We conducted a prospective evaluation of cord blood (CB)–derived adoptive cell therapy, after salvage chemotherapy, for patients with advanced myeloid malignancies and poor prognosis. Previously, we ...reported safety, feasibility, and preliminary efficacy of this approach. We present updated results in 31 patients who received intensive chemotherapy followed by CB infusion and identify predictors of response. To enhance the antileukemic effect, we selected CB units (CBU) with shared inherited paternal antigens and/or noninherited maternal antigens with the recipients. Twenty-eight patients with acute myeloid leukemia (AML), 2 with myelodysplastic syndrome, and 1 in chronic myeloid leukemia myeloid blast crisis were enrolled; 9 had relapsed after allogeneic transplant. Response was defined as <5% blasts in hypocellular bone marrow at 2 weeks after treatment. Thirteen patients (42%) responded; a rate higher than historical data with chemotherapy only. Twelve had CBU-derived chimerism detected; chimerism was a powerful predictor of response (P < .001). CBU lymphocyte content and a prior transplant were associated with chimerism (P < .01). Safety was acceptable: 3 patients developed mild cytokine release syndrome, 2 had grade 1 and 2 had grade 4 graft-versus-host disease. Seven responders and 6 nonresponders (after additional therapy) received subsequent transplant; 5 are alive (follow-up, 5-47 months). The most common cause of death for nonresponders was disease progression, whereas for responders it was infection. CB-derived adoptive cell therapy is feasible and efficacious for refractory AML. Banked CBU are readily available for treatment. Response depends on chimerism, highlighting the graft-versus-leukemia effect of CB cell therapy. This trial was registered at www.clinicaltrials.gov as #NCT02508324.
•CB-derived adoptive cell therapy is a feasible and efficacious therapeutic approach for patients with refractory AML.•Treatment response depends on the development of CBU-derived chimerism.
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Introduction: Pulmonary complications constitute a major cause of morbidity and mortality in the post-hematopoietic cell transplant (HCT) period. While Chest X-ray (CXR) is customarily used for ...screening, we have utilized chest computed tomography (CT) within one month of transplant. Here we aim to characterize the prevalence of abnormalities and their impact on the eligibility for allogenic (allo) HCT and outcomes post-transplant.
Methodology: We conducted a single center retrospective study of all patients who were evaluated for allogenic HCT from January 2013 through December 2020 in New York Presbyterian Hospital - Weill Cornell Medicine (NYP-WCM). All patients who had chest CT as part of their pre-transplant evaluation were included for analysis.
Results: We identified 478 patients who had Chest CT screening. In 396 CT chest was normal or confirmed previous abnormalities. Eighty-two patients (17%) had previously undetected abnormalities (Figure 1). The most frequent abnormalities were pulmonary nodules (defined as nodules of 4 mm or greater) in 27 patients (31%), ground-glass opacities (GGO) in 21 patients (25%), Pneumonia in 18 patients (21%). Miscellaneous findings not related to the primary disease were found in 12 patients (14%) including thyroid nodules, breast nodules and hemangioma of the liver. A new malignancy was found in 6 patients (7%) and incidental pulmonary embolism (PE) in 2 patients (2%) (Figure 2). There were 5 (6%) patients who were ultimately excluded from transplant due to CT chest findings (simultaneous CXR showed abnormalities in only 1 out of 5). Three of those patients were found to have invasive fungal infection, and the other two had unrecognized metastatic lung cancer. For 19 patients (23%), transplant was delayed for diagnostic procedure and/or treatment of pulmonary findings (CXR showed abnormalities in only 3 patients out of 19). The most common reason for delay was lung infection requiring treatment. Thirty-two patients (41%) out of 77 patients with abnormal CT scan who eventually underwent transplant, have died . Sixteen died after relapse, and 16 from non-relapse mortality (NRM) with pulmonary complications playing a role in 13 patients (Figure 3).
Conclusion: 17% of patients who had a pre-transplant CT chest had abnormalities that warranted further evaluation. In 23% of these patients, these findings led to a delay in transplant for further optimization. Six percent were deemed ineligible for transplant due to absolute contraindications that were incidentally discovered on chest CT. Initial screening CXR failed to identify a significant number of abnormalities. Our data suggests that chest CT imaging should be part of the routine pre-transplant evaluation.
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No relevant conflicts of interest to declare.
•CD34 selected haploidentical cells were combined with umbilical cord blood (haplo-cord) stem cells as donor source.•Rapid neutrophil (median, 11 days) and platelet recovery (median, 19 days) was ...achieved because of the haploidental-graft durable hematopoiesis resulting from the umbilical cord blood graft with a very low incidence of chronic GVHD (8%).•Forty-two patients with advanced lymphoma or CLL were treated and had 3-year OS, PFS, and GVHD relapse-free survival rates of 65%, 62%, and 52% respectively.
Limited studies have reported on outcomes for lymphoid malignancy patients receiving alternative donor allogeneic stem cell transplants. We have previously described combining CD34-selected haploidentical grafts with umbilical cord blood (haplo-cord) to accelerate neutrophil and platelet engraftment. Here, we examine the outcome of patients with lymphoid malignancies undergoing haplo-cord transplantation at the University of Chicago and Weill Cornell Medical College. We analyzed 42 lymphoma and chronic lymphoblastic leukemia (CLL) patients who underwent haplo-cord allogeneic stem cell transplantation. Patients underwent transplant for Hodgkin lymphoma (n = 9, 21%), CLL (n = 5, 12%) and non-Hodgkin lymphomas (n = 28, 67%), including 13 T cell lymphomas. Twenty-four patients (52%) had 3 or more lines of therapies. Six (14%) and 1 (2%) patients had prior autologous and allogeneic stem cell transplant, respectively. At the time of transplant 12 patients (29%) were in complete remission, 18 had chemotherapy-sensitive disease, and 12 patients had chemotherapy-resistant disease. Seven (17%), 11 (26%), and 24 (57%) patients had low, intermediate, and high disease risk index before transplant. Comorbidity index was evenly distributed among 3 groups, with 13 (31%), 14 (33%), and 15 (36%) patients scoring 0, 1 to 2, and ≥3. Median age for the cohort was 49 years (range, 23 to 71). All patients received fludarabine/melphalan/antithymocyte globulin conditioning regimen and post-transplant graft-versus-host disease (GVHD) prophylaxis with tacrolimus and mycophenolate mofetil. The median time to neutrophil engraftment was 11 days (range, 9 to 60) and to platelet engraftment 19.5 days (range, 11 to 88). Cumulative incidence of nonrelapse mortality was 11.6% at 100 days and 19 % at one year. Cumulative incidence of relapse was 9.3% at 100 days and 19% at one year. With a median follow-up of survivors of 42 months, the 3-year rates of GVHD relapse free survival, progression-free survival, and overall survival were 53%, 62%, and 65%, respectively, for these patients. Only 8% of the survivors had chronic GVHD. In conclusion, haplo-cord transplantation offers a transplant alternative for patients with recurrent or refractory lymphoid malignancies who lack matching donors. Both neutrophil and platelet count recovery is rapid, nonrelapse mortality is limited, excellent disease control can be achieved, and the incidence of chronic GVHD is limited. Thus, haplo-cord achieves high rates of engraftment and encouraging results.
Pituitary hormone deficiency occurs in ∼1:4,000 live births. Approximately 3% of the cases are due to mutations in the alpha isoform of POU1F1, a pituitary-specific transcriptional activator. We ...found four separate heterozygous missense variants in unrelated individuals with hypopituitarism that were predicted to affect a minor isoform, POU1F1 beta, which can act as a transcriptional repressor. These variants retain repressor activity, but they shift splicing to favor the expression of the beta isoform, resulting in dominant-negative loss of function. Using a high-throughput splicing reporter assay, we tested 1,070 single-nucleotide variants in POU1F1. We identified 96 splice-disruptive variants, including 14 synonymous variants. In separate cohorts, we found two additional synonymous variants nominated by this screen that co-segregate with hypopituitarism. This study underlines the importance of evaluating the impact of variants on splicing and provides a catalog for interpretation of variants of unknown significance in POU1F1.
Introduction: Allogeneic hematopoietic cell transplantation (allo-HCT) is curative for patients with myelofibrosis (MF). Here, we evaluated the impact of donor type cord blood transplant supported by ...CD34+ cells (haplo-cord) vs adult matched donor on outcomes in MF. Methods: All adult patients with primary or secondary (post-ET or post-PV) MF, including those progressing to acute leukemia (AML) who underwent their first allo-HCT at NewYork-Presbyterian Hospital/Weill Cornell Medicine between 01/2015 and 06/2022 were included. Results: 40 patients were transplanted. Median age was 63 years (range 21-77). 23% had a Karnofsky performance scale (KPS) of <80. Two had undergone splenectomy prior to HCT. The median spleen size was 18cm (10-28). Median number of pre-HCT molecular mutations was 2 (range 0-7). 16 (40%) had MF-3 (Table 1). 24 (60%) underwent a matched sibling donor (MSD) (n=9) or unrelated donor (MUD) (n=15) HCT, and 16 (40%) underwent a cord-based (CB) HCT. 39 received Fludarabine/Melphalan +/- low dose total body irradiation (TBI), one underwent myeloablative conditioning with TBI/etoposide based on extensive extramedullary disease. The median time to neutrophil engraftment in the MSD/MUD group was 14 days (IQR 14-18) vs 30 days in the CB group (IQR 15-36) and (p=0.1). The median time to platelet engraftment was 22 days (IQR 17-38) in MSD/MUD vs 49 days (IQR 26-60) in the CB group (P=0.07). The CI of absolute neutrophil count (ANC) and platelet engraftment by day 60 for MSD/MUD vs CB was 92% (95% CI 65-98%) vs 80% (95% CI 45-94%) (p=0.09) and 75% (95% CI 51%- 88%) vs 59% (95% CI 27-81%) (p=0.36), respectively. One patient in the MSD/MUD died without neutrophil engraftment compared to 3 in CB group. 5 patients in each group died without platelet engraftment. Median follow-up for all alive patients was 53 months. Overall survival (OS) for the cohort was 62% at 1 year (95% CI 49-79) and 34% at 3 years (95% CI 21-55). OS at 3 years was similar between MSD/MUD group and CB (32% vs 37%, P=0.9) (figure 1). Graft versus host disease relapse free survival (GRFS) at 3 years was not significantly different in MSD/MUD group, compared to CB group (15% vs 33%, P=0.64). Cumulative incidence of relapse at 3 years in MSD/MUD group was 28% (95% CI 10-49), and 12% (95% CI 1.8-34) in CB group (p=0.356). Non-relapse mortality (NRM) at 1 year was 33% (95% CI 15-52) in MSD/MUD group and 38% (95% CI 15-61) in CB group. NRM at 3 years was 54% (95% CI 29-73) in MSD/MUD group and 48% (95% CI 19-72) on CB group (P=0.95). Discussion: In our small cohort, we showed that OS after haplo-cord transplant was comparable to adult matched donors' grafts (MSD or MUD). While the haplo-cord platforms have been shown to decrease the time to engraftment (11 days for neutrophils and 22 days for platelets) compared with double cord transplants or haploidentical transplants (van Besien K et al . Haematologica 2016, van Besien K et al. Blood Adv 2019), in patients with MF, we saw a trend towards delayed engraftment compared to patients transplanted with adult matched donors' grafts (MSD or MUD). This suggests that the CD34 selected cells may not be able to provide an adequate myeloid bridge and overcome the low cellular content in the CB for adult patients with extensive marrow fibrosis. Larger studies are needed to compare best alternative graft (CB-based versus haploidentical or mismatched unrelated donors) for patients with MF that lack a matched donor.
Introduction:Acute myeloid leukemia (AML) is heterogenous disease with a range of cytogenetic and molecular changes. Several molecular mutations identified in AML patients at diagnosis have ...prognostic implications and play important roles in guiding induction and consolidative treatment decisions. The prognostic impact of mutations peri allogeneic stem cell transplant are less well characterized. In this study, we examine the significance of pre and by D100 Post-transplant mutation status in AML patients underwent Fludarabine/Melphalan conditioned reduced intensity allogeneic stem cell transplant (SCT).
Methods:AML patients who are in morphologic complete remission (CR1 or greater) with available molecular mutation at diagnosis, within 6 weeks prior to allogeneic SCT, and by 100 days post-transplant were included. Variables analyzed included baseline demographics, clinical variables (CIBMTR disease risk index (DRI), type of transplant, ELN risk, performance status) and 23 recurring molecular mutations. Analysis was also performed by grouping mutations into six pre-defined gene groups based on gene function (Table 2). Multivariable cox regression analysis was adjusted for age, gender, DRI and molecular mutation. Backward selection method was used to select the best combination of genes that is associated with overall survival (OS) and relapse-free survival (RFS).
Results: A total of 142 AML patients with molecular genetic data available from 2014 to June, 2020 at Weill Cornell Medicine/New York Presbyterian Hospital were analyzed. Clinical characteristics of the patients are summarized in Table 1. The median age was 58 years (range 20 -78). Total of 261 mutations were detectable at diagnosis (Table 3). Prior to allo SCT and by D100, the detectable mutations were 87 and 40 respectively, which represent 56 and 26 patients. High-dose chemotherapy was less effective on clearing DNMT3A, ASXL1, TET2 (DAT) or IDH mutations, resulting in over-representation of DAT and IDH mutations prior to transplant.
With a median follow-up time of 25 months, the median overall survival for the group was 40.8 months. The presence of mutations in TP53 at diagnosis was associated with worse OS by both univariate (HR 3.67, p=0.0030, CI 1.56-8.68) and multivariate analysis (HR 4.75, p=0.0014, CI 1.82-12.39) with median OS reduced from 49.3 to 19.3 months (p=0.002). High CIBMTR DRI (HR 0.17, p=0.0018, CI 0.05-0.51) predicted reduced OS and RFS, and Age >60 at diagnosis was associated with worse OS (HR 1.7 CI 1.04-3, p 0.03).
Presence of any molecular mutation prior to transplant did not impact OS or RFS. For patients with any persistent mutations by D100 post-transplant, both OS (HR 2.04, p 0.027, CI 1.08-3.8) and RFS (HR 1.99, p 0.025, CI 1.09-3.6,) were reduced in the univariate analysis, but not on multivariate analysis (HR 1.88, p 0.5, CI 0.99-3.49). Analysis based on six mutational groups (table 2) did not show any difference in their OS or RFS. However, worse RFS was independently associated with persistent IDH1 (HR 3.8, p 0.004, CI 1.07-56,), TET2 (HR 3.9, P 0.04, CI 1.04-14.1), and FLT3-ITD (HR 4.5, p 0.01, CI 1.7-52). Worse OS was independently associated with persistent TET2 (HR 3.9, p 0.013, CI 1.04-14.1), with a trend towards worse OS for IDH1, FLT3-ITD, with a trend towards worsening OS and RFS for ASXL1 (OS HR 7.4, p 0.06, CI 0.86 -63; RFS HR 4.9, p 0.06, CI 0.9-26) and DNMT3A (OS HR 2.3, p 0.12, CI 0.86-6.9; RFS 2.9, p 0.08, CI 0.98-8). Association with worse clinical outcomes remained significant after multivariate analysis for TET2 (both OS HR 3.98 p 0.041, CI1.07- 32 and RFS HR 5.8, p 0.032, CI 1.1- 29), IDH1 (RFS HR 8.02, p 0.049, CI 1.02 - 65) and FLT3-ITD (RFS HR 11.4, p0.010, CI 2.2- 80).
Conclusions:Presence of TP53 mutations was associated with worse OS. Presence of pre-transplant mutation did not impact RFS or OS. Persistent presence of mutations in TET2, IDH1 and FLT3-ITD after Fludarabine/melphalan conditioning regimen allogeneic SCT were associated with shorter RFS and OS (in the case of TET2) independent of CIBMTR DRI. This analysis supports association of adverse outcomes in AML patients with selected persistent mutations by D100 post-transplant in reduced intensity transplant setting. Post-transplant strategies that can further eliminate persistent mutations should be investigated in prospective studies.
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Lee: Pin Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Innate: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees. Desai: Kura Oncology: Consultancy; Bristol Myers Squibb: Consultancy; Agios: Consultancy; Takeda: Consultancy; Janssen R&D: Research Funding; Astex: Research Funding. Ritchie: Protaganist: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Speakers Bureau; Celgene/BMS: Consultancy, Other: travel support, Speakers Bureau; Bristol Myers Squibb: Consultancy, Research Funding; ARIAD Pharmaceuticals: Ended employment in the past 24 months, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria; Astellas: Consultancy, Research Funding; NS Pharma: Research Funding; Abbvie: Consultancy, Honoraria; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Roboz: MEI Pharma - IDMC Chair: Consultancy; Daiichi Sankyo: Consultancy; Helsinn: Consultancy; Jazz: Consultancy; Bristol Myers Squibb: Consultancy; Glaxo SmithKline: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; Mesoblast: Consultancy; Blueprint Medicines: Consultancy; Jasper Therapeutics: Consultancy; AbbVie: Consultancy; Actinium: Consultancy; Agios: Consultancy; Amgen: Consultancy; Astex: Consultancy; Astellas: Consultancy; AstraZeneca: Consultancy; Bayer: Consultancy; Janssen: Research Funding; Pfizer: Consultancy; Roche/Genentech: Consultancy.
Background : Most older patients (pts) with relapsed or refractory (R/R) AML cannot tolerate intensive treatment and are not eligible for curative allogeneic hematopoietic cell transplant (alloHCT). ...131I-apamistamab, an anti-CD45 radioimmunoconjugate, delivers high dose targeted radiation to hematopoietic cells, allowing for myeloablation and eradication of leukemic cells while sparing toxicity to healthy organs. 131I-apamistamab led induction and conditioning can thus provide these pts with access to alloHCT. Methods: The SIERRA trial (NCT02665065) is a multi-center, randomized, controlled Phase 3 study comparing the rate of durable complete remission (dCR) lasting >6 months (mos) after complete remission with/without platelet recovery (CR/CRp) between two groups: 131I-apamistamab led induction and conditioning followed by alloHCT vs physician's choice of conventional care (CC). Pts were randomized (1:1) to CC or 131I-apamistamab with fludarabine and total body irradiation (2 Gy) followed by alloHCT. CR/CRp assessment was 28-56 days post alloHCT or 28-42 days post initiation of therapy on the CC group. Pts in the CC group not achieving leukemia-free state could crossover (CO) to 131I-apamistamab. Here we report the results of a post hoc analysis to determine if the presence of various risk factors (i.e., Karnofsky Performance Status (KPS) <90, HCT Comorbidity Index >3, age >65, adverse-risk cytogenetics, venetoclax failure prior to randomization) influenced achievement of dCR in pts treated with 131I-apamistamab. Results: In total, 153 pts were randomized (CC, n=76; 131I-apamistamab, n=77). All pts who received the therapeutic dose of 131I-apamistamab (n=66) underwent alloHCT vs 14 (18.2%) in the CC group. Of evaluable pts, dCR rates at 6 mos were 22% in the 131I-apamistamab group vs 0% in the CC group (95% CI;12.29, 34.73; p<0.0001). A total of 19 pts (13, 131I-apamistamab group; 6, CO) achieved dCR. Table 1 shows the pt, disease, and transplant characteristics of dCR vs. non-dCR pts. Eight of the 19 pts (42.1%) had primary induction failure and the median time to randomization from diagnosis was 5.4 mos. Approximately 50% of pts (9/19) had adverse-risk cytogenetics. Over 35% (7/19) of the pts had failed prior venetoclax and the median number of prior treatments was 3 (range 1-5). A total of 10/19 (52%) pts had KPS of <90% and a comorbidity index of >3. There was no difference in the rate of dCR when stratifying by number of risk factors for a given pt (0 to 5) with 27% for pts with 0-1 risk factors, 14% for pts with 2-3 risk factors, and 11% for pts with 4-5 risk factors (p=0.251). Conclusion: Pts with R/R AML who have multiple risk factors such as adverse risk cytogenetics, age >65, venetoclax failure, high comorbidity index or poor KPS are typically not considered for alloHCT due to high transplant-related mortality and post-transplant relapse rates. 131I-apamistamab was effective in achieving durable responses in R/R AML pts irrespective of the presence of multiple risk factors and successfully enabled alloHCT in such pts due to its targeted mechanism of action.
Background : Allogeneic hematopoietic cell transplant (alloHCT) is the only potentially curative therapy for patients (pts) with relapsed or refractory (R/R) AML. Only a minority undergo alloHCT as ...they typically have dismal outcomes due to high relapse rates, especially those with TP53 mutations and active disease. Additionally, older pts cannot tolerate intensive treatment and hence are not eligible for alloHCT. 131I-apamistamab, an anti-CD45 radioimmunoconjugate, delivers high dose targeted radiation to hematopoietic cells, allowing for myeloablation and eradication of leukemic cells. 131I-apamistamab led induction and conditioning can thus provide these pts access to alloHCT potentially leading to better disease control and outcomes even in pts with the TP53 mutation. Methods: The SIERRA trial (NCT02665065) is a multi-center, randomized, controlled Phase 3 study comparing the rate of durable complete remission (dCR) lasting ≥6 months (mos) after complete remission with/without platelet recovery (CR/CRp) between two groups: 131I-apamistamab led induction and conditioning followed by alloHCT vs physician's choice of conventional care (CC). Pts were randomized (1:1) to CC or 131I-apamistamab with fludarabine and total body irradiation (2 Gy) followed by alloHCT. CR/CRp assessment was 28-56 days post alloHCT or 28-42 days post initiation of therapy in the CC group. Pts in the CC group not achieving leukemia-free state could crossover (CO) to 131I-apamistamab. We report the characteristics and outcomes of all pts with TP53 mutation who were enrolled in the SIERRA trial. Results: In total, 153 pts were randomized (CC, n=77; 131I-apamistamab, n=76). All pts who received the therapeutic dose of 131I-apamistamab (n=66) underwent HCT vs 14 (18.2%) in the CC group. Of evaluable pts, dCR rates at 6 months were 22% in the 131I-apamistamab group vs 0% in the CC group (95% CI;12.29, 34.73; p<0.0001). A total of 37 pts with TP53 mutation were enrolled (CC=20; 131I-apamistamab =17) with a prevalence of 24.2%. Table 1 shows the baseline characteristics of these pts. Median overall survival (OS) for pts in the 131I-apamistamab group, who were TP53 negative was 6.37 mos compared to 5.72 mos for the TP53 mutation positive pts (HR=0.66; 95% CI 0.37, 1.18; p=0.16). In the CC group (including CO pts), the median OS for TP53 positive pts was 2.96 mos. When the CC group without CO were analyzed, the median OS was 6.51 mos and 1.66 mos for the TP53 mutation negative and positive groups respectively (HR=0.28; 95% CI 0.12, 0.67; p=0.0022). For TP53 mutation positive pts who received 131I-apamistamab ( 131I-apamistamab plus CO pts), the median OS was 5.49 mos compared to a median 1.66 mos in pts who did not receive 131I-apamistamab (CC pts without CO) (HR=0.23; 95% CI 0.10, 0.52; p=0.0002) (Figure 1). Conclusion: Pts with TP53 mutated R/R AML have a dismal prognosis and are seldom offered alloHCT due to high post-transplant relapse rates. 131I-apamistamab led alloHCT significantly improves survival outcomes in pts with TP53 mutations, commensurate with rates observed in pts with wildtype TP53, thereby overcoming the negative impact of this mutation. These data clearly support the use of 131I-apamistamab led induction and conditioning and alloHCT in R/R AML, including in patients with a TP53 mutation.
Introduction: Haplo-cord transplantation - the co-infusion of a single umbilical cord graft with CD34-selected cells from a haplo-identical donor, offers an alternative stem cell source for patients ...lacking HLA-matched donors. The T-cell depleted haplo-graft acts as a myeloid bridge until replaced by durable cord hematopoiesis.
Anti-thymocyte globulin (ATG) is routinely used in haplo-cord preparative regimens to reduce graft failure, graft vs. host disease (GVHD) and graft vs. graft reactions. ATG depletes T-lymphocytes through Fas-mediated apoptosis, but also indirectly stimulates T-cell destruction through antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC) (de Koning, Blood Adv. 2018). Excessive depletion of cord lymphocytes may compromise immune reconstitution and graft vs. tumor effects.
G-CSF administration early post-transplant may sensitize cord lymphocytes to the cytotoxic effects of residual ATG. G-CSF drives myeloid precursor proliferation and activates phagocytosis, facilitating increased ADCP and ADCC of ATG-coated cells (de Koning, Blood Adv, 2018). Prior to the publication of this data, our institutional practice was to administer G-CSF to haplo-cord transplant recipients from day +6 until neutrophil engraftment. In April 2018, we altered our practice - withholding routine G-CSF treatment. We here compare our transplant outcomes 1 year before and after this practice shift.
Methods: We examined consecutive adult patients with hematologic malignancy that underwent haplo-cord transplantation conditioned with fludarabine and melphalan with or without total body irradiation (400 cGy) at Weill Cornell Medicine, between 04/2017 and 04/2019. All patients received rabbit ATG (Thymoglobulin) 1.5 mg/kg on days -5, -3 and -1 (total dose 4.5 mg/kg). Data was collected as part of study 01810588 registered at clinicaltrials.gov.
Probabilities of relapse, relapse-related mortality (RRM) and non-relapse mortality (NRM) were generated using cumulative incidence (CI) estimates to accommodate competing risks. Probabilities of overall survival (OS) and progression-free survival (PFS) were calculated using Kaplan-Meier estimates and inter-group comparison performed by log-rank testing. Variables with potential survival impact were evaluated in a Cox proportional hazards regression model.
Results: The study included 59 haplo-cord recipients - 30 who received G-CSF (GCSF group) and 29 who did not (NO GCSF group). Groups were well matched for age, weight, disease, DRI, baseline lymphocyte count, CMV recipient/donor status and TBI treatment (Table). Neutrophil engraftment occurred at a median of 10 days in the GCSF group vs. 14 days in the NO GCSF group (p=0.0002), and platelet recovery at a median of 20 and 22 days (p=-0.61). Primary graft failure occurred in 1 GCSF patient and 2 NO GCSF patients (p=0.53).
The incidence of acute GVHD (grade II-IV) by day 100 was 10% in both groups (p=0.97). There was no significant difference between GCSF and NO GCSF in the CIs of relapse, RRM or NRM at 1yr. No difference was found in 1yr OS or PFS on univariate analysis (Table). After adjusting for patient age, weight, lymphocyte count prior to ATG, disease subtype, CIBMTR disease risk index (DRI), Karnofsky performance status (KPS), comorbidity score and TBI exposure, in multivariate analysis, no effect on OS or PFS was observed.
CMV reactivation was observed in 40% (GCSF) vs. 21% (NO GCSF) (p=0.11). The trend towards lower reactivations in the NO GCSF may in part be due to the introduction of letermovir prophylaxis for CMV positive transplant recipients in 02/2018. Acknowledging the limited follow up of NO GCSF patients, we note a trend towards improved CD4 counts at 1yr in this group - median 271 cells/μL (n=6, IQR25-75 = 240-342) vs. 155 cells/μL in the GCSF group (n=16, IQR25-75 = 111-473) (p=0.17).
Conclusion: Our data shows that G-CSF can safely be eliminated from haplo-cord transplant. We see a delay in neutrophil engraftment but no adverse effect on early morbidity or mortality outcomes. We continue to withhold early G-CSF while assessing long-term outcomes. Longer follow-up is needed in our cohort to enable a systematic analysis of immune reconstitution. Early CD4+ cell recovery after ATG treatment has been shown to improve OS, PFS, NRM and RRM (Admiraal, Lancet Hem 2015 & 2017).
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Van Besien:Miltenyi Biotec: Research Funding.
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