Higher NRM Research Articles

Haploidentical hematopoietic stem cell transplantation for hematologic malignancies: a novel conditioning regimen with anti-T lymphocyte immunoglobulin instead of anti-thymocyte globulin for in vivo T cell depletion.

We evaluated the safety and efficacy of a novel protocol for haploidentical stem cell transplantation (haplo-SCT) in 312 patients with hematologic malignancies. The protocol evolved from the Beijing platform replacing ATG with ATLG; adding Fludarabine and removing cytarabine and Simustine. GVHD prophylaxis combined Basiliximab and low-dose cyclophosphamide post-transplant; overall, the conditioning duration was shortened. Median times to neutrophil and platelet recovery were both 11 days. Graft rejection occurred in 0.96% of patients. Cumulative incidences of grades II-IV and III-IV acute GVHD by day 200 were 35.3% and 8.9%, respectively. Probabilities of total and extensive chronic GVHD at 2 years were 40.7% and 14.7%. CMV viremia was observed in 35.6% of patients, with a 1.9% 100-day CMV pneumonia incidence and no CMV-related mortality. Cumulative incidences of non-relapse mortality at 100 days, 1 year, and 2 years were 2.9, 4.4, and 6.6%. The 4-year OS, RFS, and GRFS rates were 78.9, 70.7, and 47.3%. Older recipient age was associated with higher NRM, while positive pre-transplant MRD predicted worse OS, RFS, and higher relapse incidence. Our novel protocol for haplo-SCT is associated with low infection rates and acceptable risks of graft failure, severe GVHD, and mortality, representing a safe and effective haploidentical transplantation strategy.

Lower relapse incidence with haploidentical versus matched sibling or unrelated donor hematopoietic cell transplantation for core-binding factor AML patients in CR2: A study from the Global Committee and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Allogeneic hematopoietic cell transplantation (allo-HCT) is recommended for core-binding factor mutated (CBF) AML patients achieving second complete remission (CR2). However, approximately 20% of patients may relapse after transplant and donor preference remains unclear. We compared in this EBMT global multicenter registry-based analysis the allo-HCT outcomes using either haploidentical (Haplo), matched siblings donors (MSD), or 10/10 matched unrelated donors (MUD). Data from 865 de novo adult CBF AML patients in CR2 receiving allo-HCT in 227 EBMT centers from 2010 to 2022 were analyzed, in which 329 MSD, 374 MUD, and 162 Haplo-HCTs were included. For the entire cohort, 503 (58%) patients were inv(16)/CBFB-MYH11 and 362 patients (42%) were t(8;21)/RUNX1-RUNX1T1 AML. On multivariate analysis, Haplo-HCT was associated with a lower Relapse Incidence (RI) compared to either MSD (hazard ratio [HR] = 0.56, 95% CI 0.32-0.97; p < .05) or MUD (HR = 0.57, 95% CI: 0.33-0.99, p < .05). No significant difference was observed among the 3 types of donors on LFS, OS and GRFS. CBF-AML with t(8;21) was associated with both higher RI (HR = 1.79, 95% CI 1.3-2.47; p < .01) and higher NRM (HR = 1.58, 95% CI 1.1-2.27; p < .01) than CBF-AML with inv(16), which led to worse LFS, OS and GRFS. To conclude, for CBF-AML patients in CR2, Haplo-HCTs were associated with a lower RI compared to MSD and MUD allo-HCTs. There was no difference on LFS, OS or GRFS. CBF AML patients with inv(16) had a better progonosis than those with t(8;21) after allo-HCT in CR2.

Immunosuppression-Free Status at 1 Year after Haploidentical Hematopoietic Cell Transplantation with Post-Transplantation Cyclophosphamide

The development of chronic graft-versus-host disease (GVHD) in 1-year survivors after matched related or unrelated hematopoietic cell transplantation was shown to be associated with higher nonrelapse mortality (NRM) and worse overall survival (OS). The impact of chronic GVHD requiring immunosuppression (IS) for recipients of haploidentical transplantation (HIDT) with post-transplantation cyclophosphamide (PTCy) who have survived to 1 year post-transplantation has not been studied previously and was investigated for this analysis. A total of 322 adult patients who underwent HIDT at our center were included in this study. The effect of IS-free status on post-transplantation outcomes was assessed. The median follow-up for survivors was 63.9 months (range, 18.3 to 165 months). A total of 163 patients (65%) were IS-free at 1 year post-HIDT. Baseline characteristics of this group were similar to those of patients still requiring IS, except for higher percentages of female donor-male recipient pairs (28% versus 15%; P =.03) and female donors (48% versus 30%; P =.008). Logistic regression to identify patients more likely to be on IS at 1 year post-HIDT identified the use of a female donor as a significant risk factor (odds ratio, 2.11; P = .009). In a Cox regression analysis, patients requiring IS at 1 year post-transplantation had higher NRM (hazard ratio [HR], 4.18; 95% confidence interval [CI], 1.80 to 6.72; P < .001) and showed a trend toward worse disease-free survival (DFS) (HR, 1.59; 95% CI, .95 to 2.66; P =.08), with no impact on OS (HR, 1.44; 95% CI, .90 to 2.31; P = .13) or relapse (HR, .77; 95% CI, .37 to 1.61; P = .49). These results indicate that use of a female donor is a significant risk factor for requiring IS at 1 year post-HIDT. Additionally, chronic GVHD requiring IS at 1-year post-HIDT no significant effect on relapse but is associated with higher NRM and a trend toward worse DFS.

A Multi-Center Retrospective Analysis of Outcomes Post Allogeneic Stem Cell Transplantation in AML Patients with TET2 Mutations: A Study on Behalf of the Global Committee and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

Background Mutations in TET2 present in about 15% of adult AML are reported in some limited series as an adverse prognostic factor for overall survival. However the impact of allogeneic hematopoietic cell transplantation (allo-HCT) for the treatment of these patients remains unclear. We addressed this issue in a EBMT global multi-center registry-based study. Patients and Methods 644 adult AML patients with TET2 mutations receiving first non ex-vivo depleted allo-HCT from 2013-2022 in 127 centers were analyzed. All patients achieved first complete remission (CR1) before allo-HCT. Results The median age of the 644 AML patients was 59.4 (range, 18.1-86.3) years. 556 patients (86.3%) had de novo, and 88 (13.7%) had secondary AML, respectively. 367 (57.2%) patients were male. The median interval from diagnosis to allo-HCT was 4.9 (IQR, 3.8-6.2) months. Patients were categorized into favorable -(N=23, 3.9%), intermediate-(N=475, 79.8%) and adverse (N=97, 16.3%) risk categories according to cytogenetic characteristics. Conditioning regimen was myeloablative (MAC) in 46.7% of patients. 149 patients (23.1%) received a matched-sibling donor, 176 (27.3%) a haploidentical donor (Haplo), 268 (41.6%) a 10/10 unrelated donor (UD) and 51 (7.9%) a 9/10 UD allo-HCT, respectively. For the entire cohort, with a median follow-up of 1.9 years, the 30-day cumulative incidence of engraftment was 97.6%. The 100-day cumulative incidence of grade II-IV aGVHD was 22.9% and the 2-year cumulative incidence of extensive cGVHD was 13.7%. In addition, the 2-year relapse incidence and NRM were 23.2% and 12.8%, respectively. Finally, the 2-year OS, LFS and GRFS were 69.8%, 63.9% and 49.8%, respectively. In multivariable analyses, a donor type 9/10 UD was associated with a higher RI (HR=2.33, 95% CI 1.21-4.48; p=0.01), a lower LFS (HR=2.20, 95% CI 1.31-3.70; p&amp;lt;0.01) and OS (HR=2.29, 95% CI 1.33-3.96; p&amp;lt;0.01) as compared to MSD as reference. Compared to MSD, 10/10 UD and Haplo had similar outcomes. The adverse-cytogenetic group was associated with higher RI (HR=1.85, 95% CI 1.19-2.86; p&amp;lt;0.01), and higher incidence of grade II-IV acute GVHD (HR=1.74, 95% CI 1.14-2.64; p=0.01) as compared to other groups combined as reference. Compared to de novo AML (reference), secondary AML was associated with lower LFS (HR=1.49, 95% CI 1.03-2.15; p&amp;lt;0.05) and OS (HR=1.68, 95% CI 1.15-2.45; p&amp;lt;0.01). When age increased, patients faced higher RI (HR for 10y increment=1.24, 95% CI 1.01-1.53; p&amp;lt;0.05) and extensive chronic GVHD (HR=1.34, 95% CI 1.02-1.77; p&amp;lt;0.05), which translated into higher NRM (HR=1.66, 95% CI 1.23-2.24; p&amp;lt;0.01), lower LFS (HR=1.36, 95% CI 1.14-1.62; p&amp;lt;0.01) and OS (HR=1.60, 95% CI 1.31-1.96; p&amp;lt;0.01). Later year of transplantation was associated with lower incidence of II-IV acute GVHD (HR for 2y increment=0.76, 95% CI 0.63-0.92; p&amp;lt;0.01), chronic GVHD (HR=0.67, 95% CI 0.54-0.83; p&amp;lt;0.01) and extensive chronic GVHD (HR=0.72, 95% CI 0.52-0.99; p&amp;lt;0.05). Female to male, patient CMV status and interval between diagnosis and HCT did not affect significantly the transplant outcomes in multivariable analysis. Conclusion No significant difference was observed in outcomes of AML patients with TET2 mutations following MSD, HAPLO and 10/10 UD allo-HCTs, while 9/10 UD was associated with higher relapse incidence and lower survival outcomes. Higher patient age, secondary AML and adverse cytogenetics predicted worse transplant outcomes. GVHD prevention improved with time for these patients.

Incidence, risk factors, and impact of early cardiac toxicity after allogeneic hematopoietic cell transplant.

This study investigates early cardiac events (ECEs) occurring during the first 180 days after allogeneic hematopoietic cell transplant (allo-HCT) in 416 adults receiving posttransplant cyclophosphamide (PTCY) (n= 258) or not receiving PTCY (n= 158). Total body irradiation (TBI) was given to 133 (31.9%) patients, of whom 111 (83.4%) received TBI combined with PTCY. The day+180 cumulative incidence function (CIF) of ECEs was 8.4%, with heart failure (n= 13) and pericardial complications (n= 11) being the most prevalent complications. The incidence of ECEs was higher in patients receiving PTCY, and receiving TBI. ECEs were more prevalent in haploidentical HCTs than in matched sibling donor, 10/10 HLA-matched unrelated donor, and 9/10 HLA-mismatched unrelated donor allo-HCTs. As for the ECE risk from the combination of PTCY and TBI, the multivariate analysis reported that patients receiving PTCY without TBI, TBI without PTCY, and TBI with PTCY were at higher risk for ECEs compared with patients receiving neither PTCY nor TBI. Pre-existing cardiac morbidity predicted ECEs. However, using high-dose CY-containing preparative regimens did not increase the risk for cardiac toxicity at+180 days after allo-HCT. ECEs were associated with higher nonrelapse mortality and lower overall survival. Considering that PTCY and TBI were predictors for ECEs, and the impact of this complication on transplant mortality, the implementation of cardiac monitoring plans could be appropriate in patients receiving these medications.

Impact of donor age and relationship on outcomes of peripheral blood haploidentical hematopoietic cell transplantation

Here we describe a retrospective analysis of outcomes in 299 patients who underwent peripheral blood haplo-HCT with PTCy from July 2009 through May 2021 and their association with donor characteristics. Patients had mostly acute leukemias and high or very high DRI. Multivariate analyses were conducted examining OS, NRM, relapse, cytokine release syndrome, acute and chronic GVHD. Donor characteristics included age, sex, relationship, ABO status, CMV status, and HLA match grade. Our analysis revealed increasing donor age was associated with higher NRM (compared to age <30; age 30–44 HR, 1.65; P = 0.110, age >44 HR, 1.80; P = 0.056) but lower relapse risk (compared to age <30; age 30–44 HR, 0.61; P = 0.034, age > 44 HR, 0.71; P = 0.132). There were no differences in CRS, aGVHD or cGVHD. We found no difference in outcomes based on the donor-recipient relationship. No differences were found based on HLA match grade or DRB1 match status. Increasing donor age was associated with lower relapse risk but higher NRM, resulting in no difference in OS based on donor age. Other donor factors including relationship (parent/sibling/child/ maternal), CMV status, donor sex, HLA match grade, and DRB1 status were not associated with outcomes.

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

Allogeneic Stem Cell Transplantation in Mantle Cell Lymphoma; Insights into Its Potential Role in the Era of New Immunotherapeutic and Targeted Therapies: The GETH/GELTAMO Experience.

Allo-SCT is a curative option for selected patients with relapsed/refractory (R/R) MCL, but with significant NRM. We present the long-term results of patients receiving allo-SCT in Spain from March 1995 to February 2020. The primary endpoints were EFS, OS, and cumulative incidence (CI) of NRM, relapse, and GVHD. We included 135 patients, most (85%) receiving RIC. After a median follow-up of 68 months, 5-year EFS and OS were 47 and 50%, respectively. Overall and CR rates were 86 and 80%. The CI of relapse at 1 and 3 years were 7 and 12%. NRM at day 100 and 1 year were 17 and 32%. Previous ASCT and Grade 3-4 aGVHD were associated with a higher NRM. Grade 3-4 aGVHD, donor type (mismatch non-related), and the time-period 2006-2020 were independently related to worse EFS. Patients from 1995-2005 were younger, most from HLA-identical sibling donors, and were pretreated less. Our data confirmed that allo-SCT may be a curative option in R/R MCL with low a CI of relapse, although NRM is still high, being mainly secondary to aGVHD. The arrival of new, highly effective and low toxic immunotherapeutic or targeted therapies inevitably will relegate allo-SCT to those fit patients who fail these therapies, far away from the optimal timing of treatment.

Graft-Vs-Host Disease (GvHD) Prophylaxis with Post-Transplant Cyclophosphamide (PTCy) and Thymoglobulin (ATG) Are More Important Determinants of Cytomegalovirus (CMV) Reactivation after Allogeneic Hematopoietic Cell Transplantation (HCT) Than Ex-Vivo T-Cell Depletion in the Era of Pre-Emptive Therapy

Background:Cytomegalovirus (CMV) is a common cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT) despite major advances in diagnostic techniques and antiviral prophylactic strategies. The relative impacts of donor/recipient CMV serologic status, disease-specific and transplant-related prognostic factors on the risk of CMV reactivation and survival are undefined.Methods:We studied the outcome of 199 patients (median age, 46 years; range 17-71 years) receiving allogeneic HCT at National University Cancer Institute of Singapore (NCIS) between January 2016 and December 2020. Their hematologic diseases included AML (n=92), ALL (n=46), MDS (n=19), lymphomas (n=19), MPN (n=7) and others (n=16) such as refractory myelomas and aplastic anemias. The conditioning regimens used were either myeloablative (n=80) or reduced intensity conditioning (n=119) prior to an allograft from different donor sources. T-cell depletion (TCD) was used for GVHD prophylaxis in 124 patients; and this included post-transplant cyclophosphamide (PTCy, n=31), ex-vivo T-cell receptor alpha-beta / CD45RA depletion (TCRab/CD45RA) (ex-vivo TCD, n=31) for haploidentical HCT, or thymoglobulin (ATG, n=62) for matched unrelated donor (MUD) HCT.Results:With a median follow-up duration of 15.6 months (range, 0.2-63.6 months), 136 (68.3%) patients had CMV reactivation (median onset, 27.5 days) while 6 (3.0 %) patients developed clinically significant CMV disease, such as colitis, retinitis and encephalitis. The cumulative incidences of CMV reactivation within the first 100 days among the recipients of matched unrelated donor (MUD) (n=60), mismatched related donor or unrelated donor (MMRD/MMUD) (n=60), umbilical cord blood (UCB) (n=18) and matched related donor (MRD) (n=61) HCT were 71.6 %, 61.7 %, 50.0 % and 32.7 %, respectively (p<0.001).There were no statistically significant differences in overall survival (OS, p=0.830) and disease-free survival (DFS, p=0.983) at 5 years between CMV-seropositive (D+/R+ or D-/R+, n=181) and CMV-seronegative recipients (D-/R- or D+/R-, n=18). There were also no significant differences in the cumulative incidences of CMV reactivation within 100 days (p=0.879), CMV end-organ disease (p=0.522) and non-relapse mortality (NRM, p=0.202), respectively. HCT-CI score of ≥1 (p=0.005) and the use of reduced intensity conditioning regimen (p<0.001) were associated with a higher NRM at 2 years. There was also a trend towards higher NRM among patients with peak CMV DNA titers of above 1000 IU/ml, but this did not reach statistical significance (p=0.188).The secondary objective of this study was to determine the risk factors associated with CMV reactivation within the first 100 days post-transplant. There was no statistically significant impact of the donor or recipient CMV serostatus (p=0.790) on the risk of CMV reactivation. In multivariable analysis, the use of any T-cell depletion (p<0.001) was a significant predictor of CMV reactivation. In a subset analysis comparing the 3 different methods of TCD, the use of ATG (p=0.004) and PTCy (p=0.005) was found to be associated with an increased risk of CMV reactivation, but not in patients receiving ex-vivo TCD (p=0.184) (Figure 1). Notably, patients receiving ex-vivo TCD haploidentical HCT was not associated with a higher risk of CMV reactivation as compared to the recipients of MRD HCT without any TCD.Conclusions:Our study concluded that CMV serologic status did not affect the incidence of CMV reactivation, NRM, OS and DFS in patients undergoing allogeneic HCT. The use of PTCy and ATG for GVHD prophylaxis, remains the most important risk factor for CMV reactivation in the era of pre-emptive therapy and hence, the need for aggressive prevention strategies in this vulnerable group of patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Therapy-Related Acute Myeloid Leukemia (t-AML) and the Advantage of Intensive Chemotherapy: Real-Life Analysis from Two Regional French Centers

Rational: Patients with t-AML are those previously treated for primary malignancy and are categorized with poor prognosis. t-AML treatment options include intensive chemotherapy (IC), hypomethylating agents (HMA) or low dose cytarabine (LDC). However, survival remains poor and allogeneic hematopoietic cell transplantation (Allo-HCT) could lead to better outcomes. The aim of this analysis is to assess the outcome of all consecutive t-AML pts from two regional centers in France, based on treatment intensity, and to identify prognostic factors.Patients and Methods: between January 2006 and December 2019, 112 adult pts diagnosed with t-AML occurring after treatment of solid tumors (ST; n=72), hematologic malignancies (HM; n=34) or autoimmune diseases (AID; n=6). Pts received chemotherapy and/or radiotherapy or high dose chemotherapy followed by autologous hematopoietic cell transplantation (Auto-HCT) in some. All eligible t-AML pts received intensive chemotherapy (IC, n=55) with the combination of anthracycline and cytarabine in 48 pts and CPX-351 in 7 pts. Unfit pts received non-IC (9 LDC, 24 HMA). The third study group (24 pts) received best supportive care (BSC). Fifteen pts underwent HSCT in first CR.Statistical analysis: We performed a descriptive analysis of the baseline characteristics and each treatment group was compared with a Kruskal-Wallis test and a Pearson's Chi-square test. Survival curves (Kaplan-Meier method) were compared with a log-rank test. Univariate and multivariate analyses on survival, relapse and NRM were done using Cox regression, Gray test, Fine & Gray regression. The bilateral level of significance was set at 5%. All analyses and graphics were made under the R program (v3.5.1). A pair-matched control analysis with de novo AML was performed only on pts who received IC matched for age, cytogenetics and ELN 2010 classification.Results: A total of 112 t-AML pts were identified, 56 were males (50%) with a median age of 68 yrs (19-87) at t-AML diagnosis. Before t-AML, 72 pts had ST (64.5%), 34 HM (30.5%) and 6 AID (5%). Forty-six pts (41%) received chemotherapy alone for their primary cancer, 17 (15%) radiotherapy alone, 49 (44%) radio chemotherapy, 17 (15%) auto-HCT and 6 (5%) long-term methotrexate for AID. Median interval from treatment of previous ST or HM to t-AML diagnosis was 4.7 years in ST, 6.6 years in HM and 21 years in AID (p=0.03). At t-AML diagnosis, 42% of pts presented an unfavorable karyotype and 44% an unfavorable ELN 2010 classification. Regarding molecular alterations, FLT3-ITD, FLT3-TKD, NPM1 and IDH1/2 mutations were observed in 6.9, 2.3, 11.5 and 2.3% of pts respectively. MECOM1 was overexpressed in 25.5% of cases. Among treated pts (n=88), 43 pts (49%) achieved CR: 4 from 33 (12%) in non-IC pts (3 in HMA and 1 in LDC) and 39 from 55 (71%) in IC pts. Fifteen pts (17%) underwent Allo-HCT with a median interval between AML diagnosis and Allo-HCT of 4.7 mo (2.6-17.5). The best response after transplantation was CR in 10 pts; at the last follow up, 4 pts are alive (3 in CR and 1 in relapse) and 11 died (5 from relapse, 5 from TRM causes and 1 from another subsequent malignancy). Overall, with a median follow up of 5.5 mo (0-144), the median OS and DFS were 9 mo (5.9-13.5) and 6.3 mo (5.3-10.3) respectively (Figure). There was a significant difference between the 3 treatment groups concerning OS (p<0.001) and DFS (p<0.001) with a significant difference in OS between IC and non-IC groups (p=0.02). In the 88 treated t-AML pts, with a median follow up of 8.2 mo (0.3-144), the median OS was 13.5 mo (10.3-19.6) and the median DFS was 8.2 mo (7-13.7). Multivariate analysis for total and treated populations showed no impact of all variables related to previous malignancies except for auto-HCT pre-t-AML (significant negative impact on OS, DFS, NRM), WBC at t-AML diagnosis (negative impact on OS, DFS) and chemotherapy (positive in total population on OS, DFS, NRM and negative impact of IC on OS and NRM in treated pts) . In IC treated pts, we showed, in a pair-matched analysis with de novo AML, no difference in term of OS and DFS due to a significant higher CI of NRM (p=0.045) at 24 mo (40% in t-AML versus 27.4% for de novo AML) and a lower CI of relapse (NS) at 24 mo (33% in t-AML versus 47.6% for de novo AML).Conclusion: The prognosis of t-AML remains poor and our study showed the advantage of using intensive chemotherapy whenever possible and, in comparison with de-novo AML, a higher NRM and a lower incidence relapse. [Display omitted] DisclosuresNicolini: Sun Pharma Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kartos Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Research Funding; Incyte Biosciences: Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; BMS: Honoraria.

Impact of Intensified Conditioning and DLI for Relapsed/Refractory Acute Leukemia: Real-World Data from China Registry

Background Patients with acute leukemia who become refractory to chemotherapy have poor prognosis, with limited therapeutic options. Intensified conditioning and DLI have shown improved survival and good tolerability in this patient cohort in clinical trials, but have never been tested in randomized trials and real world data are scarce. We aimed at analyzing the impact of clinical and treatment-related factors on transplant outcome in an unselected, population-based cohort.Methods Through the Chinese Blood and Marrow Transplantation Registry Group (CBMTRG), we identified 932 patients with refractory/relapsed acute leukemia receiving MSD or HID HCT during the period of 2003 to 2016. The median follow-up of survivors was 39 months.Results The 3-year leukemia free survival (LFS) rates were 40% for acute myeloid leukemia (AML) and 27% for acute lymphoblastic leukemia (ALL). In AML, LFS was not significantly improved with intensified conditioning alone (33% VS 41%, P=0.10), LFS was increased to 55% with the additional DLI (p=0.05, fig 1); In ALL, LFS was significantly improved with intensified conditioning alone (11% VS 30%, P=0.047), LFS was further increased to 51% with the additional DLI (p=0.004, fig 2). Multivariable analyses run separately in AML and ALL (Table). DLI was associated with a marked trend toward lower relapse, significantly lower NRM and higher LFS in AML and a significantly lower relapse and higher LFS in ALL in comparison to non-DLI, and no difference in ALL in terms of non-relapse mortality. Intensified conditioning was associated with a significantly lower relapse and higher LFS despite higher NRM in ALL in comparison to non-intensified conditioning; there was no impact of intensified conditioning in AML. In addition, HID was independently correlated with reduced relapse in both AML and ALL in comparison to MSD. Younger patient age was independently correlated with reduced NRM in both AML and ALL. Furthermore, in separate analyses in HID and MSD HCT, DLI had superior outcomes in both HID and MSD HCT while intensified conditioning only had influence on MSD outcomes; Similarly, the impact of patient age was only shown in MSD HCT. Besides, for AML patients with information on cytogenetics, poor cytogenetics resulted in higher relapse and lower LFS after MSD HCT in comparison to good or intermediate cytogenetics while there was no difference regarding cytogenetics in HID HCT.Conclusions These data suggest that both DLI and intensified conditioning improved outcomes and are valid options in the treatment of refractory/relapsed acute leukemia, with the role of DLI more prominent and more extensive. HID had more GVL effect than MSD in some circumstances. By a population-based approach (the largest for HID group) from the real-world data, we were able to provide novel data on transplant outcomes in refractory/relapsed acute leukemia, applicable to routine clinical practice outside the setting of clinical trials. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Allelic HLA Matching and Pair Origin Are Favorable Prognostic Factors for Unrelated Hematopoietic Stem Cell Transplantation in Neoplastic Hematologic Diseases: An Italian Analysis by the Gruppo Italiano Trapianto di Cellule Staminali e Terapie Cellulari, Italian Bone Marrow Donor Registry, and Associazione Italiana di Immunogenetica e Biologia dei Trapianti

HLA molecules are important for immunoreactivity in allogeneic hematopoietic stem cell transplantation (HSCT). The Gruppo Italiano Trapianto di Cellule Staminali e Terapie Cellulari, Italian Bone Marrow Donor Registry, and Associazione Italiana di Immunogenetica e Biologia dei Trapianti promoted a retrospective observational study to evaluate HLA matching and the impact of allelic HLA mismatching and non-HLA factors on unrelated Italian HSCT outcomes. From 2012 to 2015, 1788 patients were enrolled in the study. The average donor age was 29 years and the average recipient age was 49 years. As a conditioning regimen, 71% of the patients received myeloablative conditioning. For GVHD prophylaxis, 76% received either antithymocyte or anti-T lymphocyte globulin, cyclosporine A, and methotrexate. Peripheral blood was the stem cell source in 80%. The median duration of follow-up was 53 months. Regarding HLA matching, 50% of donor-recipient pairs were 10/10 matched, 38% had 1 mismatch, and 12% had 2 or more mismatches. A total of 302 pairs shared Italian origin. Four-year overall survival (OS), progression-free survival, GVHD-free relapse-free survival, and relapse rates were 49%, 40%, 22%, and 34%, respectively. The 4-year NRM was 27%, and the 100-day cumulative incidence of grade ≥II acute GVHD (aGVHD) was 26%. In multivariate analysis, 9/10 and ≤8/10 HLA allele-matched pairs were associated with worse OS (P=.04 and .007, respectively), NRM (P=.007 and P < .0001, respectively), and grade III-IV aGVHD (P=.0001 and .01, respectively). Moreover, the incidences of grade II-IV aGVHD (P=.001) and chronic GVHD (P=.002) were significantly lower in Italian pairs. In conclusion, 10/10 HLA matching is a favorable prognostic factor for unrelated HSCT outcome in the Italian population. Moreover, the presence of 2 HLA-mismatched loci was associated with a higher NRM (P < .0001) and grade II-IV aGVHD (P=.006) and a poorer OS (P=.001) compared with 1 HLA-mismatched locus in early or intermediate disease phases. Finally, we found that Italian donor and recipient origin is a favorable prognostic factor for GVHD occurrence.

Impact of extended infusional mesna prophylaxis on the incidence of BK viruria and hemorrhagic cystitis following post-transplantation cyclophosphamide and CTLA4Ig-based haploidentical transplantation.

Hemorrhagic cystitis (HC) has been reported with increased frequency following post-transplantation cyclophosphamide (PTCy)-based haploidentical hematopoietic cell transplantation (HCT) along with a strong association with BK viruria. We prospectively evaluated the incidence of BK viruria and HC in 115 patients (median age 20years, 2-65) undergoing PTCy-based haploidentical HCT with (n = 71) or without (n = 44) CTLA4Ig. HC prophylaxis consisted of a continuous infusion of mesna 30min prior and 48h post-PTCy. The overall incidence of BK viruria was 65.7%. None with BK viruria < 104 copies/ml developed clinical symptoms (n = 65). The incidence of BK viruria ≥ 104 copies/ml was 7.1% (n = 8) and 75% developed HC. The incidence of HC was 5.4% at a median of 30days. Both BK viruria ≥ 104 copies/ml and HC were strongly associated with acute GVHD (p < 0.001). A higher NRM was observed in those with BK viruria ≥ 104 copies/ml, related to GVHD and its complications (41.7% vs 12.6%, p = 0.04). The incidences of acute GVHD, vis-à-vis, overall BK viruria, BK viruria ≥ 104 copies/ml, and HC, tended to be lower in patients receiving CTLA4Ig. Thus, extended infusional mesna, coupled with significant reduction in alloreactivity along with possible preservation of antiviral immunity associated with the use of CTLA4Ig, was probably responsible for a much lower incidence of BK viruria and resultant HC than reported previously following PTCy-based haploidentical HCT.

Efficacy of Autologous and Allogeneic Hematopoietic Cell Transplantation in Waldenström Macroglobulinemia: A Systematic Review and Meta-Analysis

Background Waldenstrom macroglobulinemia (WM) is an indolent IgM-producing lymphoproliferative disorder that remains incurable. Although it is an indolent disease, patients with a high international prognostic scoring system (IPSS)-WM have an overall survival (OS) of less than 4 years. Furthermore, 15% of IPSSWM low-risk patients also develop progressive disease after achieving remission with first-line therapy. Both autologous hematopoietic cell transplantation (AHCT) and allogeneic (allo)-HCT are prescribed for treatment of WM despite lack of randomized controlled studies. Methods We performed a comprehensive search of the medical literature using PubMed/Medline and EMBASE on September 10, 2019. We extracted data on clinical outcomes related to benefits (OS, progression-free survival [PFS] and overall response rate [ORR]) and harms (relapse rate [RR] and non-relapse mortality [NRM]), independently by two authors. Our search strategy identified a total of 339 references. Fifteen studies (8 AHCT [n=291 patients], 7 allo-HCT [n=311 patients]) were included in this systematic review/meta-analysis (Figure 1). Results Median age for AHCT recipients ranged from 49 to 60 years. 58% and 41% of AHCT recipients received melphalan and BEAM conditioning respectively. Pooled OS rate post AHCT was 70% (95% CI=51-87%) with high heterogeneity (I2=87%). Pooled PFS rate post AHCT was 50% (95% CI 38%-61%) with moderate heterogeneity (I2=59%). Pooled NRM was 4% (95% CI 1-7%) with low heterogeneity (I2=0%). In the case of allo-HCT recipients, the median age ranged from 43 to 57 years and 52% received a reduced intensity conditioning regimen. Pooled OS rate post allografting was 57% (95% CI 50-65%) with low heterogeneity (I2=19%). Pooled PFS was 49% (95% CI 42-56%) with low heterogeneity (I2=15%). Pooled NRM was 29% (95% CI 24-34%) with low heterogeneity (I2=0%) (Figure 2). Pooled ORR post AHCT and allo-HCT were 90% (95% CI 82-96%) and 86% (95% CI 76%-95%) respectively, both with moderate heterogeneity. RR post AHCT and allo-HCT was 42% (95% CI 30-55%) and 23% (95% CI 18-28%) respectively, both with moderate heterogeneity, respectively (Figure 3). Conclusions The results of our meta-analysis show that both AHCT and allo-HCT result in encouraging OS and PFS. Allo-HCT does appear to have circa 2-fold lower risk of relapse compared to AHCT based on our analysis. This potential advantage of allografting is offset by a higher NRM. Large multicenter prospective studies are needed to determine which WM patient population would derive the most benefit from an allo-HCT.

Extended Infusion of Prophylactic Mesna Along with CTLA4Ig in Post-Transplantation Cyclophosphamide Based-Haploidentical Transplantation Is Associated with Reduced Incidence of BK Viruria and Hemorrhagic Cystitis

<h3>Background & Methods</h3> Post-transplantation cyclophosphamide (PTCy)-based HCT has been associated with an increased frequency of hemorrhagic cystitis (HC), dominantly associated with BK viruria. We prospectively evaluated the incidence of BK viruria and HC in 115 patients [(median age 20 years, 2-65), malignant(87) and non-malignant(28)], undergoing PTCy-based haploidentical HCT with CTLA4Ig (n=71) or without (n=44). Conditioning was predominantly myeloablative (74%). As prophylaxis for HC, continuous infusion of Mesna was used from 30 minutes prior to PTCy at 50% of the daily dose of Cy every 8 hourly for 72 hours. Development of HC before day+15 was termed as ‘early HC' and later was referred to as ‘HC'. <h3>Results</h3> The overall incidence of BK viruria was 65.7%. None with BK viruria < 10⁴ copies/ml developed clinical symptoms (n=65). The incidence of BK viruria ≥ 10⁴ copies/ml (‘high BK viruria') was 7.1 % (n=8) and 75% developed HC. The incidence of HC was 5.4 % at a median of 30 days. Only 3.1% (events-2/66) of patients greater than 18 years of age had high BK viruria compared to 12.4% (events-6/49) in those who were younger than 18 years (p=0.05). The overall incidence of grade 2-4 acute GVHD was 16.9% (95%CI, 13.4-20.4). Overall BK viruria was higher in those with acute GVHD (92.1% vs 60.6 in those without acute GVHD, p=0.002, Figure 1A). Acute GVHD preceded the development of high BK viruria in 7 out of 8 patients with a median onset at 22 days (14-36 days). The incidence of high BK viruria in patients with acute GVHD was 36.8% (95% CI 25.7-37.9), compared to 1.1% (95% CI 0.1-2.2) in those without acute GVHD (p=0.0001). The incidence of HC in those with acute GVHD was likewise significantly higher (26.7%; 95%CI, 16.5-36.9 vs 1.1%; 95% CI 0.1-2.2, p=0.0001, Figure 1B). Overall BK viruria was significantly lower in those receiving CTLA4Ig (54.1% vs 89.4% in those without CTLA4Ig, p=0.001, Figure 2A). The incidences of both high BK viruria (4.3% with vs 11.9% without CTLA4Ig, p=0.08) and HC (2.9% with vs 9.5% without CTLA4Ig p=0.09, Figure 2B) tended to be lower in those receiving CTLA4Ig-based protocols. A higher NRM was observed in those with BK viruria ≥ 10⁴ copies/ml, related to GVHD and its complications (41.7% vs 12.6%, p=0.04). <h3>Conclusions</h3> In conclusion, our study demonstrates that extended infusion of Mesna, along with reduction in alloreactivity with the use of CTLA4Ig were probably responsible for a much lower incidence of BK viruria and resultant HC, than previously reported following PTCy-based haploidentical HCT.

NK CD56brightCD16neg reconstitution over Time (NK56-index) Significantly Impacts Long Term Outcome in Allogeneic Hematopoietic Stem Cell Transplantation

Background:Natural Killer Cells are innate immune system cells important in host defenses against viruses and tumor cells. Two subpopulations are well described: NK CD56bright CD16neg (NK56++16-) which is less frequent in peripheral blood (PB) and associated with high cytokine production, and NK56dim16pos (NK56+16+), more frequent in PB and associated with high cytotoxic activity. In allogeneic hematopoietic stem cell transplantation (allo-HSCT), NK cells are important for infection control, and also for the disease control. The mismatch between donor NK cell receptors and host HLA may lead to a stronger graft versus leukemia (GVL), possibly modulating graft versus host disease (GVHD). However, only a few studies evaluated NK subpopulations recovery after HSCT and the impact on transplant outcomes. Objectives: The aim of the study was to analyze NK cells subpopulations reconstitution after HSCT and their possible impact on HSCT endpoints: relapse, GVHD (acute and chronic), transplantation related mortality and overall survival. Patients and Methods: Overall, 77 patients from 4 HSCT centers (60 % male, median age 17 years, range 1-74), receiving bone marrow (BM, 47%), umbilical cord (UCB, 30%) or peripheral blood (PB, 23%) from unrelated (80%) or related donors (20%) were studied. The most common diagnosis was acute leukemia (AML 38%, ALL 34%). Most patients received myeloablative conditioning (MAC) regimens (61%). Antithymocyte globulin (ATG) was used in 27 patients (35%) and total body irradiation (TBI) in 40 (52%). Median follow up time was 82 months (22-107). NK subpopulations were quantified by multiparametric flow cytometry at engraftment and days 3, 7, 14, 21 and 60 after engraftment. We have then elaborated graphs plotting cells counts over time (until 60 days) and calculated the area over the curve (AOC) for each subpopulation [NK56++16- (NK56-index) and NK56+16+ cells (NK16-index)], considering 0.5x10e9/L as cut-off value for both subpopulations. A higher AOC represents a more profound NK deficiency. Using receiver operating characteristic (ROC) curves we determined cut offs for the AOC that could provide the best correlation with survival. Results:The overall survival (OS) in 80 months was significantly worse in patients with NK56 deficiency, defined by a NK56-index &gt; 14592.31 cells/mm3.days (29% x 73% for non- deficient, p=0.0001, Figure 1). NK56 deficient patients also had a higher cumulative incidence (CI) of non-relapse related mortality (NRM: 35% x 15%, p=0.03, Figure 2). GVHD (acute or chronic) was similar between low NK56-index and high NK-56 index patients. In multivariate analysis, high NK56index remained significantly associated with worse OS [hazard ratio (HR) 3.5; 95% confidence interval (95%CI) 1.6-7.6], and higher NRM (HR 2.9; 95%CI 1.0-8.0). There were no significant correlations between NK16-index with any of the analyzed HSCT outcomes. Conclusion: A higher NK56-index is significantly associated with worse outcome in long term survival and non relapse related mortality in patients submitted to allogeneic hematopoietic stem cell transplantation. This strategy might be helpful in identifying risk groups and possible earlier therapeutic interventions. Disclosures No relevant conflicts of interest to declare.

The Optimal Treatment Strategy for Adult Patients with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia in First Complete Remission in the Era of High-Intensity Chemotherapy

The Optimal Treatment Strategy for Adult Patients with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia in First Complete Remission in the Era of High-Intensity Chemotherapy

The Easix Score Is Associate with Overall Survival and Non-Relapse Mortality after Ex-Vivo CD34+-Selected Allogeneic HCT.

Background The EASIX (Endothelial Activation and Stress Index) score has been shown to be associated with NRM and overall survival (OS) after reduced intensity alloHCT. We aimed to validate EASIX in patients who underwent a calcineurin-inhibitor (CNI)-free alloHCT using ex-vivo CD34-selection. Design We included 364 adult patients who underwent first CD34-selected alloHCT between July 2006-December 2016 using the CliniMACS CD34 Reagent System (Miltenyi Biotech) as GVHD prophylaxis. The EASIX score (LDH*Creatinine/platelet counts) was calculated at several timepoints (pre-HCT [day -30 to day -10], day 30, day 100 and onset of acute GVHD). For EASIX scores post-HCT, a landmark analysis was conducted at the given timepoint. A log transformation using base 2 (log2) was applied to all EASIX variables to reduce skew. The Kaplan-Meier and cumulative incidence methods were used to estimate OS and NRM/acute GVHD, respectively. Cox models (cause-specific for NRM and acute GVHD) were used to evaluate differences in outcomes. Relapse and death or relapse, were considered competing risks for NRM and acute GVHD, respectively. Results Median age was 55 years (range 19-73). Most patients had myeloid diseases (47% AML, 28% MDS and 4% CML) and all patients received myeloablative conditioning (MAC). With a median follow-up among survivors of 4.7 years (range, 0.7-11.8), 1 and 3-year OS was 78.6% (95% confidence interval [CI], 74.0-82.4) and 61.8% (95% CI, 56.5-66.7), respectively. The cumulative incidence of NRM at 1 and 3 years was 15.1% (95% CI, 11.7-19.0) and 24.2% (95% CI, 19.9-28.8), respectively. The 1-year cumulative incidences of grades 1-4, 2-4, and 3-4 acute GVHD were 40.1% (95% CI, 35.1-45.1), 29.4% (95% CI, 24.8-34.1) and 11.0% (95% CI, 8.0-14.5), respectively. Pre-HCT EASIX was not significantly associated with OS, NRM, or acute GVHD. A higher day 30 EASIX score was significantly associated with increased risk of death (HR=1.35 [95% CI, 1.19-1.52], p Conclusions EASIX score at day 30 and at day 100 post-ex-vivo CD34-selected alloHCT is associated with higher NRM and inferior OS. Despite a CNI-free platform, endothelial injury is an important contributor to poorer outcomes after MAC. EASIX provides a simple, complimentary tool to predict allo-HCT outcomes in these patients.

Complete Remission with Incomplete Count Recovery (CRi) Prior to Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia Is Associated with a High Non-Relapse Mortality without Increased Relapse Risk

Abstract Background: For the majority of patients with acute myeloid leukemia (AML), allogeneic hematopoietic cell transplantation (HCT) offers the best prospect of long-term survival. However both the risk of relapse and non-relapse mortality remain stubborn barriers to successful outcome. Remission status is one of the strongest predictors of outcome, and while conventional risk stratification models account for this, complete remission with incomplete count recovery (CRi) is typically ascribed the same predictive value as complete remission (CR). Methods: In this single center retrospective study we assessed the impact of incomplete count recovery on outcome of allogeneic HCT for AML. Patients' disease status was classified immediately prior to HCT as complete remission (CR), complete remission with incomplete count recovery (CRi) or no complete remission (no CR/CRi). The conventional definition of complete remission (&amp;lt;5% marrow blasts by morphology) was employed and incomplete count recovery was defined as platelet count &amp;lt;100 x 109/L and/or absolute neutrophil count &amp;lt; 1 x 109/L. Measurable residual disease (MRD) was defined by detectable disease by a contemporaneously accepted standard methodology at the time of transplant (e.g. PCR or immunophenotyping). The primary outcome measure was overall survival, and secondary endpoint of non-relapse mortality and relapse were also assessed. Results: Between January 2005 and December 2017, 155 patients underwent allogeneic HCT for AML in our institution. Disease status was defined as CR in 82 (53%), CRi in 54 (35%) and no CR/CRi in 19 (12%). No significant demographic or transplant characteristics were observed between the groups. With a median follow-up of 3.4 [0.1 - 12.8] years, survival at 3 years was 42.5% for the whole cohort with significant differences between the three groups: 54.3% for CR, 34.8% for CRi and 13.4% for no CR/CRi (p&amp;lt;0.001; fig 1A; HR 1.94 for CRi, and 3.4 for no CR). These differences remained after corrections for standard transplant risk factors. The significant differences in overall survival between CR and CRi groups were accounted for by increased non-relapse mortality (7.5% vs. 24.2% at 100 days and 28.7 vs 44.9% at 3 years (p=0.003), fig 1B). The overall cumulative incidence (CI) of relapse at 3 years was 32.4%, and while those patients transplanted not in CR/CRi has a significantly increased CI of relapse (55.3%, p=0.006), there were no significant differences between the CR and CRi groups (25.1 and 36.7% respectively (p=0.441; fig 1C). Patients without MRD (n=107) had a lower incidence of relapse compared to those with MRD (n=48, 21.9% vs. 48.1%, p=0.009), however MRD negative patients with incomplete recovery still had a significantly worse 3-year survival than those with complete recovery (37.5 vs 56.7, p=0.006) resulting from higher NRM (46.4% vs 30.4%%, p=0.003, fig 1D). Discussion: CRi patients have a poorer survival and higher NRM than CR patients with full marrow recovery, without evidence of increased relapse. While death from NRM is a competing risk for relapse, the increased incidence of relapse remains overtly demonstrable in those patients transplanted not in CR/CRi, despite an equally high NRM. Additionally, the persistently increased NRM in CRi patients without MRD, suggests that the poorer survival may result from poor fitness for transplant and increased susceptibility to transplant related complications rather than an imminent relapse. With the advent of increasingly sensitive MRD technologies, these data may suggest that further pre-transplant optimization to promote marrow recovery may be permissible in order to minimize NRM without risking increased risk of relapse in CRi patients. Figure 1. Figure 1. Disclosures Apperley: Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Incyte: Honoraria, Speakers Bureau.

Inferior Outcome of Allogeneic Stem Cell Transplantation in First Complete Remission for Secondary AML As Compared to De Novo Disease: Results from a Retrospective, Registry-Based Analysis on Behalf of the Acute Leukemia Working Party of the EBMT

Background: Acute myeloid leukemia (AML) secondary to haematological neoplasia or other malignant diseases, defined as secondary AML (sAML), is thought to have an inferior prognosis as compared with de novo AML. However, when corrected for other risk factors such as age and cytogenetic risk, differences are less clear. In particular, it is uncertain whether outcome after allogeneic stem cell transplantation (alloSCT) is different. Thus, the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT) performed a registry-based analysis to compare results after alloSCT for sAML versus de novo AML.Methods: Inclusion criteria were age >= 18y and alloSCT for de novo or sAML from a matched related, matched unrelated or T-cell replete haploidentical donor between 2000 and 2016. Patients without information on cytogenetics were excluded. 11439 patients with de novo and 1325 with sAML were identified. A multivariate Cox model was performed to account for imbalances of risk factors between the two cohorts; it was stratified for different stages at alloSCT, due to a significant interaction between stage at transplant and diagnosis (de novo or secondary) . In a second approach, a matched pair analysis of secondary versus de novo AML was done, using the following criteria for matching: Age (+/-3 years), stage at alloSCT, Karnofsky performance score, conditioning intensity, in and ex vivo T cell depletion, donor type, donor/recipient sex and CMV-status combination, cytogenetics, and graft source.Results: Median follow up after alloSCT was 36 and 33 months for de novo and sAML, respectively. In a multivariate Cox model focusing on transplants in first complete remission (CR1), sAML was associated with a higher non-relapse mortality (NRM; HR=1.32; p<10-5) and relapse incidence (HR=1.28; p=0.0002), and a lower leukemia-free survival (LFS, HR=1.30;, p<10-5), overall survival (OS, HR=1.32; p<10-5 ) and GvHD/relapse free survival (GRFS, HR=1.20; p<10-5 ), as compared to de novo AML. Other prognostic factors for OS were age (p=<10-5), cytogenetics (intermediate, p=0.002, poor, p=<10-5), patient/donor sex combination (female in male, p=<10-5) KPS (<>80, p=0.003) and donor type (unrelated (UD) 10/10 match, p=0.007; UD 9/10 match, p=10-5; haplo, p=0.002)., Three-year cumulative incidence of relapse and non-relapse mortality after alloSCT in CR1 were 28.5%/16.4% for de novo AML (n=7691), and 35%/23.4% for sAML (n=909), 3-year overall survival (OS), leukemia-free survival (LFS) and GvHD-relapse-free survival (GRFS) were 60.8%, 55.1% and 38.6%for de novo and 46.7%, 41.6% and 28.4% for sAML. (Figure 1). In contrast, when focusing on patients transplanted for primary refractory disease (sAML, n=199, de novo AML, n=607) or for relapsed leukemia (sAML, n=124, de novo AML, n=1009), Cox models did not identify sAML as a relevant factor for outcome. Risk factors for OS in advanced disease stages are presented in Table 1.Using the criteria described above, 877 well-matched pairs were identified. The pair-matched analysis confirmed the above findings: Over all patients, sAML was associated with higher NRM (p=0.004) and lower LFS (p=0.004), OS (p=0.008) and GRFS (0.04). However, when the analysis was stratified by stage at SCT, again differences were only seen among patients transplanted in CR1 (719 pairs, 82%), but not after alloSCT in advanced disease.Conclusion: Our large-scale, registry-based analysis identified sAML as an independent risk factor for outcome after alloSCT in first complete remission. In primary refractory and relapsed AML, other factors such as age, cytogenetics and performance status were of higher relevance. This data may help to improve risk stratification and prognostic estimates after alloSCT for sAML. [Display omitted] DisclosuresSchmid:Jazz Pharma: Honoraria, Other: Travel grant, Speakers Bureau. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Beelen:Medac: Consultancy, Other: Travel Support. Mohty:MaaT Pharma: Consultancy, Honoraria.