Reduced-intensity Regimen Research Articles

CT-374: Outcomes of Allogeneic SC Transplant in Hematological Malignancy Patients Using a Busulfan 3 (9.6 mg/kg)-Based Conditioning Regimen

Introduction Busulfan is often used in a myeloablative conditioning regimen at an IV dose of 12.8 mg/kg (BU4). A reduced intensity regimen using 6.4 mg/kg (BU2) is commonly used in older patients or those with comorbid diseases. Data on use of BU3 (9.6 mg/kg) based regimen are limited. At KFSHRC, the busulfan-based MAC regimen’s IV-BU dose is 12.8 mg/kg (BU4), but for those who do not tolerate the full MAC, BU can be reduced to 9.6 mg/kg (BU3). Objective To study the outcomes of hematological malignancy patients who received allo-HCT using BU3-based conditioning from matched related or unrelated donors. Methods A retrospective analysis of the KFSHRC-BMT Database for patients who received allo-HCT between October 2005 and December 2019. Results A total of 65 patients were identified: 47 AML (72.3%), 8 MDS (12.3%), 8 myelofibrosis (12.3%), and 2 CML (3.1%) patients. Median age was 52 years (16–66), and 35 (54%) were males. Pre-transplant status showed 57% were in CR1, 17% in CR2, and 3% not in CR. Fifty-seven (88%) patients received PBSC, 6 (9%) received BM source, and 2 (3%) received both PBSC and BM from HLA-matched related [N= 61 (93%)] or unrelated [N=4 (7%)] donors. Forty (61.5%) patients received Bu/Flu as a conditioning regimen, 14 (21.5%) received Bu/Cy, 7 (10.8%) received Bu/Flu/ATG, and 4 (6.2%) received Bu/Cy/ATG. GVHD prophylaxis consisted of cyclosporine and methotrexate for all patients. Fifty-two (80%) patients had comorbidities with comorbidity index between 1–2 in 29 (44.6%) patients and more than 2 in 23 (35.4%). Sixty-two (95%) patients engrafted; median ANC and platelet engraftment were 18 days. Acute GvHD grade II–IV and III–IV occurred in 29% and 14%, respectively. Chronic GvHD occurred in 55% and was extensive in 24% of patients. With median follow-up of 60.5 months, the 2 year- and 5 year-OS were 58.5% and 44.1% respectively. The 2 year- and 5 year-DFS were 52.9% and 44.5%, respectively. Cumulative incidence of relapse and NRM at 2 years were 29.5% and 17.4%, respectively. Day +100 TRM was 10.7%. Conclusions Allogeneic SCT using BU3-based regimen appears feasible to use in patients who are not suitable for a fully myeloablative (BU4) regimen. TRM, DFS, and OS rate were comparable to reports from studies using a BU4-based regimen, warranting prospective studies in these patients.

Survival Advantage of Treosulfan Plus Fludarabine Before Allogeneic Hematopoietic Cell Transplantation for Older or Comorbid Patients With Myeloid Malignancies

We have previously shown an advantage of a myeloablative conditioning regimen with reduced toxicity (Fludarabine 150 mg/m2, Treosulfan 42 g/m2, FluTreo) compared to a reduced-intensity regimen. We aimed to determine long-term safety and efficacy of FluTreo. We prospectively studied consecutive patients who received FluTreo in our center (2014-2019) on the basis of age (≥50 years), hematopoietic cell transplantation comorbidity index (HCT-CI) ≥2, or both. FluTreo recipients were then compared to a historical control group. We studied 68 FluTreo recipients, with a median age of 58.5 years and HCT-CI of 3. We calculated cumulative incidence (CI) of acute (grade 2-4) and moderate/severe chronic graft-versus-host disease (GVHD) (29.9% and 25%, respectively). The 3-year CI of treatment-related mortality was 19.1%, associated only with acute GVHD (P < .001). With a median follow-up of 27.3 (range 5.7-84.5) months in surviving patients, the 3-year overall survival (OS) was 56.6%, and disease-free survival (DFS) was 54.9%. Median survival has not yet been reached. Among pretransplantation and transplantation factors, only HCT-CI was associated with DFS and OS (P = .022 and P = .043, respectively). FluTreo recipients aged ≥50 with HCT-CI ≤ 2 had favorable DFS and OS compared with patients aged ≥50 with HCT-CI ≤2 after myeloablative conditioning. Our real-world study confirms that HCT with FluTreo expands the transplant population with favorable outcomes compared to previously used conditions. The choice of HCT in patients of a rather older age and comorbidity index needs to be revisited.

Impact of time to diagnosis on Mayo stages, treatment outcome, and survival in patients with AL amyloidosis and cardiac involvement.

To study the impact of time to diagnosis on cardiac Mayo stages, treatment outcome, and overall survival. We retrospectively analyzed 77 consecutive patients diagnosed between 2015 and 2020 with AL amyloidosis and cardiac involvement. Medical history was recorded in standardized form with the help of a questionnaire. Time from onset of symptoms of cardiac failure to diagnosis was correlated with the severity of cardiac involvement in modified Mayo 2004 and revised Mayo 2012 staging systems (rs =0.30, 95% CI: 0.07-0.50, P=.007 and rs =0.25, 95% CI: 0.01-0.45, P=.03). Patients with advanced Mayo 2004 stages received reduced-intensity regimens and had a lower probability to achieve adequate hematologic- and cardiac response after first-line treatment than patients with early stages (rs =0.28, 95% CI: 0.04-0.48, P=.01 and rs =0.72, 95% CI: 0.55-0.82, P<.0001) and poorer overall survival (P=.0004). Compared with patients diagnosed within the first year, patients diagnosed after 13-18 or ≥19months from first symptoms had a 3- to 5 times higher risk of dying. Our data indicate that there is a 12-month window within which the diagnosis of AL amyloidosis needs to be established to avoid early deterioration and death. Sensitizing physicians and raising awareness for the disease are crucial for timely diagnosis and may improve the outcome of the disease.

Hematopoietic Cell Transplantation Rescues Inflammatory Bowel Disease and Dysbiosis of Gut Microbiota in XIAP Deficiency

X-linked inhibitor of apoptosis protein (XIAP) deficiency is an infrequent inborn error of immunity that is often associated with refractory inflammatory bowel disease (IBD). The natural course of XIAP deficiency is typically associated with poor prognosis, and hematopoietic cell transplantation (HCT) is the only curative treatment. To study (1) the effect of HCT on patients with XIAP deficiency undergoing HCT, (2) the status of XIAP deficiency-associated IBD after HCT, and (3) the gut microbiota of XIAP deficiency-associated IBD before and after HCT. A nationwide survey of patients with XIAP deficiency was conducted. A spreadsheet questionnaire was collected from the physicians. Feces samples collected from the patients before and after HCT and their healthy family members were analyzed. Twenty-six patients with XIAP deficiency underwent HCT by the end of March 2020, and 22 patients (84.6%) survived. All the survivors underwent a fludarabine-based reduced-intensity condition regimen. Acute graft-versus-host disease was observed in 17 patients (65.4%). Nineteen patients experienced refractory IBD before undergoing HCT. IBD improved remarkably after HCT. After HCT, the colonoscopic and pathological symptoms were restored to normal, and the pediatric ulcerative colitis activity index improved significantly. Gut microbiota indicated dysbiosis before HCT; however, it was improved to resemble that of the healthy family members afterHCT. This study revealed that HCT has a favorable outcome for XIAP deficiency. HCT rescues gut inflammation and dysbiosis in patients with XIAP deficiency.

Donor CD3 Chimerism After Allogeneic Transplantation Predicts Probability Of Relapse For Patients Treated For Acute Myelogenous Leukemia (AML), Acute Lymphoblastic Leukemia (ALL), and Non-Hodkgin's Lymphoma (NHL)

Introduction The ability to predict relapse in patients after HSCT is crucial for tailoring therapy including pre transplant conditioning regimens and post transplant interventions. Donor bone marrow CD34+ cell chimerism analyses has previously been reported to be predictive for post transplant relapse for acute leukemia. Rapid immune reconstitution after HSCT may be important in the development of a robust graft versus leukemia response. Methods We performed for a sequential series of patients a retrospective analysis of donor cell chimerism (DCC) of peripheral blood CD3+ cells at 4 week intervals starting at day 28 after transplantation. Donor bone marrow CD34+ chimerism was evaluated at day 84 after transplantation. Percent chimerism was measured by PCR based amplification of short tandem repeats (STR). From 2009-2012, percent DCC data were collected for patients with ALL (n=39), NHL (n=26), and AML (n=68). Median age at diagnosis was 45 (range 25-69), 51 (range 23-66), and 57 (range 38-75), respectively. Patients received either PBSC or bone marrow cells from related (n=81) or unrelated donors (n=52). At transplantation, patients with ALL were in CR1 (n=27), CR2 (n=4), CR3 (n=1), PIF (n=3), relapse (n=2), PR (n=5); patients with NHL were in PR (n=9), CRU1 (n=4), CRU2 (n=3), Cr1 (n=4), CR2 (n=3), CR3 (n=4); patients with AML were in CR1 (n=38), CR2 (n=6), relapse (n=8), PIF (n=13). Conditioning regimens for patients with ALL were cyclophosphamide (cy) and fractionated total body irradiation (TBI) (n=27) or fludarabine (flu) and melphalan (mel) (n=11). Patients with NHL were conditioned with flu/cy and rituximab (n=15), or flu/mel (n=8). Patients with AML were conditioned with either a myeloablative regimen of flu/busulfan+TBI (n=51), or a reduced intensity regimens of flu/mel or flu/cy/TBI (n=16). Those who had NHL or AML and received unrelated donor cells were given rituximab. Post transplant immunosuppression was tacrolimus and methotrexate for most patients. Patients were censored for relapse or death. For analysis of DCC, patients who relapsed or did not relapse were divided into quartiles by diagnosis. The probability of relapse was tested for quartile groups using chi square analysis. Adjustments were not made for competing risks. Results ALL patients in the upper three quartiles of CD3+ DCCs (1 of 34 patients, median=100%, range=84-100%, [Table 1][1]) compared to patients in the bottom quartile were less likely to relapse (3 of 7 patients, median=94%, range=82-95%, p<0.002). Similarly, the upper 2 quartiles of NHL patients who had at least 95% day 28 CD3+ DCC were less likely to relapse (2 of 16 patients, median 95%, range 63-100%, p<0.007, [Table 1][1]). 7 of 48 patients with AML in the upper 3 quartiles who had day 28 CD3+ DCC of at least 90% (median=100%, range 60-100%) relapsed, trending lower compared to those in the lower quartile (p<0.06). CD3+ DCCs for day 56 and day 84 were not statistically significant for predicting future relapse. View this table: Table 1 CD3+ DCC at 28 days Day 84 CD34+ DCCs were also analyzed as described. The upper quartile of patients with ALL who did not relapse achieved a 100% DCC (1 of 23 patients relapsed, median 100%, range 82-100%, [Table 2][2]). Those that did not achieve 100% DCC for CD34+ cells by day 84 more likely to relapse (p<0.009). For patients with NHL, the upper 3 quartiles of those who did achieve 83% CD34+ DCC (1 of 7, median=90%, range 83-100%, p<0.008) by day 84 were less likely to relapse. The same method was used for patients with AML and those that did achieve 90% CD34+ DCC for cells by day 84 were not likely to relapse (5 of 35, median=96%, range=63-100%, p<0.09). View this table: Table 2 CD34+ DCC at 84 days Conclusions These findings suggest that failure to achieve early donor cell engraftment predicts for relapse. Relapse remains a major cause for treatment failure. Improvements in transplant conditioning may improve early lymphoid (CD3+) and myeloid (CD34+) engraftment and decrease the risk of disease relapse. Early monitoring of CD3+ DCC may identify patients who would benefit from post transplant intervention. Disclosures: No relevant conflicts of interest to declare. [1]: #T1 [2]: #T2

Impact of Donor Type on Long-Term Outcomes of Hematopoietic Cell Transplantation for Adult Acute Lymphoblastic Leukemia during First Remission

Background: Standard therapy for adult patients with high-risk acute lymphoblastic leukemia (ALL) consists of hematopoietic cell transplantation (HCT) including autologous-HCT (AUTO) and allogeneic-HCT from a matched-sibling donor (MSD) or matched unrelated donor (MUD). When a conventional donor is not available, HCT from a partially-mismatched unrelated donor (MMUD), cord blood transplantation (CBT) or a familial haploidentical donor (HID) is considered.Aim: Although HCT outcomes of those alternative strategies are advancing with optimization of pre-conditioning regimens with immunosuppressive agents, there are still subjects to debate. We tried to analyze the long-term HCT outcomes according to the donor types including MMUD, double CBT (DCBT) and AUTO as an alternative choice compared to the conventional donors.Methods: We enrolled 661 adult ALL patients who underwent transplantation from 1995 to 2015 in their first remission (CR1). Patients with acute undifferentiated leukemia (AUL, n=5) and mixed phenotype acute leukemia (MPAL, n=52) in the same department were also enrolled and median age was 33 years old (range, 15-65). Before 2010, our treatment strategy for ALL patients in CR1 was to offer allogeneic or autologous HCT according to the donor availability and the presence of high-risk features. After 2010, DCBT was mainly used for patients who were not available with conventional donors. For myeloablative regimen, we administered cyclophosphamide (120 mg/kg) combined with TBI (1320 cGy), and reduced intensity regimen was applied for elderly or patients with comorbid conditions which consisted of fludarabine (150 mg/m2 in total) and melphalan (140 mg/m2 in total). Conditioning regimen for AUTO was TBI (1200 cGy), ARA-C (9g/m2 in total) and melphalan (100mg/m2 in total), and fludarabine (150mg/m2 in total) was used for DCBT instead of melphalan. Graft-versus-host disease (GVHD) prophylaxis was attempted by administering calcineurin inhibitors (cyclosporine for MSD, tacrolimus for others) plus methotrexate or mycophnolate mofetil (for DCBT). Antithymocyte globulin (ATG) was administered to the patients who received grafts from MMUD.Results: Engraftment was successful in all donor types, but neutrophil and platelet recovery was significantly delayed only after DCBT (median recovery for neutrophil and platelet was 25 and 33.5 days respectively). After median follow-up of 80.4 months (range, 6.5-259.1), 7-year OS for the entire 661 patients was 57.0%. In detail, 7-year OS for MSD, MUD, MMUD, DCBT, and AUTO was 56.9%, 56.8%, 62.6%, 65.1% and 48.6% (p=0.423). MSD, MUD and MMUD showed similar relapse rate (27.5%) and non-relapse mortality (NRM) rate (20.6%), but DCBT showed significantly higher NRM rate (29.6%) and AUTO showed significantly higher relapse rate (41.6%). In contrast, DCBT showed lower relapse rate (7.2%) and AUTO showed lower NRM rate (9.7%). Interestingly, 7-year GVHD and relapse-free survival (GRFS) for MSD, MUD, MMUD, and DCBT was 34.1%, 15.0%, 40.9%, and 50.3%, respectively, which was related with higher incidence of severe chronic GVHD in MUD (27.6%) and MSD (14.1%) compared to DCBT (4.2%, p < 0.001). In high-risk subgroup (n=517) including 233 Philadelphia chromosome (Ph)-positive ALL, 7-year OS for MSD, MUD, MMUD, DCBT, and AUTO was 54.9%, 58.1%, 57.8%, 60.7%, and 33.3%, respectively. But the 7-year GRFS for MSD, MUD, MMUD, and DCBT was 30.7%, 14.5%, 35.3%, and 47.7%, respectively, which revealed lower relapse rate (8.7%) and low severe chronic GVHD (2.6%) of DCBT. Multivariate analysis showed that old age and AUTO was related with poor OS in high-risk ALL patients group, and old age and poor-risk karyotype and MUD transplant without ATG were related with poor GRFS.Conclusion: Our data showed similar transplant outcomes of alternative donors such as DCBT and ATG-applied MMUD compared to conventional donor transplants in ALL patients in CR1. In addition, GRFS was rather superior in patients treated with DCBT. Our long-term transplantation outcome results revealed that DCBT might be a good alternative choice for patients who are not available with conventional allogeneic donors, and AUTO may be considered for selected standard-risk patients with low NRM rate without a risk of GVHD. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Safety and Efficacy of Tcralpha/Beta and CD19 Depleted Haploidentical Stem Cell Transplantation Following Reduced Intensity Conditioning in Children: Results of a Prospective Multicenter Phase I/II Clinical Trial

We report one year follow-up data on safety and efficacy from the first prospective, multi-center, open-label, single-arm phase I/II clinical trial of TCRalpha/beta and CD19-depleted haploidentical stem cells grafts which were generated with the CliniMACS plus System (Miltenyi Biotec, Germany) and transplanted after reduced-intensity conditioning in pediatric patients with various malignant and non-malignant diseases (www.clinicaltrialsregister.org; 2011-005562-38). 30 patients were enrolled in the pediatric cohort of the trial and received single agent MMF as short-term GVHD prophylaxis (40mg/kg/day for 30 days). The grafts were manufactured in 4 GMP sites. The kinetics of immune cell reconstitution were measured in two core labs using standardized phenotypic analyses and the MACSQuant flow cytometer (Miltenyi Biotec, Germany). We previously reported the outcome of the first 100 days. This report covers a median follow-up of 367 days.Results: Thirty patients from six hospitals were treated (13 female, 17 male; median age 7 years, range 1 - 17 years). 10 patients had ALL, 8 AML, 6 solid tumors (soft tissue sarcomas and neuroblastomas), 3 MDS/MPS, and 1 each with lysosomal storage disorder, SCID, and Wiskott Aldrich syndrome. Disease status in acute leukemias/MDS were: CR1 (n=4), relapsed/refractory (n=17). 5/6 patients with solid tumors had relapsed metastatic disease. The conditioning regimen consisted of 15 or 30 mg ATG (Fresenius/Grafalon) or 7 Gy total nodal irradiation, 160 mg/m2 fludarabine, 10 mg/kg thiotepa, and 140 mg/m2 melphalan. The median numbers of CD34+ cells, TCRab+ cells and CD20+ cells infused per kg bw were 14.6 x 106 (range, 4 - 54.9), 14 x 103 (range, 0.62 - 40.6) and 0.55 x 105 (range, 0.04 - 1.85), respectively. Main cellular components of the graft were NK and TCRgd+ cells (median 6.67 x 107 and 1.58 x 107 cells per kg bw, respectively) with consistently high log depletions of TCRab+ and CD19+ cells: 4.75 and 3.44, respectively.None of the 30 recipients developed severe acute GVHD grades III - IV. The vast majority of patients (97%) experienced no or only grade I acute GVHD despite minimal GVHD prophylaxis after transplantation. One patient had acute GVHD grade II. Chronic GVHD was observed in two out of 23 patients (9%): one with skin and one with gut/liver involvement. In both cases GVHD was extensive.Twenty-four patients were evaluable for assessment of immune reconstitution until 1 year or discontinuation. Figure 1 shows fast and stable reconstitution of T, B and NK cells. TCRab+ T cells continued to increase during the observation period up to a median value of 741 cells/µL (range, 245 - 3132), whereas TCRgd+ T cells remained stable after reaching a plateau around day 20.ADV reactivation in 16 patients contributed most to infectious complications following transplantation. Of these 6 patients developed ADV disease. Within the first year after transplantation 3 patients died of overwhelming of ADV infection. One EBV reactivation was observed but recovered completely. 8 patients experienced CMV reactivation after transplantation. 7 of 8 patients recovered. Another 2 patients had CMV reactivation prior to transplant, but recovered shortly after engraftment. No CMV disease was observed within the first year. 6 patients had bacterial sepsis but recovered. In one patient CMV reactivation continued until death due to sepsis after graft failure.At a median of 367 days (range, 14 - 809) among the 30 recipients, 16 are alive at time of last follow-up, 8 died of relapse, 3 died of ADV infection, 1 died of sepsis after graft failure and 1 died of ARDS. 1 patient is lost to follow-up. Of the 8 patients who died of relapsed disease, 4 had active disease at time of transplant, 2 were in remission and 2 had disease status not evaluable. Cumulative incidences of relapse and NRM were 27% and 16% at one year, respectively. Kaplan-Meyer estimates of overall survival and DFS were 64% and 60% at one year, respectively.Conclusion: The CliniMACS TCRab+ / CD19+ depletion system yielded a large number of CD34+ cells, NK cells and TCRgd+ cells, that could be infused safely into pediatric patients with minimal risk of severe acute and chronic GVHD. The immune reconstitution was rapid. Coupled with a reduced-intensity regimen, the overall TRM was low. However, further efforts have to be made to avoid ADV associated infections. [Display omitted] DisclosuresLang:Miltenyi Biotec GmbH: Patents & Royalties, Research Funding. Bader:Novartis, Medac, Amgen, Riemser, Neovii: Consultancy, Honoraria, Research Funding. Karitzky:Miltenyi Biotec GmbH: Employment. Holtkamp:Miltenyi Biotec GmbH: Employment. Siewert:Miltenyi Biotec GmbH: Employment. Pflitsch:Miltenyi Biotec GmbH: Employment. Handgretinger:Miltenyibiotec GmbH: Patents & Royalties: Co-patent holder of TcR alpha/beta depletion technologies, Research Funding.

Low Dose Donor Lymphocyte Infusion (DLI) Is Effective As Prophylactic Therapy for Mixed Chimerism in the Setting of In-Vivo T Cell Depleted Allogeneic Hematopoietic Cell Transplantation

Introduction: Donor lymphocyte infusion (DLI) has been used as a preemptive therapy for those with mixed donor chimerism (MDC) or in the presence of minimal residual disease or as salvage therapy for relapse of disease post allogeneic stem cell transplantation (allo SCT). The efficacy of DLI and the ease of therapy are balanced by the potential for significant toxicity with 100-day DLI-related mortality rate approaching 20%. A number of strategies have been employed in an effort to avoid the major complication of DLI, namely Graft-versus-host disease (GVHD). These strategies include the use of escalating doses of T cells (1 x 10 6 - 1 x 10 8/ kg) and manipulations of the T cells prior to infusion. We conducted a retrospective study of the prophylactic role of low dose DLI (< 5 x 10 6 /kg) in patients with mixed chimerism in the setting of in-vivo T cell depleted allo SCT.Methods: We identified 33 consecutive patients who underwent allo SCT with T cell depletion conditioning regimen with a minimum of 100-day post-transplant follow up. Five patients qualified for our study. MDC was defined by CD3 or CD33 subsets <=95% of the donor and trending down in two or more consecutive samples measured at 100-day or beyond. Full donor chimerism (FDC) was > 95% of CD3 or CD33 subsets. We adopted two myelo-ablative and 1 reduced intensity conditioning with in-vivo T cell depletion in all regimens. Myelo-ablative regimens: Fludarabine 30 mg IV day -8 to day -4 and Busulfan 3.2 mg IV from day -5 to day -2. GVHD prophylaxis consisted of anti-thymocyte globulin for a total dose of 7.5 mg/kg IV from day -4 to day -2 and tacrolimus starting day -1 (FB-ATG regimen). Carmustine 300 mg/ m2 IV day -6, Cytarabine 400 mg/ m2 and etoposide 200mg/ m2 IV on day -5 to day -3, melphalan 140 mg/ m2 IV on day -2. GVHD prophyalxis consisted of alemtuzumab 20 mg IV on day -5 to day -2 and tacrolimus starting day -1 (BEAM-C regimen). Reduced intensity regimen consisted of Fludarabine 30mg/m2 on day -6 to day -2 and melphalan 140 mg/ m2 on day -2. GVHD prophylaxis consisted of alemtuzumab 20 mg IV daily from day -8 to day -5 and tacrolimus starting day -1 (FMC regimen). Demographic, disease and transplant variables were collected.Results: The median age was 52 (range: 28-57) years. There was 1 patient each with diagnoses of T-cell Acute Lymphoblastic Leukemia, Acute Myelogenous Leukemia, Relapsed Hodgkin Lymphoma, Chronic Lymphocytic Leukemia, and Chronic Myelomonocytic Leukemia. Three patients had received FMC regimen and 1 each received FB-ATG and BEAM-C regimen. All five patients had MDC in CD3 subset and FDC in CD33 subset pre-DLI. The median CD3 chimerism pre-DLI was 21% (9%-81%). None of the patients were diagnosed with acute or chronic GVHD pre-DLI. The median time to DLI infusion was 6 (3-9.5) months. The median CD3 dose of the DLI was 3 (range: 3-10) x 106 /kg. The median time for conversion of MDC to FDC was 3 (2-7.5) months. All 5 patients converted to FDC in CD3 subset. One out of five patients needed a second DLI (CD3 cell dose: First DLI 3 x 106 /kg and second DLI 10 x 106 /kg) due to persistent MDC in CD3 subset (Table 1). One patient (20%) developed steroid responsive acute GVHD of the skin, GI and liver (grade III) following DLI (CD 3 dose 3 x 106 /kg) and this has evolved into extensive cGVHD which is under partial remission. At 1 year follow up: none relapsed and the OS was 100%.Conclusion: Low dose DLI (CD 3 dose starting at 3-4 x 106 /kg) is highly effective (80%) as a prophylactic therapy for conversion of MDC to FDC with minimal risk of GVHD in the setting of in-vivo T cell depleted allo SCT. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Genetic Ontogeny Defines Distinct Prognostic Subgroups in AML Patients Age 60 and Older Following Hematopoietic Stem Cell Transplantation

▪BackgroundThe prognosis for older adults diagnosed with acute myeloid leukemia (AML) is poor. The response to conventional chemotherapy in these patients is frequently brief, and long-term survival is largely limited to those who undergo allogeneic hematopoietic stem cell transplantation (HSCT). However, mortality after transplantation HSCT is also high, with deaths attributable both to relapsed AML and to transplant-related complications. There is thus a critical need for strategies that can reliably discern older AML patients who are most likely to benefit from current transplantation approaches and those for whom novel approaches should be developed.We have previously shown that genetic characteristics can divide AML patients into three clinically distinct categories: (1) TP53 -mutated AML; (2) “secondary-type” AML, defined by mutations in any of eight genes with high specificity for the presence of antecedent myelodysplastic syndrome; and (3) “de novo” type AML, defined by absence of TP53 and secondary-type mutations. We showed that older patients with de novo-type AML have improved response to standard induction chemotherapy and significantly superior event-free survival than those with either secondary-type or TP53- mutated AML. Since disease burden prior to HSCT has been linked to post-HSCT outcomes, we hypothesized that diagnostic ontogeny classification would be associated with relapse and survival among older AML patients receiving HSCT in first complete remission.MethodsWe identified AML patients age 60 or older who underwent HSCT at Dana-Farber Cancer Institute (DFCI; Boston, MA) in first complete remission between 2012-2016, for whom next-generation sequencing of the diagnostic AML sample was available. Based on targeted gene panel sequencing of recurrent myeloid driver alterations, we classified AML as TP53 -mutated, secondary-type (SRSF2, SF3B1, U2AF1, ZRSR2, BCOR, ASXL1, EZH2, or STAG2 mutations), or de novo type (neither TP53 mutation nor secondary-type mutations). We extracted data on clinical outcomes from the medical record and assessed the impact of diagnostic AML genetics on overall survival and cumulative incidence of relapse following HSCT.ResultsFifty-five patients met inclusion criteria, with a median age of 67 (range 60-76). All had received intensive induction chemotherapy; nine (16.4%) received myeloablative conditioning regimens, while the remainder received reduced intensity regimens. Of the 55 patients, 13% (n=7) had TP53 mutations, 40% (n=22) had secondary-type mutations, and 47% (n=26) had de-novo type mutations. Patients with de-novo type mutations had significantly superior 2-year overall survival than those with secondary-type mutations, who in turn had significantly superior survival than those with TP53 mutations (82.2% versus 48.1% versus 14%, p<0.001 for all comparisons, Figure 1A). These differences reflected a significant difference in the 2-year cumulative incidence of relapse following HSCT (100% for TP53 versus 56.7% for secondary-type versus 33.4% for de-novo type mutations, p<0.001 for all comparisons, Figure 1B).ConclusionIn our cohort of older AML patients who underwent HSCT in first complete remission after intensive induction chemotherapy, genetic ontogeny classification at the time of diagnosis was significantly associated with overall survival and rate of relapse after HSCT. Our findings, which merit further evaluation in a larger cohort, suggest that genetic classification of ontogeny can form the basis of a robust prognostic model that accurately predicts post-HSCT outcomes in older AML patients. [Display omitted] DisclosuresKoreth:Amgen Inc.: Consultancy; Millennium Pharmaceuticals: Research Funding; Prometheus Labs: Research Funding; Kadmon Corp: Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Nikiforow:Kite Therapeutics: Membership on an entity's Board of Directors or advisory committees. Armand:Sigma Tau: Research Funding; Sequenta/Adaptive: Research Funding; Affimed: Research Funding; Infinity: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Genmab: Consultancy; Roche: Research Funding; Pfizer: Consultancy, Research Funding; Merck & Co., Inc.: Consultancy, Research Funding; Tensha: Research Funding; Otsuka: Research Funding. Antin:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Lindsley:MedImmune: Research Funding; Jazz Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy.

Higher Fludarabine and Cyclophosphamide Exposures Lead to Worse Outcomes in Reduced-Intensity Conditioning Hematopoietic Cell Transplantation for Adult Hematologic Malignancy

Reduced-intensity conditioning regimens using fludarabine (Flu) and cyclophosphamide (Cy) have been widely used in hematopoietic cell transplantation (HCT) recipients. The optimal exposure of these agents remains to be determined. We aimed to delineate the exposure-outcome associations of Flu and Cy separately and then both combined on HCT outcomes. This is a single-center, observational, pharmacokinetic (PK)-pharmacodynamic (PD) study of Flu and Cy in HCT recipients age ≥18 years who received Cy (50 mg/kg in a single dose), Flu (150 to 200 mg/m2 given as 5 daily doses), and total body irradiation (TBI; 200 cGy). We measured trough concentrations of 9-β-D-arabinosyl-2-fluoradenine (F-ara-A), an active metabolite of Flu, on days -5 and -4 (F-ara-ADay-5 and F-ara-ADay-4, respectively), and measured phosphoramide mustard (PM), the final active metabolite of Cy, and estimated the area under the curve (AUC). The 89 enrolled patients had a nonrelapse mortality (NRM) of 9% (95% confidence interval [CI], 3% to 15%) at day +100 and 15% (95% CI, 7% to 22%) at day +180, and an overall survival (OS) of 73% (95% CI, 63% to 81%) at day +180. In multivariate analysis, higher PM area under the curve (AUC) for 0 to 8 hours (PM AUC0-8 hr) was an independent predictor of worse NRM (P < .01 at both day +100 and day +180) and worse day +180 OS (P < .01), but no associations were identified for F-ara-A trough levels. We observed lower day +100 NRM in those with both high F-ara-ADay-4 trough levels (≥40 ng/mL; >25th percentile) and low PM AUC0-8 hr (<34,235 hr ng/mL; <75th percentile), compared with high exposures to both agents (hazard ratio, 0.06; 95% CI, 0.01 to 0.48). No patients with low F-ara-ADay-4 (<40 ng/mL; <25th percentile) had NRM by day +100, regardless of PM AUC. The interpatient PK variability was large in F-ara-ADay-4 trough and PM AUC0-8 hr (29-fold and 5.0-fold, respectively). Flu exposure alone was not strongly associated with NRM or OS in this reduced Flu dose regimen; however, high exposure to both Flu and Cy was associated with a >16-fold higher NRM. These results warrant further investigation to optimize reduced-intensity regimens based on better PK-PD understanding and possible adaptation to predictable factors influencing drug clearance.

HLA-haploidentical vs matched unrelated donor transplants with posttransplant cyclophosphamide-based prophylaxis

Posttransplant cyclophosphamide (PTCy) graft-versus-host disease (GVHD) prophylaxis has enabled haploidentical (Haplo) transplantation to be performed with results similar to those after matched unrelated donor (MUD) transplantation with traditional prophylaxis. The relative value of transplantation with MUD vs Haplo donors when both groups receive PTCy/calcineurin inhibitor/mycophenolate GVHD prophylaxis is not known. We compared outcomes after 2036 Haplo and 284 MUD transplantations with PTCy GVHD prophylaxis for acute leukemia or myelodysplastic syndrome in adults from 2011 through 2018. Cox regression models were built to compare outcomes between donor types. Recipients of myeloablative and reduced-intensity regimens were analyzed separately. Among recipients of reduced-intensity regimens, 2-year graft failure (3% vs 11%), acute grades 2 to 4 GVHD (hazards ratio [HR], 0.70; P = .022), acute grades 3 and 4 GVHD (HR, 0.41; P = .016), and nonrelapse mortality (HR, 0.43; P = .0008) were lower after MUD than with Haplo donor transplantation. Consequently, disease-free (HR, 0.74; P = .008; 55% vs 41%) and overall (HR, 0.65; P = .001; 67% vs 54%) survival were higher with MUD than with Haplo transplants. Among recipients of myeloablative regimens, day-100 platelet recovery (95% vs 88%) was higher and grades 3 and 4 acute (HR, 0.39; P = .07) and chronic GVHD (HR, 0.66; P = .05) were lower after MUD than with Haplo donor transplantation. There were no differences in graft failure, relapse, nonrelapse mortality, and disease-free and overall survival between donor types with myeloablative conditioning regimens. These data extend and confirm the importance of donor-recipient HLA matching for allogeneic transplantation. A MUD is the preferred donor, especially for transplantations with reduced-intensity conditioning regimens.

Addition of Rituximab in Reduced Intensity Conditioning Regimens for B-Cell Malignancies Does Not Influence Transplant Outcomes: EBMT Registry Analyses Following Allogeneic Stem Cell Transplantation for B-Cell Malignancies.

Rituximab (R) is increasingly incorporated in reduced intensity conditioning (RIC) regimens for allogeneic hematopoietic cell transplantation (alloHCT) in patients with B-cell malignancies, not only to improve disease control, but also to prevent graft-versus-host disease (GVHD). There are no randomized prospective data to validate this practice, although single center data and the CIBMTR analysis have shown promising results. We aimed at validation of these findings in a large registry study. We conducted a retrospective analysis using the EBMT registry of 3,803 adult patients with B-cell malignancies undergoing alloHCT (2001–2013) with either rituximab (R-RIC-9%) or non-rituximab (RIC-91%) reduced intensity regimens respectively. Median age and median follow up were 55 years (range 19.1–77.3) and 43.2 months (range 0.3–179.8), respectively. There was no difference in transplant outcomes (R-RIC vs RIC), including 1-year overall survival (69.9% vs 70.7%), 1-year disease-free survival (64.4% vs 62.2%), 1-year non-relapse mortality (21% vs 22%), and day-100 incidence of acute GVHD 2-4° (12% vs 12%). In summary, we found that addition of rituximab in RIC regimens for B-cell malignancies had no significant impact on major transplant outcome variables. Of note, data on chronic GVHD was not available, limiting the conclusions that can be drawn from the present study.

Augmented Reduced-Intensity Regimen Does Not Improve Postallogeneic Transplant Outcomes in Acute Myeloid Leukemia

PURPOSEReduced-intensity conditioning (RIC) regimens have extended the curative potential of allogeneic stem-cell transplantation to older adults with high-risk acute myeloid leukemia (AML) and myelodysplasia (MDS) but are associated with a high risk of disease relapse. Strategies to reduce recurrence are urgently required. Registry data have demonstrated improved outcomes using a sequential transplant regimen, fludarabine/amsacrine/cytarabine-busulphan (FLAMSA-Bu), but the impact of this intensified conditioning regimen has not been studied in randomized trials.PATIENTS AND METHODSTwo hundred forty-four patients (median age, 59 years) with high-risk AML (n = 164) or MDS (n = 80) were randomly assigned 1:1 to a fludarabine-based RIC regimen or FLAMSA-Bu. Pretransplant measurable residual disease (MRD) was monitored by flow cytometry (MFC-MRD) and correlated with outcome.RESULTSThere was no difference in 2-year overall survival (hazard ratio 1.05 [85% CI, 0.80 to 1.38] P = .81) or cumulative incidence of relapse (CIR) (hazard ratio 0.94 [95%CI, 0.60 to 1.46] P = .81) between the control and FLAMSA-Bu arms. Detectable pretransplant MFC-MRD was associated with an increased CIR (2-year CIR 41.0% v 20.0%, P = .01) in the overall trial cohort with a comparable prognostic impact when measured by an unsupervised analysis approach. There was no evidence of interaction between MRD status and conditioning regimen intensity for relapse or survival. Acquisition of full donor T-cell chimerism at 3 months abrogated the adverse impact of pretransplant MRD on CIR and overall survival.CONCLUSIONThe intensified RIC conditioning regimen, FLAMSA-Bu, did not improve outcomes in adults transplanted for high-risk AML or MDS regardless of pretransplant MRD status. Our data instead support the exploration of interventions with the ability to accelerate acquisition of full donor T-cell chimerism as a tractable strategy to improve outcomes in patients allografted for AML.

Short telomere length predicts nonrelapse mortality after stem cell transplantation for myelodysplastic syndrome

AbstractAllogeneic hematopoietic stem cell transplantation is the only potentially curative treatment for patients with myelodysplastic syndrome (MDS), but long-term survival is limited by the risk of transplant-related complications. Short telomere length, mediated by inherited or acquired factors, impairs cellular response to genotoxic and replicative stress and could identify patients at higher risk for toxicity after transplantation. We measured relative telomere length in pretransplant recipient blood samples in 1514 MDS patients and evaluated the association of telomere length with MDS disease characteristics and transplantation outcomes. Shorter telomere length was significantly associated with older age, male sex, somatic mutations that impair the DNA damage response, and more severe pretransplant cytopenias, but not with bone marrow blast count, MDS treatment history, or history of prior cancer therapy. Among 1267 patients ≥40 years old, telomere length in the shortest quartile was associated with inferior survival (P < .001) because of a high risk of nonrelapse mortality (NRM; P = .001) after adjusting for significant clinical and genetic variables. The adverse impact of shorter telomeres on NRM was independent of recipient comorbidities and was observed selectively among patients receiving more intensive conditioning, including myeloablative regimens and higher dose melphalan-based reduced-intensity regimens. The effect of shorter telomeres on NRM was prominent among patients who developed severe acute graft-versus-host disease, suggesting that short telomere length may limit regenerative potential of mucosal tissues after acute injury. MDS patients with shorter telomere length, who have inferior survival driven by excess toxicity, could be considered for strategies focused on minimizing toxic effects of transplantation.

Allogeneic Hematopoietic Cell Transplantation for Relapsed and Refractory Philadelphia Negative B Cell ALL in the Era of Novel Salvage Therapies

Introduction of novel salvage therapies and expansion of the donor pool within the past decade have allowed more patients with relapsed/refractory (r/r) B cell acute lymphoblastic leukemia (B-ALL) to receive allogeneic hematopoietic cell transplantation (alloHCT). The impact of each salvage therapy on transplant outcomes have not been compared. Our primary objective was to determine post-HCT relapse-free survival (RFS) in adult patients with r/r Philadelphia-chromosome negative (Phneg) B-ALL. We retrospectively studied alloHCT outcomes in 108 adult patients with r/r Phneg B-ALL transplanted in morphological remission achieved by salvage therapy. Salvage therapies were chemotherapy-based combination (n=45, 42%), blinatumomab (n=43, 40%), inotuzumab (n=14, 13%), or CAR T cells (n=6, 6%). The 2-year RFS and overall survival (OS) were 44% and 50%, respectively. In multivariable analysis, conditioning with reduced-intensity or non-myeloablative regimens (hazard ratio [HR]=2.23, 95% confidence interval [CI], 1.31-3.80; P=.003), having received ≥3 lines of therapies prior to transplant (HR=2.66, 95% CI, 1.56-4.54; P < .001), and inotuzumab (HR=2.42, 95% CI, 1.14-5.12; Wald P value=.021) were independently associated with lower RFS. Blinatumomab (HR=1.10, 95% CI, 0.62-1.96) had comparable RFS to chemotherapy. Incidence of hepatic sinusoidal syndrome was highest with inotuzumab (P < .001); however, 30-day mortality and intensive care unit admissions were not different per salvage therapy. The alloHCT in r/r Phneg B-ALL after remission induction with blinatumomab or chemotherapy led to encouraging outcomes if morphologic CR was achieved. In contrast, pretransplantation inotuzumab therapy was associated with inferior RFS. Larger studies are warranted to confirm our observations. Early transplantation after relapse and the utilization of myeloablative conditioning, when feasible, were key factors associated with improved outcomes after alloHCT in these patients.

Early Response Predicts Long-Term Improvement or Stabilization of Persons with Multiple Sclerosis Treated with Hematopoietic Stem Cell Transplantation

Introduction: Hematopoietic stem cell transplantation (HSCT) has been widely employed for autoimmune disorders under myeloablative and non-myeloablative regimens. The main indication for HSCT in this setting is multiple sclerosis (MS) in its relapsing-remitting form and related disorders such as neuromyelitis optica or clinical isolated syndrome. Results have varied, but response rates and prognostic features are still unkown along the spectrum of disease and conditioning regimens. Methods: People with MS (PwMS) autografted from March 2015 to March 2020 with a reduced intensity regimen (Cy/G-CSF + Rituximab) (NCT 02674217), were followed longitudinally every 3 months to assess the Expandable Disease Status Scale (EDSS). All patients with complete follow-up data were included in this study and two different cohorts were made according to PwMS that were followed by 12 or 24 months. The primary outcome was improvement or stabilization of EDSS at 12 months and 24 months. All potential prognostic factors were collected from electronic medical record of patients with complete sociodemographic, clinical and laboratory data. In order to identify prognostic factors related to responses, univariate analyses were carried out with logistic regression; variables that showed a p value &amp;lt;0.15 were included in the multivariate analyses (using age, sex, type of MS, previous history of EDSS as covariates) with logistic regression. All patients signed a consent to authorize intervention and contact for follow-up and the protocol study was approved by the Institutional Ethics Committee. Results: Two cohorts were formed according to follow-up periods. Cohort 1 (12 months follow-up) comprised of 200 pwMS, 133 (66.5%) being female and 47 (33.5%) male. Their features are shown in Figure 1A. Cohort 2 (24 months follow-up) was formed by 93 pwMS, 60 (64.5%) being female and 33 (35.5%) male. Their features are shown in Figure 1B. In cohort 1, 149 pwMS (74.5%) had a response while 51 (25.5%) did not. Mean change of EDSS between baseline and 12 months post-HSCT was -0.42 (range -7 to 4). In cohort 2, 54 patients (58%) had a response while 39 (42%) did not. Mean change of EDSS between baseline and 24 months post-HSCT was -0.02 (range -4 to 7). In cohort 1, baseline EDSS ≥4 was identified as a predictor of 12 months response in multivariate analysis (OR 0.02, p 0.02, 95% CI 0.1- 0.8). Also, early response at 3 months post-HSCT in the univariate (OR 8.5, p &amp;lt;0.0001, 95% CI 3.9 - 18.4) and multivariate (OR 10.3, p &amp;lt;0.0001, 95% CI 4.6 - 23.2) analyses presented as a predictor of 12 months response. In cohort 2, early response at 6 months predicted response at 24 months post-HSCT in the univariate (OR 16.1, p &amp;lt;0.0001, 95% CI 4.8 - 53.6) and multivariate analysis (OR 28, p &amp;lt;0.0001, 95% CI 5.8 - 133.8). Furthermore, duration of disease &amp;gt;10 years showed an association with a negative response at 24 months as well in the univariate (OR 0.3, p 0.008, 95% CI 0.1 - 0.7) and multivariate analyses (OR 0.1, p 0.002, 95% CI 0.04 - 0.5). These results are shown in Figure 1C and 1D. Conclusions: Early response at 3 or 6 months may be robust measures that could translate in long term improvement or stabilization of disease. Although the effects showed in this study are profound and were replicated on two cohorts, these results should be interpreted with caution and a longer follow-up could confirm these findings. Disclosures No relevant conflicts of interest to declare.

A Prospective Haploidentical Peripheral Blood Stem Cell Transplant Study Using a Pre-Defined Conditioning Regimen Intensity Based on Age and the Hematopoietic Cell Transplantation Comorbidity Index- Anzhit 1: Encouraging Preliminary Survival Outcomes at One Year Follow up

Background HLA-matched sibling and unrelated donors are not always available for patients that are in need of an allogeneic haematopoietic stem cell transplant. Partially HLA-mismatched related (haploidentical) donors can be identified for the vast majority of patients but these transplants were historically complicated by excessive graft versus host disease (GVHD), nonrelapse mortality (NRM), and poor overall survival (OS). Haploidentical haematopoietic stem cell transplantation (Haplo HSCT) has become increasingly common over the last ten years, predominately due to the successful use of post-transplant cyclophosphamide (PTCy) in mitigating graft versus host disease (GVHD). Most studies using PTCy have been retrospective with various conditioning regimens and stem cell sources making interpretation of results difficult. ANZHIT-1 is a prospective Australian multi-centre phase II study of Haplo HSCT with defined conditioning and GVHD prophylaxis regimens. Methods: This is an ethics approved Phase II study (ACTRN: 12617000151336) conducted between 2015-2020 at six Australian allogeneic HSCT centres. All patients received peripheral blood Haplo HSCT from haploidentical family members. The reduced intensity regimen (RIC) was fludarabine, cyclophosphamide and 200cGy TBI and the myeloablative regimen (MAC) was fludarabine with IV busulfan 3.2mg/kg x 4. PTCy 50mg/kg D+3, D+4 was used with MMF (to D35) and a calcineurin inhibitor (CNI) as GVHD prophylaxis. CNIs were weaned and ceased by D+120 in patients who did not have evidence of GVHD. Choice of conditioning regimen was based on age and hematopoietic cell transplantation comorbidity index (HCT-CI) scores. Patients who had an HCTCI &amp;gt;3 or age &amp;gt;50yrs received RIC. Data collection was through the Australian Bone Marrow Transplant Recipient Registry. Survival was analysed using the Kaplan-Meier method. Results: Seventy eight patients were included in the study with a median follow up of 402.5 days (28-1259). There was a male predominance (66%). The median age was 53 years (range 18-69) and the median HCT-CI score was 1 (range 0-5). Thirty nine patients had acute myeloid leukaemia, 12 acute lymphoblastic Leukaemia, 14 Non Hodgkin lymphoma or Hodgkin lymphoma, 4 myelodysplastic syndrome and 9 other diagnoses. The majority received RIC (59%). Median neutrophil and platelet engraftment times were 18 days (range: 12-92) and 28 days (range: 13-262) respectively. Acute GVHD grade III-IV occurred in 14.1% of patients whilst chronic GVHD occurred in 20.5%. Moderate to severe cGVHD according to NIH consensus criteria occurred in 10.3% of patients. Overall survival probability at one year was 74.1% (95% CI: 52.9-86.8) for MAC recipients and 77.8% (95% CI: 61.6-87.8) for RIC recipients (Figure 1). Non relapse mortality (NRM) at D100 and 1 year were 2.2% and 8.7% respectively in the RIC group compared to 6.3% and 18.8% respectively in the MAC group. Causes of NRM included infection (n=5), GVHD (n=3) and VOD, respiratory failure and multi-organ failure in one patient each. Haemorrhagic cystitis and poor graft function were relatively common post-transplant morbidities but rarely contributed to NRM. Despite the use of peripheral blood stem cells and early weaning of CNIs, only 3/11 NRM deaths were due to GVHD. Relapse was the most common cause of death in the RIC group with 17.4% of patients relapsing at a median of 114 days (range 36-564) compared to only 6.3% at a median of 90.5 days (range 64-154) in the MAC group. Conclusion: This prospective Haplo HSCT trial utilising PTCY demonstrates encouraging overall survival rates. The RIC regimen had a promising toxicity profile but early relapse remains a concern despite early weaning of CNIs. In contrast, the MAC regimen is associated with a low relapse rate but NRM at one year remains significant. Further refinement of the conditioning and GVHD prophylaxis regimens will be incorporated in the follow-on study, ANZHIT-2, which will begin accrual in late 2020. Disclosures Bajel: Pfizer: Honoraria; Amgen: Honoraria, Speakers Bureau; Novartis: Honoraria; Astellas: Honoraria; Abbvie: Honoraria. Greenwood:Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hamad:Novartis: Honoraria; Abbvie: Honoraria.

A Single-Arm, Open-Label Phase 1 Study of Itacitinib (ITA) with Calcineurin Inhibitor (CNI)-Based Interventions for Prophylaxis of Graft-Versus-Host Disease (GVHD; GRAVITAS-119)

A Single-Arm, Open-Label Phase 1 Study of Itacitinib (ITA) with Calcineurin Inhibitor (CNI)-Based Interventions for Prophylaxis of Graft-Versus-Host Disease (GVHD; GRAVITAS-119)

The apheresis content analysis in Allo-HSCT represents reliable influential factors on graft-versus-host disease and overall survival

BackgroundHematopoietic stem cell transplantation (HSCT) is an established treatment for hematologic malignancies. However the post-HSCT outcome can be affected by multiple pre-transplant, transplant, and post-transplant factors. The cellular content of graft could be possible factors influencing the graft-versus-host disease (GVHD) and overall survival (OS) as transplantation outcomes. PurposeThe aim of this study was to assess the impact of infused CD34+ cells, CD3+ cells, and MNC count on the patients’ survival and incidence of graft-versus-host disease (GVHD). Material and methodsWe analyzed 87 patients with hematological malignancies who underwent allogeneic hematopoietic stem cell transplantation at the Taleghani Stem Cell Transplantation and Cell therapy center, Tehran, Iran from January 2016 to December 2018. Patients were conditioned with either myeloablative conditioning regimen or reduced-intensity regimen. ResultA CD34+ cell dose < 4.35 × 106/kg and CD3+ cell dose < 365 × 106/kg was associated with higher survival and lower acute and chronic GVHD incidence, although their association was not statistically significant. Moreover, there was a significant association between MNC count < 6.15 × 108/kg and acute GVHD incidence. ConclusionGraft cell dose, lower than the cut-off level, could lead to better outcomes after allogeneic transplantation. However, this study showed that future investigations are required in a larger population of patients in order to determine the exact effect of allogeneic graft cell dose on transplantation outcome.

Values of Hematopoietic Cell Transplantation-Specific Comorbidity Index, Comorbidity/Age Index and Augmented Comorbidity/Age Index in Recipients of Haploidentical Stem Cell Transplantation Using Ptcy As Gvhd Prophylaxis: A Retrospective Study of 223 Cases

Introduction: Pre-transplant comorbidities, which may impact the success of allogeneic stem cell transplantation (AlloSCT) can be appreciated through 3 different scoring systems. The Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) allows to predict non-relapse mortality (NRM) and survival (Sorror, Blood 2005). Its prognostic value was further augmented by the addition of donor age (&amp;lt; vs ≥40 yo) (Comorbidity/Age index, C/AI, Sorror, JCO 2014) then of pre-transplant ferritin (&amp;lt; or &amp;gt;2500 µg/L) and albumin (&amp;lt;3 g/dL vs 3-3.5 g/dL vs &amp;gt;3.5g/dL) serum levels as well as platelet count (&amp;lt; vs &amp;gt;100 109/L) (Augmented Comorbidity/Age index, AC/AI, Elsawy, BBMT 2019). The performance of these 3 scores has not been evaluated in haploASCT using post-transplant cyclophosphamide (PTCY), a procedure in constant expansion worldwide. Material and Methods: We studied retrospectively the impact on non-relapse mortality (NRM), overall (OS) and disease-free (DFS) survival of the 3 comorbidity scores on a cohort of 223 patients (pts) having received a haploSCT with PTCY. All pts had pre-transplant ferritin and albumin levels and platelet counts available. These parameters were evaluated at the time of the pre-transplant check-up or just before conditioning (median from transplant: 20 days, range: 4-49). Results: Pts were recruited in 4 French centers (Nantes n=127; Angers n=45; Besançon n=29, Brest n=22). They had received haploSCT between October 2013 and January 2020. There were 136 males and 87 females with a median age of 55 yo (16-71, &amp;gt;40 years n=172). The majority of pts had a myeloid disease (n=157) and received a reduced intensity regimen (n=161, myeloablative n=30; sequential n=32). Respectively, 132 and 91 pts had low/intermediate and high/very-high Disease-Risk Index (DRI). All pts received PTCY, cyclosporine and mycophenolate mofetyl as graft versus host disease (GVHD) prophylaxis. Donors had a median age of 40.8 years (19.4-71.7). Median HCT-CI, C/AI and AC/AI scores were 2 (0-8), 3 (0-9) and 3 (0-11), respectively. The HCT-CI score was &amp;lt;2 in 139 patients, CA/I was &amp;lt;3, 3-4 and &amp;gt;5 in 110, 83 and 30 pts, respectively, while the AC/AI score was &amp;lt;4 in 112 cases. With a median follow-up for alive patients of 35.6 months (6-77), 3-year OS, DFS and NRM were 47.8+3%, 46+3% and 29.4+6%, respectively. In univariate analysis, better 3-year OS and DFS were associated with lymphoid diseases (OS: 60.4+6% vs 42.3+4%, p=0.02; DFS: 56.2+6% vs 41.6+4%, p=0.04), low/intermediate DRI (OS: 59.1+4% vs 30.1+7%, p&amp;lt;0.001; DFS: 56.3+4% vs 31.1+5% p&amp;lt;0.001), donor age &amp;lt;40 years (OS: 58.1+4% vs 36.2+5% p=0.004; DFS: 55.4+4% vs 35.7+4% p=0.01), and albumin level (&amp;lt;3g/dL OS: 33.3+12% vs 3-3.5g/dL 46.1+8% vs &amp;gt;3.5g/dL 50.1+4%, p=0.03; &amp;lt;3g/dL DFS: 30+12% vs 3-3.5g/dL 44.5+8% vs &amp;gt;3.5g/dL 47.4+3%, p=0.05). OS and DFS were not impacted by ferritin levels, platelet count, recipient age, gender, nor any of the 3 comorbidity scores. A lower 3-year NRM was observed in younger pts (&amp;lt;55 yo) (21.8% vs 36.8%, p=0.02) and in those with a younger donor (&amp;lt;40 yo) (20.5% vs 39.2%, p=0.003). NRM was not associated with gender, type of disease, DRI, ferritin, albumin, platelet counts nor any of the 3 comorbidity scores. In multivariate analysis, each comorbidity score was compared to DRI, donor and patient age, type of disease and pre-transplant albumin levels. DRI and donor age remained associated with OS and DFS. This was also the case for recipient age, except when considering a high C/AI index score. Finally, an older age of recipients and donors remained associated with higher NRM. Conclusion: HCT-CI, C/AI and AC/AI do not to predict survivals nor NRM in haploSCT with PTCY, suggesting that pre-transplant comorbidities should not be a contra-indication to this procedure. As donor age is the only factor predicting survivals and NRM in this series, while multiple donors are generally available in the haploSCT setting, the selection of a younger donor should be the rule whenever possible for all patients. Disclosures Hunault: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Diachi: Membership on an entity's Board of Directors or advisory committees; Jansen: Honoraria; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Deconinck:ImmunoGen: Consultancy, Research Funding; Stemline: Consultancy. Thepot:astellas: Honoraria; novartis: Honoraria; sanofi: Honoraria; celgene: Honoraria. Le Gouill:Loxo Oncology at Lilly: Consultancy; Roche Genentech, Janssen-Cilag and Abbvie, Celgene, Jazz pharmaceutical, Gilead-kite, Loxo, Daiichi-Sankyo and Servier: Honoraria. Chevallier:Incyte Corporation: Honoraria.