Hematologic Relapse Research Articles

Immediate Allogeneic Hematopietic Stem Cell Transplantation for Patients with NPM1-Mutated AML in Molecular Relapse

BackgroundAccording to ELN 2017 classification NPM1-mutated AML is characterized as favorable or intermediate risk depending on the coexistence of FLT3 mutations. For pts with favorable risk profile allogeneic hematopoietic stem cell transplantation (HSCT) in first complete remission (CR) is not recommended. Because NPM1 mutations are stable, and persisting or increasing levels are a strong predictor of relapse, regular monitoring of measurable residual disease (MRD) by quantitative PCR (qPCR) is recommended. Early HSCT in molecular relapse can be an effective treatment strategy and avoid possible complications of reinduction chemotherapy. From 2014 we started to search for a donor immediately after molecular relapse and proceed to HSCT without reinduction chemotherapy.MethodsMRD was monitored at least every 3 months (mos) in all pts with NPM1-mutated AML in CR by qPCR in bone marrow or peripheral blood. Molecular relapse was defined as an increase of MRD above a cut-off of 1% NPM1/ABL1. The conditioning regimen consisted of Treosulfan (Treo, 30g/m 2) and Fludarabin (Flu, 120mg/m 2). In pts with hematological relapse or a very high NPM1 ratio at the time of HSCT Melphalan (Mel, 100mg/m 2) was added before Treo/Flu to induce aplasia. Donors were HLA-compatible unrelated donors in 10/13 pts, HLA identical sibling in 1 pt and haploidentical related donors in 2 pts. All pts were transplanted with G-CSF stimulated peripheral blood stem cells. Immunosuppression consisted of ATG and Ciclosporin in combination with MTX or MMF and posttransplant Cyclophosphamide for haploidentical HSCT (2 pts).Results17/37 pts fit for allogeneic transplantation relapsed after initial induction and consolidation therapy. 4 pts showed a hematological relapse. In 13/15 pts (median age 52 (37-72) years) a molecular relapse was detected at a median of 9 (6-42) mos after diagnosis, these pts are analyzed here. 10/13 relapses occurred within 12 mos after CR. 11/13 pts relapsed after achieving MRD negative remission, 2 pts progressed from MRD positive hematological remission. Median time from increase in MRD to HSCT was 2 (2-4) mos. Even after this short time period, 6/13 pts developed a hematological relapse before start of conditioning therapy. Together with 3 pts with a high molekular NPM1 level, these 6 pts received melphalan for induction of aplasia before starting Treo/Flu. Although hematological regeneration took longer for these pts compared to pts without melphalan, there were not more infectious or bleeding complications. All 13 pts reached complete hematological and molecular remission after HSCT. After a median follow-up of 20 (4-47) mos all pts are in CR. 2 pt relapsed 6 and 13 mos after HSCT, but reached CR again after DLI (1 pt.) and venetoclax(1pt). In all pts the duration of second CR after HSCT lasted longer than the first CR.ConclusionThis analysis shows the efficacy and feasibility of early allogeneic HSCT without reinduction chemotherapy in molecular or early hematological relapse for NPM1- mutated AML pts. For this strategy pts have to be monitored strictly at regular intervals after end of chemotherapy consolidation, because most relapses can be detected at molecular level. DisclosuresNo relevant conflicts of interest to declare.

Risk Factors and Prognosis Analysis of Patient-Specific HLA Genomic Loss Relapse Following ATG-Based T-Cell-Replete Haploidentical Hematopoietic Stem Cell Transplantation

BackgroundDevelopments in related haploidentical hematopoietic stem cell transplantation (haplo-HSCT) have made two immune systems with incompatible human leukocyte antigens (HLA) adaptable, greatly reducing transplantation-related toxicity. In the haploidentical transplantation system, patient-specific HLA antigens are a primary way in which donor immune cells exert their graft-versus-leukemia effects by alloreactivity, and therefore patient-specific HLA genomic loss is often considered a mechanism of leukemia relapse. Although the incidence and characteristics of HLA loss have been investigated in patients with myeloid leukemia who relapsed after transplantation, patient-specific HLA genomic loss in lymphoid conditions and under different transplantation regimes remain enigmatical. We herein provide the data for HLA loss relapse in lymphoid disease, as well as offer data in myeloid disease based on antithymocyte globulin (ATG) T-cell-replete conditioning.MethodsBetween May 2012 and May 2021, 106 patients were enrolled in this study, including 104 had hematological relapse and 2 had minimal residual disease (MRD) recurrence after haplo-HSCT. All data were collected from centers within the Zhejiang Provincial Workgroup of HSCT. Firstly, the patients were divided into two groups according to the type of disease: myeloid and lymphoid conditions, and secondly, they were divided into the Classic Group and the Loss Group according to whether the patients had unshared HLA genomic loss at the time of relapse or not. A two-tailed P value of 0.05 was considered statistically significant. Univariate analysis is performed using the χ2 test, Fisher exact test, and Student t test, as appropriate. A multivariate model was used to calculate the odds ratio (OR) with a 95% confidence interval (CI). Post relapse overall survival (prOS) was estimated and plotted using the Kaplan-Meier method.ResultsOf all patients, HLA loss was detected in 50.9% (54/106) patients and the occurrence was not related to disease type (P=0.44). Patients having either myeloid malignancies or lymphoid malignancies with HLA loss experienced relapse later than those with classic relapse. The demographic and baseline characteristics of patients were summarized in Table 1, and the post-relapse parameters were presented in Table 2.We next determined what factors correlating with HLA loss at relapse by multivariate analysis. For patients with myeloid malignancies, a pre-transplant underweight status based on body mass index (BMI) was a factor strongly correlated with classic type when relapse (OR=0.095, 95%CI: 0.015~0.604, P=0.013); patients suffering de novo aGVHD had an OR of 4.844 (95%CI: 1.143~20.530, P=0.032) (Figure 1). As for lymphoid conditions, patients who experiencing MRD-positivity before hematological relapse (OR=22.623, 95% CI: 1.597~320.532, P=0.021), and >180 days from HSCT to relapse (OR=5.695, 95% CI: 1.073~30.211, P=0.041) were more likely to lose unshared HLA at relapse. Yet male patients (OR=0.037, 95% CI: 0.003~0.411, P=0.037) were inclined to have classic one when relapse (Figure 1).For prognosis, in patients with myeloid conditions, the median prOS was 217 days and 215 days in the Loss Group and Classic Group, respectively (P=0.34). In the Loss Group, the white blood cell (WBC) at diagnosis was related to prOS (>50ⅹ10 9/L vs. ≤50ⅹ10 9/L: median: 157 vs. 261 days, P=0.037). For patients having male donors, patient gender was related to prOS: median prOS was 386 days for male patients and 124 days for female patients (P=0.008). For patients with lymphoid malignancies, the median prOS was 285 days and 244 days in the Loss Group and Classic Group, respectively (P=0.24). The results of the univariate analysis from the Loss Group showed that male patients (median: 40 vs. 194 days; P=0.036) and cGVHD fare (median: 114 vs. 468 days; P=0.002) were related to inferior prOS.ConclusionThe occurrence of patient-specific HLA genomic relapse after haplo-HSCT appears later than classic relapse. In myeloid malignancies, the patient pre-transplant BMI and aGVHD fare are associated with the relapsed type. In lymphoid conditions, patient sex, presence of MRD-positive results before relapse, and the time from transplantation to relapse correlate with HLA loss at relapse. Yet this study is based on a limited number of patients, further validation in other centers is warranted. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Patient-Tailored Measurable Residual Disease Monitoring in Peripheral Blood Using Deep Sequencing and Droplet Digital PCR for Early Detection of Relapse in Childhood Acute Myeloid Leukemia: A NOPHO-DBH Collaborative Study

Close surveillance of measurable residual disease (MRD) following completion of therapy for acute myeloid leukemia (AML) enables early detection of relapse in time for pre-emptive treatment. Today this is available only for the fraction of patients with recurrent targets quantifiable with standardized RT-qPCR. Patient-tailored MRD monitoring based on leukemia-specific mutations may be an attractive option in patients lacking such aberrations. In this population-based study, we used whole exome sequencing (WES) to identify leukemia-specific mutations suitable for MRD monitoring, and targeted deep sequencing (deep seq) and droplet digital PCR (ddPCR) for quantitative monitoring in children with AML. We investigated the clinical applicability of patient-tailored deep seq and ddPCR for early detection of AML relapse in peripheral blood (PB).All children (0-18 years) with de novo AML diagnosed between March 2013 and December 2018 who achieved complete remission after treatment according to the NOPHO-DBH AML 2012 protocol (EudraCT number: 2012-002934-35) in Sweden, Denmark, the Netherlands, Norway and Finland were eligible for the study (n = 179). In the study, patients had PB samples drawn at monthly intervals and biobanked for retrospective analyses of leukemia-specific mutations. In patients with a marker for RT-qPCR, samples were also analyzed with RT-qPCR with results reported back to the clinic. Included patients (n = 134) had PB samples drawn starting one month after last consolidation course or date of allogeneic stem cell transplantation and until relapse or end of follow-up (12-18 months following therapy completion), (median 11 samples/patient, range 1-28). Out of the 34 patients who experienced relapse during the study period, sufficient biological material for WES at diagnosis was available from 26 patients (21 hematologic and 5 molecular relapses as determined by RT-qPCR in patients with a suitable marker). For these 26 patients, the median time from end of therapy to relapse (hematologic or molecular) was 6.7 months (range 3.1-23.7). In 24/26 patients, leukemia-specific mutations could be identified at diagnosis. For 22/24 patients, leukemia-specific mutations were verified to be present at relapse (hematologic or molecular) either by WES or deep seq. In the remaining two patients with molecular relapse, leukemia-specific mutations were not verified at molecular relapse. In the 22 patients where leukemia-specific mutations could be detected, 55 mutations (median 3/patient, range 1-4) were quantified with deep seq (limit of detection [LoD] 0.02% variant allele frequency [VAF]) in 111 PB samples (263 analyses) with a sampling interval of 0.9 months (range 0.2-2.6). Parallel ddPCR analyses of 43 mutations from 20 of these patients were performed in 100 PB samples (206 analyses) with a median LoD of 0.04% VAF (range 0.003-0.1%). Deep seq and ddPCR were concordant in 187/206 (91%) of analyses and 84/100 (84%) of analyzed samples. Median VAF in the 113 paired analyses with MRD level above LoD was 0.34% (range 0.02-47.23) with deep seq and 0.38% (range 0.02-45.97) with ddPCR (P = 0.7). Obtained VAFs correlated strongly between the two methods (Spearman's ρ 0.91, P < 0.0001). Nineteen of the analyzed patients experienced hematologic relapse and in 17 of these, at least one mutation was detected in blood before relapse. The median lead time from MRD positivity to hematologic relapse was 3.2 months (range 0.6-7.9) when analyzed with deep seq (n = 17) and 2.6 months (range 0.5-7.9) when analyzed with ddPCR (n = 15). Lead times in patients analyzed with both deep seq and ddPCR showed comparable Kaplan-Meier curves (Fig. 1A). Additional comparison of the lead times achieved with deep seq/ddPCR and RT-qPCR of WT1 expression (n = 6) and recurrent genetic aberrations (n = 5) showed similar Kaplan-Meier curves (Fig. 1B-C). As assessed by deep seq in patients who were not pre-emptively treated, relapse kinetics varied greatly between patients; median VAF doubling time was 12 days with a range of 4-43 (n = 17).In conclusion, highly sensitive quantification of leukemia-specific mutations in a patient-tailored manner using deep seq or ddPCR enables post-treatment monitoring for the majority of children with AML. Frequent assessment in blood may allow for timely identification of pending relapses to initiate pre-emptive treatment strategies. [Display omitted] DisclosuresAbrahamsson: wedish Children´s Cancer Foundation. Research grants and 50% senior research position for clinical research on pediatric leukemia: Research Funding.

Immune Checkpoint Analysis of T Effectors and Regulatory T Cells in Patients with CML Reveals Increased Expression at Diagnosis and with Refractory Disease

Immune Checkpoint Analysis of T Effectors and Regulatory T Cells in Patients with CML Reveals Increased Expression at Diagnosis and with Refractory Disease

Real World Data of Concurrent Arsenic Trioxide and All-Trans Retinoic Acid with Minimal Use of Anthracycline in the Treatment of Acute Promyelocytic Leukemia

▪In the setting of clinical trials, high cure rates have been reported for acute promyelocytic leukemia (APL) with the chemotherapy-free combination of arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) for low-intermediate risk disease, and with the addition of gemtuzumab ozogamicin or minimal anthracycline for high-risk disease. Despite clear in-vitro synergy between ATO and ATRA, most clinical trial protocols in APL have not used these drugs concurrently beyond induction. There is limited real world data on the use of chemotherapy-free combination of ATO and ATRA with minimal anthracycline use in the treatment of APL, especially in the high risk group. We did a retrospective analysis of the clinical outcomes of patients with newly diagnosed APL treated at our center from January 2015 to May 2020 using concurrent ATO, ATRA and minimal anthracycline in a risk stratified manner. The data was frozen and analyzed as on 1st June 2021. During the study period, 167 patients were diagnosed to have APL at our hospital. Of these, we excluded 5 patients who had presented with relapsed disease and 28 patients who were treated with single agent ATO. The remaining 134 patients were treated with a uniform protocol as summarized in Figure 1a. Figure 1b shows the KM plot for EFS (2 year: 90.8±2.5%) for these 134 patients. For analysis of regimen safety and efficacy, we excluded patients who wished to pursue treatment elsewhere within the first 1 week of treatment (n=7), and patients who had severe infections or life-threatening bleeding at presentation or before therapy initiation and subsequently died (n=4). Thus, a total of 123 patients with newly diagnosed APL were included for further analysis. The median age was 35 years (IQR: 24 to 45 years). Forty-six (37.4%) were females. The median duration of symptoms prior to admission was 14 days (IQR: 7 to 28 days). Sixty-one (49.6%) had high risk APL while the remaining 62 (50.4%) had low-intermediate risk APL. During induction, 28 (22.7%) patients had major bleeding while 5 (4%) patients developed major thrombosis. Sixty-seven (55%) patients had at least one documented infection during induction therapy. The median number of packed red cell concentrates, fresh frozen plasma, platelet rich concentrates and cryoprecipitates transfused during induction therapy was 5 (IQR: 3 to 6.5), 10 (IQR: 3 to 30), 40 (IQR: 23 to 55) and 6 (IQR: 0 to 18) respectively. Nineteen (15.4%) patients developed differentiation syndrome; all were treated with steroids, 8 required transient cessation of treatment and 6 required intensive care. Eight (6.5%) patients died during induction. During induction, grade 3 hepatotoxicity was noted in 8 (6.5%) patients, 10 (8.1%) patients had ATRA related headache or benign intracranial hypertension of which 5 required transient cessation of ATRA, while 11 (8.9%) patients had transient QTc prolongation of which 6 required transient cessation of ATO. Seventeen (13.8%) patients developed symptomatic sensory neuropathy requiring treatment. None required permanent discontinuation of therapy. At a median follow up of 854 days, there were 2 (1.6%) hematologic relapses and no deaths beyond induction therapy. The 2-year OS and EFS for the cohort (n=123) are 93.4% ± 2.3% and 91.6% ± 2.6% respectively (Figure 1c). Two (1.6%) patients have developed second malignancies. In a real world setting, concurrently administered ATO and ATRA with minimal anthracycline use results in excellent long term survival, even in the high risk group. Early deaths due to delayed presentation with infections and life threatening bleeding remain an unmet need for future research along with the need for strategies to reduce treatment-related toxicities. [Display omitted] DisclosuresMathews: Christian Medical College: Patents & Royalties: US 2020/0345770 A1 - Pub.Date Nov.5, 2020; AML: Other: Co-Inventor.

First-in-Human Study of WT1 Recombinant Protein Vaccination in Elderly Patients with AML in Remission: A Single-Center Experience

BackgroundVaccination (vac) strategies to maintain remissions in AML have been pursued for decades. The usage of recombinant proteins instead of peptides allows a potential immune response to multiple epitopes, hence could be offered to all patients (pts) independent of HLA expression. Wilms' tumor 1 (WT1) protein is highly immunogenic and frequently overexpressed in AML, thus ranked as a very promising target for novel immunotherapies. Here we report a single-center experience of a phase I/II clinical trial (NCT01051063) of a first-in-human vac strategy based on WT1 recombinant protein (WT1-A10) together with vaccine adjuvant AS01 B in 5 elderly AML pts.Patients and MethodsKey eligibility criteria: overexpression of WT1 transcripts in AML blasts at diagnosis (qRT-PCR); 1 or 2 induction chemotherapies, with partial remission (PR) or morphologic complete remission with incomplete blood count recovery (CRi). The vaccine consisted of WT1-A10, a truncated WT-1 protein retaining the N-terminus (amino acids 2-281) of full length WT1 protein (429 aa) linked to the first 11 amino acids of trimethylamine N-oxide reductase signal peptide via one histidine residue combined with the liquid AS01 B adjuvant. AS01 B is an Adjuvant System containing MPL (3-O-desacyl-4´-monophosphoryl lipid A), QS-21 (Quillaja saponaria Molina, fraction 21) and liposome (50µg MPL and 50µg QS-21). One human dose of WT1-A10 + AS01 B contained 200 μg of WT1-A10 antigen. Pts received the vaccine by i.m. injection. To assess cellular response, antigen-specific stimulation of cultured PBMCs was performed with a pool of 123 15mer peptides covering the entire WT1 (1μg/ml/peptide), together with irrelevant re-stimulation plus negative control peptide. CD4 + and CD8 + T cells were serially assessed by intracellular flow cytometry for their ability to produce both IFN-γ and TNF upon antigen stimulation.ResultsA total of 5 pts (median age 69, range 63-75) were enrolled on the WT1 protein-based vac study at our institution (Table 1), receiving a total of 62 vac after a median of 3 courses (1-5) of standard chemotherapy. The repeated vac had an acceptable safety profile and were thus well tolerated. 2/5 pts experienced therapy-related toxicity, injection site pain (CTCAE v.3, grade 2) and injection site inflammation (CTCAE v.3, grade 1). Symptoms were of mild / moderate severity and resolved completely. No hematologic toxicity was noted. With a median progression-free survival of 28.8 mths (range 1-59) and median overall survival (OS) of 35.4 mths (range 3-75) from the 1st vac, this older patient cohort showed above-average clinical outcome (Table 1), pointing to a potential clinical efficacy of WT1-based vac therapy. All vaccinated pts showed highly elevated WT1 ratios before WT1-based vac therapy and normal levels after vac (Fig. 1A). Two pts demonstrated early relapse after 3 WT1 protein-based vac, and clinical benefit was observed in 3 pts: one achieved complete and sustained measurable residual disease clearance (NPM1 ratios) during WT1 vac, resulting in molecular CR at the 18th vac. The pt died from unrelated reasons 5.5 years after initial diagnosis of AML, 3.5 years after the last WT1 vac, with continued molecular CR. One pt maintained long-term hematological and molecular remission over 59 mths, until molecular relapse occurred 11 mths after the final, 21 st vac. Interestingly, in one case, a complete clonal switch occurred at hematologic relapse following 18 vac, with loss of WT1 overexpression: while the clone at initial diagnosis harbored FLT3, NPM1 and SRSF2 mutations, BRAF, KRAS and STAG2 mutations were detected at relapse (Fig. 1B), pointing to an ongoing suppression of the WT1 expressing AML clone. Flow cytometry studies were conducted in one pt to elucidate specific cellular immune responses. We noted CD4 + T cell immune responses by strong IFN-γ and TNF expression (Fig. 1C), suggestive of efficient immune stimulation post-vac, while CD8 + T cells failed to upregulate these key cytokines.ConclusionsThis vac strategy showed good feasibility, with a very acceptable safety profile, and appeared to extend remissions beyond the expected duration, together with MRD clearance. Thus, our data provide evidence of potential clinical efficacy of WT1 protein-based vac therapy in AML pts, making this maintenance approach an attractive alternative to more complex strategies, particularly in elderly pts with comorbidities. [Display omitted] DisclosuresDöhner: Abbvie: Consultancy, Honoraria; Jazz Roche: Consultancy, Honoraria; Daiichi Sankyo: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Celgene/BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Astellas: Research Funding; Agios and Astex: Research Funding. Schmitt: MSD: Membership on an entity's Board of Directors or advisory committees; TolerogenixX: Current holder of individual stocks in a privately-held company; Bluebird Bio: Other: Travel grants; Hexal: Other: Travel grants, Research Funding; Novartis: Other: Travel grants, Research Funding; Kite Gilead: Other: Travel grants; Apogenix: Research Funding. Lübbert: Teva: Research Funding; Janssen: Research Funding; Cheplapharm: Research Funding; Aristopharm: Research Funding; Syros: Honoraria; Pfizer: Honoraria; Janssen: Honoraria, Research Funding; Imago BioSciences: Honoraria; Hexal: Honoraria; Astex: Honoraria; Abbvie: Honoraria.

The Omission of High-Dose Cytarabine during Consolidation Therapy of Ph-Positive ALL Patients Treated with Nilotinib and Low-Intensity Chemotherapy Results in an Increased Risk of Relapses Despite Non-Inferior Levels of Late BCR-ABL1 MRD Response. First Results of the Randomized Graaph-2014 Study

The Omission of High-Dose Cytarabine during Consolidation Therapy of Ph-Positive ALL Patients Treated with Nilotinib and Low-Intensity Chemotherapy Results in an Increased Risk of Relapses Despite Non-Inferior Levels of Late BCR-ABL1 MRD Response. First Results of the Randomized Graaph-2014 Study

Outcomes with Natural Killer Cells Infusion after Allogeneic Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis

Background:Natural killer cells (NK) are known to be the first cells that recover after allogeneic hematopoietic stem cell transplant (HCT). NK cells have anti-leukemic and anti-viral properties and are also implicated in the graft versus leukemia (GVL) effect without causing graft versus host disease (GVHD). There is emerging evidence supporting the use of NK cells post-transplant as adoptive immunotherapy to prevent or treat the relapse of hematologic malignancies. Here, we present a systematic review and meta-analysis aimed to investigate the outcomes with NK cells infusion after HCT.Methods:A detailed literature search was conducted for the systematic review and meta-analysis according to the guidelines mentioned in the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). Population, intervention, comparison, and outcome (PICO) table was developed and three electronic databases (PubMed, Cochrane Library, and ClinicalTrials.gov) were searched through January 2021 using MeSH terms and keywords for “hematologic malignancy and natural killer cells” and “hematopoietic stem cell transplantation and natural killer cells”. No filters or publication time limits were applied for the search. A total of 988 records were identified through database searching. After excluding duplicates, review, and non-relevant articles, we selected 9 studies that reported outcomes with NK cells infusion after HCT. Quality evaluation was done using the NIH quality assessment tool and Inter-study variance was calculated using the Der Simonian-Laird Estimator. Pooled analysis was done using the ‘meta’ package (Schwarzer et al, R programming language) and proportions with 95% confidence intervals (CI) were computed.Results:We identified 9 studies with a total of 149 participants. Out of these, 53 patients were from 4 studies using NK cells for the treatment of relapsed disease after HCT (therapeutic studies) and 96 patients were from 5 studies using NK cells to prevent relapse after HCT (pre-emptive studies).Therapeutic use of NK cells for relapsed disease after HCT: A total of 53 patients from 4 studies were evaluated. The median age of patients was 44.5 (1.9-69) years, and 40% patients were male. The median follow-up was 20 (1-69) months. Overall survival (OS) was reported by two studies at 2 years and was 36.3% and 55%. The pooled complete response (CR) was 18% (95% CI 0.06-0.33, I 2 =0%, n=37) and overall response rate (ORR) was 45% (95% CI 0.20-0.71, I 2 =71%, n=53). The pooled relapse rate was 65% (95% CI 0.32-0.92, I 2 =75%, n=42). The pooled incidence of acute GVHD and chronic GVHD was 15% (95% CI 0.03-0.31, I 2 =41%, n=53) and 8% (95% CI 0.01-0.18, I 2 =0%, n=53) respectively.Pre-emptive use of NK cells to prevent relapse after HCT: A total of 96 patients from 5 studies were evaluated. The median age of patients was 33.5 (2-75) years, and 48% patients were males. The median follow-up was 23.1 (8-81.6) months. The median OS was 1 (0.63-5) years. The pooled CR was 45% (95% CI 0.21-0.70, I 2 =76%, n=83) and ORR was 89% (95% CI 0.57-1.00, I 2 =77%, n=42). The pooled relapse rate was 35% (95% CI 0.20-0.52, I 2 =55%, n=96). The pooled incidence of acute GVHD and chronic GVHD was 30% (95%CI 0.14-0.48, I 2 =61%, n=96) and 8% (95%CI 0.00-0.24, I 2 =73%, n=96) respectively.Conclusion:Infusion of NK cells after HCT to prevent relapsed disease results in favorable outcomes with an acceptable toxicity profile. Optimal use of NK cells infusions after HCT is in a pre-emptive fashion to prevent relapsed disease and the efficacy of NK cells infusions after HCT in the setting of overt hematologic relapse is modest. Our findings suggest the need for large prospective clinical trials to establish the potential benefit of NK cells infusion after HCT to prevent relapse of hematologic malignancies without increased non-relapse mortality. [Display omitted] DisclosuresAbhyankar: Incyte/Therakos: Consultancy, Research Funding, Speakers Bureau. McGuirk: Bellicum Pharmaceuticals: Research Funding; Gamida Cell: Research Funding; Novartis: Research Funding; Novartis: Research Funding; EcoR1 Capital: Consultancy; Fresenius Biotech: Research Funding; Astelllas Pharma: Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Pluristem Therapeutics: Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau.

Patient-reported outcomes in patients with hematological relapse or progressive disease: a longitudinal observational study

BackgroundPatients with hematological cancer who experience relapse or progressive disease often face yet another line of treatment and continued mortality risk that could increase their physical and emotional trauma and worsen their health-related quality of life. Healthcare professionals who use patient-reported outcomes to identify who will have specific sensitivities in particular health-related quality of life domains may be able to individualize and target treatment and supportive care, both features of precision medicine. Here, in a cohort of patients with relapsed or progressive hematological cancer, we sought to identify health-related quality of life domains in which they experienced deterioration after relapse treatment and to investigate health-related quality of life patterns.MethodPatients were recruited in connection with a precision medicine study at the Department of Hematology, Aalborg University Hospital. They completed the European Organization for Research and Treatment of Cancer questionnaire and the Hospital Anxiety and Depression Scale at baseline and at 3, 6, 9, and 12 months after the relapse diagnosis or progressive cancer. Modes of completion were electronically or on paper. Clinically relevant changes from baseline to 12 months were interpreted according to Cocks’ guidelines. We quantified the number of patients with moderate or severe symptoms and functional problems and the number who experienced improvements or deterioration from baseline to 12 months.ResultsA total of 104 patients were included, of whom 90 (87%) completed baseline questionnaires and 50 (56%) completed the 12-month assessments. The three symptoms that patients most often reported as deteriorating were fatigue (18%), insomnia (18%), and diarrhea (18%). The three functions that patients most often reported as deteriorating were role (16%) and emotional (16%) and cognitive (16%) functioning.ConclusionIn this study, patient-reported outcome data were useful for identifying negatively affected health-related quality of life domains in patients with relapsed or progressive hematological cancer. We identified patients experiencing deterioration in health-related quality of life during treatment and characterized a potential role for patient-reported outcomes in precision medicine to target treatment and supportive care in this patient group.

Novel Molecular Mechanism of Lenalidomide in Myeloid Malignancies Independent of Deletion of Chromosome 5q.

Simple SummaryLenalidomide is an immunomodulatory drug (IMiD) that has achieved clinical efficacies in multiple myeloma (MM) and myelodysplastic syndromes (MDS) with a single deletion of chromosome 5q (del(5q)). However, many patients treated with lenalidomide relapse and become resistant. Recent studies have demonstrated that lenalidomide binds a protein called cereblon (CRBN), leading to reduced protein levels of IKZF1 and IKZF3 and casein kinase 1 alpha. We have identified signaling molecules downstream of IKZF1, G protein-coupled receptor 68 (GPR68) and regulator of calcineurin 1 (RCAN1) in myeloid malignancies, including MDS and acute myeloid leukemia (AML) with or without del(5q). This review summarizes how lenalidomide exerts anti-tumor activity and highlights novel therapeutic targets that could enhance the anti-tumor activity of lenalidomide with a focus on myeloid malignancies, especially without del(5q).Lenalidomide as well as other immunomodulatory drugs (IMiDs) have achieved clinical efficacies in certain sub-types of hematologic malignancies, such as multiple myeloma, lower-risk myelodysplastic syndromes (MDS) with a single deletion of chromosome 5q (del(5q)) and others. Despite superior clinical response to lenalidomide in hematologic malignancies, relapse and resistance remains a problem in IMiD-based therapy. The last ten years have witnessed the discovery of novel molecular mechanism of IMiD-based anti-tumor therapy. IMiDs bind human cereblon (CRBN), the substrate receptor of the CRL4 E3 ubiquitin ligase complex. Binding of CRBN with IMiDs leads to degradation of the Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3) and casein kinase 1 alpha. We have found that lenalidomide-mediated degradation of IKZF1 leads to activation of the G protein-coupled receptor 68 (GPR68)/calcium/calpain pro-apoptotic pathway and inhibition of the regulator of calcineurin 1 (RCAN1)/calcineurin pro-survival pathway in MDS and acute myeloid leukemia (AML). Calcineurin inhibitor Cyclosporin-A potentiates the anti-leukemia activity of lenalidomide in MDS/AML with or without del(5q). These findings broaden the therapeutic potential of IMiDs. This review summarizes novel molecular mechanism of lenalidomide in myeloid malignancies, especially without del(5q), in the hope to highlight novel therapeutic targets.

Measurable Residual Disease Monitoring of SPAG6, ST18, PRAME, and XAGE1A Expression in Peripheral Blood May Detect Imminent Relapse in Childhood Acute Myeloid Leukemia

Overexpressed genes may be useful for monitoring of measurable residual disease (MRD) in patients with childhood acute myeloid leukemia (AML) without a leukemia-specific target. The normal expression of five leukemia-associated genes (SPAG6, ST18, MSLN, PRAME, XAGE1A) was defined in children without hematologic disease (n = 53) and children with suspected infection (n = 90). Gene expression at AML diagnosis (n=50) and during follow-up (n = 21) was compared with child-specific reference values. At diagnosis, 34/50 children (68%) had high expression of at least one of the five genes, and so did 16/31 children (52%) without a leukemia-specific target. Gene expression was quantified in 110 peripheral blood (PB) samples (median, five samples/patient; range, 1 to 10) during follow-up in 21 patients with high expression at diagnosis. All nine patients with PB sampling performed within 100 days of disease recurrence displayed overexpression of SPAG6, ST18, PRAME, or XAGE1A at a median of 2 months (range, 0.6 to 9.6 months) before hematologic relapse, whereas MSLN did not reach expression above normal prior to hematologic relapse. Only 1 of 130 (0.8%) follow-up analyses performed in 10 patients in continuous complete remission had transient expression above normal. SPAG6, ST18, PRAME, and XAGE1A expression in PB may predict relapse in childhood AML patients and facilitate MRD monitoring in most patients without a leukemia-specific target.

Dasatinib-based 2-step induction for adults with Philadelphia chromosome–positive acute lymphoblastic leukemia

AbstractThe standard treatment for adults with Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) in Japan is imatinib-based chemotherapy followed by allogeneic hematopoietic stem cell transplantation (HSCT). However, ∼40% of patients cannot undergo HSCT in their first complete remission (CR1) because of chemotherapy-related toxicities or relapse before HSCT or older age. In this study, we evaluated dasatinib-based 2-step induction with the primary end point of 3-year event-free survival (EFS). The first induction (IND1) was dasatinib plus prednisolone to achieve CR, and IND2 was dasatinib plus intensive chemotherapy to achieve minimal residual disease (MRD) negativity. For patients who achieved CR and had an appropriate donor, HSCT during a consolidation phase later than the first consolidation, which included high-dose methotrexate, was recommended. Patients with pretransplantation MRD positivity were assigned to receive prophylactic dasatinib after HSCT. All 78 eligible patients achieved CR or incomplete CR after IND1, and 52.6% achieved MRD negativity after IND2. Nonrelapse mortality (NRM) was not reported. T315I mutation was detected in all 4 hematological relapses before HSCT. Fifty-eight patients (74.4%) underwent HSCT in CR1, and 44 (75.9%) had negative pretransplantation MRD. At a median follow-up of 4.0 years, 3-year EFS and overall survival were 66.2% (95% confidence interval [CI], 54.4-75.5) and 80.5% (95% CI, 69.7-87.7), respectively. The cumulative incidence of relapse and NRM at 3 years from enrollment were 26.1% and 7.8%, respectively. Dasatinib-based 2-step induction was demonstrated to improve 3-year EFS in Ph+ ALL. This study was registered in the UMIN Clinical Trial Registry as #UMIN000012173.

Consolidation with a short course of daratumumab in patients with AL amyloidosis or light chain deposition disease

Daratumumab has major and rapid activity in AL amyloidosis with favourable toxicity. We used as a consolidation a short course of daratumumab in 25 patients with AL amyloidosis or light chain deposition disease (LCDD), who had not achieved a haematologic complete response (hemCR) after standard therapy with bortezomib, cyclophosphamide and dexamethasone (VCD). We evaluated minimal residual disease (MRD) and changes in the bone marrow (BM) microenvironment before and after consolidation using next generation flow cytometry (NGF). At the time of consolidation, 21 patients were in very good partial response (VGPR) and four in partial response (PR); all had detectable MRD. One month after consolidation completion, 8 patients (32%) achieved a hemCR, of whom 5 (20%) became also MRD negative. In the BM, we observed significant changes in B-cell precursors, naïve B-cells, T-cells, CD27+ NK & NKT cells, mast cells and erythroblasts. After a median follow-up of 25 months, none of the patients in hemCR has relapsed and all have achieved an organ response; a haematologic relapse occurred in 6/17 patients that did not achieve hemCR. In conclusion, consolidation with a short course of daratumumab can improve depth of response in patients with AL amyloidosis or LCDD and significantly affects BM environment.

Dosimetric evaluation of ovaries and pelvic bones associated with clinical outcomes in patients receiving total body irradiation with ovarian shielding.

Total body irradiation (TBI) with ovarian shielding is expected to preserve fertility among hematopoietic stem cell transplant (HSCT) patients with myeloablative TBI-based regimens. However, the radiation dose to the ovaries that preserves ovarian function in TBI remains poorly understood. Furthermore, it is uncertain whether the dose to the shielded organs is associated with relapse risk. Here, we retrospectively evaluated the relationship between fertility and the dose to the ovaries, and between relapse risk and the dose to the pelvic bones. A total of 20 patients (median age, 23 years) with standard-risk hematologic diseases were included. Median follow-up duration was 31.9 months. The TBI prescribed dose was 12 Gy in six fractions for three days. Patients’ ovaries were shielded with cylinder-type lead blocks. The dose–volume parameters (D98% and Dmean) in the ovaries and the pelvic bones were extracted from the dose–volume histogram (DVH). The mean ovary Dmean for all patients was 2.4 Gy, and 18 patients recovered menstruation (90%). The mean ovary Dmean for patients with menstrual recovery and without recovery were 2.4 Gy and 2.4 Gy, respectively, with no significant difference (P = 0.998). Hematological relapse was observed in five patients. The mean pelvis Dmean and pelvis D98% for relapse and non-relapse patients were 11.6 Gy and 11.7 Gy and 5.6 Gy and 5.3 Gy, respectively. Both parameters showed no significant difference (P = 0.827, 0.807). In conclusion, TBI with ovarian shielding reduced the radiation dose to the ovaries to 2.4 Gy, and preserved fertility without increasing the risk of relapse.

Newly proposed threshold and validation of white blood cell count at diagnosis for Philadelphia chromosome-positive acute lymphoblastic leukemia: risk assessment of relapse in patients with negative minimal residual disease at transplantation-a report from the Adult Acute Lymphoblastic Leukemia Working Group of the JSTCT.

White blood cell count (WBC) at diagnosis is the conventional prognostic factor in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Nevertheless, little is known about the impact of WBC at diagnosis considering the minimal residual disease (MRD) status at allogeneic hematopoietic cell transplantation (HCT). We evaluated adult patients with Ph+ ALL who achieved negative-MRD and received HCT in first complete remission between 2006 and 2018. The entire cohort was temporally divided into derivation (n = 258) and validation cohorts (n = 366). Using a threshold of 15,000/μL, which was determined by a receiver operating characteristic curve analysis in the derivation cohort, high WBC was associated with an increased risk of hematological relapse in both the derivation cohort (25.3% vs. 11.6% at 7 years, P = 0.004) and the validation cohort (16.2% vs. 8.5% at 3 years, P = 0.025). In multivariate analyses, high WBC was a strong predictor of hematological relapse in the derivation cohort (HR, 2.52, 95%CI 1.32-4.80, P = 0.005) and in the validation cohort (HR, 2.32, 95%CI, 1.18-4.55; P = 0.015). In conclusion, WBC at diagnosis with a new threshold of 15,000/μL should contribute to better risk stratification in patients with negative-MRD at HCT.

Comparison of Two Quantitative PCR–Based Assays for Detection of Minimal Residual Disease in B-Precursor Acute Lymphoblastic Leukemia Harboring Three Major Fusion Transcripts

Two quantitative PCR (qPCR)-based methods, for clonal immunoglobulin or T-cell receptor gene (Ig/TCR) rearrangements and for fusion transcripts, are widely used for the measurement of minimal residual disease (MRD) in patients with B-precursor acute lymphoblastic leukemia (ALL). MRD of bone marrow samples from 165 patients carrying the three major fusion transcripts, including 74 BCR-ABL1, 54 ETV6-RUNX1, and 37 TCF3-PBX1, was analyzed by using the two qPCR-based methods. The correlation coefficient of both methods was good for TCF3-PBX1 (R2=0.8088) and BCR-ABL1 (R2=0.8094) ALL and moderate for ETV6-RUNX1 (R2=0.5972). The concordance was perfect for TCF3-PBX1 ALL (97.2%), substantially concordant for ETV6-RUNX1 ALL (87.1%), and only moderate for BCR-ABL1 ALL (70.6%). The discordant MRD, positive for only one method with a difference greater than one log, was found in 4 of 93 samples (4.3%) with ETV6-RUNX1, 31 of 245 samples (12.7%) with BCR-ABL1, and none of TCF3-PBX1 ALL. None of the eight non-transplanted patients with BCR-ABL1-MRD (+)/Ig/TCR-MRD (-) with a median follow-up time of 73.5 months had hematologic relapses. Our study showed an excellent MRD concordance between the two qPCR-based methods in TCF3-PBX1 ALL, whereas qPCR for Ig/TCR is more reliable in BCR-ABL1 ALL.

Evaluation of pretreatment telomere length as a prognostic marker in intermediate-risk acute myeloid leukemia.

The current framework for risk stratification is still insufficient for highly heterogeneous intermediate-risk acute myeloid leukemia (IRC-AML), which lacks specific genomic abnormalities. In order to incorporate novel biomarkers to refine current risk stratification strategies for patients with this subtype, we investigated pretreatment telomere length (TL), which is essential for maintaining genomic stability, in 204 adults with de novo AML (non-acute promyelocytic leukemia). We found that TL measured at diagnosis did not decrease with advancing age in 204 patients with AML (R2 =0.001, P=.695). A multivariate analysis demonstrated that short TL was independently associated with an inferior relapse-free survival (hazard ratio [HR] 3.08, 95% confidence interval [CI] 1.48-6.41, P=.003); event-free survival (HR 2.14, 95% CI 1.12-4.08, P=.021); and overall survival (HR 2.26, 95% CI 1.09-4.67, P=.028) in IRC-AML patients. In addition, IRC-AML patients with short TL also exhibited an increased cumulative incidence of hematologic relapse (HR 2.32, 95% CI 1.08-5.26, P=.032). Short TL is an independent prognostic factor for poor prognosis in patients with IRC-AML and may represent a novel mechanism that links genomic stability and disease progression.

Reduction of Immunosuppression after Disease-Specific Donor Cell Chimerism Decrease Can Prevent Hematological Relapse Following Allogeneic Stem Cell Transplantation after Non-Myeloablative (NMA) Conditioning — Results of a Prospective Phase II Study. Eudract #: 2007-002420-15

Introduction: Relapse of the disease remains a major burden after stem cell transplantation (HCT) following myeloablative conditioning and even more after reduced intensity and non-myeloablative conditioning. Efforts to reduce relapse incidence involve early immunosuppression withdrawal and prophylactic buffy coat infusion in high risk patients. In this phase II study we analyzed the role of disease-specific chimerism driven immunosuppression.Methods: Between May 2008 and July 2012, 200 consecutive patients (pts) (130 male and 70 female) with a median age of 62.0 (range 26.2-74.8) years (y) with hematological malignancies were transplanted after NMA conditioning. The conditioning regimen consisted of fludarabine 30mg/m2 and total body irradiation (200 cGy) followed by immunosuppression with cyclosporine A (CSA) and mycophenolate mofetil (MMF). The primary objective of the study was to determine the incidence of relapse after a decrease of >10% disease-specific donor cell chimerism (DCC). Furthermore, the incidence of graft vs. host disease (GvHD) and the reconversion of DCC were investigated.Pts were transplanted for acute myeloid leukemia (AML; n=85; 42.5%), multiple myeloma (MM; n=31; 15.5%), myelodysplastic syndrome (MDS; n=26; 13%), chronic lymphocytic leukemia (CLL; n=22; 11%), B-Non-Hodgkin Lymphoma (B-NHL; n=11; 5.5%), T-NHL (n=6; 3.0%), acute lymphoblastic leukemia (ALL; n=7; 3.5%), myeloproliferative neoplasia (MPN; n=6; 3%), MDS/MPN (n=3; 1.5%) and chronic myeloid leukemia (CML; n=4; 2%). Donors were matched-related (MRD)(n=26;13%), matched unrelated (MUD) (n=129; 64.5%) and mismatched unrelated on allele or antigen level (n=45;22.5%).DCC analyses were performed on flow sorted cells on day (d)+ 28, d +56, d+ 84, d + 180 and every 6 months following. As a disease specific DCC line we used CD34 for AML, MDS and MPN pts, CD19 for CLL and B-NHL, CD138 for myeloma pts. The pts with T-NHL were monitored by CD3 chimerism. In addition, engraftment was monitored by CD3 chimerism.Results: Overall survival was 52.9 (95% Confidence Interval (CI) 46.4 - 60.3)% at 2y, and 43.9 (CI 37.3 - 51.6)% at 5y. Relapse incidence was median 28.2 (CI 22.1 - 34.6)% at 2 y and 30.3 (CI 23.9 - 36.9)% at 5 y. Non-relapse mortality (NRM) was 24.3 (CI 18.5-30.5)% at 2y and 30.4 (CI 23.9-37.1)% at 5y.DCC (≥90%) was observed in 116 of the 200 (58.0%) pts, 43 patients (21.5%) showed incomplete disease-specific DCC or reduction of DCC in association with hematological relapse: AML (n=17), MDS (n=4), MM (n=7), CLL (n=7), B-NHL (n=1), T-NHL (n=1), MPN (n=2), ALL (n=2), CML (n=1), MDS/MPN (n=1) and 41 patients (20%) had an isolated line specific DCC decrease after a median of 106 (28-2975) days following HCT.In the 41 pts with decrease in disease-specific DCC without hematological relapse, 1 was off immunosuppression and 3 pts had an active acute or chronic GvHD. In 37 pts CSA and MMF was reduced prematurely. 5 pts showed acute GvHD grade ≥III after reduction and 32 pts GvHD grade 0-II. Of the 37 pts, 27 (73.0%) showed no increase of DCC. 24 (88.9%) pts died, 18 due to relapse, 6 due to non-relapse causes. 3 pts are alive after salvage chemotherapy. 10 of the 37 patients (26.5%) reached full DCC after a median of 29 (21 - 267) days following immunosuppression taper and one recovered from the decrease of DCC and hematological relapse after discontinuing the immunosuppression.43 pts (15.5%) showed no full DCC with (n=12) or without hematological relapse (n=31). Following reduction of immunosuppression 32 pts relapsed, of which 4 are alive after salvage therapy. 2 pts rejected the HCT and are alive after 2nd HCT.85 AML pts were separately analysed, of which 43 experienced a complete DCC at any time point (27 are alive without relapse, 16 died due to non-relapse causes). 25 (29.4%) of which 24 pts were without active GvHD had isolated DCC decreased and were tapered. 7 converted to full DCC. All 17 pts showing no full disease specific DCC with or without simultaneous relapse relapsed. 15 pts died of relapse, 2 are alive after salvage therapy.Conclusion: Decrease of disease-specific DCC was observed in 20% of pts and in 29.4% of the AML pts. Of those 27.7 % in the total population and 29.2 % in the AML group showed recovery of DCC without hematological relapse after tapering of immunosuppression. We conclude that DCC is a useful tool to avoid relapse in the early phase of HCT while the patient is on immunosuppression. [Display omitted] DisclosuresFranke:Novartis: Honoraria, Research Funding; Pfizer: Honoraria; Takeda: Consultancy. Lange:Novartis: Honoraria, Research Funding. Schwind:Novartis: Consultancy.

Minimal-Residual Disease Guided Treatment with Azacitidine in MDS/AML Patients at Imminent Risk of Relapse: Results of the Prospective RELAZA2 Trial

Background: Although many patients (pts) with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) can achieve a complete remission (CR) by intensive chemotherapy, the majority will eventually relapse even after subsequent allogeneic hematopoietic stem cell transplantation (HSCT). Monitoring of minimal residual disease (MRD) in morphological CR has been shown to allow for predicting subsequent hematological relapse, thus opening a window for pre-emptive therapeutic interventions. We report on the results of the RELAZA2 trial (ClinicalTrials.gov NCT01462578) by the Study Alliance Leukemia (SAL) group evaluating azacitidine (AZA) as treatment of MRD to prevent relapse in patients with MDS or AML in CR after completion of standard treatment.Methods: From 2011 to 2015, 205 patients with either advanced MDS (n=27) or AML (n=178) in CR after either conventional chemotherapy only (n=58) or consecutive allogeneic HSCT (n=147) have been prospectively studied in 11 centers in Germany. MRD was centrally monitored in bone marrow or peripheral blood by starting on day 56 after completion of the last therapy followed by monthly intervals for a period of 2 years. Markers used for MRD detection confessed either the quantification of NPM1 mutation level (n=77), leukemia-specific fusion genes (DEK-NUP214 n = 1, t(8;21) n = 9, inv16 n = 10) or by a sensitive donor chimerism analysis of CD34(+) peripheral blood cells (n=108) in patients undergoing allogeneic HSCT. Patients with measurable MRD above a threshold defining imminent relapse but still being in CR preemptively received 6 cycles of AZA (75mg/m2, s.c. days 1-7). This was followed by an MRD risk-adapted AZA-based therapy for up to 18 additional months. Patients developing a hematological relapse went off study. The primary endpoint of the trial was the rate of hematological relapse after 6 cycles of AZA. We report the confirmatory analysis of the primary endpoint of those 53 patients who entered the treatment phase of the study.Results: At a median of 100 days (range 3-601) after start of screening, 53 out of 205 (26%) prospectively screened patients became MRD positive as defined by either a decrease of CD34(+) donor chimerism to <80% (n=19) or a detectable mutation level >1% (NPM1 n=31, t(8,21) n=3) while being still in hematological CR. All of these patients started AZA-based preemptive treatment. Six months after start of MRD-guided therapy, 31 out of 53 patients were still in CR (58%, 95%-CI 44-72%, p<0.001, one-sided binomial test for H0: pexp≤0.3) while a total of 22 patients (42%) relapsed after median of 3 AZA cycles. In fact, 21 patients (40%) responded with either a decline of MRD below a predefined threshold (increasing CD34(+) donor chimerism to ≥80% or mutation level <1%), while a stabilization in the absence of relapse was achieved in 10 patients (19%). Overall response rate was different between patients with (71%) or without (48%) antecedent allogeneic HSCT (p=0.007). After 6 months, 24 patients (45%) continued to receive a median of 9 (range 1-15) subsequent AZA cycles. Eventually, hematologic relapse occurred in 8 of those patients (33%), but was delayed until a median of 397 days (range 196-584 days) after initial MRD detection. Treatment was well tolerated with infections (n=4) and pneumonia (n=3) being the main severe side effects during the first 6 cycles. With a median follow-up of 13 months after start of MRD-guided preemptive treatment the actual overall and progression free survival rate is 76% and 42%, respectively.Conclusion: Pre-emptive MRD-guided therapy with AZA can prevent or substantially delay hematologic relapse in patients with MDS and AML at high-risk of relapse. Success of AZA-based MRD therapy seems to be context-dependent emphasizing the potential immunomodulatory effect of hypomethylating agents. [Display omitted] DisclosuresPlatzbecker:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Acceleron: Consultancy, Honoraria, Research Funding. Hänel:Roche: Honoraria; Novartis: Honoraria. Bug:Celgene: Honoraria, Other: Travel funding; Novartis: Honoraria, Research Funding; Astellas: Other: Travel Funding; Janssen: Other: Travel Funding; Jazz Pharmaceuticals: Other: Travel Funding; Amgen: Honoraria. Götze:Celgene: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Abbvie: Honoraria; BMS: Honoraria. Subklewe:Amgen Research (Munich): Research Funding; Amgen, Inc.: Research Funding. Schetelig:Sanofi Aventis: Consultancy, Research Funding; Roche: Honoraria; Abbvie: Honoraria; Janssen: Consultancy, Honoraria. Rollig:Janssen: Research Funding; Bayer: Research Funding. Thiede:Novartis: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Roche: Consultancy; Agendix: Employment.

Pre-Transplant Transferrin Saturation Levels As a Predictive Marker for Invasive Fungal Disease Following Allogeneic Hematopoietic Stem Cell Transplantation

▪IntroductionInvasive fungal disease (IFD) following allogeneic hematopoietic stem cell transplantation (allo-HCT) is a well-known, potentially fatal complication. Previous multicenter, prospective observational studies (Girmenia et al., 2014; Sun et al., 2015) have showed that the incidence of IFD after allo-HCT was approximately 9.0%, and risk factors were disease status, development of IFD prior to allo-HCT, alternative donor source (cord blood donor and unrelated donor), diabetes mellitus, prophylaxis of IFD, and acute or chronic graft-versus-host disease (GVHD).Iron has a pivotal role in various types of fungal growth and iron overload impairs the host immune system, leading to IFD. Moreover, some retrospective studies have reported that elevated pre-transplant serum ferritin levels, as a marker of iron overload, might be associated with the development of IFD (Dadwal et al., 2015). Although use of ferritin and transferrin saturation (TSAT) to assess iron status is extremely common, whether pre-transplant TSAT levels might be related to the development of IFD after allo-HCT has not been fully examined.We therefore investigated risk factors of IFD, including iron overload markers such as ferritin and TSAT.Patients and MethodsWe retrospectively analyzed data from consecutive patients undergoing allo-HCT between 1 April 2007 and 31 December 2014. We excluded three patients with active IFD at initiation of the conditioning regimen and two patients undergoing double-cord blood transplantation. Proven or probable IFD cases were defined as IFD. According to our institution guidelines, we administered IFD prophylaxis in all patients. We used Cox proportional hazards models with time-dependent covariates to investigate risk factors for IFD.ResultsA total of 285 patients were eligible. Twenty-one patients developed IFD within 1 year after allo-HCT. Median time to onset was 77 days (range, 8-363 days). Pathogens included Aspergillus (n=12), Candida (n=2), and others (n=7).Notably, none of our participants from HLA-matched or one-antigen mismatched sibling donors developed IFD. The significant univariate risk factors were as follows: disease status (malignancies in complete remission, non-malignancies, and chronic myelogenous leukemia in chronic phase vs. others), donor type (cord blood vs. haploidentical peripheral blood with post-transplant cyclophosphamide (PT-CY) vs. others), GVHD prophylaxis (calcineurin inhibitor (CNI) plus methotrexate (MTX) vs. CNI plus mycophenolate mofetil (MMF) vs. PT-CY vs. others), use of antithymocyte globulin (ATG), TSAT, and hematologic relapse after transplant or refractory at transplant. However, development of IFD prior to allo-HCT, diabetes mellitus, and acute or chronic GVHD were not related to the development of IFD.In the multivariate model considering pre-transplant factors, although use of ATG (hazard ratio (HR) 2.68, 95% confidence interval (CI): 1.07-6.02, P=0.04) was significant, disease status (HR 2.04, 95% CI: 0.78-5.32, P=0.15) and TSAT (HR 1.02, 95% CI: 1.00-1.03, P=0.07) were marginally but significantly associated with development of IFD. Regarding post-transplant factors, in model 2, hematologic relapse after transplant or refractory at transplant (HR 9.63, 95% CI: 3.86-24.02, P<0.01), TSAT (HR 1.02, 95% CI: 1.00-1.04, P=0.03), CNI plus MMF (vs. CNI plus MTX) among GVHD prophylaxis (HR 3.48, 95% CI: 1.07-11.30, P=0.04) were significant. In model 3, hematologic relapse after transplant or refractory at transplant (HR 10.42, 95% CI: 4.21-25.79, P<0.01), TSAT (HR 1.02, 95% CI: 1.00-1.03, P=0.05), and use of ATG (HR 2.72, 95% CI: 1.08-6.82, P=0.03) were significant. Remarkably, 33 of 55 patients who underwent ATG received PT-CY (n=55) to prevent GVHD.ConclusionOur results suggest that pre-transplant TSAT value might be useful for predicting development of IFD. Further investigation might be warranted to validate the generalizability of this marker. DisclosuresHino:Novartis: Research Funding.