GVHD Prophylaxis Research Articles

Gvhd Prophylaxis Incorporating Methotrexate in Allo-HCT for Chronic Myeloid Malignancies and sAML: A Retrospective Analysis from the Cmwp of the EBMT

Introduction: Methotrexate (MTX) given on days 1, 3, 6 (and 11) after allogeneic haematopoietic cell transplantation (allo-HCT) along with calcineurin inhibitors (CNI) was established as effective GVHD prophylaxis decades ago when myeloablative conditioning was standard. Mycophenolate mofetil (MMF) replaced MTX initially in minimal intensity conditioning protocols and then became increasingly popular due to its favorable toxicity profile. Although MMF was associated with more severe GVHD in some reports, similar survival outcomes were reported for both regimens in most randomized trials. However, two large retrospective studies from the CIBMTR reported inferior outcomes of MMF-based regimens in allo-HCT standard indications. Taking advantage of a very large sample size within the EBMT registry, the aim of this retrospective study was to determine outcome differences after allo-HCT between MTX- and MMF-based GVHD prophylaxis regimens considering subgroup heterogeneity. Patients and Methods: Eligible were patients from the EBMT registry with select chronic myeloid malignancies (CML, CMML, MDS, myelofibrosis, secondary AML) who were transplanted from matched related, matched unrelated and mismatched unrelated donors between 2007 and 2017 and received either MTX or MMF prophylaxis in combination with a CNI. Endpoints were overall (OS) and relapse-free survival (RFS), relapse incidence, non-relapse mortality (NRM), and cumulative incidence of grade 2-4 acute GVHD. Multivariable Cox regression analyses included age, conditioning intensity, TBI, diagnosis, disease stage, ATG, graft source, donor type, gender match, CMV (recipient), year of transplantation, and Karnofsky index. We tested whether the association between the type of prophylaxis and the outcome was different in patient subgroups by including interaction terms in multivariable analyses between prophylaxis type (MTX/MMF) and ATG, age, Tacrolimus, conditioning intensity, use of TBI, diagnosis, disease stage and recipient CMV status. Finally, we studied the association between the same set of variables and OS, relapse and NRM in patients after aGvHD and separately in a landmark analysis at 3 months in patients without aGvHD. Results: Overall, 13699 patients from 321 centers were included. Diagnoses were MDS (44%), Myelofibrosis (18%), CML (11%), CMML (6%), atypical CML (1%) and secondary AML (21%). The conditioning / prophylaxis combination was RIC/MMF in 34%, RIC/MTX in 22%, MAC/MMF in 12% and MAC/MTX in 32%. CNI prophylaxis was Tacrolimus (n=1248), ciclosporin (n=12286), both (n=165). Median follow up was 42.8 months (IQR 19.8-74.5 months). Unadjusted analyses demonstrated significantly better outcomes with MTX in all subgroups of patients (TBI/no TBI, RIC/MAC, diagnoses except myelofibrosis, ATG/no ATG, age at allo-HCT < or ≥60 years). Figure 1a shows OS curves for conditioning/prophylaxis combinations. The cumulative incidence of acute GVHD grade 2-4 was lower in in particular RIC patients (Figure 1b). MTX was associated with significantly reduced overall mortality (HR 0.88, 95%CI 0.81-0.95, p<0.001) and NRM (HR 0.87, 95% CI 0.78-0.96, p=0.008) in multivariable analyses in the whole cohort. In contrast, MTX prophylaxis was not significantly associated with relapse (HR 1.02, 95% CI 0.92-1.12, p=0.72) and relapse-free survival (RFS) (HR 0.94, 95% CI 0.88-1.01, p=0.11). Notably, there was no significant interaction effect between prophylaxis type and any of the eight variables (ATG, age, tacrolimus, conditioning intensity, use of TBI, diagnosis, disease stage and CMV status in recipients) tested for OS and NRM, except that the beneficial association of MTX on OS was weaker for patients with Myelofibrosis. OS after acute GVHD was significantly lower with MTX prophylaxis and this was similar in RIC and MAC. MTX did not significantly associate with improved outcome in a landmark analysis in patients without aGvHD at 3 months after allo-HCT. Conclusion: Compared to MMF, MTX-complemented calcineurin inhibitor prophylaxis was associated with favorable early OS and NRM, and in particular with favorable OS after aGVHD, in this large cohort of patients with chronic myeloid malignancies or sAML transplanted in a recent time period. This effect was observed across various subgroups. These results may have future impact on clinical practice and trial design. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

ATG-Ptcy-CSA for Gvhd Prevention in Peripheral Blood Haploidentical Hematopoietic Cell Transplantation for Adults with Hematological Malignancies

INTRODUCTION The introduction of post-transplant cyclophosphamide (PTCY) for GVHD prevention can be considered a milestone in haploidentical hematopoietic cell transplantation (haplo-HCT). And secondary to its efficacy, the use of haplo-HCT with peripheral blood stem cell (PBSC) grafts has significantly increased in last decade. However the optimal immunosuppressive agents to combine with PTCY using peripheral blood stem cell (PBSC) sources is still a matter of debate, as in a retrospective analysis conducted by CIBMTR using PBSC grafts and PTCY-based GVHD prophylaxis in the haplo-HCT setting, was associated with higher rates of acute and chronic GVHD than with using bone marrow stem cell grafts. PTCY-based prophylaxis is considered a standard of care when haploidentical donors are selected. PTCY combined with anti-thymocyte globulin and cyclosporine (PTCY-ATG-CsA) became our institutional GVHD prophylaxis for peripheral blood (PB) haplo-HCT in 2015. The present analysis aims to share updated information about our experience using ATG-PTCY-CsA for GVHD prevention in PB haplo-HCT. METHODS Between October 2015 to December 2021, 157 consecutive adults underwent haplo-HCT at our institution and were included in the study. The GVHD prophylaxis was composed of rabbit-ATG (Thymoglobulin; Genzyme-Sanofi, Lyon, France), PTCy (50 mg/kg/day on days +3 to +4), and CsA (started on day +5 and titrated to therapeutic levels ranging between 200 and 400 ng/ml). One hundred twenty (76.4%) adults received a total dose of 4.5mg/kg of ATG (0.5 mg/kg on day -3, 2 mg/kg on day -2 and 2 mg/kg on day-1), and 37 (23.5%) received 2 mg/kg (0.5 mg/kg on day -2 and 1.5 mg/kg on day -1). T-cell replete PBSC grafts were infused on day 0 in all cases. Data was collected retrospectively and updated in March 2022. To perform regression analyses, post-transplant follow-up was censored at 2 years. RESULTS Of the 157 patients, the median age was 57 years (range: 43-66), and 67 (44%) were 60 years or older. Sixty-four (44%) patients were females. Acute myeloid leukemia was the most prevalent baseline diagnosis (n=79, 50.3%), and 38 (24.2%) patients received myeloablative conditioning (MAC) regimens. Forty-six (30%) adults had a KPS ≤80%, 46 (30%) had an HCT-CI score >3, and 34 (23.4%) had a high or very-high disease risk index (DRI). Fresh products were infused in 90 (57.32%) cases. A total of 152 patients achieved engraftment. The median time for neutrophil and platelet engraftment were 17 (IQR 19-15) and 22 days (IQR: 12-28). The cumulative incidence function (CIF) of bloodstream infection at day +28 was 51.6%. The day +180 CIF of CMV and EBV reactivations were 62.5% and 65.4%, respectively, and 5 (3.2%) patients had post-transplant lymphoproliferative disorder. The CIFs of grade II-IV and grade III-IV acute GVHD estimated at day +100 were 26.3% and 9.5%, and the CIF of moderate/severe cGVHD at 1 year was 19.9%. As reported in Table 1, the use of MAC regimens (HR 2.70), the administration of 2 mg/kg of ATG (HR 4.42, P=0.003) and the selection of donors older than 40 years (HR 3.35, P=0.011) increased the risk for grade III-IV aGVHD. The infusion of frozen products was not found to be predictor for GVHD. Nevertheless, a non-significant trend to lower grade II-IV aGVHD was documented in patients receiving frozen PBSC grafts (HR 0.54, P=0.060). The median follow-up in survivors was 32 months. Overall, 73 (46.5%) patients died, and 28 (17.3%) relapsed. The leading causes of death were infection and relapse. The median of days to discontinuation of the immunosuppression in survivors was 83 days (IQR: 69-119). As shown in Figure 1, the estimated 2-year OS, RFS, NRM, CIR, and GRFS were respectively: 49.4%, 44.6%, 36.6%, 18.8%, and 35.7%. The multivariate regression analysis reported n Table 1 showed that older patients and those with high and very-high DRI were at higher risk for worse OS and higher NRM. CONCLUSION Dual T-cell depletion using PTCy and ATG (total dose of 4.5mg/kg) combined with CsA is a safe drug combination for PB haplo-HCT. The use of this prophylaxis provided an effective GVHD prevention with acceptable relapse rates. Moreover, the selection of younger donors, and the use of a total dose of 4.5mg/kg of ATG increased the effectiveness of GVHD prevention. Further research is needed to decrease rates of NRM for patients undergoing haplo-HCT using this prophylaxis. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Phase I Study of Baricitinib Gvhd Prophylaxis in HLA-Matched, Peripheral Blood Allogeneic Hematopoietic Cell Transplant

Acute graft versus host disease (aGVHD) is a leading cause of non-relapse mortality after allogeneic peripheral blood hematopoietic cell transplant (PB-HCT). JAK inhibition has been shown to be an effective treatment for steroid refractory aGVHD. We performed a single arm, open label, phase I trial to evaluate the safety of a best-in-class balanced JAK1/2 inhibitor, baricitinib (Bari), for the prevention of aGVHD after HLA-matched, allogeneic PB-HCT (Choi et al. Leukemia2018; Kim et al. Leukemia, 2022). The study enrolled 24 subjects into two dosing cohorts (2mg and 4mg daily) from 2019 - 2022. The data cut-off for this analysis was June 1, 2022. The primary objectives were to determine the incidence of graft failure at 28 days post HCT and the cumulative incidence of grade III-IV acute GVHD by day 100. The secondary objective was to determine day 180 treatment related mortality. Subjects were treated with Bari 2mg or 4mg (n = 12/cohort) oral daily from days -3 to +100, followed by a taper. All subjects received standard of care GVHD prophylaxis with tacrolimus and mini-methotrexate +/- thymoglobulin (n=19) or post-transplant cyclophosphamide (pTCy) plus mycophenolate mofetil and tacrolimus (n=5). At data cut, the median follow up was 320 days (63-368 days). The median age was 57 (range 28-72), and diagnoses included AML (16), MDS (6), and ALL (2). All subjects with AML were required to be in CR/CRi and 8 were MRD positive by flow cytometry at the time of transplant. Ten recipients had PB-HCT from sibling donors and 14 had PB-HCT matched unrelated donors. Conditioning included myeloablative regimens (MAC, n=19) or reduced intensity (RIC, n=5). GVHD prophylaxis included tacrolimus /methotrexate for all subjects in the 2mg cohort and pTCy was used in 5 / 12 subjects in 4mg dosing cohort. Thymoglobulin was allowed for MUD recipients (n=5). No events of primary graft failure were observed. The median ANC engraftment was 12.5 days (range 12-21). The median platelet engraftment was 20 days (range 13-52). Treatment related mortality at day 180 was 8% (2/24). The cumulative incidence of grade III/IV aGVHD at day 100 was 4% (1/24, occurring in the 4mg cohort), while the overall incidence of grade III/IV aGVHD at any time was 12.5% (3/24) and two of these cases occurred after Bari discontinuation. The one case of grade III aGVHD prior to day 100 was a steroid-responsive lower GI GVHD that occurred at day 21 in the 4mg cohort and did not recur with taper of immune suppression and Bari. Grade II - IV aGVHD occurred in 33% (8/24, 4 in the 2mg cohort and 4 in the 4mg cohort). Two cases were steroid refractory (one in 2mg and one in 4mg cohorts). All cases of grade II aGVHD were responsive to steroids. We found no association between GVHD prophylaxis backbone regimen and incidence of aGVHD. 11 cases of chronic GVHD (3 mild and 8 moderate severity) have been reported. Of the moderate cGVHD cases, 4 developed in the 2mg cohort and 4 in the 4mg cohort. No unexpected grade 3/4 adverse events (AE) were observed. Thromboembolic disease was an AE of special interest. Four DVTs were observed: 1 in the 2mg cohort vs. 3 in 4mg cohort. All subjects in the 4mg cohort had pulmonary embolism occurring while off Bari, one occurring at 10 months post-transplant, one at day 141 and another at day 152. Of the evaluable cases at day 100, 14/15 (93%) receiving MAC vs. 4/5 (80%) receiving RIC conditioning achieved >95% bone marrow donor engraftment, whereas, 11/16 (69%) receiving MAC vs. 4/4 (100%) receiving RIC had mixed peripheral blood CD3 T-cell chimerism. Of those with mixed CD3 chimerism at day 100, 12 remain in remission and 3 have relapsed. The incidence of disease relapse at 1 year was 21%, with 2 relapses occurring in the 2mg cohort and 3 in the 4mg cohort. Of the 8 cases with MRD positivity at transplant, 2 relapsed within 3 months of transplant and both had AML. The 1-year overall survival was 70%. The one-year refined GVHD relapse free survival (GRFS) was 33%. In conclusion, Baricitinib is safe after HLA-matched, allogeneic PB-HCT with no episodes of primary graft failure and low rates of grade III/IV acute GVHD while on therapy. A follow up efficacy study to evaluate extended duration of the 2mg dose of Bari focused on AML patients receiving HLA matched transplants and myeloablative conditioning is planned. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

HLA-Haploidentical Vs Mismatched Unrelated Donor Transplants with Post-Transplant Cyclophosphamide-Based Gvhd Prophylaxis for AML and MDS: Is There a Winner?

Introduction: Finding a suitable donor is often influenced by race and ethnicity of the patient. Despite increased donor availability through registry, a proportion of patients does not find HLA-matched donors. In such situations, haploidentical donors or mismatched unrelated donors (MMUD) are commonly considered. Post-transplant cyclophosphamide (PTcy), given on days +3 and +4 after haploidentical donor transplants (HIDT), has significantly reduced rates of GVHD and improved outcomes. Given encouraging activity, we implemented use of PTcy in combination with tacrolimus and mycophenolate for GVHD prophylaxis in HLA-MMUD transplants and have reported promising results. This raises an important clinical question: Do outcomes of HLA-haploidentical or MMUD transplants differ when using PTcy-based GVHD prophylaxis? Does PTcy overcome adverse outcomes associated with HLA-MMUD similar to HLA-haploidentical donors? Methods: We retrospectively compared outcomes of 144 adult patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) who received PTcy, tacrolimus, and mycophenolate for GVHD prophylaxis and underwent either HIDT or HLA-MMUD transplants. Propensity score-based multivariable analyses (PSCA) were performed using age, KPS, HCT-CI, diagnosis, conditioning regimen, disease status at transplant, CMV serotype, and donor/recipient sex mismatch as variables to adjust confounding effects of patient characteristics between both groups. Results: Between January 2013 and December 2021, 89 patients received HIDT and 55 received MMUD transplants. Among MMUD, 89% (n=49) were 7/8 HLA-matched and 11% (n=6) were 6/8 HLA-matched. Median age of the population was 62 years, 22% were African American, 73% had AML, 20% received myeloablative conditioning regimen. All patients received peripheral blood stem cell transplants. CRS rate was higher in the HIDT group compared to MMUD (78% vs 38%, p<0.001). The median time of onset of CRS was 1-day post-transplant, and the median duration of CRS was 3 days. Median time to neutrophil engraftment was prolonged in the HIDT group (18 vs 15 days, p<0.001), while platelet engraftment was similar (23 vs 21 days, p=0.15). Graft failure rate was 3% in both groups. The cumulative incidence of grade III-IV acute GVHD at day 100 was similar (3.4% in HIDT vs 7.3% in MMUD, p=0.30), whereas chronic GVHD at 1 year was higher with HIDT compared to MMUD transplants (28% versus 14.2%, p=0.05). At a median follow up of 2.5 years, 1-year survival was 66.7% for HIDT and 69.5% for MMUD (p=0.46), 1-year relapse-free survival (RFS) was 58.9% for HIDT and 61.7% for MMUD (p=0.48), 1-year relapse was 18.3% for HIDT and 25% for MMUD (p=0.49), and 1-year non-relapse mortality (NRM) was 22.7% for HIDT and 13.2% for MMUD (p=0.11). Using PSCA, no difference in survival, RFS, relapse, and NRM was noted between both groups. Conclusion: Our study demonstrated that transplant outcomes did not differ between HLA-haploidentical and MMUD when PTcy was used for GVHD prophylaxis. PTcy can be safely used and provided promising results in HLA-MMUD transplants. In the absence of HLA-matched donors, either haploidentical or MMUD can be used. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Post-Transplantation Cyclophosphamide Combined with Tacrolimus and Low-Dose Post-Engraftment Anti-Thymoglobulin As Gvhd Prophylaxis for Patients Undergoing Peripheral Blood Stem Cell Transplantation from Haplo Donors: A Single Center Analysis

Post-transplantation cyclophosphamide (PT-Cy) use is a recent graft-versus-host disease (GVHD) prophylaxis strategy for patients undergoing allogeneic stem cell transplantation (allo-HSCT). PT-Cy combined with two immunosuppressants is now widely used after haplo-identical (haplo) and HLA-matched peripheral blood stem cell (PBSC) transplantations with promising GVHD and GVHD and relapse-free survival (GRFS) probabilities. Although appealing, these results may benefit from improvement notably outside matched sibling donor transplantation, and should be investigated in various ethnic populations. Therefore, we report our experience of GVHD prophylaxis regimen combining PT-Cy and tacrolimus with addition of post-engraftment low-dose anti-thymocyte globulin (ATG) in allogeneic stem cell transplantation from haplo-identical donors (Haplo). Fifty-three patients were included in the analysis. All patients received myeloablative or intensified sequential conditioning regimen. The median follow-up was 397 (range, 191~762) days. The cumulative incidences of 100-day grade II-IV acute GVHD was 9.4±4.1%, and no case of grade III-IV acute GVHD was documented. The cumulative incidences of 1-year chronic GVHD and moderate-to-severe chronic GVHD were 18.9±5.4% and 7.5±3.7%, respectively. The non-relapse mortality at day+100 and 1 year were 9.4±4.4% and 11.3±4.4%, respectively. The cumulative incidence of relapse at 1 year was 3.8±2.7%. The 1-year probability of DFS and OS were 84.5% (95%CI, 75.2~95.0%) and 88.7% (95% CI, 80.5~97.6%), respectively. The 1-year GRFS was estimated as 75.0% (95%CI, 64.1~87.8%). Our results suggested that a combination of PT-Cy, tacrolimus, and low-dose post-engraftment ATG was a promising GVHD prophylaxis with low incidence of acute GVHD in the haplo-transplantation setting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

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

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

Post-Allograft Romidepsin Maintenance Mitigates Relapse Risk and Stimulates the Graft-Versus-Malignancy Effect through Enhanced NK-Cell Cytotoxicity in Patients with Aggressive T-Cell Malignancies in a Phase I/II Trial

Background: For patients with high risk, and relapsed/refractory T-cell malignancies allogeneic stem cell transplant (allo-SCT) is the only available potentially curative therapy. The efficacy of allo-SCT is limited in this population by high rates of relapse, with rates up to 55-60% post-allo-SCT. We designed a phase I/II trial, evaluating the combination of the histone deacetylases inhibitor romidepsin (rom) with FluBu conditioning, followed by romidepsin maintenance (m-rom) in patients receiving allo-SCT for T-cell malignancies (NCT02512497). Here we present an evaluation of the stimulatory effects of m-rom on the graft-versus-malignancy effect through NK-cells post-allo-SCT in the context of clinical results. Methods: This is a phase I/II clinical trial of patients with T-leukemia/lymphoma in at least a partial remission requiring an allo-SCT, <70 years of age, with a MRD/MUD donor. Patients received BuFlu (AUC 20000 or 16000) with rom, followed by tacrolimus/methotrexate GVHD prophylaxis with ATG for MUDs. An expansion cohort of up to 30 patients (total) was included. M-rom was initiated between day +28 and +100 for 1 year (2nd year optional), with built in dose reductions for toxicity. The effect of m-rom on NK-cell cytotoxicity was assessed on samples taken pre-transplant, and 1, 3, 6, 12 months post allo-SCT. NK cytotoxicity was assessed by isolating mononuclear cells from patient samples at each timepoint, comparing those on m-rom (n=10) versus those who did not receive m-Rom (n=5). Cells were targeted against K562 and T-cell lymphoma targets using the calcein-AM assay. Fine-Gray models were used to estimate PFS, OS, and cumulative incidence, and compare survival across groups. Results: To date, 28 patients have been enrolled, with a median age at transplant of 55, 50% female, 75% received MUD donor, and 68% utilized PB marrow source with 32% receiving BM. 16/28 (57%) had a diagnosis of T-cell leukemia, while 12/28 (42%) had a diagnosis of lymphoma. These included: T-ALL (18%), ETP-ALL (14%), ATLL (4%), T-PLL (21%), CTCL (7%), and PTCL (36%). 18% of patients entered transplant in a PR, while the remaining entered transplant in CR1 (61%) or CR2+ (21%). With a median follow-up time of 12 months, the median OS is 40 months (95% CI: 7.5-not reached), with a 1 and 3 year OS probability of 67% and 56%. The median PFS is 28.2 months (95% CI: 6.5-not reached), with 1 and 3-year PFS of 58% and 32%. Cumulative incidence (CI) of NRM at day 100 and 1 year were 15.6% and 19.8%. CI of grade II-IV aGHVD and extensive cGVHD were 42.9% and 19.1%. The CI of relapse (CIR) was 22.2% at 1 year (95% CI: 7.7-41.3%). There was no difference between PFS among patients with MRD versus those without MRD prior to transplant (p=0.71), and no difference in 1-year CIR (p=0.83). PFS at 1 year was substantially better in the lymphoma versus leukemia patients (78% vs 44%, p=0.02), though CIR at 1 year was not significantly different (13% vs 29%, p=0.12). No patients with PTCL relapsed, and 4/6 patients with T-PLL are alive, disease free. 16/28 (57%) of patients received m-rom with a median number of 12 cycles (range 1-39). 8 patients experienced grade 3/4 adverse events (AE), and 1 patient discontinued m-rom due to toxicity, unlikely related to romidepsin (loss of CD3 chimerism). NK-cytotoxicity was significantly higher at each time point in patients who received m-rom compared to those who did not (p<0.01). Further, when NK-cytotoxicity was assessed between the two groups after starting maintenance, NK-cytotoxicity in the m-rom group was significantly higher than in those without m-rom (p<0.0001) (Figure). Studies evaluating NK-cytotoxicity against patient T-cells are ongoing and will be presented at the ASH meeting. Conclusions: BuFluRom with m-rom is effective at decreasing relapse in patients with T-cell malignancies, with 1-year CI relapse below expected relapse rates for this set of diseases. NK-cell cytotoxicity data in a large sample set of trial patients demonstrates that m-rom enhances NK-cell cytotoxicity post allo-SCT, augmenting the GVL effect and likely accounting for at a minimum, some of the decrease in relapse seen on this trial. These results suggest long-term romidepsin past one year may decrease late relapse. Long-term follow-up is needed to evaluate these results, but these results suggest the BuFluRom regimen with m-rom should be strongly considered in patients receiving allo-SCT for T-cell malignancies to mitigate relapse. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Targeted Deletion of Activated T Cells with a Single Dose of Anti-CD137-Antibody Drug Conjugate Protects Against Acute Gvhd (AGVHD) and Promotes Tolerogenic T Cell Reconstitution after Haplo-Identical Hematopoietic Stem Cell Transplantation (HSCT)

Haplo-identical HSCT (haplo-HSCT) has substantially broadened the utility of HSCT for patients without HLA-matched donors. However, haplo-HSCT largely relies on triple immunosuppression with PT-Cy + tacrolimus + MMF, which are associated with toxicities and with defects in post-HSCT immune reconstitution. Therefore, a targeted, less globally immunosuppressive regimen could have a substantial impact on the success of HSCT. CD137 (4-1BB) is a major costimulation receptor that is rapidly upregulated on donor T cells. The immediate and restricted expression of CD137 on alloreactive T cells makes this an ideal drug target for AGVHD prevention. We have developed an anti-CD137-antibody drug conjugate (CD137-ADC) with a short T1/2 (2 days), that selectively depletes activated CD137+ T cells following a single dose. We have demonstrated the ability of this ADC to control AGVHD and enable immune reconstitution with tolerogenic subsets of donor T cells. Methods: Haplo-HSCT in non-human primates, including the assessment of donor chimerism and detailed clinical monitoring, were performed as previously reported (Tkachev et al. Science Transl. Med. 2021). We compared HSCT without GVHD prophylaxis ('NoRx') to that performed using a single dose of CD137-ADC (0.3mg/kg) given 4 hours post-HSCT. The immunologic impact of CD137-ADC was determined by flow cytometry and single-cell (sc)RNA-Seq. Results: (1) Engraftment: All CD137-ADC HSCT recipients engrafted with donor cells, with chimerism >90% by Day 28, and neutrophil and platelet engraftment at 12, and 11 days, respectively. (2) GVHD: All NoRx animals developed severe AGVHD necessitating euthanasia, with median onset of 8 days post-HSCT. In contrast, the median survival of the CD137-ADC cohort was 97 days (p<0.01). Three of 4 recipients were long-term survivors, with GVHD limited to spontaneously resolving skin AGVHD early after HSCT (Panel 1). (3) Toxicities: Importantly, no treatment-associated systemic toxicities were detected, including no CMV reactivation or end-organ disease, and no PTLD. (4) Immune impact: Flow cytometry revealed depletion of activated PD1+ CD4 central and effector-memory T cells in the CD137-ADC vs NoRx cohorts (Tcm/Tem; 1.2% vs 10.9% and 0.6 vs 7.6%, p<0.01) and PD1+ CD8 Tem (5% vs 24.3%, p<0.01), consistent with these being direct targets of the ADC. In contrast, the CD137-ADC spared OX40+PD1- CD4 Tcm/Tem compared to NoRx (11.7 vs 3%, and 12.1 vs 2.6%, p<0.01), OX40+PD1- CD8 Tem (4.1 vs 1.1%, p<0.01), CD4 naïve (9.3 vs 1.8, p<0.01) and CD8 memory stem T cells (6.3 vs 1.5%, p<0.01). Importantly, by Day 14 post-HSCT, there was restored reconstitution of proliferative OX40+ CD4 Tcm/Tem, CD28+CD127+OX40+ and CD28+CD127- CD8 transitional/effector-memory T cells (Ttm/em), followed by reconstitution of CD8 Tem, CD4 and CD8 effector T cells. However, unlike in the NoRx cohort, this reconstitution did not induce GVHD. To identify the unique T cell subtypes/states that correlated with GVHD-sparing immune reconstitution, we performed scRNA-Seq. This analysis identified 36 discrete T cell states across NoRx and CD137-ADC cohorts, with several cohort-specific clusters (Panel 2). For NoRx, we identified enrichment for a T cell cluster (Cluster 1) characterized by expression of the chemokines PF4 (CXCL4), PPBP (CXCL7), CCL23 and CCL5 along with Granzymes A/B/K and other cytotoxic molecules (KLRC2, NKG7, GNLY). In contrast, the CD137-ADC cohort showed enrichment for a CD8 T cell cluster (Cluster 2) expressing EOMES and Granzymes K/M, along with other naïve/early T cell memory-associated genes (SELL, CCR7, CXCR5, TCF7) and effector/exhaustion-associated genes (TBX21, TOX). The CD137-ADC cohort was also enriched for T cells expressing TCR gamma-9 and delta-2 chains (Cluster 3), suggesting enhanced reconstitution of the protective g9d2 T cell subset in these recipients. Conclusions: We have identified CD137-ADC as a novel targeted strategy to deplete CD137+ activated T cells early after haplo-HSCT, protecting against AGVHD with a single dose, in the absence of systemic toxicities or viral reactivation. The T cells that expand after CD137-ADC demonstrate a unique flow cytometric and transcriptomic profile, suggesting tolerogenic rather than pathogenic T cell immune reconstitution with this approach. To our knowledge, this is the first use of an ADC to control GVHD and introduces an important new prophylaxis paradigm for haplo-HSCT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Orca-Q Demonstrates Favorable GvHD-and-Relapse-Free Survival in Haploidentical Transplants without Post-Transplant Cyclophosphamide

^Salhotra, Srour, Lowsky and Abedi contributed equally Background: Allogeneic hematopoietic stem cell transplantation (alloHSCT) can be curative for a variety of malignant and nonmalignant disorders, but until recent years, access has been limited to patients with HLA-matched donors. The increased utilization of post-transplant cyclophosphamide (PTCy) has enabled patients to receive alloHSCT with haploidentical (haplo) related donors; however, high rates of cGVHD following myeloablative conditioning (MAC) regimens and high rates of relapse following reduced intensity conditioning regimens have been observed with this approach. Thus, GVHD-and-relapse free survival (GRFS) rates in this population at 1-year post-transplant remain low. Haplo alloHSCT with PTCy is also associated with high incidence of cytokine release syndrome (CRS) and infections. Orca-Q -an investigational precision engineered cell therapy- represents an alternative strategy which may be administered with single agent prophylaxis and does not require PTCy. The cellular composition of Orca-Q consists of enriched CD34+ stem cells combined with specific T- cell subsets and is intended to reconstitute the blood and immune systems. Orca-Q is hypothesized to reduce GVHD, relapse, and serious infections. Methods: Adult patients (18 to 65 years) with high-risk hematologic malignancies undergoing myeloablative conditioning (MAC) alloHSCT were enrolled between January 2019 to July 2022 on the haplo donor dose expansion arm of a multicenter phase 1 study of Orca-Q (NCT03802695). Haplo was defined as ≥ 4/8 but < 7/8 matched related donor at HLA-A, -B, -C, and -DRB1 typed using DNA-based high-resolution. Patients received only single agent tacrolimus (starting on day -1 and taper day +60 if no GVHD) as GVHD prophylaxis. PTCy was not permitted. The Orca-Q drug product was manufactured centrally at Orca Bio Manufacturing Site in Sacramento, CA from G-CSF mobilized peripheral blood apheresis. Results: The Orca-Q drug product was successfully manufactured and delivered to all subjects with a vein-to-vein time of less than 72 hours. A total of 21 patients (11 AML, 8 ALL, 2 CML in blast crisis) with > 30 days of follow up were included in this analysis. All were 4/8 HLA match at HLA-A, -B, C, and DRB1. Median age of subjects was 44 years (range 21 - 63) and median follow-up was 333 days (range 39 - 1020). Disease risk index (DRI) score was available in 20 showing 2 very high, 3 high, 13 intermediate, and 2 low risk categories. The M:F ratio was 12:9. Patients received either TBI (n=13) or non-TBI (n=8) based MAC regimens. 2 patients had Gr 1 CRS (CTCAE v5). Median neutrophil and platelet engraftment times were 13 days (range 8 - 25) and 16 days (range 12 - 25), respectively. 1 secondary engraftment failure was observed. The estimated incidence of BMT CTN MOP3 infections was 27% at 1 year. The estimated incidence of gr 2-4 aGVHD at 6 months was 14% which compares favorably with literature reports of 21% to 63% for gr 2-4 aGVHD in patients undergoing haplo transplant with PTCy-based prophylaxis.[1-5] Likewise, gr 3-4 aGVHD was rare with Orca-Q with only 1 case of gr 3 aGVHD and no gr 4 aGVHD. Of the 16 patients who had at least 3 months follow up, only 1 developed mild cGVHD. No patients had moderate-to-severe cGVHD, a notable improvement compared to historic rates of 24% to 31% for moderate-to-severe cGVHD with PTCy, despite the fact that Orca-Q patients receive only single agent GVHD prophylaxis.[1-4] 2 patients experienced disease relapse and there was a total of 5 deaths (2 due to relapse, 1 Aspergillus pulmonary infection, 1 respiratory failure associated with renal failure, and 1 COVID infection). GVHD-and-relapse free survival (GRFS) was 71% at 1 year with Orca-Q (Figure 1) which compares favorably to a GRFS of 46% reported by Sanz in the context of MAC haplo alloHSCT with PTCy.[2] Conclusions: Initial Orca-Q data demonstrates good clinical outcomes with single agent tacrolimus and no PTCy or MMF. Patients treated with Orca-Q experienced a low adverse event profile, low incidence and severity of both aGVHD and cGVHD, and improved GRFS rates, offering a potential new treatment option for patients undergoing haplo alloHSCT. This phase 1 study of Orca-Q continues to enroll patients with haplo donors across the US. References (1) Gooptu, M., et al. (2) Sanz, J., et al. (3) Wagner, J.E., et al. (4) Baker, M., et al. (5) Bashey, A., et al. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

HLA-B Leader Mismatch Positively Correlates with Survival Rate in Haplo and Cord Blood Transplantation for Acute Leukemia in Japanese Patients

Introduction： HLA class I genes contain seven exons. Exons 2, 3, and 4 generate α1, α2, and α3 extracellular domains, respectively, and exons 5, 6, and 7 encode the transmembrane region and cytoplasmic tail, respectively. Exon 1 is not involved in those synthesis, but encodes the leader peptide. Position 21 of exon 1 is invariant in HLA-A and HLA-C but dimorphic in HLA-B. Depending on the cytosine/thymine difference at this site, different HLA-B leader peptides containing either methionine [M] or threonine [T] at the second position when translated. HLA-B leader dimorphism is associated with NK cell recognition of HLA-E/NKG2A inhibitory responses, and [M] alleles have higher HLA-E expression than [T] alleles. In HLA-B-1 mismatch-unrelated allogeneic hematopoietic stem cell transplant (allo-HSCT), the HLA-B leader recipient/donor mismatch group has been reported to have a higher risk of acute GVHD than matched groups. In addition, acute GVHD is more common with HLA-DR 1 mismatched allo-HSCT in patients with [M] alleles. However, the effect of HLA-B leader mismatch on haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) and cord blood transplantation (CBT) is controversial. In addition, the effects of HLA-leader mismatch may vary among races. We evaluated the impact of HLA-B leader mismatch on CBT and haplo-PBSCT for acute leukemia (AL) in Japanese patients. Methods： We retrospectively analyzed 66 patients with AL (44 with AML, 20 with ALL (18 with B-ALL, 2 with T-ALL), and 2 with MPAL) who underwent first allo-HSCT (haplo-PBSCT or CBT) in our hospital from2006 to 2021. The median age of the patients was 38 years (range:17-64). The HCT-CI scores were 0 (low) in 29 patients, 1-2 (Int) in 18, and >2 (high) in 19. Forty-six patients were transplanted in CR and 20 were transplanted in non-CR. Thirty patients received haplo-PBSCT (18 with ATG and 12 with PTCY), and 36 received CBT. GVHD prophylaxis was FK506+MTX (15-10-10 mg/m2) in 54 patients and MMF+FK506+CY in 12. The median observation period was 405 [36-5842] days. The HLA-B leader ([M] or [T]) was determined for each allele in the recipient and donor and divided into three groups (TT, MT, and MM) using the HLA-B Leader Assessment Tool (BLEAT). Overall survival (OS), non-relapse mortality (NRM), and event-free survival (EFS) rates were assessed. A relapse or death was defined as an event. Results： The HLA-B leader phenotypes of the recipients included 47 (71%) with TT, 17 (26%) with MT, and 2 (3%) with MM; 68% were HLA-B leader-matched and 32% were mismatched (TT to MT 7, MT to TT 9, MM to MT 2, MT to MM, 3). Two-year NRM was lower in the mismatched group than in the matched group (0% vs. 22.7%, p=0.014), and the two-year OS was significantly better in the mismatched group (80.7% vs. 47.2%, p=0.01). The two-year cumulative incidence of relapse (CIR) was comparable (matched: 38.0% versus mismatched: 38.5%, p=0.78) between the two groups. The frequency of grade II-IV acute GVHD was comparable between the two groups in all patients, but in CBT, was higher in the mismatched group than in the matched group (54.5% vs. 16.0%, respectively, p=0.03). In the multivariate analysis adjusted for CR status (CR or non-CR), HCT-CI (>2), CBT, and HLA-B, leader mismatch was an independent favorable factor for OS (HR:0.24, 95%CI:0.09-0.66, p<0.01). Conclusion： HLA-B leader mismatch positively correlated with the survival rate. Evaluation of the HLA-B leader might be a useful marker for donor selection in first haplo-PBSCT and CBT for AL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Differences in Patterns of Infections Among Allogeneic Hematopoietic Cell Transplant Patients Receiving Letermovir Prophylaxis for Cytomegalovirus

Cytomegalovirus (CMV) infection remains a common complication after allogeneic hematopoietic- cell transplantation (HCT) with a significant increase in morbidity and mortality among patients who acquire such infection. Pre-emptive prophylaxis in which antiviral agents are started based on detection of CMV in the blood to prevent clinical disease has been the standard practice for many years. This approach was limited by the toxicity of available anti-CMV medications and increased complications among patients who activate CMV(1, 2). Letermovir, an antiviral agent that inhibits replication by binding to components of the terminase complex (UL51, UL56, or both) was approved in 2017 for prevention of CMV infection and disease among HCT recipients(3). Letermovir has been shown to delay polyfunctional CMV-specific cellular immune reconstitution as well as cause a decrease in absolute polyfunctional CD8+ T cell responses(4). The impact of such delayed immune reconstitution on infections other than CMV has not been widely described especially in the setting of post-transplant cyclophosphamide as GVHD prophylaxis. To study the impact of Letermovir on non-CMV infections during the first 6 months post HCT and to assess its effect on other transplant endpoints including OS, DFS, NRM, relapse, acute and chronic GVHD, we analyzed 409 consecutive patients who received their HCT at our center between 2016 and June of 2021. Letermovir prophylaxis was started at our center in January 2018 and is given to patients receiving MUD or haploidentical transplant and are either CMV+ or donor is CMV+. The final dataset included 321 subjects with the following characteristics: Median age 54 years (19-80); disease AML/ALL/MDS 81%, NHL/HD/Other 19%; donor type haplo (69%), MUD 31%; Cell Source PBSC 88%; Myeloablative conditioning 38% ; Donor/Recipient +/+ 50%, +/- 12%, -/+ 38% . The median follow up for survivors was 31.2 (11.5-52.6) months for letermovir group versus 66.2 (53.1-76.9) months for no letermovir group. Patients in the letermovir group were less likely to have received a reduced intensity regimen (22% vs 33%, p=0.05) and to have received a marrow graft (8% vs 16%, p=0.02). The survival endpoints at 3 years were OS (72.7% vs 68.8% p=0.5), DFS (64.4% vs 58.0% p=0.27), relapse (21.2% vs 28.6% p=0.08) and non-relapse mortality NRM (14.5% vs 13.5% p=0.5) for letermovir compared to no letermovir . The cumulative incidences for grade II-IV acute and moderate-severe chronic GVHD were 50.7% vs 40.2%, p=0.08 and 24.3% vs 24.1%, p=0.85 for Letermovir and no letermovir respectively The cumulative incidence of CMV reactivation was significantly lower for letermovir 24.4% compared to 57.1% for letermovir (p<0.001) figure 1, whereas non-CMV infections were similar between both groups with a trend towards lower infections for letermovir recipients 75.2% vs 83% p=0.07, figure 1. When assessing the difference in non-CMV infections per infection, there was no difference in the mean number of infections at 6 months post-HCT where patients in both groups had a mean of 2.5 infections. When looking at different types of infections between Letermovir and no letermovir groups, there was no difference in mean number of bacterial infections (1.58 vs 1.43), viral infections (0.90 vs 0.95) and fungal infections (0.16 vs 0.22), P =NS for all. Our data shows that in a large cohort of allogeneic HCT recipients, mostly haploidentical with Post-transplant cyclophosphamide, letermovir significantly decreases CMV reactivation without changing the pattern or incidence of non-CMV infections. 1. Teira P, Battiwalla M, Ramanathan M, Barrett AJ, Ahn KW, Chen M, et al. Early cytomegalovirus reactivation remains associated with increased transplant-related mortality in the current era: a CIBMTR analysis. Blood. 2016;127(20):2427-38. 2. Boeckh M, Ljungman P. How we treat cytomegalovirus in hematopoietic cell transplant recipients. Blood. 2009;113(23):5711-9. 3. Marty FM, Ljungman P, Chemaly RF, Maertens J, Dadwal SS, Duarte RF, et al. Letermovir Prophylaxis for Cytomegalovirus in Hematopoietic-Cell Transplantation. The New England journal of medicine. 2017;377(25):2433-44. 4. Zamora D, Duke ER, Xie H, Edmison BC, Akoto B, Kiener R, et al. Cytomegalovirus-specific T-cell reconstitution following letermovir prophylaxis after hematopoietic cell transplantation. Blood. 2021;138(1):34-43. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Selecting the Best Transplant Donor (HLA-Matched vs. Haploidentical) for Patients with Lymphoid Malignancy Based on Recipient HLA-B-Leader Genotype

Choosing the best donor type for allogeneic transplant (HLA-matched related (MRD) or unrelated (MUD) vs. haploidentical (HAPLO)) is typically based on the timely availability of an HLA-matched donor. There is currently no role for either patient or disease characteristics to facilitate this decision. In the context of HAPLO transplant, our group has previously demonstrated that an M+ recipient HLA-B-leader genotype (either M/T or M/M) is associated with reduced relapse risk and superior survival in patients with lymphoid, but not myeloid, malignancies (Solomon et al. TCT journal 2022). Based on this finding, we hypothesized that recipient HLA-B-leader genotype may be important in donor selection. To this end, we analyzed 352 patients with lymphoid malignancies (ALL[ 166], NHL [111], HL [39] and CLL [36]) receiving a first allogeneic transplant from an MRD [110], MUD [104] or HAPLO [138] donor. GVHD prophylaxis was PTCy-based in all HAPLO recipients, in contrast to MRD and MUD recipients who received conventional prophylaxis with calcineurin inhibitor + methotrexate. M+ or M- (T/T) genotype was seen in 165 (47%) and 187 (53%) respectively. Compared to MUD and MRD, HAPLO recipients tended to be younger (median 46 vs. 49 and 51 years respectively) and less likely to be non-Hispanic white (46% vs. 90% and 71% respectively). There were no differences in baseline characteristics between patients with M+ and M- B-leader genotype. Overall, MRD, MUD and HAPLO recipients had similar overall survival (OS, see figure). In HAPLO recipients, those with an M+ HLA-B-leader demonstrated improved 5-yr OS and DFS when compared to M- recipients (81% vs. 49%, p<0.001 and 70% vs. 42%, p=0.001, respectively), due to decreased relapse risk (18% vs. 48%, p=0.002). In multivariable analysis (MVA), controlling for other relevant variables (e.g. age, race, DRI, conditioning intensity, transplant year), M+ HAPLO transplant recipients had decreased relapsed risk (HR 0.27, p<0.001) leading to improved DFS (HR 0.34, p<0.001) and OS (HR 0.28, p<0.001). In contrast, relapse and DFS did not significantly differ according to recipient HLA-B-leader genotype in MRD or MUD recipients in either univariate or MVA. We then analyzed differences in transplant outcome according to donor type (HAPLO vs. MRD/MUD) and recipient HLA-B-leader genotype (M+ vs. M-). In univariate analysis, M+ HAPLO recipients had superior 5-yr OS and DFS when compared to M+ MRD/MUD recipients (81% vs. 52%, p=0.002 and 70% vs. 47%, p=0.008, respectively). In contrast, M- HAPLO recipients demonstrated inferior 5-yr OS and DFS when compared to M- MRD/MUD recipients (49% vs. 67%, p=0.005 and 42% vs. 57%, p=0.022, respectively) (see figure). This result was confirmed in MVA where M- HAPLO recipients demonstrated inferior OS and DFS compared to M- MRD/MUD recipients (HR 2.83, p<0.001 and HR 2.06, p=0.003 respectively). Conversely, M+ HAPLO recipients showed superior OS and DFS (HR 0.54, p=0.045 and HR 0.57, p=0.036 respectively). In summary, recipient HLA-B-leader genotype predicts relapse risk and survival following PTCy-based HAPLO transplant for lymphoid malignancy, but not MRD/MUD transplant utilizing conventional GVHD prophylaxis. As a result, recipient HLA-B-leader genotype can help guide optimal donor selection for patients with lymphoid malignancies with preference for MRD/MUD or HAPLO donor in the context of recipient M- or M+ HLA-B-leader genotype, respectively. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Single-Cell RNA-Seq Reveals an Interferon-Driven Inflammatory CD4 Naïve T Cell Subpopulation at Day 100 in Hematopoietic Stem Cell Transplant Patients That Ultimately Develop Chronic Gvhd

Background: Chronic GVHD (cGVHD) is the most significant cause of long-term morbidity and mortality after hematopoietic stem cell transplant (HCT). Improving patient outcomes requires a better understanding of biological mechanisms that underly disease, in order to develop novel risk-assignment biomarkers and therapeutic strategies. Naïve T cells (TN) are a prevailing risk factor for cGVHD, with mouse studies and clinical trial data demonstrating that graft depletion of TN cells decreases the frequency of cGVHD. Nevertheless, little is known about how TN cells progress to alloreactivity and, ultimately, to clinical cGVHD. In this study, we compared single-cell RNA sequencing (scRNA-Seq) from patients receiving unrelated donor transplantation (URD HCT) who developed mod-severe cGVHD, versus patients who were free from cGVHD, to identify disease-specific subpopulations of T cells that preceded disease. Methods: This analysis was designed to identify immune profiles in blood at Day 100 that could distinguish patients who ultimately developed cGVHD from those who remained free of this disease. Blood was drawn from patients with hematologic malignancies undergoing 8/8 HLA-matched URD HCT after myeloablative conditioning, and who received CNI/MTX GVHD prophylaxis. We focused on Day 100 samples from patients with Gr 0-2 acute GVHD who did not require systemic steroids as our starting population, and then divided these patients into those who subsequently developed moderate-severe cGVHD ('cGVHD' group, n=8; median cGVHD onset = 181 days) and patients who never developed mod-severe cGVHD through at least 2 years post-HCT (termed 'operationally tolerant' patients, 'OpTol', n = 24). Flow cytometry of longitudinal samples was performed using 16 ten-color panels, characterizing T cell reconstitution, activation, exhaustion, and naïve/memory subpopulations. Bulk RNA sequencing was performed on flow-sorted CD4 T cells (within 3h of collection) at Day 100 on patients from two central lab sites (cGVHD = 7, OpTol = 9). Statistical modeling was performed using DESeq2, followed by differential expression and Gene Set Enrichment Analysis (GSEA) with clusterProfiler. scRNA-Seq was performed on flow-sorted CD4 T cells using the 10X platform (cGVHD = 7, OpTol = 5). scRNA-Seq data was batch corrected with Harmony, annotated with SignacX and analyzed with Seurat. Results: Flow cytometry identified a higher proportion of CD4TN but not CD8TN cells in cGVHD patients that persisted longitudinally through Day 100 (25.9% vs. 10.0% at Day 100, p=0.03). Bulk transcriptome GSEA of Day 100 CD4 T cells confirmed enrichment of TN cells in cGVHD patients, but also revealed additional gene sets relating to interferon signaling (Fig. 1A). In contrast, OpTol patients revealed gene signatures relating to memory T cells and quiescence. scRNA-Seq enabled the discovery of CD4 T cell types/states enriched in patients who would develop mod-severe cGVHD. We profiled >100,000 CD4 T cells from Day 100 samples from cGVHD and OpTol patients. Unsupervised clustering identified two populations that were enriched in cGVHD vs. OpTol patients (Fig. 1B): interferon-stimulated CD4TN cells and interferon-stimulated CD4 memory cells. Both subsets show significantly higher expression of an interferon-response signature relative to all other cells (TN = 0.93, Tmem = 1.61, others = 0.14, p < 0.0001). The CD4TN subset possessed a signature for IFN-α-related stimulation (including IFI6, ISG15, IFI44L, EPSTI1) as well as IFN-γ-related genes (including STAT1, MX1). These findings further substantiate the IFN gene signature identified by bulk RNA-Seq at day 100 in cGVHD vs. OpTol patients. Conclusions: These data identified an inflammatory CD4TN cell subpopulation at day 100 in patients that go on to develop cGVHD, and suggest that CD4TN cells may harbor pathogenic cells that could predispose patients to allo-inflammatory complications. scRNA-Seq revealed a strong type I and type II interferon signaling signature in this CD4TN subset, and also identified a novel population of interferon-stimulated memory cells which may indicate a more differentiated population of alloreactive cells. These data highlight an interferon-driven transcriptome signature preceding the onset of cGVHD. Continued exploration of these cells may yield new risk-assignment biomarkers and nominate therapeutic approaches to prevent cGVHD in high-risk patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Allogeneic but Not Autologous Stem Cell Transplantation Improves Outcome in HTLV-1-Associated North American Adult T-Cell Leukemia/Lymphoma

Background: Adult T-cell leukemia/lymphoma (ATLL) is a rare mature T-cell malignancy driven by the human T-cell lymphotropic virus type I (HTLV-1) that remains challenging to treat and is associated with a dismal prognosis. While some reports have shown encouraging results with allogeneic stem-cell transplantation (allo-SCT), data remains scarce and mostly limited to Japanese patients. Patients and Methods: This is a retrospective single center analysis with 100 HTLV-1-associated North American ATLL patients. Variables collected included age, sex, ethnicity, CMV/HTLV1 serologies, karnofsky performance score (KPS), diagnosis date, disease subtype, number of prior therapy lines, transplant type, status at transplant, transplant date, prior SCT, donor sex, CMV/HTLV1 serologies, stem cell source, donor type, in-vivo T-cell depletion, engraftment, conditioning regimen, GVHD prophylaxis, maximum acute and chronic GVHD grade, relapse date when applicable, and main cause of death. The Kaplan-Meier method was used to calculate overall survival (OS) and progression-free survival (PFS). Cumulative incidence functions were used to estimate relapse incidence (RI) and non-relapse mortality (NRM) in a competing risk setting. Death and relapse were considered as competing events for acute and chronic GVHD. Univariate analyses were done using the Gray's test for cumulative incidence functions and the log rank test for OS and PFS. A Cox proportional hazards model was used for multivariate regression, results were expressed as hazard ratio (HR) with a 95% confidence interval (CI). All tests were two-sided, type-1 error was fixed at 5%. Results: One hundred patients met eligibility criteria, 18-87 years old, 69 of which were Black, 27 Hispanic, and 2 of Asian descent. Sixty-seven patients had acute ATLL and 22 lymphomatous. In total, 22 patients underwent SCT with 17 allo-SCT and 5 autologous SCT (ASCT) between 2005-2020 with a median follow-up of 62 months. Ten patients (45%) were transplanted in first complete remission (CR1), and 15 (68%) had KPS ≥90. Among patients undergoing allo-SCT, 41% had matched sibling donors (MSD), 18% matched unrelated (MUD), and 35% haploidentical. The 1-year and 3-years rates of overall survival from diagnosis of the cohort were 42% and 21%, respectively. Acute ATLL subtype was a strong predictor of worse outcome (Figure 1) with 1-year and 3-years OS of 32% vs 71% (p=0.004) and 11% vs 46% (p=0.002), respectively, compared to lymphomatous disease. To account for immortal time bias, 37 non-transplanted patients with early mortality within 4 months of diagnosis that were not able to make it to transplant were excluded from the Kaplan-Meier survival analysis. Patients undergoing transplant had improved outcomes compared to non-transplanted patients (Figure 1, Table 1), with allo-SCT reaching statistical significance in multivariate analysis compared to the non-transplant group with OS HR of 0.3 (p=0.004) compared to 0.7 (p=0.6) in ASCT vs non-transplant. In transplanted patients, the 3-year RI and NRM were 51% and 37%, respectively, and 3-year PFS and OS were 31% and 39%, respectively. Four of five patients who received ASCT rapidly relapsed with 3 dying from disease progression and one lost to follow-up, with 1-year RI of 80% vs 30% in allo-SCT (p=0.03). In exploratory multivariate analysis, patients achieving CR1 and with good baseline performance scores (KPS >90) had significantly better outcomes compared to their counterparts regardless of transplant type, and surprisingly, race was a strong and significant predictor of outcomes affecting PFS and OS with Hispanic vs Black PFS and OS HRs of 6 (p=0.04) and 10 (p=0.04), respectively. Thirteen patients died within 2 years, eight from relapse/progression including 3 ASCT patients, and 4 from transplant-related toxicities. Conclusion: Our data suggest that allo-SCT, but not ASCT, is a valid option in select ATLL patients. It also appears that patients of Hispanic descent have worse outcome post-transplant but not overall, which could be explained by lack of compatible donors or barriers to early transplant. Although this is the largest NA-ATLL transplant cohort presented to date outside of Japan and Europe, further studies are necessary to fully explain these discrepancies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Sirolimus Results in Similar Outcomes to Tacrolimus for Gvhd Prophylaxis after Haploidentical Peripheral Blood Stem Cell Transplantation with Post-Transplant Cyclophosphamide

Background Graft-versus-host disease (GVHD) prophylaxis with post-transplant cyclophosphamide (PTCy), tacrolimus (TAC) and mycophenolate mofetil (MMF) for allogeneic haploidentical (haplo) donor hematopoietic cell transplantation (HCT) has proven safe and effective. Many centers replace TAC with sirolimus (SIR) as this drug preserves regulatory T cells and may have a preferable side effect profile with less risk of kidney injury and thrombotic microangiopathy. A recent phase II single arm study reported comparable rates of grade II-IV acute GVHD with the use of SIR after haplo HCT (Bejanyan, Blood Adv. 2021). Methods We performed a retrospective cohort study comparing haplo HCT outcomes with SIR vs. TAC in combination with PTCy/MMF. All consecutive patients receiving haplo donor T cell replete peripheral blood stem cell graft HCT for hematologic malignancy at the Moffitt Cancer Center or the City of Hope Cancer Center between 2015-2020 were included. Associations with HCT related survival outcomes were assessed using Cox proportional hazard survival models. Fine and Gray regression models were used to assess associations of transplant related endpoints with competing risks. Kaplan Meier curves and cumulative incidence function curves were also plotted using the IBM SPSS analytic software version 28. Results A total of 423 patients met the inclusion criteria of which 84 (20%) received SIR and 339 (80%) received TAC. The SIR group had a higher proportion of patients >60 years (58% vs. 34%, p=<0.01), and the groups were also unbalanced in terms of diagnosis type, conditioning regimen, and cytomegalovirus serostatus (Table 1). Median follow-up was 30 months (range: 2-88 months). Neutrophil engraftment at day 30 was lower with SIR than TAC (89% vs. 95%, p=0.04), while platelet engraftment at day 60 was not significantly different (77% in SIR vs. 84% in TAC; p=0.14). For SIR and TAC, we found no significant differences in the rates of grade II-IV acute GVHD (45% vs. 47%, p=0.6), grade III-IV acute GVHD (20% vs. 15%, p=1.0) or chronic GVHD (48% vs. 55%, p=0.80). The probability of non-relapse mortality (NRM) was similar between SIR vs. TAC groups both at day 100 (19% vs. 11%, p=0.16) and at 1 year (29% vs. 28%, p=0.98) after HCT. Similarly, we observed no significant differences between the SIR and TAC groups in 2-year probabilities of relapse (23% vs. 25%, p=1.0), disease free survival (DFS; 55% vs. 55%, p=1.0) or overall survival (OS; 64% vs. 63%, p=0.99). In multivariate analysis (MVA) (Table 2), TAC was associated with faster neutrophil engraftment (OR=3.33, CI 1.20-9.26, p=0.02), but GVHD prophylaxis type had no significant impact on platelet engraftment, acute or chronic GVHD, relapse, NRM, DFS, or OS after haplo HCT. Conclusions Our study suggests that SIR is a comparable alternative to TAC in combination with PTCy/MMF for GVHD prophylaxis, resulting in overall similar clinical outcomes after peripheral blood haplo HCT. Rather than a uniform approach, the choice of TAC vs. SIR may be determined based on the side effect profile of these medications with consideration of patient medical comorbidities at HCT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Artificial Intelligence Methods to Estimate Overall Mortality and Non-Relapse Mortality Following Allogeneic Hematopoietic Cell Transplantation in the Modern Era: An EBMT Transplant Complications Working Party Study

Introduction Allogeneic hematopoietic cell transplantation (alloHCT) is a life-saving procedures for many hematological diseases. However, its toxicity counterbalances its curative potential. Several prognostic scores have been created in the last two decades. Most scores derive from small sized and monocentric cohorts of patients. Also, contemporary patients and alternative donors are usually excluded from these scores. Methods We selected patients from the EBMT registry with the following characteristics: age > 18 years old; allogeneic hematopoietic cell transplantation (alloHCT) performed between 2010 and 2019; hematological disease diagnosis (AML/ALL; MDS/MPN; NHL/HL; plasma cell dyscrasias); any disease status at transplant; use of HLA-matched (familiar or unrelated) or haploidentical donor; myeloablative or RIC/NMA conditioning regimen; peripheral blood or bone marrow graft source. The primary objective was to create a prognostic score able to predict overall mortality (OM) at +2 years. The secondary objective was to predict non-relapse mortality (NRM) at 2 years. To create a newer prognostic score, we explored the following statistic and machine-learning techniques: step-wise logistic regression, support vector machine with linear and radial kernels, random forest, gradient boosting, elasticnet. We also tested simple fully connected neural network. The score included all the pre-transplant variables with a well-known prognostic role in terms of NRM related to disease (disease type) patient (age, gender, Karnofsky score, body mass index, presence of significant comorbidities, CMV status) transplant (time from diagnosis to transplant, donor type, GVHD prophylaxis, conditioning intensity, graft type) and transplant center characteristics (JACIE accreditation, > 20 alloHCT/year). OM model development was made on 70% of the data set, optimized on 15% and validated on the 15% of remaining data. Models with the best accuracy were selected to build the prognostic score. Results A total of 48984 patients were included into the analysis (Table 1). Median follow-up time for survivors was 38.4 months. Overall mortality and NRM at +2 years were 39.5% (95% CI=39.0-40.0%) and 19.0% (95% CI=18.5-19.5%), respectively. The 5 models predicted 2-year OM and NRM with similar AUC values. Best models were, for OM, gradient boosting (XGBoost) with AUC=0.64 (95% CI 0.630-0.655) and for NRM, elasticnet with AUC=0.58 (0.566-0.594). Neural networks had slightly higher performance for NRM but has limitations regarding the explicability of results. Same results were observed also when performing the analysis with the haploidentical cohort (n=5.934, AUC 0.66 for OM and 0.57 for NRM). In the final prognostic score including all the variables, gradient boosting was used to predict OM and elasticnet to predict NRM. The score was able to furnish a personalized prediction for each patient with continuous values. Patients with the lowest score had a 2-year OM and NRM of 22.2% and 8.7%, respectively. Patients with the highest score had a 2-year OM and NRM of 81.2% and 87.1%, respectively. A visual representation of the score prediction distribution was made on the validation cohort grouping the potential results into 4 groups (figure 1). Conclusion Our score showed to be useful in improving risk stratification of OM and NRM in the current era, including haploidentical transplants and post-transplant cyclophosphamide GVHD prophylaxis which were not included in previous scores. However, a generally poor accuracy despite the robust methodology confirms previous observations highlighting that the results of a prognostic score itself should not be used to exclude patients from a life-saving procedure. In such high-risk cases, more comprehensive evaluations (e.g. geriatric scores), biological scores (e.g. EASIX scores) and the overall patient's clinical phenotype should be evaluated to establish the actual transplantation risk and help in this difficult therapeutic choice Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Sequential Use of Flamsa, FLAG, CLAG or TEC-Based Conditioning Regimen Followed By Allogeneic Hematopoietic Transplantation Results in Favorable Outcome for High Risk Acute Myeloid Leukemia, Myelodysplastic Syndrome and Myeloproliferative Neoplasia Patients: 15 Year Follow-up of the Multicenter Study in Singapore

Introduction: Allogeneic hematopoietic cell transplant (allo-HCT) is an effective consolidative treatment for patients with certain hematological malignancies and gives the best outcome when done in remission. However, patients with refractory acute myeloid leukemia (AML) or some myeloproliferative neoplasia (MPN) and myelodysplastic syndrome (MDS) deemed unable to achieve remission with standard induction are often excluded from allo-HCT with conventional conditioning regimen as pre-transplant remission could not be achieved. Recently, a sequential transplant approach, as developed by the Munich group, comprising of intensive cytoreductive chemotherapy FLAMSA (Fludarabine/Amsacrine/Cytarabine) to decrease leukemia cell burden shortly prior to conditioning regimen, has been successfully used for high-risk (HR) AML/MDS with promising results. Methods: We studied 72 patients (median age 51 years, range 17-68) with HR AML (n=57), as defined by refractory, relapsed disease, secondary leukemia, complete remission with adverse-risk cytogenetics according to ELN criteria, or high/very risk refined Disease Risk Index (DRI), MPN (n=3) and HR MDS (n=12) according to IPSS-R, undergoing allo-HCT using the sequential transplant approach in 2 transplant centers in Singapore between January 2009 and July 2022. The sequential transplant approach combined a cytoreductive chemotherapy, which consisted of either FLAMSA (n=21), FLAG [Fludarabine/Cytarabine/Granulocyte Colony Stimulating Factor (GCSF)] +/- Idarubicin (n=30), CLAG (Clofarabine +/- Cytarabine +/- GCSF) (n=18), or TEC (Thiotepa, Etoposide, Cyclophosphamide) (n=3) followed by reduced intensity (RIC) (n=61) or myeloablative (MAC) (n=11) conditioning regimen. All patients received peripheral blood stem cell from matched related donors (MRD) (n=36), mismatched related donors (MMRD) (n=7), matched unrelated donors (MUD) (n=21), or mismatched unrelated donors (MMURD) (n=8). Post-grafting immunosuppression consisted of calcineurin inhibitor and mycophenolate mofetil (MMF) in all patients. Thymoglobulin and post-transplant cyclophosphamide were added for GVHD prophylaxis for MUD/MMURD and MMRD transplant, respectively. One MMRD had selective ex vivo T-cell depleted transplant followed by MMF as GVHD prophylaxis. Results: The median time to neutrophil > 1000/μL was 11 days (range, 8-25). With a median follow-up duration of 51 months (range, 1-148), the Kaplan-Meier estimate of overall survival (OS) and leukemia-free survival (LFS) at 5 years were 42% (95% CI, 30-54) and 32% (95% CI 20-44), respectively. The cumulative incidence of relapse and non-relapse mortality (NRM) at 2 years were 47% (95% CI, 35-59) and 16% (95% CI, 9-26), respectively. Patients receiving FLAG, CLAG or TEC-based sequential regimen showed a trend towards lower NRM and relapse compared to FLAMSA-based regimen, although the difference was not statistically significant. This translated into a more favorable 5-year LFS (40% vs 13%, p=0.04), but no statistically significant difference in 5-year OS (42% vs 40%, p=0.56). Patients with refractory disease (n=49) were at higher risk of relapse compared to patients whom had achieved at least a partial remission prior to sequential allo-HCT (n=17) (2-year cumulative incidence of relapse: 59.0% vs 34.0%, p=0.02). This resulted in an inferior 5-year OS (31% vs 66%; p=0.02) and LFS (20% vs 75%, p<0.01). On multivariable analysis, only refined DRI showed significant impact on OS (p=0.01) and LFS (p=0.02) but had no significant impact on NRM and relapse. The 5-year OS for patients with intermediate/high risk and very high risk DRI were 51% and 21% (p<0.01), and the corresponding 5-year LFS were 42% and 10% (p<0.01), respectively (Figure 1 and Figure 2). Conclusions: Sequential transplant conditioning with FLAMSA, FLAG, CLAG or TEC-based cytoreductive regimen followed by allo-HCT is an effective strategy in overcoming the dismal prognosis of HR AML, MDS and MPN, including patients with high risk DRI, and enabling favorable long-term disease-free survival. More studies on effective strategies such as optimising the conditioning regimen intensity or post-transplant maintenance therapy with prophylactic donor lymphocyte infusion, are needed to further eliminate the risk of relapse, without increasing risk of treatment-related toxicity. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Tocilizumab for the Management of Cytokine Release Syndrome after Haploidentical Hematopoietic Transplant with Post-Transplant Cyclophosphamide-Based GvHD Prophylaxis

Haploidentical hematopoietic cell transplant (HaploHCT) with post-transplant cyclophosphamide (PTCy) has expanded the donor pool and made HCT available to patients without a matched donor. Cytokine release syndrome (CRS) is a syndrome of systemic inflammation with massive cytokine release, originally described after chimeric antigen receptor T cell (CAR T) therapy, is a frequent complication early after HaploHCT. Severe CRS after HaploHCT has been associated with higher non-relapse mortality (NRM) and worse overall survival (OS). Currently, no standard guidelines exist for CRS management in HaploHCT patients other than general supportive measures. Here, we described the impact of tocilizumab, an interleukin-6 receptor inhibitor used to manage CRS in CAR T therapy setting, on clinical outcomes in patients who experienced CRS after HaploHCT. We retrospectively identified a case series of 120 patients who experienced CRS after undergoing HaploHCT with PTCy-based GvHD prophylaxis at City of Hope from 06/2019 to 06/2021; of whom 11 patients received tocilizumab for CRS management. We matched these patients in a 1:2 ratio with 21 patients with CRS post-Haplo-HCT who did not receive tocilizumab (based on age, primary diagnosis, conditioning regimen, and CRS grading), then analyzed and compared OS, disease-free survival (DFS), relapse rate (RR), NRM, cumulative incidence (CIN) of grade II-IV and III-IV acute GvHD, and chronic GvHD between the two groups by univariate analysis. P-values were 2 sided at a significance level of 0.05. Table 1 summarize patient and transplant characteristics. Median age of patients in tocilizumab (TOCI) and no-tocilizumab (NO-TOCI) cohorts were 64 years (range: 27-70) and 62 years (range: 20-76). HLA 6/12 mismatch was the most common in both cohorts (81.8% in TOCI and 66.7% in NO-TOCI). All patients received mobilized peripheral blood stem cells (PBSC) as graft source. Majority of patients received non-myeloablative or reduced intensity conditioning regimens (81.8% in TOCI and 76.2% in NO-TOCI). Grade 2 CRS was most common in both cohorts (72.2% in TOCI and 71.4% in NO-TOCI); and grade 3-4 CRS was documented in 1 patient (9.1%) in TOCI and 2 patients (9.5%) in NO-TOCI cohort. Tocilizumab doses were 4 mg/kg (n=2), or 8 mg/kg (n=9). All patients but one (90.9%) received one single dose of tocilizumab and 1 patient received 2 doses of tocilizumab at 8 mg/kg/dose. All tocilizumab doses were administered either on day +3 (45%) or day +4 (55%) post-HCT (the patient with 2 doses was counted towards day +3). No high-grade tocilizumab-related side effects were documented in those 11 patients. Day 28 CIN of neutrophil engraftment was lower in TOCI compared to NO-TOCI patients (54.5% vs 76.2%, 95% CI: 21-79 and 50-90%, P=0.07 - Figure 1a). At 12 months post HaploHCT, survival outcomes were similar with NRM of 18.2 and 19% (95% CI: 3-46% and 6-38%, P=0.92); and RR of 19.5 and 14.3% (95% CI: 3-49% and 3-33%, P=0.78) in TOCI and NO-TOCI cohorts, respectively. DFS and OS were not affected by tocilizumab administration (P=0.90 and P=0.98; respectively). Three patients in TOCI and 7 patients in NO-TOCI cohort died; their causes of death were not directly related to CRS. While CIN of day 100 grade II-IV (P=0.97) and grade III-IV acute GvHD (P=0.47) were not affected by tocilizumab administration, CIN of chronic GvHD was significantly higher in TOCI compared to NO-TOCI (60.6 vs 23.8%, 95% CI: 19-86% and 8-44%, P=0.05 - Figure 1b). In conclusion, our results indicates that tocilizumab used for CRS management after in HaploHCT setting with PTCy-based GvHD prophylaxis was well tolerated and had no effect on survival outcomes. However, our study showed a trend towards delayed neutrophil engraftment and a statistically significant higher incidence of chronic GvHD in patients who received tocilizumab. It is possible that tocilizumab may interfere with T cell expansion, which could impact PTCy-mediated elimination of alloreactive T cell clones and/or affect regulatory T cells function; both mechanisms could lead to higher incidence of chronic GvHD. Using this approach to mitigate CRS risk should be reserved to patients with high grade CRS where mortality is high. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

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

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

Frequent Early Geriatric Complications after Allogeneic Hematopoietic Cell Transplantation (HCT) in Older Adults Impairs Disability-Free Survival (DiFS)

Introduction: Data continue to accumulate showing older adults with hematologic malignancies, such as AML and MDS, derive a survival benefit from HCT. However, as HCT expands into older and less fit patients (pts), the inability to describe and predict post-HCT toxicity presents a major barrier to appropriate and broader application. Standard endpoints of non-relapse mortality (NRM), organ toxicity, graft-versus host disease (GvHD), or overall survival (OS) miss important common geriatric complications (e.g., delirium, disability, falls). We aimed to estimate disability-free survival (DiFS), a composite endpoint of death, dementia or physical disability, used in older adult non-oncology trials (McNeil J, N Engl J Med 2018; 379; 1499-1508) by summarizing disability in the early post-HCT context. Methods: We reviewed electronic records for the development of disability through day 100 for pts ≥ 60 years undergoing first HCT from 2013 - 2019 at City of Hope National Medical Center. Disability events included delirium affecting instrumental ADLs (i.e., CTC ≥ 2), falls, ICU admission, or needing mobility assistance. Mobility assistance leveraged a standardized nursing flowsheet tool completed every shift for hospitalized pts, comprised of 5 categories of ambulation independence (independent, assistive equipment, assistive person, assistive equipment and person, complete dependent); mobility timepoints captured were pre-HCT, weekly starting on day 0 to d21 and at hospital discharge. Categorization of assistive person or more after HCT met the mobility assistance requirement. All pts required hospitalization post-HCT in this era. Failure events for DiFS included first disability event as above or death. Kaplan-Meier method was used to calculate DiFS at d30 and d100. A conditional landmark analysis examined the differences in unadjusted NRM among pts experiencing disability prior to d30 or d100 landmark dates and alive at the landmark date. Results: Among 699 pts, 19.7% were ≥ 70 years, 77.0% had AML/MDS/MPN, 95.6% received reduced intensity conditioning (RIC), 80.1% were conditioned with fludarabine/melphalan, and 86.7% received matched donors. Few pts needed mobility assistance pre-HCT (4.4%) although 28.3% developed mobility assistance by d21. The cumulative incidence of other disability events at d30 and d100 were: falls (4.9%, 14.3%), delirium (24.3%, 29.3%), and ICU admission (15.3%, 20.2%). NRM was 3.9% at d30 and 26.9% at 2 years. Figure 1 shows DiFS at d30 and d100 of 58.2% and 51.4%. The most common d30 disability events were delirium (41%) and mobility assistance (34.7%); all deaths by d30 (n=27) were preceded by a disability event. Baseline factors in univariate analysis associated with inferior d30 DiFS included KPS < 90% (p=.001), age ≥ 70 (.01), non-matched related donor (.003) but not HCT-CI ≥ 3, time period (<2018), conditioning regimen, GVHD prophylaxis, or baseline mobility assistance. D30 disability events were strongly linked to elevated 2 yr NRM by d30 landmark analysis (figure 2)(40% vs 15% without d30 disability events, HR=2.77; 95% CI 2.11-3.64). Similarly, disability by d100 negatively influenced d100 to 2 year NRM (HR =2.27, 95% CI: 1.65-3.11). Conclusions: HCT among older adults engenders frequent geriatric complications of delirium, loss of ambulation independence, falls and ICU admission in the early HCT period. Consequently, DiFS is approximately 60% at day 30. Further, early disability strongly predicts for higher risk of future NRM. DiFS should be further explored as a novel endpoint to summarize functional loss after older adult HCT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal