Incidence Of Relapse In Patients Research Articles

The outcome of acute leukemia patients with SET-NUP214 fusion after allogeneic stem cell transplantation.

SET-NUP214 fusion gene, also known as TAF-1-CAN and SET-CAN, is observed in acute myeloid leukemia (AML) and T-cell lymphoblastic leukemia (T-ALL). SET-NUP214 fusion in T-cell lymphoblastic leukemia is associated with chemotherapy resistance, but the prognosis of patients with AML with SET-NUP214 has rarely been reported. In the present study, we retrospectively analyzed all patients with acute leukemia including AML and T-ALL patients with SET-NUP214 fusion who underwent allogeneic stem cell transplantation (alloHSCT) in our center from July 2017 to November 2022. Of the total 11 patients, 5 patients were diagnosed with AML and 6 patients were diagnosed with T-ALL de novo. All patients received myeloablative regimens in CR1, and there were three (60%) AML patients who relapsed post-alloHSCT and three T-ALL (50%) patients who relapsed post-alloHSCT. Only one patient with AML who relapsed post-alloHSCT responded to subsequent chemotherapy plus donor lymphocyte infusion and survived the last follow-up. The estimated 1-year overall survival and 3-year overall survival for all these 11 patients were 69.3% and 38.5%, respectively. The estimated 1-year leukemia-free survival and 3-year leukemia-free survival for all patients were 69.3% and 38.5%, respectively. The research shows a high incidence of relapse for patients with acute leukemia with the SET-NUP214 fusion gene, even after alloHSCT. More clinical trials or research with larger samples are urgently needed for this group of patients.

Non-Expressed Donor KIR3DL1 Alleles May Represent a Risk Factor for Relapse after T-Replete Haploidentical Hematopoietic Stem Cell Transplantation.

KIR3DL1 alleles are expressed at different levels on the natural killer (NK) cell surface. In particular, the non-expressed KIR3DL1*004 allele appears to be common in Caucasian populations. However, the overall distribution of non-expressed KIR3DL1 alleles and their clinical relevance after T-replete haploidentical hematopoietic stem cell transplantation (hHSCT) with post-transplant cyclophosphamide remain poorly documented in European populations. In a cohort of French blood donors (N = 278), we compared the distribution of expressed and non-expressed KIR3DL1 alleles using next-generation sequencing (NGS) technology combined with multi-color flow cytometry. We confirmed the predominance of the non-expressed KIR3DL1*004 allele. Using allele-specific constructs, the phenotype and function of the uncommon KIR3DL1*019 allotype were characterized using the Jurkat T cell line and NKL transfectants. Although poorly expressed on the NK cell surface, KIR3DL1*019 is retained within NK cells, where it induces missing self-recognition of the Bw4 epitope. Transposing our in vitro observations to a cohort of hHSCT patients (N = 186) led us to observe that non-expressed KIR3DL1 HSC grafts increased the incidence of relapse in patients with myeloid diseases. Non-expressed KIR3DL1 alleles could, therefore, influence the outcome of hHSCT.

Fludarabine, Busulfan and Melphalan Based Conditioning Reduced Relapse after Allogeneic Hematopoietic Stem Cell Transplantation in Adult Patients with Myeloid Malignancies: A Multicenter Retrospective Analysis

Fludarabine in combination with full dose of busulfan has become the most popular myeloablative conditioning regimen for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with myeloid malignancies, while relapse was till the main obstacle for cure. We observed a particular low incidence of relapse in patients prepared with double alkylating agents of busulfan and melphalan in our previous single center phase II study. To further evaluate the efficacy of the regimen, we designed a multicenter retrospective study and tried to verify our previous results in large samples. The inclusion criteria were as follows: 1) adult patients (16 to 70 years old) with myeloid malignancies including acute myeloid leukemia(AML), myelodysplastic syndrome with excess blast-1 or -2(MDS-EB-1 or MDS-EB-2) and chronic myelomonocytic leukemia (CMML); 2) patients received first allo-HSCT from HLA matched sibling donors(MSDs), matched unrelated donor(MUDs), related haplo-identical donor(HIDs) or cord blood(CB); 3) conditioning regimen included busulfan (≥3.2mg/kg) and melphalan(≥100mg/m2); fludarabine, cladribine, cytarabine, etoposide or cyclophosphamide could be used in combination, while venetoclax, thiotepa and total body irradiation(TBI) were excluded. From Jan.2020 to Mar. 2022, a total of 202 patients from nine HSCT centers were enrolled in this study. Over ninety-five percent (193/202) patients received conditioning consisted of different dose of fludarabine, busulfan and melphalan. Post transplantation cyclophosphamide (PTCy) based graft-versus-host disease prophylaxis strategy was used in 167 out of all patients. The median follow-up time was 314 days (range, 8~841days) for the whole cohort and the baseline data were summarized in Table-1. Three patients developed primary engraft failure. The median time for neutrophil and platelet recovery were 13 days (range, 9~22 days) and 14 days (range, 9~121 days), respectively. The 100-day cumulative incidence of grade II-IV acute GVHD was 10.9±4.1% and the 2-year cumulative incidence of moderate/severe chronic GVHD was 17.4±5.2%. At last follow-up, eighteen patients died of non-relapse reasons and sixteen patients relapsed including eight patients were still alive. Thus the 2-year non-relapse mortality (NRM) was 8.9%±0.6% and cumulative incidence of relapse (CIR) at 2-year was 7.9±1.9%. The 2-year overall survival (OS) and disease free survival (DFS) were 79.9%±4.3% and 72.4±5.5%, respectively. Subgroup analysis showed no significant difference in OS and DFS when grouping by sex, age(＜50y vs. ≥50y), diagnosis (AML vs. MDS), disease risk index (DRI, low risk vs. intermediate risk vs high/very high risk) and transplantation conditioning intensity( TCI, low vs. intermediate vs. intensive). These results identified with our previous study and supported that busulfan and melphalan based conditioning was associated with low relapse rate and acceptable NRM in adult patients with myeloid malignancies. Randomized controlled clinical trial should be warranted to evaluate this regimen further. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Safety and outcomes of maintenance therapy with third-generation tyrosine kinase inhibitor after allogeneic hematopoietic cell transplantation in Philadelphia chromosome positive acute lymphoblastic leukemia patients with T315I mutation

Studies using third-generation tyrosine kinase inhibitor (TKI) as maintenance therapy after hematopoietic cell transplantation (HCT) for patients with Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL) harboring the T315I mutation remain scarce. We conducted a cohort study to evaluate the safety and outcomes of ponatinib maintenance therapy after HCT in Ph+ALL patients with T315I mutation. BCR-ABL kinase domain mutations were assessed using direct sequencing. Twenty-six Ph+ALL patients with T315I mutation who received allogeneic HCT were enrolled. After HCT, ponatinib was administered as a prophylactic regimen (n = 12) or a preemptive therapy (n = 7). Seven patients did not receive maintenance therapy. Adverse events (AEs) occurred in 69.4 % of patients with ponatinib maintenance, but most presented with mild toxicities. Serious non-hematological AEs were not observed. The 5-year disease-free survival (DFS), overall survival (OS), and cumulative incidence of relapse in patients receiving prophylactic ponatinib were 81.5 %, 91.7 %, and 18.5 %, respectively, whereas they were 39.8 %, 46.0 %, and 48.4 % in the total cohort, respectively. The measurable BCR-ABL transcripts in the first three months after HCT was associated with poor DFS and OS, even with ponatinib therapy. We concluded that maintenance therapy with ponatinib is safe after HCT. Patients with T315I mutation who received prophylactic regimen showed promising results with an acceptable relapse rate and encouraging survival. However, patients with measurable BCR-ABL transcripts early post-transplant had poor outcomes.

Lower levels of cyclosporine between days 0 and +21 may reduce later relapses without increasing graft-versus-host disease in children and adolescents with acute lymphoblastic leukemia who undergo myeloablative TBI-based allogeneic hematopoietic cell transplantation.

The degree of immunosuppression required for adequate graft-versus-host disease (GVHD) prevention, while keeping an adequate graft-versus-leukemia effect, in children with acute leukemia has not been established. We report the results of a retrospective comparison of cyclosporine levels and relapse rate in children and adolescents with acute lymphoblastic leukemia (ALL). Patients <21 y/o with ALL in remission who underwent TBI-based hematopoietic cell transplantation from related or unrelated donors between 2008 and 2021 were included. Cyclosporine levels were measured twice a week and we calculated the area under the curve (AUC) from D0 to D + 7, D + 14, and D + 21. We included 76 patients. There was a trend towards a lower incidence of relapse in patients with a mean AUC < 200 ng/ml at D + 21 (HR=0.41; p=.08). The 5-year relapse rate was 26.9% for patients with a mean AUC < 200 ng/ml at D + 21 and 43.9% for patients with a mean AUC≥200 ng/ml at D + 21. Relapse protection was restricted to relapses happening after D + 120 (HR=0.21; p=.04). Our results show evidence that pediatric patients with ALL might benefit from lower cyclosporine levels between D0 and D + 21 without a detectable increase in GVHD. Large prospective studies comparing different cyclosporine levels are awaited.

Comparison of Peritonitis Relapse Incidence in End-Stage Renal Disease Patients with Peritoneal Dialysis According to the Culture Results

Background: Peritoneal dialysis (PD) is one of the modalities of renal replacement therapy (RRT) in end-stage renal disease (ESRD). One of the complications that are often found in the use of PD is peritonitis. Presence of the culture from the peritoneal fluid was known to be associated with the incidence of peritonitis relapse among ESRD patients with PD. Aim: Comparing the incidence of relapse in patients with continuous ambulatory peritoneal dialysis (CAPD) with culture-negative and culture-positive in RSUD Dr. Saiful Anwar Malang. Methods: This study measured the incidence of relapse after administration of CAPD peritonitis therapy. Descriptive data are presented in percentages, and numerical data is presented in Mean ± SD. The analysis test was carried out using the Mann-Whitney with p&lt;0.05, significant. Results: According to the culture results, it was found that 25.4% (18 of 71 PD peritonitis cultures) were culture-negative in patients with CAPD peritonitis. This result is slightly higher than the ISPD recommendation, with 20% culture-negative results. There were 3 out of 53 relapses in culture-positive subjects and 1 in 18 relapses in culture-negative subjects. There was no significant difference in the two groups, with an OR of 0.721 in the culture-positive group lead the culture-positive tended to experience no relapse by 0.721 times less than the patient with culture-negative. Conclusion: In peritoneal dialysis peritonitis, there was no significant difference in the incidence of relapse in the positive and culture-negatives.

Time to remission of proteinuria and incidence of relapse in patients with steroid-sensitive minimal change disease and focal segmental glomerulosclerosis: the Japan Nephrotic Syndrome Cohort Study.

Minimal change disease (MCD) is characterized by a nephrotic syndrome usuallysteroid-sensitive and a high incidence of relapse of proteinuria. Previous cohort studies have reported conflicting results regarding the association between the time to remission and incidence of relapse. This multicenter prospective cohort study included 102 adult patients with steroid-sensitive MCD or focal segmental glomerulosclerosis from a 5-year cohort study of primary nephrotic syndrome, the Japan Nephrotic Syndrome Cohort Study, who achieved remission of proteinuria within 2months of immunosuppressive therapy (IST). The association between the time to remission of proteinuria after immunosuppressive therapyand incidence of relapse was assessed using Cox proportional hazards models adjusted for clinically relevant factors. Remission was observed at 3-7, 8-14, 15-21, 22-28, and 30-56days after initiation ofimmunosuppressive therapyin 17 (16.7%), 37 (36.3%), 21 (20.6%), 13 (12.7%), and 14 (13.7%) patients, respectively. During a median observation period of2.3years after the end of the 2nd month after initiationofimmunosuppressive therapy, 46 (45.1%) patients relapsed. The time to remission was associated with the incidence of relapse in an inverse U-shaped pattern (multivariable-adjusted hazard ratios [95% confidence intervals] of the time to remission of 3-7, 8-14, 15-21, 22-28, 30-56days: 1.00 [reference], 1.76 [0.56, 5.51], 6.06 [1.85, 19.80], 5.46 [1.44, 20.64], and 2.19 [0.52, 9.30], respectively). The time to remission was identified as a significant predictor of relapsein steroid-sensitive patients.

Prognostic significance of DEK-NUP214 fusion gene in patients with acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation

Objective: To investigate the dynamic change and clinical impact of DEK-NUP214 fusion gene in patients with acute myeloid leukemia (AML) receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods: Real-time quantitative polymerase chain reaction (RQ-PCR) and multicolor flow cytometry (FCM) were used to detect DEK-NUP214 gene expression and leukemia-associated immunophenotype (LAIP) in 15 newly diagnosed patients with positive DEK-NUP214 and receiving allo-HSCT from September 2012 to September 2017 at Peking University People's Hospital. The clinical outcome was analyzed using Kaplan-Meier survival curves. The impact of DEK-NUP214 expression was analyzed by log-rank test. Results: The subjects were followed-up with a median period of 657 (62-2 212) days. The median DEK-NUP214 expression level at diagnosis was 488% (274%-1 692%). Thirteen patients achieved complete remission before allo-HSCT. Thirteen patients had a residual DEK-NUP214 expression of 0.38% (0.029%-738.9%) before allo-HSCT. After allo-HSCT, DEK-NUP214 expression in 9/13 patients remained positive, which dropped by around 500 folds (5.7-5 663.0 folds) within a month post-transplant. Five patients died and 2 patients relapsed. The 3-year cumulative incidence of relapse in patients with positive DEK-NUP214 before transplant was 17.5%±11.3% and the 3-year overall survival was 60.5%±13.8%. After allo-HSCT, DEK-NUP214-negative patients had a better outcome. Conclusion: Quantitative monitor of DEK-NUP214 fusion gene could be a sensitive indicator of MRD status after allo-HSCT.

Long-Term Outcome of Patients Receiving Extracorporeal Photopheresis for Acute and Chronic Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation for Hematological Malignancies: Results from an Observational Study on 106 Patients

Graft-versus-host disease (GVHD), and complications of its treatment are the major causes of morbidity and mortality following allogeneic hematopoietic cell transplantation (allo-HCT). Even with the use of standard GVHD prophylaxis with classical administration of Anti-thymocyte globulin (ATG), calcineurin inhibitors (CNIs) and methotrexate, the incidence of acute and chronic forms of GVHD remains not negligible. Extracorporeal photopheresis (ECP) has shown very promising results as curative strategy for GVHD but also when used prophylactically.The primary objective of this observational study was to perform an exhaustive description concerning patients receiving ECP after steroid resistance for either acute or chronic GVHD following allo-HCT, secondary objectives were to evaluate the efficacy and long-term outcomes.We included 106 patients who underwent allo-HCT between years 2001 and 2016, 65 (61%) were males, median age at allo-HCT was 52 years (20-67). Major diagnoses were acute leukemias (N=48, 45%), myelodysplastic syndromes (N=18, 17%) and multiple myeloma (N=12, 11%). Before transplantation, 56 (53%) patients were in complete remission or in chronic phase. Donors were identical siblings in 51% of patients, matched unrelated in 24%, mismatched unrelated in 24% and haploidentical in 1%. Cells source was peripheral blood in 65%, bone marrow in 27% and cord blood in 8%. Conditioning regimens were of reduced intensity in 62% and myeloablative in 38%. ATG was used during conditioning in 67% of patients. GVHD prophylaxis consisted on cyclosporine A (CsA) alone in 22 (21%) patients, CsA + mycophenolate mofetil in 29 (27%), CsA + methotrexate in 28 (26%), the rest received other combinations.In acute GVHD, first treatment consisted in methyl-prednisolone 2mg/Kg/day in combination with CNIs; and in chronic GVHD, it was methyl-prednisolone 0.5 - 1 mg/Kg/day + CNIs. ECP was performed using peripheral venous access. The ECP used the CELLEX system from Therakos®. ECP was initiated after transplantation either for acute GVHD [N=25 (24%), 12 grade III and 13 grade IV] affecting skin alone (N=5), gut alone (N=12), gut + liver (N=8); or for chronic GVHD [N=81 (76%), 15 (14%) limited and 66 (62%) extensive]. A total of 3300 ECP sessions were performed, majority (N=91, 85%) were twice a week; the median number of sessions/patient was 22 (min: 2, max: 132) for a median duration of 2.5 months (range: 0.5-48). ECP response evaluation was assessed after 4 weeks of treatment, patients were considered responding to ECP if more than 50% resolution of clinical GVHD manifestation of the organ involved was registered.Among the 25 patients treated for acute GHVD, one was not evaluable because of disease progression and early death, 16/24 (67%) were responders to ECP and 8/24 (33%) were not responders and died later from GVHD associated to other complications. Among the 81 patients with chronic GVHD, 63/81 (78%) were responders and had tapering of ECP, the remaining 18 patients had limited response were associated to infection, had other complications and died later. Of note, in both forms of acute and chronic GVHD, responding patients had more skin or mucosa forms whereas non-responding patients has more organ-involved forms especially liver and gut.After a median follow-up of 21 months, 52 (49%) patients are alive and 54 (51%) died with 39 (24%) from TRM causes (26 of them from GVHD) and 13 (26%) from relapse. Patients with acute GVHD had a median OS of 6 months with a survival probability at 2 years of 35% [95%CI: 14-56], those with chronic GVHD had a median OS of 72 months with a survival probability at 2 years of 68% [95%CI: 56-78]. The cumulative incidence of relapse for the whole population at 2 years was 16.7% (95% CI: 10-24), when stratifying according to the GVHD group, patients with chronic GVHD had lower relapse rate at 2 years with 12.6% (95% CI: 6-21) versus 31% (95% CI: 13-52) for those with acute GVHD, p=0.05.In conclusion, we confirm that ECP is an effective treatment for GVHD with overall response rate of more than 74%. Interestingly, we observed a low relapse incidence in patients receiving ECP for longer time as in the case of chronic GVHD, which could be related to the GVL effect itself but also a possible involvement of the ECP. As patients with advanced phase of GVHD were poor responders, we suggest that an early use of ECP in the acute phase of the inflammation before organ damage, could lead to optimal results. [Display omitted] DisclosuresNicolini:Incyte Biosciences: Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ARIAD: Honoraria, Speakers Bureau.

Rabbit Anti-Thymocyte Globulin Kills Leukemic Stem Cells to a Greater Degree Than Healthy Hematopoietic Stem Cells

Background: Rabbit anti-thymocyte globulin (ATG, Thymoglobulin) is given with hematopoietic cell transplant (HCT) conditioning to prevent graft-versus-host disease (GvHD). Recently we showed that in vitro ATG at clinically relevant concentrations kills not only T cells but also leukemic blasts (Dabas et al., BBMT 2016). This might explain the non-increase in relapse incidence in patients given ATG vs no ATG (Walker et al., Lancet Oncol 2016). Nevertheless, relapse of leukemia is still the most frequent cause of HCT failure. After chemotherapy (without HCT), non-relapse is associated with eradication of leukemic stem cells (LSCs). By extrapolation, non-relapse after HCT may also require the eradication of LSCs. We have shown that ATG kills LSCs, however, at a relatively high concentration of 50 mg/L. We next studied whether at that high concentration ATG kills also healthy hematopoietic stem cell (HSCs), as attempts to achieve the high concentration clinically would be indicated only if ATG killed LSCs but not HSCs.Study design: To study the cytotoxic effect of ATG on LSCs and HSCs, we used cryopreserved blood mononuclear cells (MNCs) from 8 newly diagnosed acute myeloid leukemia (AML) patients as a source of LSCs. The median percentage of blasts in the blood of the AML patients was 53% (range 24% to 90%). Healthy volunteers' cryopreserved blood MNCs (n=8) or cryopreserved filgrastim-mobilized apheresed blood MNC grafts from healthy donors (n=17) were used as the source of HSCs. The MNCs from the blood of AML patients and healthy volunteers were magnetically enriched for CD34+ cells (Miltenyi Biotech). This was not needed for the grafts as they contained a sufficient number of CD34+ cells for the assay of ATG killing. By flow cytometry, we measured stem cell killing induced by 15 min incubation with ATG (50 mg/L) and active complement (human serum). For negative control, cells were incubated with ATG in the presence of no active complement (heat-inactivated human serum). The LSCs and HSCs were phenotypically defined as CD45dim/neg, side scatterlow, CD34+, CD38neg and negative for the lineage markers (CD14, CD16, CD19, CD56, CD3, CD235a and CD41a). Dead cells were identified as 7-amino-actinomycin D positive (7AAD+).Results: Treatment of LSCs with 50 mg/L ATG in the presence of complement resulted in median 43% dead (7AAD+) cells (background subtracted). In contrast, treatment of blood HSCs and graft HSCs resulted in 3% and 13% dead cells, respectively (Figure 1).Conclusion: Here we show that in vitro LSCs are more sensitive to ATG mediated killing than healthy HSCs. However, the killing of LSCs occurs only at a relatively high ATG concentration (50 mg/L) which is ~5-fold higher than the maximum serum concentration achieved with a typical ATG dose (4.5 mg/kg). If ATG had the anti-LSCs activity also in vivo, using high dose ATG (leading to serum concentration of 50 mg/L) in patients could result in simultaneous decrease of both GVHD and relapse. Given the minimal effect on HSCs, the high dose ATG might not jeopardize engraftment. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Repetitively Administered Low-Dose Donor Lymphocyte Infusion for Prevention of Relapse after Allogeneic Stem Cell Transplantation in Patients with High-Risk Acute Leukemia.

Simple SummaryPatients with high-risk acute leukemia (AL) have a high risk of relapse after allogeneic stem cell transplantation (allo-SCT). Prophylactic donor lymphocyte infusion (pro-DLI) has shown significant efficacy in reducing relapse rate but its widespread application has been limited due to concerns of graft versus host disease (GVHD) development. In the present study, we tested the safety and efficacy of a novel method of pro-DLI based on repetitive administration of low lymphocyte doses. Low-dose pro-DLI was administered every two months for at least 3-years. Forty-four high-risk AL patients with a median age of 53-years who underwent allo-SCT from a matched-sibling (38pts) or a matched-unrelated donor (6pts) received pro-DLI. Acute and chronic-GVHD developed in 14% and 12% of patients. With a median follow-up of 44-months, the cumulative incidence of relapse and non-relapse mortality was 12% and 13%, while the overall survival was 78%. Prolonged up to 3-years low-dose pro-DLI administered every two months is safe and effective in reducing relapse rate in patients with high-risk AL. The low-dose repetitive administration DLI strategy reduced the risk of DLI-mediated GVHD, while the prolonged repeated administration helped in preventing relapse, possibly by inducing a sustained and prolonged immunological pressure on residual leukemic cells. Background: Patients with high-risk acute leukemia have a high risk of relapse after allogeneic stem cell transplantation (allo-SCT). In an effort to reduce the relapse rate, various therapeutic methods have been implemented into clinical practice. Among them, prophylactic donor lymphocyte infusion (pro-DLI) has shown significant efficacy. However, the widespread application of pro-DLI has been restricted mostly due to concerns regarding the development of graft versus host disease (GVHD). In the present study, we tested the safety and efficacy of a novel method of prophylactic-DLI based by repetitive administration of low lymphocyte doses. Methods: DLI was administered to patients with high-risk acute leukemia at a dose of 2 × 106/kg CD3-positive cells. DLI at the same dose was repeated every two months for at least 36 months post-allo-SCT, or until relapse or any clinical or laboratory feature suggested GVHD, whichever occurred first. Forty-four patients with a median age of 53 years (range 20–67) who underwent allo-SCT between 2011 and 2020 were included in our study. Thirty-three patients with high-risk acute myeloid leukemia (AML) and 11 with high-risk acute lymphoblastic leukemia (ALL) after allo-SCT from a matched sibling (MSD, no = 38 pts) or a matched-unrelated donor (MUD, no = 6 pts) received pro-DLI. Twenty-three patients were in CR1, all with unfavorable genetic features; 12 patients were in CR2 or beyond; and 9 patients had refractory disease at the time of transplant. Ten out of 23 patients in CR1 had detectable minimal residual disease (MRD) at the time of allo-SCT. Disease risk index (DRI) was high and intermediate in 21 and 23 patients, respectively. Conditioning was myeloablative (MAC) in 36 and reduced intensity (RIC) in 8 patients, while GVHD prophylaxis consisted of cyclosporine-A in combination with low-dose alemtuzumab in 39 patients or with low-dose MTX in 5 patients, respectively. Results: Thirty-five patients completed the scheduled treatment and received a median of 8 DLI doses (range 1–35). Fifteen out of 35 patients received all planned doses, while DLI was discontinued in 20 patients. Reasons for discontinuation included GVHD development in nine, donor unavailability in seven, disease relapse in three, and secondary malignancy in one patient, respectively. Nine patients were still on treatment with DLI, and they received a median of four (range 2–12) doses. Fourteen percent of patients developed transient grade-II acute GVHD while 12% developed chronic GVHD post-DLI administration. Acute GVHD was managed successfully with short course steroids, and four out of five patients with cGVHD were disease-free and off immunosuppression. With a median follow-up of 44 months (range 8–120), relapse-free (RFS) and overall survival (OS) were 74%, (95% CI, 54–87%) and 78%, (95% CI, 58–89%) respectively, while the cumulative incidence of non-relapse mortality (NRM) was 13% (95% CI, 4–28%). The cumulative incidence of relapse in patients with intermediate and high DRI is 7% and 15%, respectively. Conclusion: Prolonged—up to three years—low-dose pro-DLI administered every two months is safe and effective in reducing relapse rate in patients with high-risk acute leukemia. The low-dose repetitive administration DLI strategy reduced the risk of DLI-mediated GVHD, while the prolonged repeated administration helped in preventing relapse, possibly by inducing a sustained and prolonged immunological pressure on residual leukemic cells. This novel strategy deserves testing in larger cohort of patients with high-risk acute leukemia.

A hypodiploid karyotype in childhood B-cell precursor acute lymphoblastic leukemia

The detection of genetic markers associated with poor prognosis is crucial to the selection of an appropriate treatment plan for B-cell precursor acute lymphoblastic leukemia (BCP-ALL). A hypodiploid karyotype in patients with BCP-ALL has an unfavorable impact and serves as a criterion for the stratification of patients into a high-risk group. However, the survival rates of patients with a hypodiploid karyotype remain poor. Russian treatment protocols for childhood acute lymphoblastic leukemia do not include a hypodiploid karyotype in risk stratification criteria. In order to determine the prognostic value of a hypodiploid karyotype and the clinical characteristics of BCP-ALL in patients with a hypodiploid karyotype, we analyzed the survival rates of 2,700 patients included in a multicenter study. Our study was approved by the Independent Ethics Committee and the Scientific Council of the D. Rogachev NMRCPHOI of the Ministry of Healthcare of the Russian Federation. All patients underwent karyotyping and fluorescence in situhybridization (FISH) testing. A hypodiploid karyotype was detected in 27 patients. Eighteen out of 27 patients had a hypoploid clone (according to karyotyping results), 2 patients had a doubled near-haploid clone (according to karyotyping and FISH results); in 7 patients with a normal karyotype or in the absence of mitosis, hypodiploidy was determined only by FISH test. BCP-ALL with hypodiploidy is usually associated with increased WBC count at disease onset. The median WBC count in the study group was 24.2 (3.4–206.0) × 109/l vs 10.3 (0.2–1290.0) × 109/l in the control group. The number of patients with initial leukocytosis &lt; 30 × 109/l in the study group was significantly lower than in the control group (p&lt; 0.062). Remission was achieved in 26/27 patients. The event-free survival rates in patients with hypodiploidy were significantly lower than in those without hypodiploidy: 50 ± 11% vs 72 ± 8% (p&lt; 0.0001). The overall survival was 64 ± 10% and 90 ± 1%, respectively (p&lt; 0.0001). The cumulative incidence of relapse in patients with a hypodiploid karyotype was higher (42.6 ± 10.9%) than in the controls (22.3 ± 8.1%) (p&lt; 0.0001). The patients who received more intense treatment for intermediate- and high-risk groups showed better survival rates than those in the standard-risk group: 62 ± 13% vs 40 ± 15% (р= 0.59); the cumulative incidence of relapse according to the risk group was 26.4 ± 12.1% and 60 ± 16.9%, respectively (р= 0.19).The highest risk of relapse was observed in a group that included patients with near-haploidy and low hypodiploidy (26–39 chromosomes; 52.9 ± 14.4%). The event-free survival in this group was 36 ± 13%. The results of treatment of patients with BCP-ALL and hypodiploidy according to the national guidelines turned out to be comparable to the international ones. Patients with BCP-ALL and hypodiploidy should be initially stratified to the most intense treatment arm. In order to identify patients with hypoploidy, standard karyotyping is required; where needed, it can be supplemented by FISH analysis

Adequate asparaginase is important to prevent central nervous system and testicular relapse of pediatric Philadelphia chromosome‐negative B‐cell acute lymphoblastic leukemia

Asparaginase (Asp) is one of the most important drugs for treating acute lymphoblastic leukemia (ALL). However, off-protocol Asp administration (OPAA) or hypersensitivity may disturb its pharmacokinetic profile. In this retrospective study, we sought to determine whether OPAA and hypersensitivity to Escherichia coli asparaginase (E. coli Asp) impaired extramedullary relapse prevention in a pediatric ALL cohort treated according to SCMC-ALL-2005 protocol from 2005 to 2014 at the Shanghai Children's Medical Center (SCMC). In total, 676 patients were enrolled in this study, including 369 with OPAA and 60 exhibiting hypersensitivity to E. coli Asp. At the end of the most recent follow-up, 58 patients had extramedullary relapse. The 5-year cumulative extramedullary relapse incidence in patients with OPAA was 11.01%, whereas that in patients without OPAA was 5.28% (P=.0036). Moreover, the 5-year cumulative extramedullary relapse incidence in patients that exhibited hypersensitivity to E. coli Asp was 16.48%, whereas that in patients without hypersensitivity was 7.59% (P=.0195). Concerning the relapse site, OPAA not only increased central nervous system (CNS) relapse but testicular relapse as well. Based on Fine and Gray multivariate analysis, OPAA and hypersensitivity to Asp were independent risk factors for extramedullary relapse. In conclusion, to prevent extramedullary relapse of ALL, adequate duration to administrate Asp was more important than the total dosage, and more attention should be paid to Asp inadequate due to hypersensitivity. This article is protected by copyright. All rights reserved.

Silver Lining: Reduced Relapse with Chronic GVHD after Transplant for MDS.

Chronic GVHD following hematopoietic cell transplantation is associated with reduced relapse incidence in patients with leukemias. This impact has been investigated in myelodysplastic syndrome, showing a beneficial impact of limited chronic GVHD on transplant outcomes in a cohort of more than 3,000 patients.See related article by Konuma et al., p. 6483.

Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group

AbstractAll-trans-retinoic acid (ATRA) increases the efficacy of chemotherapy when used for induction and maintenance treatment of acute promyelocytic leukemia (APL), but its role in consolidation is unknown. Since November 1996, 426 patients with newly diagnosed APL have received induction therapy with ATRA and idarubicin. Before November 1999 (LPA96 study), consolidation therapy consisted of 3 courses of anthracycline monochemotherapy. After November 1999 (LPA99 study), patients with intermediate and high risks of relapse received consolidation therapy with ATRA and increased doses of anthracyclines. Of the 384 patients who achieved complete remission (90%), 382 proceeded to consolidation therapy. Seven patients died in remission (1.8%). The 3-year cumulative incidence of relapse for patients in the LPA96 and LPA99 studies was 17.2% and 7.5%, respectively (P = .008). Patients treated with ATRA in consolidation therapy showed an overall reduction in the relapse rate from 20.1% to 8.7% (P = .004). In intermediate-risk patients the rate decreased from 14.0% to 2.5% (P = .006). This improved antileukemic efficacy also translated into significantly better disease-free and overall survival. A risk-adapted strategy combining anthracycline monochemotherapy and ATRA for induction and consolidation therapy of newly diagnosed APL results in improved antileukemic efficacy and a high degree of compliance.

Centromeric KIR AA Individuals Harbor Particular KIR Alleles Conferring Beneficial NK Cell Features with Implications in Haplo-Identical Hematopoietic Stem Cell Transplantation.

Simple SummaryWe have recently shown a broad disparity of Natural Killer (NK) cell responses against leukemia, highlighting good and bad responders resting on the Killer cell Immunoglobulin-like Receptors (KIR) and HLA genetics. In this study, we deeply investigated KIR2DL NK cell repertoire in combining high-resolution KIR allele typing and multicolor flow cytometry from a cohort of 108 blood donors. Our data suggest that centromeric (cen) AA individuals display more efficient KIR2DL alleles (L1*003 and L3*001) to mount a consistent frequency of KIR2DL+ NK cells and to confer an effective NK cell responsiveness. The transposition of our in vitro observations in T-replete haplo-identical Hematopoietic Stem Cell Transplantation (HSCT) context led us to observe that cenAA HSC grafts limit significantly the incidence of relapse in patients with myeloid diseases after T-replete haplo-identical HSCT. As NK cells are crucial in HSCT reconstitution, one could expect that the consideration of KIR2DL1/2/3 allelic polymorphism could help to refine scores used for HSC donor selection.We have recently shown a broad disparity of Natural Killer (NK) cell responses against leukemia highlighting good and bad responders resting on the Killer cell Immunoglobulin-like Receptors (KIR) and HLA genetics. In this study, we deeply studied KIR2D allele expression, HLA-C recognition and functional effect on NK cells in 108 blood donors in combining high-resolution KIR allele typing and multicolor flow cytometry. The KIR2DL1*003 allotype is associated with centromeric (cen) AA motif and confers the highest NK cell frequency, expression level and strength of KIR/HLA-C interactions compared to the KIR2DL1*002 and KIR2DL1*004 allotypes respectively associated with cenAB and BB motifs. KIR2DL2*001 and *003 allotypes negatively affect the frequency of KIR2DL1+ and KIR2DL3+ NK cells. Altogether, our data suggest that cenAA individuals display more efficient KIR2DL alleles (L1*003 and L3*001) to mount a consistent frequency of KIR2DL+ NK cells and to confer an effective NK cell responsiveness. The transposition of our in vitro observations in the T-replete haplo-identical HSCT context led us to observe that cenAA HSC grafts limit significantly the incidence of relapse in patients with myeloid diseases after T-replete haplo-identical HSCT. As NK cells are crucial in HSCT reconstitution, one could expect that the consideration of KIR2DL1/2/3 allelic polymorphism could help to refine scores used for HSC donor selection.

The ADAMTS13 Family: In-Patient Trends and Outcomes of Thrombotic Thrombocytopenic Purpura

Introduction: Thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening disorder characterized by microangiopathic hemolytic anemia, thrombocytopenia, neurological symptoms, renal dysfunction and other end organ failure. It is associated with inherited or acquired antibody-mediated deficiency of ADAMTS13 resulting in an inability to cleave von Willebrand factor. It occurs in approximately 3 in 1 million adults and 1 in 10 million children annually. First line therapy is plasmapheresis, typically coupled with steroids. Patients recovering from TTP may demonstrate persistent or intermittent ADAMTS13 deficiency without symptoms or thrombocytopenia. Most relapses of acquired TTP occur in the first week after stopping plasma exchange. There are multiple factors contributing to relapses, which include age &amp;gt; 60, severe neurological symptoms at presentation and a persistently elevated lactate dehydrogenase. Thus young patients with low ADAMTS13 activity are appropriate candidates for prophylactic treatment. The early initiation of immune-modulatory therapy targeting the antibody inhibitor of ADAMTS13 could potentially reduce the number of plasma exchange procedures required to achieve remission, increase the response rate and decrease the incidence of relapses in patients with TTP. Since TTP is a rare disease, the aim of our study was to outline the trends and outcomes of hospitalizations due to TTP using the nationally representative database for future use in risk stratification and treatment protocols. Methods: We performed retrospective study using the National Inpatient Sample database, a part of the Healthcare Cost and Utilization Project (HCUP) of the agency for Healthcare Research and Quality (AHRQ). We extracted the study cohort of adult admissions with TTP from 2007-2017 by using International Classification of Diseases (9th/10th editions) Clinical Modification diagnosis codes. In the final study cohort we only included patients who received plasmapheresis to restrict patient population with active TTP disease. This approach has been validated in prior publications from administrative databases. Other diagnosis of interests and other comorbidities were identified by ICD-9/10-CM codes and Elixhauser comorbidity software. We utilized Cochran Armitage trend test and survey logistic multivariable regression modeling to analyze trends and predictors of outcomes with weighted analysis. Statistical analyses were performed using SAS software, version 9.4. Results: There were a total 22,054 hospitalizations due to TTP, which increased from 1,620 in 2007 to 1,870 in 2017. The median age was 47-years (IQR:33-60) with 25% hospitalizations among the age group of 18-34 years, 66.1% were females, 46.7% were Caucasians followed by 39.2% African American race. The overall length of stay was 16-days which declined from 17-days in 2007 to 15-days is 2017 (pTrend&amp;lt;0.001). In the study cohort, 14.5% were discharged to a facility, and 9.8% died during the hospitalization. In trend analysis, in-hospital mortality decreased (13.4% in 2007 to 8.02% in 2017; pTrend&amp;lt;0.001) but discharge to facilities increased (8.9% in 2007 to 14.4% in 2017; pTrend&amp;lt;0.001). Furthermore, in multivariable regression analysis, increasing age (OR 1.4; 95%CI 1.3-1.5; p&amp;lt;0.001), Caucasians (OR 1.4; 95%CI 1.2-1.7; p&amp;lt;0.001), pneumonia (OR 1.8; 95%CI 1.4-2.5; p&amp;lt;0.001), septicemia (OR 3.4; 95%CI 2.6-4.5; p&amp;lt;0.001), cardiovascular events (OR 2.2; 95%CI 1.5-3.2; p&amp;lt;0.0001), electrolytes imbalance (OR 1.4; 95%CI 1.1-1.9; p=0.005), and liver disorders (OR 1.7; 95%CI 1.1-2.6; p=0.02) were associated with higher odds of in-hospital mortality. Conclusion: In this study, we described national trends of hospitalizations and outcomes of TTP. We observed in-hospital mortality has decreased coupled with an increase in discharge to facilities over the past decade. We also identified risk factors for poorer outcomes, including advanced age, caucasian background and associated sepsis, revealing higher odds of in-hospital mortality. Early identifications of these potential risk stratifiers may play a crucial role in initiating early treatment in addition to identifying populations who may benefit from immune-modulatory therapy along with prophylactic plasma exchange. Disclosures No relevant conflicts of interest to declare.

Impact of central nervous system (CNS) prophylaxis on the incidence of CNS relapse in patients with high-risk diffuse large B cell/follicular grade 3B lymphoma

Although overall survival in diffuse large B cell lymphomas (DLBCL) has improved, central nervous system (CNS) relapse is still a fatal complication of DLBCL. For this reason, CNS prophylaxis is recommended for patients at high risk of CNS disease. However, no consensus exists on definition of high-risk patient and optimal CNS prophylaxis. Systemic high-dose methotrexate in combination with R-CHOP has been suggested as a potential prophylactic method, since methotrexate penetrates the blood-brain barrier and achieves high concentration in the CNS. In this retrospective analysis, we report treatment outcome of 95 high-risk DLBCL/FL grade 3B patients treated with R-CHOP or its derivatives with (N = 57) or without (N = 38) CNS prophylaxis. At a median follow-up time (51 months), CNS relapses were detected in twelve patients (12.6%). Ten out of twelve (83%) of CNS events were confined to CNS system only. Median overall survival after CNS relapse was 9 months. Five-year isolated CNS relapse rates were 5% in the prophylaxis group and 26% in the group without prophylaxis. These findings suggest that high-dose methotrexate-containing prophylaxis decreases the risk of CNS failure.

The impact of total body irradiation-based regimens on outcomes in children and young adults with acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplantation.

Total body irradiation (TBI)-based conditioning is the standard of care in the treatment of acute lymphoblastic leukemia (ALL) that requires allogeneic hematopoietic stem cell transplantation (HSCT). However, TBI is known to be associated with an increased risk of late effects, and therefore, non-TBI regimens have also been utilized successfully. A recent study showed that patients that were next-generation sequencing-minimal residual disease (NGS-MRD) negative prior to allogeneic HSCT had a very low risk of relapse, and perhaps could avoid exposure to TBI without compromising disease control. We examined outcomes at our institution in patients that received a TBI or non-TBI regimen, as well as explored the impact of NGS-MRD status in predicting risk of relapse post transplant. This retrospective analysis included 57 children and young adults with ALL that received their first myeloablative allogeneic HSCT from 2012 to 2017 at the University of California San Francisco. Our primary endpoint was the cumulative incidence of relapse at 3 years post transplant. We demonstrated similar cumulative incidence of relapse for patients treated with either a TBI or non-TBI conditioning regimen, while NGS-MRD positivity prior to transplant was highly predictive of relapse. The presence of acute graft-versus-host disease was associated with decreased relapse rates, particularly among patients that received a TBI conditioning regimen and patients that were NGS-MRD positive prior to HSCT. Our data suggest that the decision to use either a TBI or non-TBI regimens in ALL should depend on NGS-MRD status, with conditioning regimens based on TBI reserved for patients that cannot achieve NGS-MRD negativity prior to allogeneic HSCT.

Inferior Outcomes for Older Patients in the Adolescent and Young Adult (AYA) Population with Burkitt Lymphoma Treated with Intensive Immunochemotherapy: An International Study of 108 Patients

Introduction: Non-endemic Burkitt lymphoma (BL) is a rare and highly aggressive B-cell malignancy, of whom a substantial number are adolescents and young adults (AYAs). In this particular group of patients, the balance between efficacy and long-term toxicities is of major concern, due to the long expected remaining lifetime. In this study, we investigated the outcomes for AYA patients treated with intensive immunochemotherapy. Patients and methods: Patients were identified through queries to clinic based and population-based lymphoma registries from six countries (Australia, Canada, Denmark, Norway, Sweden, and USA). All diagnoses were confirmed by local investigators; patients with classical BL histology plus detectable MYC translocation, were included. Patients between 18 and 39 years of age at diagnosis treated with intensive immunochemotherapy (DA-EPOCH-R or more intensively) were evaluated in pre-specified age groups. All treatment protocols included rituximab. Overall survival (OS) was defined as the time from diagnosis until death from any cause or censoring, while event-free survival (EFS) was defined as the time from diagnosis until unplanned re-treatment, progression/relapse, death, or censoring, whichever came first. Response evaluation was assessed using established response criteria based on CT and/or PET/CT imaging. Survival curves were computed using the Kaplan-Meier estimator. The cumulative incidence of relapse in patients reaching complete remission (CR) or CR unconfirmed (CRu) was computed by Aalen-Johansen estimator. The 5-year restricted loss of lifetime (RLOL) was defined as the area between the patient and general population survival curves until 5-years. The general population survival was retrieved from publicly available lifetables stratified on age, sex, calendar year, and country. Results: In total, 108 AYA BL patients were included. The median age was 30 years, ranging between 18 and 39 and 82% were male. The majority had advanced stage disease (Ann Arbor stage III-IV, 76%), extranodal involvement (87%), and elevated LDH (67%). Seven patients (6%) had CNS involvement at the time of diagnosis. The chemotherapy regimens used were CODOX-M/IVAC (51%), BFM/GMALL (34%), hyper-CVAD (7%), DA-EPOCH (5%), and others (3%). Among 74 patients for whom data on tumor lysis were available, 10 (14%) developed clinical tumor lysis upon start of chemotherapy, all presenting with advanced stage and extranodal disease. The response rate was 91% (89 in CR/CRu and 2% in partial remission). At a median follow-up of 53 months, 15 had an event and 10 died. The 2-year OS and EFS for the total population was 92% (87-97%, Figure 1) and 88% (82-94%), respectively. For 13 patients aged 18-21 2-year OS and EFS were both 100%, while 2-year OS and EFS for 43 patients aged 22-30 were 98% (93-100%) and 93% (85-100%), respectively. The 2-year OS and EFS for patients aged 31-39 were 86% (76-96%) and 80% (69-91%), respectively. For patients in CR/CRu and available date of response evaluation, the 2-year post-remission OS was 99% (97-100%) and the 2-year relapse risk was 2% (0-5%), with no relapses after 6 months. Compared to the general population, the RLOL was 0.8 months (-0.5-2.2 months). Nine patients did not respond to primary treatment (SD or PD), all which belonged to the age group 31-40 years (P&lt;0.001 versus age group 18-30 years). The oldest age group had an inferior OS compared to younger patients (P=0.008), largely due to non-responders having poor subsequent survival with a 1-year OS of 33%. Conclusion: The outcomes of AYA BL patients following intensive immunochemotherapy are excellent with high remission rates and low risk of relapse in general. However, even among young patients age remained prognostic, with patients 31 years or older having inferior OS and lower response rate to first-line treatment. In patients achieving CR, survival was similar to that of the general population over the median follow-up of 4.5 years, illustrating the need to focus on survivorship issues in these individuals. Figure 1: Overall survival for BL patients following intensive immunochemotherapy for all patients and for age groups (18-21, 22-30, and 31-39 years). Figure 1 Disclosures Jørgensen: Gilead: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Holte:Novartis: Honoraria, Other: Advisory board. Molin:Roche Holding AG: Honoraria; Merck &amp; Co., Inc.: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda Pharmaceuticals: Honoraria. Ekstroem Smedby:Takeda: Honoraria, Other: Grant funding, Research Funding; Celgene: Honoraria, Other: Grant funding, Research Funding; Janssen Cilag: Honoraria, Other: Grant funding, Research Funding. Song:Takeda: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria; Amgen: Honoraria. Gerrie:Lundbeck, Seattle Genetics: Consultancy, Honoraria. Cheah:Roche, Janssen, MSD, Gilead, Loxo Oncology, Acerta, BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel expenses; Celgene, Roche, Abbvie: Research Funding. El-Galaly:Roche: Employment, Other: Travel support; Takeda: Other: Travel support.