloablative allogeneic SCT. A large subset of patients after SCT develop chronic kidney disease. They can be broadly classified into thrombotic microangiopathy, nephrotic syndrome, and calcineurin toxicity. Dialysis requirement after SCT is associated with mortality exceeding 80%. Given the higher morbidity and mortality related to development kidney disease, nephrologists need to be aware of the various causes and best treatment options.

413 - Outcomes for Myelofibrosis Patients Following Myeloablative Allogeneic Stem Cell Transplantation Using the Orca-T Graft from HLA-Matched Related and Unrelated Donors

413 - Outcomes for Myelofibrosis Patients Following Myeloablative Allogeneic Stem Cell Transplantation Using the Orca-T Graft from HLA-Matched Related and Unrelated Donors

Treating Relapsed/Refractory Acute Myeloid Leukemia with Chidamide, Fludarabine, Cytarabine and Granulocyte-Colony Stimulating Factor with Subsequent Bridging to Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation.

Treating Relapsed/Refractory Acute Myeloid Leukemia with Chidamide, Fludarabine, Cytarabine and Granulocyte-Colony Stimulating Factor with Subsequent Bridging to Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation.

Prognostic factors and impact of CMV reactivation on acute myeloid leukemia patients after HLA-matched myeloablative allogeneic stem cell transplantation in a high CMV prevalence country

IntroductionRelapse of acute myeloid leukemia (AML) after allogeneic stem cell transplantation (allo-SCT) leads to dismal outcomes. This study aimed to identify high-risk patients and explore the effects of cytomegalovirus (CMV) reactivation in a high CMV-seropositive population. MethodsThe study involved a single-center retrospective cohort in Thailand, analyzing clinical risk factors and CMV-mediated immune responses, correlated with transplant outcomes in AML patients. ResultsEighty-five patients with AML in complete remission (CR) undergoing HLA-matched myeloablative allo-SCT between 2011 and February 2021 were enrolled. The relapse rate was 27.1% with the median time of 7 months after transplantation. The 3-year relapse-free-survival (RFS) and overall-survival (OS) were 72.2% and 80.8%, respectively. The disease status (>CR1) and absence of chronic graft-versus-host disease (cGVHD) were independently significant adverse prognostic factors of RFS and OS. Ninety-two percent of recipient-donor pairs were both CMV seropositive. The CMV reactivation occurred in 54.1% of the patients. The clinically significant CMV infection rate was 49.4%. No CMV syndrome/disease or CMV-related mortality occurred. One-year cumulative incidence of relapse among CMV-reactivation and non-reactivation groups were 14.3% and 25.6%, respectively, without a statistically significant difference. Transplantation-related mortality was 11.1%. ConclusionsThe transplantation beyond CR1 and absence of cGVHD are powerful prognostic factors associated with inferior RFS and OS. In a high CMV prevalence country, there appears to be no impact of CMV reactivation on relapse in AML patients undergoing an allo-SCT.

Outcomes for Myelofibrosis Patients Following Myeloablative Allogeneic Stem Cell Transplantation Using the Orca-T Graft from HLA-Matched Related and Unrelated Donors

Background: Allogeneic stem cell transplantation (allo SCT) is the only potentially curative therapy for patients with intermediate-2 and high-risk myelofibrosis (MF). Allo SCT for MF has historically been challenging as many patients are transplanted with active or advanced disease and immune reconstitution in MF patients is often hindered by inflammation and bone marrow fibrosis. When compared to non-SCT therapies, MF patients who receive allo SCT achieve long-term survival benefits. However, it comes with an upfront cost of an increased risk of non-relapse mortality in the first year after allo SCT (Gowin K et al, Blood Av 2020). Therefore, there is an unmet need to improve on the early outcomes of transplantation for MF.Methods: We reviewed MF patients who underwent myeloablative allo SCT with Orca-T derived from HLA matched donors on NCT01660607 and NCT04013685. Orca-T is an investigational cellular product comprising stem and immune cells that leverages highly purified donor regulatory T cells to control alloreactive immune responses. Single agent GVHD prophylaxis was administered as tacrolimus or sirolimus.Results: We present outcomes for 7 MF patients with DIPSS risk of int-1 (n=1), int-2 or higher risk MF (n=6) treated with the Orca-T graft and compared this to 6 MF patients who underwent standard of care (SOC) allo SCT at Stanford, between 2017 - 2021 (Table 1). All patients were high or very high-risk based on MIPSS70 plus score v, 2.0. All patients had 10/10 HLA-matched donors, except 1 of 7 Orca-T patients who had 9/10 HLA-matched donor. All but 1 patient in both, Orca-T and SOC, recipients had prior Jakafi exposure.All Orca-T recipients had splenomegaly with spleen size of 16.3 - 23 cm. Engraftment occurred at median of D+13 (range 10-29) and 6 of 7 patients had 100% CD3 donor chimerism at D+100. 1 patient was 90% CD3 donor chimerism at D+100 but achieved 100% CD3 donor chimerism at D+180. All patients had significant marrow fibrosis, MF grade 2 or 3, before allo SCT. Regression of marrow fibrosis to MF grade 0 or 1 was noted by D+ 100 in 7 of 7 Orca-T recipients but only in 1 of 6 SOC patients. Orca-T recipients did not have grade 2-4 acute GVHD and 1 of 7 recipients had extensive chronic GVHD. Tacrolimus was tapered off in 3 of 7 patients at D+180. SOC recipients had 2 of 6 recipients with grade 2-4 acute GVHD, 3 of 6 recipients with extensive chronic GVHD and only 1 recipient was taken off tacrolimus at D+180. There were no deaths in Orca-T recipients and 2 deaths in SOC recipients before D+180, cause of death was acute GVHD and relapse. Finally, when compared to standard allo SCT, Orca-T recipients may have a reduced frequency and severity of infections without significant consequences while the SOC patients had severe and often multiple infections.Conclusion: Our data indicates that Orca-T graft was well tolerated and potentially efficacious in MF patients undergoing allo SCT. We observed early regression of marrow fibrosis at D+100 in all Orca-T recipients. This limited data suggests that Orca-T may afford an early resolution of an inflammatory microenvironment that allows for robust immune reconstitution and potentially lower incidence of serious infections. Orca-T is under continued investigation to reduce early non-relapse mortality for MF. [Display omitted] DisclosuresGandhi: CareDx Inc: Honoraria; Gamida Cell: Consultancy, Membership on an entity's Board of Directors or advisory committees. Muffly: Pfizer, Amgen, Jazz, Medexus, Pfizer: Consultancy; Astellas, Jasper, Adaptive, Baxalta: Research Funding; Adaptive: Honoraria, Other: fees for non-CME/CE services: , Research Funding. Shiraz: Kite Pharma-Gilead: Research Funding. Fernhoff: Orca Bio: Current Employment. McClellan: Orca Bio: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Gotlib: Allakos: Consultancy; Cogent Biosciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Chair for the Eligibility and Central Response Review Committee, Research Funding; PharmaEssentia: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kartos: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Deciphera: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Blueprint Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Meyer: Triursus Therapeutics: Current holder of stock options in a privately-held company; GigaImmune: Current holder of stock options in a privately-held company; Orca Biosystems: Research Funding; Indee, Jura: Consultancy.

Radiation-Free myeloablative allogeneic hematopoietic stem cell transplantation for adult acute lymphoblastic leukemia: A comparison of outcomes between patients with and without central nervous system involvement

For patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), total body irradiation (TBI) has been particularly advocated as a part of the conditioning regimen in case of extramedullary involvement in sanctuary sites such as the central nervous system (CNS), to ensure greater tissue penetration. In resource-limited countries lacking TBI facilities; however, ALL patients undergo radiation-free myeloablative conditioning, though its impacts on post-HSCT outcomes of the patients with pre-HSCT CNS involvement have not been analyzed. In this 14-year series of 278 adult (> 18 y) ALL patients undergoing TBI-free busulfan/cyclophosphamide conditioning allo-HSCT, we found that the long-term probabilities of overall survival, disease free survival, relapse and non-relapse mortality were not significantly different between CNS-involved and CNS-spared patients. Moreover, there was no statistically significant difference in the incidence of post-HSCT CNS relapse between CNS-involved and CNS-spared patients. Pre-HSCT cranial radiation therapy (CRT) showed no significant preventive effect on the likelihood of post-HSCT CNS relapse. Through multivariable regression analysis, grade III-IV acute graft-versus-host disease (GvHD), extensive chronic GvHD and post-HSCT relapse were ascertained as independent determinants of mortality (Adj.R2 = 53.9 %, F(12,265) = 28.1, P < 0.001), while other parameters including Philadelphia translocation, pre-HSCT CNS involvement and CRT were found to have no independent effect. Although this study was not an attempt to compare TBI-based vs. non-TBI conditioning, the TBI-free myeloablative allo-HSCT was shown to be feasible and an option for adult ALL patients with CNS involvement, considering the comparable outcomes between patients with and without CNS involvement.

Ex Vivo T Cell-Depleted and In Vivo T Cell-Depleted Allogeneic Stem Cell Transplantation in Patients with Acute Myeloid Leukemia in First Complete Remission Resulted in Similar Overall Survival Survival: On Behalf of the ALWP of the EBMT and the MSKCC

Background. Myeloablative allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a well-established therapy for adult patients with acute myeloid leukemia (AML) in first complete remission (CR1) with intermediate or high-risk cytogenetics. However regimen-related toxicities, in particular graft-versus-host disease (GVHD) have limited its widespread use. Therefore several strategies have been developed to deplete T cells in order to prevent GVHD. In vivo T-cell depletion (TCD) using antithymocyte globulin (ATG) with an unmanipulated graft is widely used in some centers in Europe, while other centers have develop an effective platform based on ex-vivo TCD CD34 selected (CD34+) graft. The aim of the current study was to compare these two strategies for GVHD prevention.Patients and methods. This retrospective analysis assessed the outcome of all consecutives patients over 18 years at time of transplant with an AML in CR1 with intermediate or high risk cytogenetics who received an in-vivo or ex-vivo T cell depleted myeloablative allo-HSCT using busulfan or total body irradiation based conditioning regimen between 2005 and 2011 and reported to the EBMT ALWP registry centers or at Memorial Sloan Kettering Cancer Center (MSK), respectively. Patients treated in EBMT centers received in vivo TCD with either thymoglobuline or grafalon ATG. In addition, all patients in the ATG group received GVHD prophylaxis consisting of a calcineurin inhibitor in combination with another drug. Patients treated at MSK received an ex-vivo TCD graft (CD34+). TCD was performed by immunomagnetic CD34+ cell selection of peripheral blood grafts. No additional GVHD prophylaxis was administered in those patients. Main transplant outcomes including refined GVHD-free/relapse-free survival (GRFS) were evaluated.Results. A total of 525 patients were included (363 ATG, 162 CD34+) with a median age of 46 (19-77) and 58 (range, 20-73) years, respectively (p<0.001). The ATG cohort had more unrelated donors (67.5% vs. 54.9%, p=0.006). Median follow-up was significantly longer in the CD34+ cohort [58.0 (range, 6-139.0), vs. 24.5, 51.9-131.0) months, p<0.001], therefore all patients were censored at 2 years for comparison between groups. There were no additional differences between cohorts including donor/recipient gender, CMV status and cytogenetic risk. The CD34+ cohort had less relapse (21.6% vs. 30%, p=0.03), grade II-IV aGVHD (11.3% vs. 21.2%, p=0.006), III-IV aGVHD (1.3% vs. 6.2%, p=0.01), cGVHD (2.5% vs. 27.6%, p<0.0001) and extensive cGVHD (0.6% vs. 11.3%, p=0<0.0001) and a higher GRFS (61% vs. 47%, p=0.0007) while there was no difference regarding OS (67.6% vs. 56.4%, p=0.31), LFS (61% vs. 57.9%, p=0.29) and NRM (17.4%, vs 12.1%, p=0.16). In multivariate analysis, the cumulative incidence of grade II-IV aGVHD and chronic GVHD were higher in the ATG cohort [HR 2.0 (95% CI 1.1-3.7), p=0.02 and HR 15.1 (95% CI 5.3-42.2), p<0.0001]. There were no statistical differences between both approach in terms of relapse, NRM, OS, and LFS. Parameters associated with a lower GRFS were ATG group, adverse cytogenetic and use of an unrelated donor [HR 1.7 (95% CI 1.2-2.5) p=0.001; HR 1,7 (95% CI 1.3-2.2) p=0.0002 and HR 1.5 (95% CI 1.1-2.0) p=0.01]. Cytogenetic status (high risk versus intermediate risk) also has a significant impact on relapse incidence [HR 2.1 (95% CI 1.4-3.0), p<0.0001] and LFS [HR 1.7 (95% CI 1.2-2.3) p=0.0006]. Finally there was significantly more death related to infection in the CD34 group (16/52, vs. 19/112, p=0.04).Conclusion. The cumulative incidence of acute (total and severe) and chronic GVHD were higher after allo-HSCT with ATG, leading to a lower GRFS in those patients. In contrast, enhance immunosuppression in the CD34+ group lead to a higher incidence of infectious related death. Overall NRM, OS and LFS are similar after ex-vivo CD34 selected and in-vivo ATG TCD allo-HSCT from related/unrelated donors in patients with AML in CR1 and intermediate/high-risk cytogenetic. Both approaches are associated with a good disease control and a high OS, and should be compared in a prospective randomized trial. DisclosuresMohty:Sanofi: Honoraria, Speakers Bureau.

Phase II Study of High Dose Cytarabine Followed By Pembrolizumab in Relapsed/Refractory Acute Myeloid Leukemia (AML)

Introduction: Outcomes are dismal for patients (pts) with relapsed/refractory (R/R) AML. Innate and adaptive immune aberrations exist in AML pts leading to immune escape. We have previously shown that there is an increased expression of multiple co-inhibitory molecules including programmed death-1 (PD-1) in the peripheral blood of AML pts at diagnosis, and these levels persist in pts with refractory disease (Knaus H, et al. Blood [Abstract] 2015). We hypothesized that administration of pembrolizumab after high dose cytarabine (HiDAC) salvage chemotherapy would stimulate a T-cell mediated anti-leukemic immune response leading to improved efficacy in R/R AML.Methods: A multicenter phase II study of age-adjusted HiDAC (<60 years: 2 gm/m2 IV Q12hours days 1-5; >=60 years: 1.5 gm/m2 IV Q12hours days 1-5) followed by pembrolizumab 200 mg IV on day 14 is being conducted in R/R AML pts 18-70 years. The primary endpoint of this study is the rate of complete remission (CR)/CR with incomplete recovery (CRi) after HiDAC followed by pembrolizumab. The study design is a Simon's like two-stage design (n=37 pts) with relaxed stopping for futility. Relaxed stopping refers to overall response rate (CR/CRi+partial remission [PR]) when stopping rule for futility is applied in the first stage. The null hypothesis that the CR/CRi rate for HiDAC followed by pembrolizumab is 20% will be tested against a one-sided alternative hypothesis yielding a type 1 error rate = 5% and power = 84% when the CR/CRi rate of HiDAC followed by pembrolizumab = 40%. Continuous monitoring for toxicity will be performed to assess for unacceptable toxicity. Overall responders will receive maintenance phase pembrolizumab 200 mg IV Q3weeks for up to 2 years until relapse/progression. Pts can proceed to allogeneic stem cell transplant (SCT) before or after maintenance phase (SCT must be >=30 days from last dose of pembrolizumab). Correlative studies include serial peripheral blood and bone marrow flow cytometry, mRNA-sequencing, and T cell receptor (TCR) clonality studies to determine predictive biomarkers of response.Results: 13 pts enrolled on this study between August, 2016-July, 2017 (Table 1). There have been 0 unacceptable toxicities to date. Immune-related adverse events have included grade 2 hyperbilirubinemia (n=1), grade 3 hepatic enzymes (n=1), both resolved promptly after systemic corticosteroids, as well as self-resolving grade 3 rash (n=1). Additionally, 1 pt developed grade 3 pulmonary edema without evidence of pneumonitis that resolved spontaneously without steroids. Of the 10 evaluable pts (as of July 1, 2017), overall response rate = 50% (CR/CRi: 4/10= 40%; PR = 1/10=10%), meeting the threshold to proceed to stage 2. Two pts have proceeded to a myeloablative allogeneic SCT in CR (one of whom received 2 cycles of maintenance pembrolizumab) and remain in CR. Post-SCT, both pts developed steroid-responsive acute GVHD of skin, one pt developed a transient increase in hepatic enzymes that was responsive to steroids, and one pt developed moderate chronic GVHD. Four pts have received maintenance pembrolizumab: 2 pts relapsed (median duration of CR = 3.9 months; range: 2-5.7 months), one pt proceeded to SCT after 2 cycles, and one pt initially achieved a PR and remains with stable disease after 11 cycles of maintenance pembrolizumab. No pts have died in remission. 30-day and 60-day mortality = 0% and 10%, respectively. Preliminary findings from the first 6 pts (3 responders vs. 3 non-responders) revealed increased diversity of TCR Vβ repertoire from pre-treatment peripheral blood CD8+ T-cells in responders when compared with non-responders using Shannon entropy analysis (p=0.0058; Figure 1).Conclusions: Early results of a multicenter phase II study demonstrate the feasibility of adding immune checkpoint blockade with pembrolizumab after HiDAC chemotherapy in R/R AML. An overall response rate of 50% is encouraging in a high-risk R/R AML cohort though ongoing findings are imperative to evaluate the efficacy and future role of pembrolizumab in AML. Interestingly, in a small cohort of patients, broadening of the immune repertoire, perhaps by increasing T cell responses beyond endogenous viral responses, was associated with response to PD-1 blockade. Future directions include a comprehensive immune biomarker discovery approach to determine predictors of response to immune checkpoint blockade in AML. [Display omitted] DisclosuresZeidner:Tolero Pharmaceuticals: Honoraria; Agios: Honoraria; Merck: Research Funding; Takeda: Research Funding; Tolero Pharmaceuticals: Research Funding; Celgene: Honoraria. Vincent:Merck: Research Funding; Pharmacyclics: Research Funding; Nanostring: Membership on an entity's Board of Directors or advisory committees. Foster:Shire: Honoraria; Incyte: Honoraria; Macrogenics: Research Funding; Celgene: Research Funding; Amgen: Honoraria; Pfizer: Research Funding; Celator: Research Funding. Coombs:Pharmacyclics: Honoraria; H3 Biomedicine: Honoraria. Gojo:Merck: Research Funding; Amgen: Research Funding; Amgen: Honoraria; Novartis: Research Funding. Serody:Merck: Research Funding.

Isolated Extramedullary Relapse After Human Leukocyte Antigen-Matched Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemia Patients: Case Reports and Literature Review

Isolated extramedullary relapse (iEMR) of acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is rare and has a dismal prognosis. Among 67 patients with AML after allo-HSCT, iEMR and bone marrow relapse occurred in 6% and 20.9%, respectively, with a median time to relapse of 11.5 and 6.5 months, respectively. Here, we presented 4 iEMR-AML cases. Common relapse locations occurred in the central nervous system, skin, and lymph nodes. We also report a rare case of cardiac iEMR that responded to chemoradiotherapy. Two cases responded to local/systemic treatments, which resulted in prolonged survival. Another case had iEMR in the presence of chronic graft-versus-host disease. Bone marrow relapse occurring after iEMR was typical and found in three-fourths of the cases. In conclusion, iEMR-AML occurrence after allo-HSCT is not rare in Thai patients. Its unpredictability and lack of graft-versus-leukemia effect highlight the importance of monitoring EMR carefully and promptly providing treatments once it is detected.

Comparison of immune reconstitution between anti-T-lymphocyte globulin and posttransplant cyclophosphamide as acute graft-versus-host disease prophylaxis in allogeneic myeloablative peripheral blood stem cell transplantation.

Anti-T-cell lymphocyte globulin (ATLG) and posttransplant cyclophosphamide (PTCy) are now widely used strategies to prevent graft-versus-host disease (GVHD) after allogeneic stem cell transplantation. Data comparing immune reconstitution (IR) between ATLG and PTCy is scarce. This retrospective study conducted at the University Medical Center Hamburg-Eppendorf (UKE) compares PTCy (n=123) and ATLG (n=476) after myeloablative allogeneic peripheral blood stem cell transplant. Detailed phenotypes of T, B natural killer (NK), natural killer T (NKT) cells were analyzed by multicolor flow at day 30, 100 and 180 posttransplant. Incidence of infections, viral reactivations, GVHD and relapse were collected. Neutrophil engraftment was significantly delayed in the PTCy group (median day 12 vs. day 10, P<0.001) with a high incidence of infection before day+100 in the PTCy arm but a higher Epstein-Barr virus reactivation in the ATLG arm and comparable cytomegalovirus reactivation. Overall incidence of acute GVHD was similar but moderate/severe chronic GVHD was seen more often after PTCy (44% vs. 38%, P=0.005). ATLG resulted in a faster reconstitution of CD8+ T, NK, NKT and gdT cells while CD4 T cells and B cells reconstituted faster after PTCy. Similar reconstitution was observed for T-regulatory cells and B cells. Non-relapse mortality relapse incidence, disease-free survival, and overall survival did not differ significantly between both arms. Even though differences in IR were related to a decreased incidence of infection and moderate/severe cGVHD in the ATLG group they had no impact on any of the other long-term outcomes. However, it remains undetermined which regimen is better as GVHD prophylaxis.