5-year Cumulative Incidence Of Relapse Research Articles

Pharmacokinetic-Guided Busulfan Based Myeloablative Versus Fixed Dose Reduced Intensity Conditioning Regimen in Patients Older Than 55 Years Undergoing Allogeneic Stem Cell Transplantation for High Risk Hematological Malignancies

BACKGROUND Reduced intensity conditioning (RIC) combining fludarabine, busulfan and ATG is commonly used in patients with advanced age and/or comorbid conditions, thus deemed unfit for standard myeloablative conditioning (MAC) regimens (i.e. BuCy or CyTBI12). Although non-relapse mortality (NRM) is dramatically reduced with RIC, relapse remains a major concern. In younger patients, myeloablative doses of busulfan in combination with fludarabine (i.e. myeloablative reduced toxicity conditioning [MA-RTC] regimen) produce similar antitumor effect compared with standard MAC while keeping low NRM. The feasibility of such an approach for older patients is not known. We hypothesized that a pharmacokinetics (PK) guided strategy could improve the safety of busulfan administration, allowing the use of myeloablative doses in older patients. STUDY DESIGN AND METHODS We compared the outcome of patients older than 55 years with hematological malignancies included in a prospective monocentric single arm trial (BxPK: NCT02483325) evaluating the feasibility of PK-guided busulfan doses in myeloablative conditioning regimen (BxPK group: fludarabine 150 mg/m² + IV busulfan targeted AUC 5300 x 4 days + ATG 5 mg/kg) before matched sibling (MSD) or unrelated (URD) donor AlloSCT, with a retrospectively enrolled control cohort of patients with same inclusion criteria, treated during the same period but receiving fixed busulfan dose RIC regimen including fludarabine (150 mg/m²), IV busulfan (260 mg/m²) and ATG (5 mg/kg) [Bx2 group]. The primary objective was 2-year progression-free survival (PFS). Hazard ratio of BxPK vs. Bx2 were adjusted by age, disease risk index (DRI), donor type and hematopoietic cell transplantation comorbidity index (HCT-CI). RESULTS We analyzed 83 consecutive patients (BxPK: n=27; Bx2: n=56) without significant difference in baseline characteristics between both conditioning groups. In the BxPK and Bx2 groups: median age was 65 (range: 57-70) and 63 (range: 55-70) years, respectively (p = 0.552); 10/10 URDs were used for 15 (56%) and 37 (66%) patients, respectively (p = 0.493); HCT-CI was ≥ 3 in 18 (67%) and 28 (50%) patients , respectively (p = 0.232); and DRI was high in 5 (19%) and 5 (9%) patients, respectively (p = 0.369). Based on PK data from day-6 busulfan administration, 22 (81%) patients had dose adjustment (increased and decreased dose in 12 and 10 patients, respectively) in the BxPK group. Median busulfan AUC on day-2 (post adjustment) was 5287 µmol.min (range: 3326-7556). Four patients had AUC > 6000 µmol.min on day-2. Grade 3-4 mucositis (BxPK vs Bx2: 52% vs. 11%, p < 0.001) and nausea (BxPK vs Bx2: 11% vs 0%, p = 0.050) were more frequently observed in the BxPk group. No difference was observed between BxPK and Bx2 patients in grade 3-4 liver (BxPK vs Bx2: 15% vs 11%, p = 0.810), renal (BxPK vs Bx2: 0% vs 1.8%, p = 1) and gastrointestinal tract (BxPK vs Bx2: 11% vs 0%, p = 0.450) toxicities. There was a trend to higher cumulative incidence of grades 2-4 acute graft-versus-host disease (GVHD) at 100 days in the BxPK group (BxPK vs Bx2: 41% vs 29%, p = 0.058) while no difference was observed in 2-year chronic GVHD (BxPK vs Bx2: 41% vs. 36%, p = 0.547). Those trends were confirmed by multivariate analyses (acute GVHD: HR 2.22, 95Cl [1.10-4.48], p = 0.026; chronic GVHD: HR 1.30, 95Cl [0.60-2.80], p=0.502) With a median follow up of 33 months (range: 9-60), 2-year NRM was 19% and 18% (p=0.960) in the BxPK and Bx2 group, respectively. Multivariate analysis confirmed the absence of significant increase in the risk of NRM in the BxPK group (HR 1.11, 95CI [0.36-3.45], p = 0.859). The 2-year cumulative incidence of relapse was 19% and 31% (p=0.269) in the BxPK and Bx2 group, respectively (HR 0.55, 95IC [0.20-1.56], p = 0.264). No significant difference in 2-year PFS (BxPK vs Bx2: 62% vs. 51%, p = 0.391) and OS (BxPK vs Bx2: 70% vs. 61%, p = 0.667) was observed. CONCLUSION In patients older than 55 years who are usually candidates for RIC regimen, the use of PK-guided busulfan myeloablative dose allows delivering higher antitumor intensity without increasing NRM. Beyond the feasibility, we observed low incidence of relapse (19%) and promising OS (70%) suggesting that conditioning intensification may lead to long term disease control. These trends need to be confirmed in a larger comparative study for validating the optimal conditioning intensity in older and/or unfit patients. Disclosures Stoppa: takeda: Other: travel fees; celgene: Other: travel fees, lecture fees. Vey:Novartis: Consultancy, Honoraria; Janssen: Honoraria. Chabannon:Novartis: Other: speaker's fees; Celgene: Other: speaker's fees; Sanofi SA: Other: research support, speaker's fees, hospitalities; Gilead: Other: speaker's fees, hospitalities; EBMT: Other: Working Party Chair, Board member; Fresenius Kabi: Other: research support; Miltenyi Biotech: Other: research support; Terumo BCT: Other: speaker's fees. Blaise:Pierre Fabre medicaments: Honoraria; Sanofi: Honoraria; Molmed: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria.

Improved Outcomes for Patients Receiving High-Doses of IL-21 Ex Vivo Expanded NK Cells after Haploidentical Transplantation (haploSCT): Long-Term Follow-up of a Phase 1/2 Clinical Trial with Comparison to CIBMTR Controls

Background: Disease relapse following allogeneic stem-cell transplantation remains unacceptably high and there is an urgent need for new therapies that decrease relapse rates and improve survival post-transplant. Natural killer (NK) cells have potent antitumor effects, particularly those expended with mb-IL21 from peripheral blood. Preliminary data from a phase-1 dose-escalation study of up to 1x108 NK cells/Kg/dose and multiple dosing yielded promising results and a favorable safety profile (Ciurea SO.Blood.2017;130:18657). This report presents long-term follow-up from a phase-1/2 clinical trial in patients with high-risk myeloid malignancies (AML/MDS/CML) (clinicaltrials.gov NCT01904136) and a comparison with CIBMTR controls. Methods: Patients received conditioning with fludarabine 160 mg/m2, melphalan 140 mg/m2 and 2GyTBI, post-transplant cyclophosphamide-based GVHD prophylaxis and bone marrow graft from a haploidentical donor. Ex vivo expanded NK cells were generated from peripheral blood mononuclear cells of the same donor with a K562 feeder cells expressing mb-IL21 and 41BB and infused fresh on Day-2, and cryopreserved on Day+7 and +28 (up to Day+90). 1x108/Kg/dose was chosen for the phase 2 trial. An independent matched-pair analysis was done using controls from the CIBMTR database stratified by conditioning intensity. Results: 24/26 patients treated to date were evaluable (one short follow-up and one excluded as ineligible). 80% (19/24) of patients received all 3 doses of NK cells. The median age was 45 years (range 18-59), median follow-up was 43.6 months (range 15.1-60.9). Thirteen patients (54%) were females. 5 patients had donor-specific anti-HLA antibodies (DSA). The median HCT-CI was 2 (range 0-8), 12 patients (50%) had HCT-CI>3. 17 patients (72%) had AML/MDS and 7 (28%) advanced CML. Of AML/MDS patients, 10 (59%) had high-risk cytogenetics, 7 (41%) had measurable residual disease, 9 (53%) had intermediate/adverse-risk ELN2017 and 5 (29.4%) had primary induction failure. No infusion reactions or significant adverse events were observed to date. All patients (100%) achieved engraftment after a median of 19 days (range 14-42). The cumulative incidence (CI) of grade 2-4 aGVHD was 29.2% at Day100 and 41.7% at 1-year post-transplant. Only one patient developed severe grade 3-4 aGVHD and one patient had extensive cGVHD. Only one patient relapsed (a patient with DSA who did not receive desensitization prior to transplantation), 1-year CI of relapse was 5.9%. The CI of TRM at 1-year for patients without DSA was 21%. The median overall survival and progression-free survival (PFS) were not reached. The 1-year and 3-year PFS for all patients and patients without DSA was 70.8% and 66.1%, and 79% and 72.9% for patients without DSA, respectively (Figure 1). One-year and 3-years GRFS for all patients and patients without DSA was 70.8% and 66.1%, and 79% and 72.9%, respectively. An independent matched-pair analysis (at least 1:1) was conducted by CIBMTR after the first 18 patients treated on study in 07/2018 with RIC (N=57) or MAC (N=61) controls. The relapse was 1/18 vs 25/57 for RIC (p=0.037) and 15/61 for MAC (p=0.07), while the 1-year PFS was 82% vs 49% for RIC and 64% for MAC (p=0.21) (Figure 1). Updated results of this analysis will be presented at the meeting. Conclusions: Results from this long-term follow-up analysis confirm very low relapse rate and excellent GRFS after haploSCT for patients treated with high-doses of NK cells expanded with mbIL21 stimulation. A prospective multi-center phase 2 BMTCTN study will evaluate the safetly and efficacy of high doses of NK cells for the prevention of relapse in patents with AML/MDS receiving haploSCT. Figure 1 Disclosures Ciurea: Miltenyi: Research Funding; Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees, Other: stock holder; MolMed: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees. Bashir:Kite: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; StemLine: Research Funding; Acrotech: Research Funding; Celgene: Research Funding; Imbrium: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Pasquini:Novartis: Research Funding; Kite Pharmaceuticals: Research Funding; BMS: Research Funding; Medigene: Consultancy; Amgen: Consultancy; Pfizer: Consultancy. Lee:Kiadis Pharma: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

Outcome in Adolescent and Young Adult (AYA) Patients Compared to Younger Patients Treated for High-Risk B-Lymphoblastic Leukemia (HR B-ALL): Report from the Children's Oncology Group Study AALL0232

Introduction: Adolescent and young adult (AYA) patients (>16 years of age) with high-risk B acute lymphoblastic leukemia (HR B-ALL) have inferior outcomes compared to HR B-ALL patients 1-15 years of age, primarily due to relapse and toxicity. In a prior Children's Oncology Group (COG) HR B-ALL study 1961 (1996 - 2002), 12.7% of patients were AYA (ages 16 - 21 years) with 5-year event-free survival (EFS) and overall survival (OS) of 71.5% and 77.5% respectively. Here we report the outcomes of the most recently completed HR B-ALL COG study AALL0232, comparing AYA and younger patients. Methods: COG study AALL0232 was a Phase 3 randomized trial for patients 1-30 years of age with newly diagnosed HR B-ALL utilizing a 2 x 2 factorial design with an augmented intensityBerlin-Frankfurt-Münster (BFM) backbone. Patients were randomized to two weeks of dexamethasone versus four weeks of prednisone during Induction therapy and high dose methotrexate (HD-MTX) versus escalating Capizzi methotrexate plus pegaspargase (C-MTX) during Interim Maintenance I. Between 2004 and 2011, 3,154 patients enrolled, with 3,081 eligible and evaluable for induction. AYA patients comprised 20% (16-21 years, n= 558; 22-30 years, n=47). Results: The study was amended in 2008 due to an excess incidence of osteonecrosis observed in patients older than 10 years of age who were randomized to dexamethasone. Thereafter, they were nonrandomly assigned to prednisone during induction. The dexamethasone delivered during delayed intensification was also rescheduled from continuous (days 1-14) to discontinuous (days 1-8 and 15-22) delivery. 5-year EFS and OS were 65.1% and 76.9% for AYA patients compared to 77.9% and 87.1% for younger patients (p<0.0001) (Figures 1 and 2). 5-year cumulative incidence of relapse was 18.4% for AYA patients and 13.4% for younger patients (p=0.005), largely due to marrow relapse (13.8% versus 9.0%; p<0.0001). Additionally, fewer AYA patients achieved remission (<5% blasts) at end of Induction, (95.7% versus 97.2%; p=0.078). Day 29 bone marrow minimal residual disease (MRD) <0.01% was achieved in 55.9% of AYA patients compared to 73.9% of younger patients and MRD >1.0% to <10% was reported in 14.8% of AYA compared to 7.3% of non-AYA (p<0.001). Although there was no significant difference in induction mortality (2.5% versus 1.7%; p=0.20), post-induction remission deaths due to toxicity were significantly higher in AYA (5.8% versus 2.6%; p=0.0002). Compared to younger patients, AYAs were more likely to have Ph-like features (17.5% versus 12.1%, p=0.032) and less likely to have ETV6-RUNX1 fusions (3.9% versus 16.3%, p<0.0001). Conclusions: The COG trial AALL0232, which enrolled the largest number of AYA patients to date on a pediatric B-ALL study, demonstrated significantly inferior survival and greater rates of treatment related toxicity compared to younger patients. Although treatment intensification strategies have improved outcomes in younger patients, these have not translated into the same survival benefit in those older. The higher incidence of Ph-like genomic lesions in this group of patients potentially offers a therapeutic opportunity to incorporate targeted therapies for AYA. Thus, future trials must identify novel strategies to not only improve outcomes but further reduce toxicity in the AYA cohort. Disclosures Burke: Amgen, Inc.: Consultancy, Speakers Bureau. Raetz:Pfizer: Research Funding. Gastier Foster:Bristol Myers Squibb (BMS): Other: Commercial Research; Incyte Corporation: Other: Commercial Research. Borowitz:Beckman Coulter: Honoraria. Hunger:Novartis: Consultancy; Jazz: Honoraria; Bristol Myers Squibb: Consultancy; Amgen: Consultancy, Equity Ownership. Loh:Medisix Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees.

Successful Treatment of Chimeric Antigen Receptor T Cell Therapy in Refractory or Relapsed Acute Leukemia Patients with TP53 alterations

Backgrounds: Refractory or relapsed(R/R) acute leukemia (AL) patients with TP53 alterations have a dismal outcome with current therapy. Recently, chimeric antigen receptor T cells (CAR-T) therapy has emerged as a novel immunotherapy modality in treating patients with R/R acute B lymphocytic leukemia (B-ALL) patients, with consistently high response rates and durable remissions and even cures across multiple studies. However, successful treatment of CAR-T therapy in R/R AL with TP53 alterations has been a challenge. Here, we conducted a phase II trial testing efficacy and toxicities of CAR-T therapy in R/R AL patients with TP53 alterations. Methods: The second generation CAR-T cells were successfully made from 9 patients' autologous lymphocytes and 2 donors' allogeneic lymphocytes and qualified tests were done before infusion to patients. CAR constructs used were humanized CAR targeting CD19, CD22 or tandem CD19 and CD22 according to the expression levels of each target on blasts. In this ongoing trial, 11 R/R AL patients with TP53 alterations (10 with TP53 mutations and 1 with TP53 deletions) including 2 relapsed after allo- allogeneic hematopoietic stem cell transplantation were included to evaluate the efficacy and safety of CAR-T therapy. Among the enrolled 11 R/R patients, 9 patients were diagnosed with B-ALL, 1 was diagnosed with acute myeloid leukemia (AML) and 1 was diagnosed with mixed phenotype acute leukemia (MPAL) (B-ALL and AML). After leukapheresis, all patients received fludarabine-based lymphodepletion chemotherapy with FLAG regimen (Fludarabine 30mg/m2 × 5d, Cytarabine 2g/m2 × 5d and Granulocyte-colony stimulating factor 300ug ×6d) in two cases, FC regimen (Fludarabine 30mg/m2 × 3d and Cyclophosphamide 300mg/m2 × 3d) in five cases, and FC+DAC regimen (Decitabine 50mg × 3d, Fludarabine 30mg/m2 × 3d and Cyclophosphamide 300mg/m2 × 3d) in four cases. Two days after chemotherapy, autologous/allogeneic CAR-T cells were infused within 2 to 4 days in a dose-escalation. Results: With a median (range) dose of 1×107/kg (0.1-1.5×107/kg) CAR-T cells, we observed a high response rate with 10/11 (90.9%) evaluated R/R patients achieved complete remission (CR) and 9/11 (81.8%) patients achieved molecular CR (mCR). Moreover, Most cases (8/11, 72.7%) only experienced mild to moderate cytokine release syndrome (CRS) and no neurological toxicity were observed. With a median follow-up of 10 months, 3 cases died of progressive disease including 1 case failed to response to CAR-T therapy, 1 case achieved CR and relapsed after CAR-T therapy and 1 case achieved mCR after CAR-T therapy and relapsed after the following allo-HSCT, and the left 8 cases still kept in mCR and alive. The one-year overall survival (OS) and leukemia-free survival (LFS) rates were 68.4% and 78% respectively. The 2-year cumulative incidence of relapse was 22.2%, and the non-relapse mortality rate was 0%. Further subgroup analysis showed that all 6 cases who received decitabine therapy (DAC group) achieved and maintained in mCR, while only 2 cases achieved and kept in mCR and 3 cases died from progressive disease in the cases without receiving decitabine therapy (Non-DAC group). The median OS and LFS for Non-DAC group was 10 and 16.375 months respectively, while the median OS and LFS for DAC group were unreached. Relative IL-6 and CRP levels increased dramatically in DAC group than that in Non-DAC group. However, there were no significant difference on treatment related toxicities between cases in DAC group and Non-DAC group. Conclusions: Our trial indicates that CAR-T therapy is a safe and powerful salvage approach to R/R AL patients with TP53 alterations and application of decitabine may fuel CAR-T therapy and reduce the relapse rate without increasing therapy related mortality incidences in this high risk population. Disclosures No relevant conflicts of interest to declare.

Post-Transplant Cyclophosphamide for Gvhd Prophylaxis in Matched Unrelated Donor Transplantation Compared to ATG-Based Prophylaxis

Background: Post-transplant high dose cyclophosphamide (PT-CY) effectively prevents graft-versus-host disease (GVHD) after unmanipulated HLA-haploidentical hematopoietic stem cell transplantation (HSCT). The use of PT-CY in HLA-identical donor is less explored. In this study, we analyzed the results of PT-CY for GVHD prophylaxis in matched unrelated donor (MUD) HSCT and compared them with those obtained after prophylaxis with anti-thymocyte globulin (ATG), methotrexate (MTX) and cyclosporine (CsA). Methods: 132 matched unrelated donor HSCT from 4 Spanish centers have been analyzed: 60 performed between 2010 and 2018 using ATG-MTX-CsA and 72 performed between 2014 and 2018 using PT-CY. Results: Baseline characteristics and post-transplant complications are shown in Table 1. Peripheral blood was used as graft source in 92% of the patients in the ATG group and in 78% in the PT-CY group. GVHD prophylaxis consisted in rabbit ATG either 2mg/kg days -4 to -2 (41 patients, 68%) or 0.5mg/m2 on day -3 followed by 1mg/kg days -2 and -3 (19 patients, 32%), MTX days +1, +3, +6 and +11, and CsA from day -1 in the ATG group. The PT-CY group received cyclophosphamide 50 mg/kg/d on days +3 and +4, followed by either CsA or tacrolimus plus mycophenolate mofetil (MMF) from day +5 in 30 patients (42%), or cyclophosphamide on days +3 and +5 combined with CsA or tacrolimus in 42 patients (58%; 16 out of them also received sirolimus due to 9/10 HLA-match). Cumulative incidence of grade II-IV (67% vs 46%, p=0.008) and III-IV (34% vs 3%, p=0.003) acute GVHD, were significantly higher in the ATG group (Figure 1). There were no differences in the 2-year cumulative incidence of chronic moderate to severe GVHD (23% vs 24%, p=0.86). After a median follow-up of 78 months for the ATG group and 26 months for the PT-CY group, no differences were found in the 2-year overall survival (58% vs 60%, p=0.475), 2-year event-free survival (51% vs 50%, p=0.961) and the composite endpoint of GVHD-free and relapse-free survival (44% vs 40%, p=0.742). The 2-year cumulative incidence of relapse (22% vs 26%, p=0.67) and non-relapse mortality (NRM) (24% vs 22%, p=0.68) were also similar between both groups. However, NRM in the ATG group was due to GVHD in 9 out of 16 patients, while in the PT-CY group NRM was mostly due to infections and organ toxicity and only 3 out of 15 patients died due to GVHD. The incidence of sinusoidal obstruction syndrome was low in both groups (0% vs 4%, p=0.11). CMV reactivation rates were similar (40% vs 51%, p=0.191). However, both hemorrhagic cystitis and EBV reactivation were higher in the ATG group (56% vs 12%, p=0.00, and 5% vs 0%, p=0.05, respectively). Conclusions: In our experience, GVHD prophylaxis using PT-CY combined with additional immunosuppression after MUD HSCT, using mostly peripheral blood as graft source, resulted in lower incidence of aGVHD compared to prophylaxis based on ATG-MTX-CsA. Although no impact on non-relapse mortality was observed, GVHD associated mortality was higher in the ATG group as well as cystitis and EBV reactivations. Prospective studies with longer follow-up are needed to confirm these observations. Disclosures No relevant conflicts of interest to declare.

Genomic Landscape and Risk-Stratification for De Novo Acute Myeloid Leukemia with Normal Cytogenetics and No NPM1 or FLT3-itd Mutation

Introduction-About 25% of persons with new-diagnosed acute myeloid leukemia (AML) have normal cytogenetics and no NPM1 or FLT3-ITD mutation. The prognosis and best therapy of these persons is controversial. Methods-We evaluated 809 consecutive newly diagnosed adult with normal cytogenetics and 231 of whom had no NPM1 or FLT3-ITD mutation identified by targeted regional sequencing. 158 achieved a complete remission within 2 cycles of induction therapy and were assigned to 2 different post-remission strategies: (1) 6 courses of consolidation chemotherapy (N=95); or (2) 2-4 courses of consolidation chemotherapy and an allotransplant (N=63). Results-In multi-variable analyses a WBC ≥13·6×10E+9/L, mutated IDH2, not having a bi-allelic CEBPA mutation at diagnosis, a positive measurable residual disease (MRD)-test during consolidation and not receiving an allotransplant were independently associated with a higher cumulative incidence of relapse (CIR) and worse event-free survival (EFS). Amongst subjects with IDH2 mutations, non-bi-allelic CEBPA mutations or a positive MRD-test, subjects receiving an allotransplant had a lower 5-year CIR (16% [95% confidence interval, 6, 26%]; vs. 83% [72, 95%]; hazard ratio, HR=8·77 [4·05, 13·49]; P < 0·001) and better 5-year EFS (74% [60, 88%] vs. 15% [5, 25%]; HR=0·16 [0·09, 0·29]; P < 0·001). In contrast, in subjects with none of these adverse predictive variables there was no difference in CIR and EFS between those receiving an allotransplant and those who did not. Conclusions-Our data suggest a strategy to identify which persons with AML with normal cytogenetics and no NPM1 or FLT3-ITD mutation benefit from an allotransplant. Trial Registration: Registered in the www.clinicaltrials.gov, NCT01455272 and NCT02185261. Keywords: Acute myeloid leukemia, mutations, prognosis, targeted regional sequencing, measurable residual disease, risk stratification. *Correspondence Profs. Guo-Rui Ruan and Xiao-Jun Huang Peking University Peoples Hospital and Institute of Hematology No.11 Xi-Zhi-Men South Street, Beijing 100044, China T 86-10-88324672 F 86-10-88324672 Disclosures No relevant conflicts of interest to declare.

Characteristics and Outcomes of Therapy-Related Versus De Novo Acute Myeloid Leukemia with Normal Karyotype

Characteristics and Outcomes of Therapy-Related Versus De Novo Acute Myeloid Leukemia with Normal Karyotype

Reduced Relapse Risk in Children with Acute Myeloid Leukemia (AML) Who Experience Septic Shock (SS)

Background: Relapse remains the major clinical risk in children with AML, and persistent minimal residual disease (MRD) poses a particular therapeutic challenge as a presumably chemoresistant cell population. We previously showed innate immune stimulation can generate durable memory immune responses against leukemia cells in preclinical MRD models (Blood 2009 114:2459; Leukemia 2018 32: 539). These treatments mimic the "danger" signal provided by SS and may offer novel immunotherapeutic approaches for patients who fail or are not eligible for targeted immunotherapies. Demonstrating a protective effect of SS against AML relapse would support clinical development of innate immune stimulants. We hypothesized 1) SS is associated with a decreased risk of AML relapse among children who were able to achieve remission after induction, and 2) this effect is most pronounced in children with persistent MRD, who are more likely to have both SS exposures and relapses. Methods: We used a previously assembled cohort of children with de novo AML using Pediatric Health Information System (PHIS) data merged with patients on two clinical trials from the Children's Oncology Group (COG; PLOS One 2015 10:e0143480). We developed and validated a method to detect SS exposures in PHIS using vasopressor billing codes (PBC 2019 10.1002/pbc.27713 #2024) and used COG data for demographics, treatment, and outcomes. SS exposures were captured starting 7 days from first chemotherapy until last day of the last treatment course or 30 days prior to relapse. Follow-up for relapse and non-relapse mortality (NRM) began after the end of Induction II and continued to last contact, off-study date, or until 5 years from diagnosis. Cumulative incidences of relapse (CIR) and NRM (CIN) were estimated treating each other as competing risks. Sub-distribution hazard regression models were used to estimate crude and adjusted sub-hazard ratios (subHR) and associated 95% confidence intervals (CI) of relapse in relation to SS. SS was treated as a time-varying exposure, so each patient became SS-exposed once the first SS occurred. Demographic and clinical characteristics were evaluated as potential confounders of the associations of interest. Results: We identified 569 COG-PHIS patients with AML who achieved complete remission by the end of Induction II. In this cohort, 188 (33%) experienced SS during therapy. Older age, Black non-Hispanic race-ethnicity, Hispanic ethnicity, and receipt of stem cell transplant (SCT) were associated with SS exposure (Table 1). Median follow-up was 1122 days (IQR 413-1745) from the end of Induction II. Relapse occurred in 220 (38.7%) patients and was associated with male sex and genetic risk (Table 1). Positive end-Induction I MRD approached a significant association with relapse. CIRs were similar among SS-exposed and unexposed patients in the overall cohort and in MRD-negative patients (Figs. 1A-B). Among children with persistent MRD, SS-exposed patients had a lower 5-year CIR than unexposed patients (43% vs. 60.1%; Fig. 1C). Adjusted subHR for relapse for the overall cohort was 0.82 (CI: 0.61-1.11); for the MRD-negative subgroup, adjusted subHR was 0.86 (CI: 0.61-1.21); and for the MRD-positive subgroup, 0.57 (CI: 0.31-1.05). These effects were consistently in the protective direction but did not reach statistical significance. In a sensitivity analysis restricting duration of the exposure effect to 12 months, SS exposure in the overall cohort was associated with a risk reduction (adjusted subHR 0.65; CI: 0.45-0.92). NRM occurred in 28 (4.9%) and was associated with high-risk therapy on AAML1031 and with positive MRD, with a near-significant association with SCT (not shown). SS-exposed patients had a higher 5-year CIN (10.4% v. 2.8%; Fig. 1D). Conclusions: Using merged clinical trial and administrative data, we identified a potentially protective effect of exposure to a strong immune stimulus (SS) that was most pronounced in children with persistent MRD. This suggests immune surveillance for low-level AML can be induced and supports investigation of innate immune stimulant therapy for this very poor prognosis childhood leukemia. While NRM is higher among SS-exposed patients, clinical trials of innate immune stimulants would comprise controlled interventions expected to result in markedly less toxicity than unpredictable SS exposures. Repeated dosing may prolong the effect duration beyond 12 months. Disclosures Fisher: Merck: Research Funding; Pfizer: Research Funding; Astellas: Other: Data Safety Monitoring Board Chair for an antifungal study.

More precisely defining risk peri-HCT in pediatric ALL: pre- vs post-MRD measures, serial positivity, and risk modeling

AbstractDetection of minimal residual disease (MRD) pre– and post–hematopoietic cell transplantation (HCT) for pediatric acute lymphoblastic leukemia (ALL) has been associated with relapse and poor survival. Published studies have had insufficient numbers to: (1) compare the prognostic value of pre-HCT and post-HCT MRD; (2) determine clinical factors post-HCT associated with better outcomes in MRD+ patients; and (3) use MRD and other clinical factors to develop and validate a prognostic model for relapse in pediatric patients with ALL who undergo allogeneic HCT. To address these issues, we assembled an international database including sibling (n = 191), unrelated (n = 259), mismatched (n = 56), and cord blood (n = 110) grafts given after myeloablative conditioning. Although high and very high MRD pre-HCT were significant predictors in univariate analysis, with bivariate analysis using MRD pre-HCT and post-HCT, MRD pre-HCT at any level was less predictive than even low-level MRD post-HCT. Patients with MRD pre-HCT must become MRD low/negative at 1 to 2 months and negative within 3 to 6 months after HCT for successful therapy. Factors associated with improved outcome of patients with detectable MRD post-HCT included acute graft-versus-host disease. We derived a risk score with an MRD cohort from Europe, North America, and Australia using negative predictive characteristics (late disease status, non–total body irradiation regimen, and MRD [high, very high]) defining good, intermediate, and poor risk groups with 2-year cumulative incidences of relapse of 21%, 38%, and 47%, respectively. We validated the score in a second, more contemporaneous cohort and noted 2-year cumulative incidences of relapse of 13%, 26%, and 47% (P < .001) for the defined risk groups.

Influence of donor KIR genotypes on reduced relapse risk in acute myelogenous leukemia after hematopoietic stem cell transplantation in patients with CMV reactivation

Multiple retrospective studies have demonstrated an association between cytomegalovirus (CMV) reactivation and reduced risk of AML relapse. However, the potential mechanism explaining this association remains elusive. We investigated a homogeneous cohort of 288 adult patients with AML in remission who received allogeneic hematopoietic stem cell transplantation (HCT) from matched sibling/unrelated donors between 1995 and 2011. The 5-year cumulative incidence of relapse was greater in patients without CMV reactivation compared with those with reactivation (30.2% vs. 12.1%, p = 0.001) in a landmark analysis. In multivariate analyses CMV reactivation was independently associated with reduced relapse risk (HR: 0.49 [0.25-0.95], p = 0.036) and increased non-relapse mortality (26.5% vs. 13.1%, p = 0.002) resulting in similar 5-year overall survival (64.5% vs. 59.1%, p = 0.8). In further subgroup analyses the protective effect of CMV reactivation was significant in patients who received HCT from donors with KIR Bx compared to KIR AA (11.7% vs. 29.5%, p = 0.01). Likewise, the protective effect of CMV reactivation was more significant when the donors had 2DS1 activating KIR (11.5% vs. 30.7%, p = 0.05) compared with those without 2DS1 (14.3% vs. 27.5%, p = 0.12). Our data independently confirmed the association between CMV reactivation and AML relapse, suggesting the involvement of donor KIR genotypes and NK cell-mediated graft-versus-leukemia effect.

Flow cytometric detection of leukemic blasts in cerebrospinal fluid predicts risk of relapse in childhood acute lymphoblastic leukemia: a Nordic Society of Pediatric Hematology and Oncology study

Central nervous system (CNS) involvement by cytospin is associated with increased risk of relapse in childhood acute lymphoblastic leukemia. We investigated if flow cytometric analysis of cerebrospinal fluid (CSF) at diagnosis improves the prediction of relapse. This prospective cohort study included patients (1.0-17.9 years) treated according to the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol. CSF flow cytometry samples were obtained at 17 centers, preserved with Transfix®, and analyzed at a central laboratory. One-hundred and seventy-one (25.4%) of 673 patients were positive by flow cytometry (CNSflow+). The 4-year cumulative incidence of relapse was higher for patients with cytospin positivity (CNScyto+) (17.1% vs. 7.5%), CNSflow+ (16.5% vs. 5.6%), and cytospin and/or flow positivity (CNScomb+) (16.7% vs. 5.1%). In Cox regression analysis stratified by immunophenotype and minimal residual disease day 29 and adjusted by sex, predictors of relapse were age (hazard ratio [HR] 1.1, 95% CI 1.1-1.2, P < 0.001), white blood cell count at diagnosis (HR 1.4, 95% CI 1.1-1.6, P < 0.001), and CNScomb+ (HR 2.2, 95% CI 1.0-4.7, P = 0.042). Flow cytometric analysis of CSF improves detection of CNS leukemia, distinguishes patients with high and low risk of relapse, and may improve future risk stratification and CNS-directed therapy.

Haploidentical transplantation using posttransplant cyclophosphamide as GVHD prophylaxis in patients over age 70.

Hematologic malignancies in older people are unlikely to be cured with chemotherapy alone. Advances in allogeneic blood or marrow transplantation (alloBMT), especially nonmyeloablative (NMA) conditioning and the use of haploidentical donors, now make this therapy available to older people; however, long-term outcomes and predictors of success are unclear. We reviewed the outcomes of 93 consecutive patients aged 70 and older (median, 72; range, 70-78), who underwent haploidentical BMT at Johns Hopkins Hospital between 1 September 2009 and 1 April 2018. All patients received NMA conditioning and posttransplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis. The 2-year overall survival was 53%, and 2-year event-free survival was 43%. The 180-day cumulative incidence (CuI) of nonrelapse mortality (NRM) was 14%, and the 2-year CuI was 27%. The 2-year CuI of relapse was 30%. Of 78 patients who were alive and had their weight recorded on day 180, weight loss predicted subsequent NRM (subdistribution hazard ratio, 1.0; 95% CI, 1-1.13; P = .048). In conclusion, haploidentical BMT with PTCy is feasible and relatively safe in septuagenarians. Although early, 6-month NRM was relatively low at 14%, but overall NRM continued to climb to 27% at 2 years, at least in part because of late deaths that appeared to be somewhat age related. Further studies to elucidate predictors of NRM are warranted.

Low-dose post-transplant cyclophosphamide and anti-thymocyte globulin as an effective strategy for GVHD prevention in haploidentical patients

BackgroundLow-dose post-transplant cyclophosphamide (PTCy) in conjunction with anti-thymocyte globulin (ATG) appears as a potentially effective graft-versus-host disease (GVHD) prevention strategy in haploidentical hematopoietic cell transplant (haplo-HCT). Our study aims to assess the efficacy of this regimen.MethodsWe extended our prospective study in patients treated with low-dose PTCy (14.5 mg/kg on days 3 and 4) in ATG/granulocyte colony-stimulating factor (G-CSF)-based regimen and compared the results to the contemporary cohort of patients without low-dose PTCy (ATG cohort). Both study cohort and control are transplanted from maternal donor or collateral relatives.ResultsWe identified 239 consecutive patients (ATG-PTCy cohort = 114; ATG cohort = 125). All patients but one in ATG cohort achieved myeloid engraftment by day 30 post-HCT. We found that both the cumulative incidence of 100-day grade III–IV aGvHD and non-relapse-mortality (NRM) in the ATG-PTCy cohort was significantly reduced than that in the ATG group (5% vs 18%; P = 0.003; and 6% vs 15%; P= 0.045); the 2-year cumulative incidences of relapse and overall survival were comparable between the two cohorts (13% vs 14%; P = 0.62; and 83% vs 77%; P = 0.18, respectively). Furthermore, GVHD-free, relapse-free survival (GRFS) was significantly improved in the ATG-PTCy arm (63% vs 48%; P = 0.039). In multivariate analysis, the joint treatment resulted in lower grade II–IV acute GVHD (HR 0.58; P = 0.036), grade III–IV aGvHD (HR 0.28; P = 0.006), chronic GVHD (HR 0.60; P = 0.047), NRM (HR 0.26; P = 0.014), and higher GRFS (HR 0.59; P = 0.021) but slower myeloid and platelet recovery (HR 0.29 and 0.30; both P < 0.001).ConclusionsThese results suggested that ATG/PTCy (low-dose) can reduce both acute and chronic GVHD as compared with standard ATG-based prophylaxis using maternal donor or collateral relatives at particular high GVHD risk.

Effects of chemotherapy combined with donor lymphocyte infusion on chronic graft-versus-host disease and prognosis in minimal residual disease positive patients after allogeneic hematopoietic stem cell transplantation

目的探讨异基因造血干细胞移植（allo-HSCT）后微小残留病（MRD）阳性患者接受化疗联合供者淋巴细胞输注（Chemo-DLI）后慢性移植物抗宿主病（cGVHD）的临床特点以及其严重程度对患者预后的影响。方法纳入接受allo-HSCT后出现MRD阳性的急性白血病患者，给予Chemo-DLI治疗，采用美国国立卫生研究院（NIH）标准评估cGVHD的特点及严重程度，并分析其对预后的影响。结果共有54例（59.3%）患者在Chemo-DLI后出现cGVHD，中位发生时间为DLI后70（13~504）d。分别有6例（6.6%）、21例（23.1%）、27例（29.7%）患者发生轻度、中度、重度cGVHD。未发生cGVHD、轻中度cGVHD、重度cGVHD患者Chemo-DLI后5年复发率分别为61.9%（95%CI 45.3%~78.5%）、15.1%（95%CI 1.1%~29.1%）、26.6%（95%CI 9.2%~44.0%）（χ2=18.901，P<0.001）。未发生cGVHD、经典型cGVHD、重叠综合征患者Chemo-DLI后5年复发率分别为61.9%（95%CI 45.3%~78.5%）、19.9%（95%CI 8.1%~31.7%）、28.6%（95%CI 0.0%~65.0%）（χ2=18.307，P<0.001）。cGVHD与治疗后的非复发死亡无关。未发生cGVHD、轻中度cGVHD、重度cGVHD患者Chemo-DLI后5年无白血病生存（LFS）率分别为24.0%（95%CI 9.1%~38.9%）、77.2%（95%CI 60.8%~93.6%）、64.9%（95%CI 45.7%~84.1%）（χ2=24.447，P<0.001）。未发生cGVHD、经典型cGVHD、重叠综合征患者Chemo-DLI后5年LFS率分别为24.0%（95%CI 9.1%~38.9%）、75.5%（95%CI 62.7%~88.3%）、42.9%（95%CI 1.8%~84.0%）（χ2=25.665，P<0.001）。未发生cGVHD、轻中度cGVHD、重度cGVHD患者Chemo-DLI后5年总生存（OS）率分别为50.0%（95%CI 31.1%~68.9%）、87.9%（95%CI 74.7%~100.0%）、71.0%（95%CI 52.0%~90.0%）（χ2=9.517，P=0.009）。未发生cGVHD、经典型cGVHD、重叠综合征患者Chemo-DLI后5年OS率分别为50.0%（95%CI 31.1%~68.9%）、83.9%（95%CI 72.8%~95.0%）、51.4%（95%CI 6.2%~96.6%）（χ2=10.673，P=0.005）。多因素分析显示，移植前处于第1次完全缓解期、经典型cGVHD与Chemo-DLI后较低的复发风险和较好的生存相关。结论在allo-HSCT后MRD阳性患者中，Chemo-DLI干预后的cGVHD可以降低急性白血病患者的复发风险并改善生存；表现为重叠综合征的患者，需要积极控制cGVHD以改善预后。

Clinical observation of maintenance treatment with low-dose decitabine after transplantation for patients with high-risk acute lymphoblastic leukemia

Objective To investigate the efficacy and safety of maintenance treatment with low-dose decitabine after allogeneic stem cell transplantation (allo-HSCT) for high-risk acute lymphoblastic leukemia (ALL). Methods The data of 10 patients with high-risk ALL who received maintenance therapy with low-dose decitabine after allo-HSCT in the First Affiliated Hospital of Zhengzhou University from July 2016 to March 2018 was collected. The incidence of post-transplant relapse and graft-versus-host disease (GVHD) and the safety of the treatment protocol were analyzed. The cumulative incidence of relapse (CIR) rate, disease-free survival (DFS) rate and overall survival (OS) rate were estimated by Kaplan-Meier method. Results Two patients relapsed and the median relapse time of these 10 patients was 575 days after transplantation. The 1-year CIR, OS and DSF rates were 16.7%, 100.0% and 83.3%, respectively. At the end of follow-up, the DFS time after transplantation of 2 patients with p53 mutation were 23 months and 11 months, respectively. There was no induction or alleviation of GVHD caused by decitabine treatment. Nine patients developed grade Ⅰ-Ⅱ myelosuppression. Three patients had unexplained thrombocytopenia after transplantation and their platelet counts recovered after decitabine treatment. Conclusion Maintenance therapy with low-dose decitabine has low hematologic toxicity without increasing GVHD, which could be a maintenance treatment option to prevent relapse after transplantation for patients with high-risk ALL. Key words: Leukemia, lymphocytic, acute; Allogeneic hematopoietic stem cell transplantation; Recurrence; Low-dose decitabine

Chromosomal Abnormalities and Prognosis in NPM1-Mutated Acute Myeloid Leukemia: A Pooled Analysis of Individual Patient Data From Nine International Cohorts.

Nucleophosmin 1 (NPM1) mutations are associated with a favorable prognosis in acute myeloid leukemia (AML) when an internal tandem duplication (ITD) in the fms-related tyrosine kinase 3 gene (FLT3) is absent (FLT3-ITDneg) or present with a low allelic ratio (FLT3-ITDlow). The 2017 European LeukemiaNet guidelines assume this is true regardless of accompanying cytogenetic abnormalities. We investigated the validity of this assumption. We analyzed associations between karyotype and outcome in intensively treated patients with NPM1mut/FLT3-ITDneg/low AML who were prospectively enrolled in registry databases from nine international study groups or treatment centers. Among 2,426 patients with NPM1mut/FLT3-ITDneg/low AML, 2,000 (82.4%) had a normal and 426 (17.6%) had an abnormal karyotype, including 329 patients (13.6%) with intermediate and 83 patients (3.4%) with adverse-risk chromosomal abnormalities. In patients with NPM1mut/FLT3-ITDneg/low AML, adverse cytogenetics were associated with lower complete remission rates (87.7%, 86.0%, and 66.3% for normal, aberrant intermediate, and adverse karyotype, respectively; P < .001), inferior 5-year overall (52.4%, 44.8%, 19.5%, respectively; P < .001) and event-free survival (40.6%, 36.0%, 18.1%, respectively; P < .001), and a higher 5-year cumulative incidence of relapse (43.6%, 44.2%, 51.9%, respectively; P = .0012). These associations remained in multivariable mixed-effects regression analyses adjusted for known clinicopathologic risk factors (P < .001 for all end points). In patients with adverse-risk chromosomal aberrations, we found no significant influence of the NPM1 mutational status on outcome. Karyotype abnormalities are significantly associated with outcome in NPM1mut/FLT3-ITDneg/low AML. When adverse-risk cytogenetics are present, patients with NPM1mut share the same unfavorable prognosis as patients with NPM1 wild type and should be classified and treated accordingly. Thus, cytogenetic risk predominates over molecular risk in NPM1mut/FLT3-ITDneg/low AML.

Clinical research of HLA-haploidentical peripheral hematopoietic stem cell transplantation following reduced intensity conditioning regimen with hematological malignancy patients over 50 years old

目的分析减低剂量预处理单倍型外周血造血干细胞移植（RIC-haplo-PBSCT）治疗50岁以上恶性血液肿瘤患者的疗效。方法18例50岁以上恶性血液肿瘤患者纳入研究，男8例，女10例，中位年龄52（50~66）岁；急性髓系白血病（AML）8例，慢性髓性白血病（CML）2例，骨髓增生异常综合征（MDS）5例，急性淋巴细胞白血病（ALL）2例，急性NK细胞白血病（ANKL）1例；采用FAB+ATG（氟达拉滨+阿糖胞苷+白消安+兔抗人胸腺细胞免疫球蛋白）减低剂量预处理方案，输注供者高剂量非去T细胞外周血造血干细胞（PBSC），应用强化移植物抗宿主病（GVHD）预防方案及感染防控措施。结果16例患者在移植后15 d获得完全供者嵌合，其中1例在移植后1个月发生移植排斥，其余2例在移植后15 d为混合嵌合并于移植后1个月发生移植排斥。急性GVHD发生率为61.1%（95%CI 49.6%~72.6%），Ⅱ~Ⅳ度急性GVHD发生率为35.4%（95%CI 21.1%~49.7%），Ⅲ/Ⅳ度急性GVHD发生率为13.8%（95%CI 4.7%~22.9%）。2年慢性GVHD累积发生率为38.2%（95%CI 25.5%~50.9%），未发生广泛型慢性GVHD。中位随访14.5（3~44）个月，2年总生存率、无病生存率分别为72.6%（95%CI 60.1%~85.1%）、63.7%（95%CI 49.2%~78.2%），2年累积复发率为31.2%（95%CI 16.5%~45.9%），2年非复发死亡率为12.5%（95%CI 4.2%~20.8%）。结论RIC-haplo-PBSCT治疗50岁以上恶性血液肿瘤患者可获得较好的疗效。

Efficacy of Hyper-CVAD/MA and CHALL-01 regimens in the treatment of Philadelphia chromosome-positive adult acute lymphoblastic leukemia patients under 60 years old

目的比较传统Hyper-CVAD/MA方案及借鉴儿童急性淋巴细胞白血病（ALL）的新化疗方案CHALL-01在≤60岁成人Ph阳性ALL（Ph+ ALL）中的临床疗效。方法回顾性分析2007年1月至2017年12月第二军医大学附属长海医院及长征医院收治的158例Ph+ ALL患者（除外慢性髓性白血病急变期患者），其中Hyper-CVAD/MA组63例，CHALL-01组95例，诱导及巩固化疗期间联合酪氨酸激酶抑制剂（TKI）治疗，有合适供者的患者进行造血干细胞移植，并用TKI进行维持治疗。结果经过1~2个疗程的诱导治疗，91.1%（144/158）患者获得完全缓解（CR），其中Hyper-CVAD/MA组CR率为90.5%（57/63），CHALL-01组CR率为91.6%（87/95），两组间差异无统计学意义（χ2=0.057，P=0.811）。随访截止于2018年6月，共134例CR患者可进一步分析，其中Hyper-CVAD/MA组53例，CHALL-01组81例。CHALL-01组达到分子学缓解的比例显著高于Hyper-CVAD/MA组（完全分子学反应率：44.4%对22.6%，主要分子学反应率：9.9%对18.9%）（χ2=7.216，P=0.027）。Hyper-CVAD/MA组和CHALL-01组4年总生存率分别为44.81%（95%CI 30.80%~57.86%）和55.63%（95%CI 39.07%~69.36%）（P=0.037），4年无病生存率分别为37.95%（95%CI 24.87%~50.93%）和49.06%（95%CI 34.24%~62.29%）（P=0.015）。两组在4年累积复发率（P=0.328）及无复发死亡率（P=0.138）上差异无统计学意义。CHALL-01组肺部感染发生率较Hyper-CVAD/MA组明显减低（43.4%对67.9%，χ2=7.908，P=0.005）。结论CHALL-01方案治疗成人Ph+ ALL疗效优于Hyper-CVAD/MA方案，肺部感染发生率低，分子学缓解率高，可以提高Ph+ ALL患者的生存率。

Chronic graft-versus-host disease could ameliorate the impact of adverse somatic mutations in patients with myelodysplastic syndromes and hematopoietic stem cell transplantation.

Somatic mutations in patients with myelodysplastic syndromes (MDS) undergoing allogeneic hematopoietic stem cell transplantation (HSTC) are associated with adverse outcome, but the role of chronic graft-versus-host disease (cGVHD) in this subset of patients remains unknown. We analyzed bone marrow samples from 115 patients with MDS collected prior to HSCT using next-generation sequencing. Seventy-one patients (61%) had at least one mutated gene. We found that patients with a higher number of mutated genes (more than 2) had a worse outcome (2years overall survival [OS] 54.8% vs. 31.1%, p = 0.035). The only two significant variables in the multivariate analysis for OS were TET2 mutations (p = 0.046) and the development of cGVHD, considered as a time-dependent variable (p < 0.001), correlated with a worse and a better outcome, respectively. TP53 mutations also demonstrated impact on the cumulative incidence of relapse (CIR) (1year CIR 47.1% vs. 9.8%, p = 0.006) and were related with complex karyotype (p = 0.003). cGVHD improved the outcome even among patients with more than 2 mutated genes (1-year OS 88.9% at 1year vs. 31.3%, p = 0.02) and patients with TP53 mutations (1-year CIR 20% vs. 42.9%, p = 0.553). These results confirm that cGVHD could ameliorate the adverse impact of somatic mutations in patients with MDS with HSCT.

Highly sensitive chimerism detection in blood is associated with increased risk of relapse after allogeneic hematopoietic cell transplantation in childhood leukemia.

Analysis of chimerism in blood post-HCT using STR-PCR is routinely applied in parallel with quantification of MRD to predict relapse of leukemia. RQ-PCR chimerism is 10- to 100-fold more sensitive, but clinical studies in children are sparse. We analyzed IMC in blood samples following transplantation for acute lymphoblastic or myeloid leukemia in 56 children. IMC was defined as a minimum increase of (a) 0.1% or (b) 0.05% recipient DNA between two samples. The risk of relapse was higher in children with IMC of both 0.1% and 0.05% compared to children without IMC (HR 12.8 [95% CI: 3.9-41.4; P<.0001] and 7.6 [95% CI: 2.2-26.9; P<.01], respectively). The first IMC was detected at a median of 208days prior to relapse. The 5-year cumulative incidence of relapse for children with a single IMC was 45.5% (CI 12.3-74.4) and 41.0% (14.2-66.6) for IMC above 0.1% and 0.05%, respectively. However, in 47 and 38 children never attaining IMC>0.1% and >0.05%, 10 and 8 children relapsed, respectively. In a landmark analysis, no association was found between IMC prior to 90days post-HCT and subsequent relapse by either classification of IMC and AUC for RQ-PCR chimerism was 54.2% (95 CI 27.7- 84.8). Although limited by a retrospective design, these results indicate that monitoring of RQ-PCR chimerism in peripheral blood may have a role in early detection of relapse in acute childhood leukemia.