Cumulative Incidence Of Relapse Rate Research Articles

PF216 ROLE OF MEASURABLE RESIDUAL DISEASE (MRD) IN REDEFINING COMPLETE RESPONSE (CR) IN ELDERLY PATIENTS WITH ACUTE MYELOID LEUKEMIA (AML): RESULTS FROM THE PETHEMA‐FLUGAZA PHASE III CLINICAL TRIAL

Background:The general outcome of elderly patients with AML is poor, even for those achieving morphological CR. However, the role of MRD in redefining CR remains poorly investigated in elderly AML due to the reluctance of treating with intensive chemotherapy and the renewed interest in low‐intensity therapy such as hypomethylating agents (HMA).Aims:To help defining the role of MRD assessment by multidimensional flow cytometry (MFC) and therapeutic decision making in older AML patients treated with semi‐intensive chemotherapy vs HMA.Methods:285 AML patients (median age, 75) were included in the phase 3 PETHEMA‐FLUGAZA trial and were randomized to receive 3 induction cycles with fludarabine and cytarabine (FLUGA) followed by 6 consolidation cycles with reduced intensity FLUGA, vs 3 induction cycles with 5‐azacitidine (AZA) followed by 6 consolidation cycles with AZA. After consolidation, patients continued with the same treatment if MRD ≥0.01% or stopped if MRD <0.01%. MRD was prospectively assessed after induction and consolidation among patients in CR with or without incomplete blood count recovery. At diagnosis, the EuroFlow AML panel was used to identify leukemia‐associated immunophenotypes (LAIP). At CR, bone marrow samples were stained with 8‐color combinations based on previously identified maturation arrest, lineage commitment and LAIPs. MRD was assessed with an estimated sensitivity of 0.01%.Results:On intention‐to‐treat, 38/141 (27%) patients achieved CR after 3 cycles of FLUGA and 31/144 (21.5%) after 3 cycles of AZA (p = .33). Among patients in CR with previously identified LAIP, 14/69 (20%) achieved a negative MRD status whereas the remaining 55 (80%) had persisting MRD: 56% with ≥0.1% MRD and 24% with <0.1% MRD. Regarding the effect of semi‐intensive chemotherapy vs HMA on depth of response, we observed a non‐significant trend toward higher MRD‐negative rates among patients in CR after FLUGA vs AZA (25% vs 15%, respectively; p = .38).The 2‐year rates of cumulative incidence of relapse (CIR) for MRD‐positive ≥0.1%, <0.1% and MRD‐negative patients were 95%, 74% and 45%, respectively (HR, 0.45; p < .001). Of note, the CIR of patients in CR but persistent MRD were similarly poor as compared to those in partial remission (HR, 1.2; p = .54). Furthermore, MRD‐positive patients with adverse cytogenetics displayed the poorest outcome with significantly higher 2‐year CIR rates than MRD‐positive cases with intermediate/favorable cytogenetics (HR, 2.0; p = .01). Among patients in CR and persistent MRD, 2‐year CIR rates showed a non‐significant trend towards slightly more frequent relapses in those treated with FLUGA vs AZA (91% vs 77%, respectively; HR, 1.6; p = .12). On multivariable analysis for CIR including MFC‐MRD and cytogenetics, both retained significant prognostic value. The median overall survival (OS) for MRD‐positive ≥0.1%, <0.1% and MRD‐negative patients was 13, 12 and 21 months, respectively. On multivariable analyses for OS including age, WBC count, cytogenetic grouping and secondary disease, persistent MRD showed a trend for independent prognostic value (HR, 2.4; p = .08).Summary/Conclusion:This study reveals that sensitive MFC‐MRD assessment supersedes CR and is an independent prognostic factor in older patients with AML, treated with semi‐intensive chemotherapy or HMA. Nevertheless, the risk of relapse among the few patients with no MRD (5%) remains high after stopping treatment, and warrants innovative approaches aimed at maintaining an MRD‐negative CR status. Updated follow‐up and molecular data will be presented at the meeting.

Allogeneic Hematopoietic Stem Cell Transplantation, Especially Haploidentical, May Improve Long-Term Survival for High-Risk Pediatric Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia in the Tyrosine Kinase Inhibitor Era.

The role of allogeneic hematopoietic stem cell transplantation (allo-HSCT), particularly haploidentical (haplo)-HSCT, in pediatric patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in the tyrosine kinase inhibitor (TKI) era is unclear. This study aimed to identify prognostic factors and explore the role of haplo-HSCT in the treatment of Ph+ ALL in the TKI era. We analyzed clinical data of Ph+ ALL patients aged 1 to 18 years who received imatinib added to intensive chemotherapy at the start of induction therapy. Among the 68 patients who completed at least 2 consolidation cycles, 44 underwent transplantation (transplant arm) and 24 received continuous TKI with chemotherapy (nontransplant arm). At the 3-year follow-up the cumulative incidence of relapse (CIR), event-free survival (EFS), and overall survival (OS) were 23.5%, 73.4%, and 80.3%, respectively. Multivariate analysis showed that hematologic response (whether complete remission [CR] was achieved) at the induction end, BCR-ABL levels (whether major molecular response [MMR] was achieved) at 3 months, and transplantation were independent affecting factors for CIR, EFS, and OS. In the risk stratification analysis based on the first 2 prognostic factors mentioned above, no significant difference existed between the transplant and nontransplant arms for the probabilities of 3-year OS, EFS, and CIR in the standard-risk group (no poor prognostic factors). Meanwhile, OS, EFS, and CIR rates were significantly better in the transplant arm in the high-risk group (≥1 poor prognostic factor). Among the 44 patients in the transplant arm, 37 underwent haplo-HSCT. Achieving CR at the induction end, MMR at 3 months, and haplo-transplant were also independent favorable factors of CIR, EFS, and OS in the nontransplant and haplo-HSCT arms. Haplo-HSCT showed a significant survival advantage in the high-risk group only. Hematologic response at the induction end and BCR-ABL levels at 3 months are likely to be useful for identifying pediatric Ph+ ALL patients at a high risk of relapse in the TKI era. Children with Ph+ ALL in first CR may benefit from allo-HSCT, particularly those at high risk. Haplo-HSCT could achieve good long-term survival for pediatric Ph+ ALL. Thus, haplo-HSCT can be an alternative approach for high-risk Ph+ ALL patients.

Haplo-SCT Mediates Stronger GVL Effect Than HLA-Matched Sibling Allograft By Significantly Reducing Leukemia Burden

For AML patients with positive pre-transplant minimal residual disease (MRD), determined by multicolor flow cytometry (MFC), haploidentical stem cell transplantation (haplo-SCT) could achieve lower CIR rates than human leukocyte antigen (HLA)-matched sibling donor transplantation (MSDT) (J Hematol Oncol. 2017;10(1):134).However, these data only provide indirect evidence supporting the idea that haplo-SCT might have a strong graft-versus-leukemia (GVL) effect compared with MSDT. Therefore, direct evidence is needed to determine whether treating AML with haplo-SCT has a stronger GVL effect.The real time-polymerase chain reaction (RT-PCR) has greater sensitivity and specificity than MFC for detecting leukemia-specific genes, such as RUNX1/RUNX1T1, and provides a better estimation of the leukemia burden. Based on the levels of RUNX1/RUNX1T1 transcripts determined by RT-PCR, our group found that treating high risk cases with t(8;21) AML, who did not achieve major molecular remission (MMR, defined as a >3-log reduction in RUNX1/RUNX1T1 transcripts), with allogeneic stem cell transplantation (allo-SCT) could reduce the CIR compared with chemotherapy alone (22.1% vs 78.9%, P < 0.0001). These findings suggest that allo-SCT is necessary for high-risk t(8;21) AML patients, which provides an opportunity to investigate whether haplo-SCT has a superior GVL effect compared with MSDT in treating AML. Therefore, we focused on t(8;21) AML cases with positive MRD pre-transplant who underwent allogeneic SCT. The purpose of this study was to investigate and provide direct evidence that a haploidentical allograft has superior anti-leukemia effects compared with a HLA-matched sibling allograft.In the present study, One hundred and thirty-five t(8;21) acute myeloid leukemia (AML) patients with positive pre-transplantation minimal residual disease who underwent a haplo-SCT or MSDT were enrolled in this study. The levels of RUNX1/RUNX1T1 transcripts were monitored and quantified by real-time quantitative PCR. The 3-year cumulative incidence of relapse (CIR), non-relapse mortality (NRM), leukemia-free survival (LFS), and overall survival (OS) were 19%, 21%, 60%, and 61%, respectively. The levels of RUNX1/RUNX1T1 were significantly lower in Haplo-SCT patients compared with MSDT patients at 60 (P=0.039) and 90 (P=0.004) days after transplant (Figure 1). Compared with pre-transplant, the leukemia burden in the haplo-SCT group was significantly more reduced than in the MSDT group at 30 (P=0.068), 60 (P=0.005), 90 (P<0.0001), and 180 (P=0.032) days after transplant. The 3-year CIR rates for the haplo-SCT and MSDT patients were 14% and 28%, respectively (P=0.036). The 3-year LFS (68% vs. 47%, P=0.025) and OS (71% vs. 48%, P=0.040) after haplo-SCT were significantly higher than the rates after MSDT. In multivariate analysis, haplo-SCT was associated with a lower incidence of relapse (HR: 0.141; P=0.001) and a better LFS (HR: 0.187; P<0.0001) and OS (HR: 0.215; P=0.001). Our results provide direct evidence that a haplo-SCT has stronger graft-versus-leukemia effects than MSDT in patients with t (8;21) AML by significantly reducing the leukemia burden.Figure 1. Kinetics of log-transformed leukemia burden reduction (evaluated by RT-PCR for RUNX1/RUNX1T1) in all patients and subgroup cases who either received haplo-SCT or MSDT, using a repeated measures ANOVA. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Role of Measurable Residual Disease (MRD) in Redefining Complete Response (CR) in Elderly Patients with Acute Myeloid Leukemia (AML): Results from the Pethema-Flugaza Phase III Clinical Trial

Background: Incidence of AML is highest among the elderly and the general outcome is poor as compared to young patients, even those who tolerate intensive induction chemotherapy and achieve morphological CR. However, the role of MRD in redefining CR in elderly AML remains poorly investigated due to the reluctance to treat them with intensive chemotherapy, the renewed interest in low-intensity therapy such as hypomethylating agents (HMA), and the lack of molecular MRD markers in most patients.Aim: To help defining the role of MRD assessment by multidimensional flow cytometry (MFC) and therapeutic decision making in older AML patients treated with semi-intensive chemotherapy vs HMA.Methods: A total of 285 AML patients (excluding APL) with a median age of 75 were included in the phase III PETHEMA-FLUGAZA clinical trial and were randomized to receive 3 induction cycles with fludarabine and cytarabine (FLUGA) followed by 6 consolidation cycles with reduced intensity FLUGA, vs 3 induction cycles with 5-azacitidine (AZA) followed by 6 consolidation cycles with AZA. After consolidation, patients continued with the same treatment if MRD ≥0.01% or stopped if MRD <0.01%. MRD was prospectively assessed after induction and consolidation among patients in CR with or without incomplete blood count recovery, in a central laboratory blinded for clinical outcomes. At diagnosis, the EuroFlow panel for MDS/AML (first-five 8-color combinations) was used to identify leukemia-associated immunophenotypes (LAIP). Patients without a LAIP (6%) were excluded from this analysis. At CR, bone marrow samples were immunophenotyped with ≥2 8-color combinations based on previously identified maturation arrest, lineage commitment and LAIPs, maintaining markers' position from diagnosis to MRD to provide a digital fingerprint of leukemic blasts at diagnosis during MRD assessment. Over 1 million events per tube were measured for assessing MRD with an estimated sensitivity of 0.01%. The cumulative incidence of relapse (CIR) was calculated from the date of CR to the date of relapse, considering death without relapse as a competing event.Results: On intention-to-treat, 38/141 (27%) patients achieved CR after 3 cycles of FLUGA, and 31/144 (21.5%) after 3 cycles of AZA (P =.33). Among patients in CR with previously identified LAIP, 14/69 (20%) achieved a negative MRD status whereas the remaining 55 (80%) had persisting MRD: 56% with ≥0.1% MRD and 24% with 0.01%-0.09% MRD. Of note, negative MRD rates were particularly lower among AML patients with myelodysplasia-related changes as compared to other subtypes (11% vs 27%, respectively; P=.09). Regarding the effect of semi-intensive chemotherapy vs HMA on depth of response, we observed a non-significant trend toward higher MRD-negative rates among patients in CR after FLUGA vs those treated with AZA (26% vs 15%, respectively; P=.28).The 2-year CIR rates for MRD-positive and MRD-negative patients were 88% and 47%, respectively (HR, 3.3; P =.001). Of note, the CIR of patients in CR but with persistent MRD were similarly poor as compared to those in partial remission (HR, 0.82; P =.48). Furthermore, MRD-positive patients with adverse cytogenetics displayed the poorest outcome with significantly higher 2-year CIR rates than MRD-positive cases with intermediate/favorable cytogenetics (HR, 2.1; P =.008). Interestingly, among patients in CR and persistent MRD, 2-year CIR rates showed a non-significant trend towards slightly more frequent relapses in those treated with FLUGA vs AZA (91% vs 77%, respectively; HR, 1.7; P =.09). On multivariable analysis for CIR including MFC-MRD and cytogenetics, MFC-MRD (HR, 3.6; P =.001) and cytogenetics (HR, 2.0; P =.007) retained significant prognostic value. The median overall survival (OS) for MRD-positive and MRD-negative patients was 17 and 29 months, respectively (P =.04). On multivariable analyses for OS including age, WBC count, cytogenetic grouping and secondary disease, persistent MRD showed a trend for independent prognostic value (HR, 2.4; P =.07).Conclusions: This study reveals that sensitive MFC-MRD assessment supersedes CR and is an independent prognostic factor in older patients with AML, treated with semi-intensive chemotherapy or HMA. Nevertheless, the risk of relapse among the few patients with no MRD (5%) remains high after stopping treatment, and warrants innovative approaches aimed at maintaining an MRD-negative CR status. DisclosuresSan-Miguel:Janssen: Honoraria; BMS: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Sanofi: Honoraria; Roche: Honoraria. Montesinos:Novartis: Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Speakers Bureau.

Combining the Number of Infectious Episodes and Interval of Chemotherapy to Transplantation May Predict a Transplant Outcome in Patients with Acute Myeloid Leukemia: A Retrospective Analysis of JALSG AML201 Study

Abstract Background Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for acute myeloid leukemia (AML), but non-relapse mortality (NRM) remains obstacles to this treatments. Therefore, precise comorbidity evaluation before transplantation is crucial for better outcomes. One of the most frequently used tools for assessing the risk profile of transplant recipients is the hematopoietic cell transplantation comorbidity index (HCT-CI), which only incorporates information of the antibiotics use on day 0 as an infection-related factor, however, some important components, such as the number and severity of infectious episodes, are not included. Methods From December 2001 to December 2005, 1,057 newly diagnosed adult AML patients were registered to JALSG AML201 (Blood 2011; 117: 2358-65, 2366-72). Of them, the 121 evaluable patients who underwent allo-HSCT in the first hematological complete remission were analyzed. We have checked the above mentioned components, in addition to the interval from the last chemotherapy to transplantation, in these 121 patients and analyzed whether these factors might affect the subsequent transplant outcome. Results The median age was 37 years (range, 15-61). Regarding cytogenetic risk, 7 (6%), 92 (76%), and 15 (12%) patients were categorized as favorable, intermediate and high risk, respectively. The median follow-up period after transplantation was 939 days (range 19-2204). At 2 years after allo-HSCT, overall survival, leukemia free survival, cumulative incidence of relapse (CIR), and NRM for all patients were 73.2%, 65.4%, 19.4%, and 15.8%, respectively. A total of 106 (88%) patients developed at least one infectious episode as 102 (84%) patients faced to febrile neutropenia (FN), 45 (37%) patients experienced severe infection (≥ grade 3), and 27 (22%) patients eventually developed sepsis. Regarding the episode of FN, 52 (43%) patients experienced more than 2 times during chemotherapy. The median cycles of chemotherapy before transplantation was 4 (range, 1-6) and the median interval from the first day of last chemotherapy to transplantation was 77 days. The ROC curve indicated mild correlations between NRM and the interval with an area under the curve of 52% and the cutoff value at 113 days. The number of infectious episodes or severity of infection did not carry a significant impact on NRM at 2 years as 19.2% in FN with ≥3 episodes vs. 13.2% in FN with 0-2 episodes; p=0.18, 18.0% in patients with severe infection vs. 14.5% in patients without severe infection; p=0.49. However, in view of bone marrow transplant (BMT) recipients (n=76), multiple FN episodes was significantly associated with higher NRM (23.5% vs. 7.2% at 2 years, p=0.029) (Fig 1A). While, the relative shorter interval (&lt;113 days) from the first day of last chemotherapy to transplantation might have a negative impact on NRM as 19.4% vs. 6.2% at 2 years, p=0.054 (Fig 1B), but not affect CIR rate (18.4% vs. 22.3% at 2 years, p=0.67). Furthermore, the relative shorter interval in BMT recipients with multiple FN episodes showed a significant adverse impact on NRM (32.0% vs. 0% at 2 years, p=0.038) (Fig 1C). Conclusion Combining the number of infectious episodes and interval of chemotherapy to transplantation may predict a transplant outcome in AML patients. Providing an adequate interval from the last chemotherapy to transplantation may reduce NRM especially in BMT recipients who developed multiple FN episodes during induction or consolidation chemotherapy. Figure 1. Figure 1. Disclosures Kiyoi: Astellas Pharma Inc.: Research Funding; Novartis Pharma K.K.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Sanofi K.K.: Research Funding; Celgene Corporation: Research Funding; FUJIFILM Corporation: Research Funding; Phizer Japan Inc.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Bristol-Myers Squibb: Honoraria. Naoe:Nippon Shinyaku Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Fujifilm Corporation: Patents &amp; Royalties, Research Funding; Pfizer Japan Inc.: Research Funding; Toyama Chemical Co., Ltd.: Research Funding.

Assessment of Treatment Effects By Measurable Residual Disease Monitoring in NPM1-Mutated AML Patients Randomized for Gemtuzumab-Ozogamicin (GO) within the AMLSG 09-09 Trial of the German-Austrian AML Study Group (AMLSG)

Assessment of Treatment Effects By Measurable Residual Disease Monitoring in NPM1-Mutated AML Patients Randomized for Gemtuzumab-Ozogamicin (GO) within the AMLSG 09-09 Trial of the German-Austrian AML Study Group (AMLSG)

IKZF1plus Defines a New Minimal Residual Disease-Dependent Very-Poor Prognostic Profile in Pediatric B-Cell Precursor Acute Lymphoblastic Leukemia.

Purpose Somatic deletions that affect the lymphoid transcription factor-coding gene IKZF1 have previously been reported as independently associated with a poor prognosis in pediatric B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). We have now refined the prognostic strength of IKZF1 deletions by analyzing the effect of co-occurring deletions. Patients and Methods The analysis involved 991 patients with BCP ALL treated in the Associazione Italiana Ematologia ed Oncologia Pediatrica-Berlin-Frankfurt-Muenster (AIEOP-BFM) ALL 2000 trial with complete information for copy number alterations of IKZF1, PAX5, ETV6, RB1, BTG1, EBF1, CDKN2A, CDKN2B, Xp22.33/Yp11.31 (PAR1 region; CRLF2, CSF2RA, and IL3RA), and ERG; replication of findings involved 417 patients from the same trial. Results IKZF1 deletions that co-occurred with deletions in CDKN2A, CDKN2B, PAX5, or PAR1 in the absence of ERG deletion conferred the worst outcome and, consequently, were grouped as IKZF1plus. The IKZF1plus group comprised 6% of patients with BCP ALL, with a 5-year event-free survival of 53 ± 6% compared with 79 ± 5% in patients with IKZF1 deletion who did not fulfill the IKZF1plus definition and 87 ± 1% in patients who lacked an IKZF1 deletion ( P ≤ .001). Respective 5-year cumulative relapse incidence rates were 44 ± 6%, 11 ± 4%, and 10 ± 1% ( P ≤ .001). Results were confirmed in the replication cohort, and multivariable analyses demonstrated independence of IKZF1plus. The IKZF1plus prognostic effect differed dramatically in analyses stratified by minimal residual disease (MRD) levels after induction treatment: 5-year event-free survival for MRD standard-risk IKZF1plus patients was 94 ± 5% versus 40 ± 10% in MRD intermediate- and 30 ± 14% in high-risk IKZF1plus patients ( P ≤ .001). Corresponding 5-year cumulative incidence of relapse rates were 6 ± 6%, 60 ± 10%, and 60 ± 17% ( P ≤ .001). Conclusion IKZF1plus describes a new MRD-dependent very-poor prognostic profile in BCP ALL. Because current AIEOP-BFM treatment is largely ineffective for MRD-positive IKZF1plus patients, new experimental treatment approaches will be evaluated in our upcoming trial AIEOP-BFM ALL 2017.

Allogeneic Stem Cell Transplantation versus Tyrosine Kinase Inhibitors Combined with Chemotherapy in Patients with Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia

Here we compare outcomes between the tyrosine kinase inhibitors (TKIs) plus chemotherapy regimen and allogeneic hematopoietic stem cell transplantation (transplantation cohort) in patients with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) and explore factors associated with prognosis. Data from 145 Ph+ ALL patients were analyzed retrospectively. Patients were treated with imatinib plus chemotherapy and then transplantation or continuous TKIs with chemotherapy based on patient preference. A total of 145 Ph+ ALL patients were recruited for this study (median age, 37 years; range, 14 to 65). Among these patients, 81 were men (55.9%) and 86 underwent IKZF1 detection, which identified 59 patients (68.6%) with IKZF1 deletions. After treatment 136 patients (95.8%) achieved complete remission (CR) eventually. With a median follow-up of 33 months (range, 4 to 114) for CR patients, 77 patients (57.9%) underwent transplantation and 56 (42.1%) received continuous TKIs with chemotherapy. At the 4-year follow-up the cumulative incidence of relapse (CIR), disease-free survival (DFS), and overall survival (OS) were 29.4% (95% confidence interval [CI], 24.9% to 34.4%), 60.9% (95% CI, 56.5% to 65.3%), and 69.2% (95% CI, 65.1% to 73.3%), respectively. Multivariate analysis showed that WBC counts < 30 × 109/L at diagnosis (hazard ratio [HR], 4.2; 95% CI, 1.9 to 9.2; P < .001; HR, 2.6; 95% CI, 1.4 to 4.9; P = .003; HR, 2.7; 95% CI, 1.4 to 5.4; P = .003), 3-log reduction of BCR-ABL levels from baseline after 2 consolidation cycles (HR, 4.4; 95% CI, 1.9 to 9.9; P < .001; HR, 3.1; 95% CI, 1.7 to 5.9; P < .001; HR, 3.5; 95% CI, 1.9 to 8.7; P = .001; defined as “minimal residual disease low level”), and transplantation (HR, 5.0; 95% CI, 2.2 to 11.2; P < .001; HR, 3.3; 95% CI, 1.7 to 6.4; P < .001; HR, 4.1; 95% CI, 1.9 to 8.7; P < .001) were the favorable factors of CIR, DFS, and OS. According to the first 2 risk factors, CR patients were divided into 3 groups: low risk (no factor, n = 42, 31.6%), intermediate risk (1 factor, n = 73, 54.9%), and high risk (2 factors, n = 18, 13.5%). In the low-risk group at the 4-year follow up no significant difference existed between the transplant and nontransplant arms for the probabilities of CIR (8.5% versus 7.7%, P = .671), DFS (88.2% versus 83.9%, P = .426), and OS (96.6% versus 83.3%, P = .128). In the intermediate- and high-risk groups at the 4-year follow-up, CIR (23.6% versus 36.9%, P = .017; 37.5% versus 100.0%, P < .001), DFS (62.4% versus 43.8%, P = .048; 56.2% versus 0%, P < .001), and OS (76.1% versus 47.7%, P = .037; 51.4% versus 6.3%, P = .001) rates were significantly better in the transplant arm than in the nontransplant arm. In surviving patients of the low-risk group, no difference in complete molecular response (CMR) rates (85.7% versus 72.7%, P = .379) between the transplant and nontransplant arms was found. However, in the intermediate-risk group the proportion of CMR was significantly higher in the transplant arm than in the nontransplant arm (82.8% versus 42.9%, P = .006). In the high-risk group 4 of 7 transplant patients (57.1%) were in CMR, and no patients survived in the nontransplant arm. Allogeneic hematopoietic stem cell transplantation confers significant survival advantages for Ph+ ALL patients compared with TKIs plus chemotherapy, especially in intermediate- and high-risk patients.

The dynamics of RUNX1-RUNX1T1 transcript levels after allogeneic hematopoietic stem cell transplantation predict relapse in patients with t(8;21) acute myeloid leukemia

BackgroundThe optimal monitoring schedules and cutoff minimal residual disease (MRD) levels for the accurate prediction of relapse at all time points after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remain unclear in patients with t(8;21) acute myeloid leukemia (AML).MethodsRUNX1-RUNX1T1 transcript levels were measured in bone marrow samples collected from 208 patients at scheduled time points after transplantation (1530 samples in total).ResultsA total of 92.3% of the requested samples were collected, and 74.0% of patients had complete sample collection. The 1-, 3-, and 6-month RUNX1-RUNX1T1 transcript levels could significantly discriminate between continuous complete remission and a hematologic relapse at 1.5–3, 4–6, and 7–12 months but not at >3, >6, and >12 months, respectively. Over 90% of the 175 patients who were in continuous complete remission had a ≥3-log reduction in RUNX1-RUNX1T1 transcript levels from the time of diagnosis at each time point after transplantation and a ≥4-log reduction at ≥12 months. A <3-log reduction within 12 months and/or a <4-log reduction at ≥12 months was significantly related to a higher 3-year cumulative incidence of relapse (CIR) rate in both the entire cohort and the patients with no intervention after HSCT (58.4 vs. 2.2%, 76.5 vs. 2.0%; all P < 0.0001). Patients who had received a preemptive donor lymphocyte infusion when the increase in RUNX1-RUNX1T1 transcripts was ≤1-log according to the above dual cutoff values had significantly lower 1-year CIR rate after intervention than the patients who had received an infusion when the increase was >1-log (0 vs. 55.0%, P = 0.015).ConclusionsRUNX1-RUNX1T1 transcripts with a <3-log reduction from diagnosis within 12 months and/or a <4-log reduction at ≥12 months after allo-HSCT could accurately predict relapse and may prompt a timely intervention in patients with t(8;21) AML.

Is the outcome of childhood acute myeloid leukemia with t(8;21) inferior in Saudi Arabia? A multicenter SAPHOS leukemia group study

Background: Despite the confirmed favorable prognosis of childhood t(8;21) acute myeloid leukemia (AML), recent reports suggest heterogeneity in survival outcomes in this subtype of AML may be influenced by ethnicity. Therefore, we aimed to assess the outcome of childhood t(8;21) AML in an Arab population to evaluate if survival outcomes were inferior and determine the predictive relevance of additional cytogenetic abnormalities. Methods: This multicenter retrospective study analyzed 175 de novo AML children of 14 years of age or younger consecutively diagnosed between January 2005 and December 2012. Survival outcomes were analyzed and patients with t(8;21) were stratified on the basis of karyotype into sole and additional cytogenetic groups. Results: A total of 33 (18.9%) patients had t(8;21) AML. Complete remission (CR) was achieved in 31 (93.9%) patients. The 5-year overall survival, event-free survival, cumulative incidence of relapse (CIR), and remission death rates were 59.9 ± 9.2, 45.6 ± 9.1, 36.4, and 9.1%, respectively. Despite the administration of hematopoietic stem-cell-transplant salvage therapy in first relapse, five out of 11 (45.5%) relapsed patients died of disease. Subanalysis of sole vs. additional cytogenetic abnormalities revealed no significant difference in outcome. Conclusion: In the present study, childhood t(8;21) AML was associated with inferior survival and resistance to salvage therapy compared to reports from international groups. The inferior outcomes were unrelated to additional cytogenetic abnormalities. Further detailed genetic studies are warranted to unmask the biological and clinical differences between racial/ethnic groups. Given the high CR rate of childhood t(8;21) AML, further modification of postremission therapy to improve the CIR rate is needed.

Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: To Allogeneic Stem Cell Transplantation or Not? a Single Center Experience

Objectives: Compare the outcomes of allogeneic stem cell transplantation (allo-HSCT) versus a combination of imatinib and chemotherapy in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). Explore prognostic factors and indentify those who may enjoy long-term survival without the risk of allo-HSCT.Methods: Between May 2006 to November 2015, data of consecutive newly-diagnosed Ph+ALL patients <65 years treated at Peking University People’s Hospital were analyzed retrospectively. Patients received imatinib 400mg daily plus CODP regimen as induction chemotherapy. After achieving a complete remission (CR), they received imatinib with 8 cycles of alternating reduced-intensity hyper-CVAD regimen as consolidation chemotherapy. Patients in CR continued maintenance imatinib, vincristine, and prednisone for 2 years, which was followed by imatinib indefinitely. Patients eligible for allo-HSCT underwent it based on their own choice after at least 2 cycles of consolidation regimen during their first CR. Minimal residual disease (MRD) for BCR-ABL by quantitative polymerase chain reaction was monitored after each cycle of induction and consolidation chemotherapy and every 3 months later. Dasatinib was used as the second-line tyrosine kinase inhibitors (TKI) once imatinib-resistance occurred.Results: 122 Ph+ALL patients were included. 64 patients were male (52.5%). Median age was 36 years (range, 14-65 years). 2 patients (1.6%) died before response assessment, and 115 (95.8%) achieved CR. With a median followed-up period of 20 months (range, 1-98 months) in all patients and 28 months (range, 4-98 months) in 99 survivors, 65 patients (56.5%) underwent allo-HSCT and 50 (43.5%) received continuous imatinib with chemotherapy. Cumulative incidence of relapse (CIR), disease-free survival (DFS) and overall survival (OS) rates at 3 years were 17.3%, 79.0% and 81.5%, respectively. Multivariate analyses in the total CR patients showed that BCR-ABL reduction <3 logs from baseline after 2 cycles of consolidation chemotherapy (defined as MRD high level; HR=7.7, 95%CI 2.0-25.0, P=0.002; HR=2.9, 95%CI 1.1-7.1, P=0.026; HR=7.6, 95%CI 1.6-13.7, P=0.009) and imatinib plus chemotherapy (HR=7.1, 95%CI 2.6-20.0, P<0.001; HR=6.1, 95%CI 2.4-15.8, P<0.001; HR=5.6, 95%CI 2.0-15.8, P=0.001) were factors associated with increasing CIR and shorter DFS and OS. In addition, WBC equal or more than 30 X 109/L at diagnosis (HR=2.3, 95%CI 1.1-6.2, P=0.032; HR=4.1, 95%CI 1.3-13.2, P=0.016) was associated with shorter DFS and OS. In an attempt to determine whether choice of therapy contributed to outcome differences among patients with or without common poor prognostic factors (WBC equal or more than 30 X 109/L at diagnosis and MRD high level) for DFS and OS, we categorized the entire cohort into low-risk (possessing none of the factors, n=33), intermediate-risk (possessing any one of the factors, n=45), or high-risk (possessing at least 2 factors, n=24). In the low-risk cohort, choice of therapy did not influence the outcomes. In the intermediate- and high- risk cohorts, treatment with allo-HSCT was significantly superior to imatinib plus chemotherapy, with 3-year CIR, DFS and OS rates of 3.4% versus 44.3% (P=0.001) and 6.2% versus 55.6% (P=0.009); 88.2% versus 51.3% (P=0.001) and 93.8% versus 37.5% (P=0.027); 91.7% versus 56.3% (P=0.001) and 93.8% versus 41.0% (P=0.021), respectively. (Figure)Conclusions Our data suggest that allo-HSCT is a viable option for all patients with Ph+ALL. It is superior to a combination of imatinib and chemotherapy, conferring significant survival advantages to intermediate- and high-risk patients. However, the outcomes of imatinib plus chemotherapy and allo-HSCT are equally good in low-risk patients. For such patients, allo-HSCT may be considered as a salvage potion if there is evidence of TKI(s) resistance so long as the MRD is carefully monitored. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Excess Treatment-Related Mortality in Obese Children and Adolescents with Acute Myeloid Leukemia on AAML0531: A Report from the Children's Oncology Group

Background: Therapy for children with acute myeloid leukemia (AML) is intensive and treatment-related mortality (TRM) occurs in about 5 to 10% of patients. Previous data illustrated that obese children and adolescents with AML treated according to CCG 2961 were more likely to experience TRM, with HR 2.66 (95% CI 1.38-5.11; P = 0.003), when compared to middleweight patients. Since this trial, the backbone of AML chemotherapy and supportive care have changed and thus, it is unknown whether the impact of obesity persists in contemporary trials. The objective was to determine whether obesity was associated with increased TRM, reduced survival and prolonged compared to middleweight patients with AML.Methods: AAML0531 enrolled patients between August 14, 2006 and June 15, 2010. For this analysis, we included patients 0 to 18 years of age with de novo AML. Chemotherapy consisted of 5 cycles of chemotherapy and patients were randomized to receive or not receive gemtuzumab once during Induction I and Intensification II. Best allogeneic donor hematopoietic stem cell transplantation (HSCT) was recommended for those with > 15% bone marrow blasts after Induction I in those without favorable risk cytogenetics and poor risk cytogenetics irrespective of response following Induction I. Matched family donor HSCT was recommended for those with good response after Induction I with standard risk cytogenetics and an available donor.Obesity was defined using definitions from the Centers for Disease Control and Prevention (CDC). Underweight was defined as a body mass index percentile less than 5th percentile, and obese 95th percentile and greater. Categories were determined using z-scores for the weight-for-height data for those 0 to 2 years of age.All outcomes were censored at the time of HSCT. The primary outcome was TRM, defined as death as first event occurring on therapy or within 30 days of going off therapy. Cumulative incidence of TRM was estimated treating relapse and failure as competing events. Kaplan Meier analysis was conducted for overall survival (OS), event free survival (EFS), and disease free survival (DFS). Cumulative incidence of relapse rate (RR) was estimating treating deaths as competing events.Results: There were 1004 patients included. When comparing middleweight and obese patients, there was no significant difference in gender (P=0.814), white vs non-white race (P=0.116), cytogenetic risk group (all P>0.05) or MRD positivity after Induction 1 (P=0.750). The median age was higher for obese patients (12.0 vs 9.4 years; P=0.007 years) compared with middle weight patients. The proportion of patients who were Hispanic or Latino patients was higher among obese compared with middle weight patients (28% vs 17%; P=.001). Survival outcomes are shown in Table 1.When evaluating median time to neutrophil recovery, obese patients, when compared to middleweight patients, had shorter duration of neutropenia for cycles 1-3 (P<0.05).Conclusions: TRM rates continue to be higher for obese patients treated with contemporary AML protocols. Toxicity is not mediated through prolonged neutropenia. Future work should compare the rate of toxicity among obese versus non-obese patients and evaluate the impact of underweight status. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

PRAME overexpression predicted good outcome in pediatric B-cell acute lymphoblastic leukemia patients receiving chemotherapy

To investigate the prognostic value of PRAME expression in pediatric acute lymphoblastic leukemia(ALL), we measured PRAME transcript levels at diagnosis in 191 patients(146 B-ALL; 45T-ALL)receiving chemotherapy only. PRAME overexpression was defined as transcript levels higher than 0.30%, which is the upper limit of normal bone marrow and the optimal cutoff value derived from ROC curve analysis. PRAME overexpression was identified in 45.5% of patients. In B-ALL, PRAME overexpression was significantly associated with lower CIR(cumulative incidence of relapse), higher DFS (disease-freesurvival), and OS(overall survival) rates at 3 years, respectively (5.8% vs. 14.9%, P=0.014; 94.2% vs. 85.1%, P=0.014; 96.0% vs. 87.4%, P=0.039). PRAME overexpression had no impact on outcome in T-ALL patients. Among B-ALL patients with non-poor cytogenetic risk, those with PRAME overexpression showed significantly lower CIR, higher DFS and OS rates at 3 years, respectively (8.47% vs. 14.5%, P=0.009; 96.5% vs. 85.5%, P=0.009; 98.4% vs. 88.0%, P=0.023). Furthermore, PRAME overexpression was an independent good prognostic factor for relapse in all B-ALL patients and B-ALL patients with non-poor cytogenetic risk. Therefore, the prognostic significance of PRAME overexpression differed by ALL subtype; It predicted good outcome in pediatric B-ALL receiving chemotherapy.

Successful Therapy Reduction and Intensification for Childhood Acute Lymphoblastic Leukemia Based on Minimal Residual Disease Monitoring: Study ALL10 From the Dutch Childhood Oncology Group.

Outcome of childhood acute lymphoblastic leukemia (ALL) improved greatly by intensifying chemotherapy for all patients. Minimal residual disease (MRD) levels during the first months predict outcome and may select patients for therapy reduction or intensification. Patients 1 to 18 years old with ALL were stratified on the basis of MRD levels after the first and second course of chemotherapy. Thereafter, therapy was substantially reduced in patients with undetectable MRD (standard risk) and intensified in patients with intermediate (medium risk) and high (high risk) levels of MRD. Seven hundred seventy-eight consecutive patients were enrolled. The method of analysis was intention-to-treat. Outcome was compared with historical controls. In MRD-based standard-risk patients, the 5-year event-free survival (EFS) rate was 93% (SE 2%), the 5-year survival rate was 99% (SE 1%), and the 5-year cumulative incidence of relapse rate was 6% (SE 2%). The safety upper limit of number of observation years was reached and therapy reduction was declared safe.MRD-based medium-risk patients had a significantly higher 5-year EFS rate (88%, SE 2%) with therapy intensification (including 30 weeks of asparaginase exposure and dexamethasone/vincristine pulses) compared with historical controls (76%, SE 6%). Intensive chemotherapy and stem cell transplantation in MRD-based high-risk patients resulted in a significantly better 5-year EFS rate (78%, SE 8% v 16%, SE 8% in controls). Overall outcome improved significantly (5-year EFS rate 87%, 5-year survival rate 92%, and 5-year cumulative incidence of relapse rate 8%) compared with preceding Dutch Childhood Oncology Group protocols. Chemotherapy was substantially reduced safely in one-quarter of children with ALL who were selected on the basis of undetectable MRD levels, without jeopardizing the survival rate. Outcomes of patients with intermediate and high levels of MRD improved with therapy intensification.

High Post-Remission WT1 Expression Is a Predictive Marker for Subsequent Molecular Relapse and Poor Survival Outcome in Adult Patients with Acute Promyelocytic Leukemia (APL)

Background: Acute promyelocytic leukemia (APL) is classified into favorable-risk group and long-term overall survival (OS) is estimated at around 80%. Relapse rate of APL is relatively lower than another acute myeloid leukemia (AML) subtypes, but we still confront relapse in 10-20% and some relapsed cases are hardly cured even after hematopoietic cell transplantation (HCT). Therefore, it is important to find out patients with high-risk of relapse and early intervention should be considered. In APL, PML-RARa RQ PCR is used as a marker for residual disease, but the marker is not useful for pre-emptive management for relapse prevention because its positivity directly indicates relapse of disease. WT1 expression is a well-known marker in AML, and the expression is higher in APL than the other AML subtypes (Cilloni et al., leukemia, 2002). We monitored WT1 decrement along the treatment courses to identify its significant role as a marker for relapse prediction.Methods: In this study, 117 APL patients with a median follow-up duration of 38.5 months (range, 9.7-81.3) from 2008 to 2014 were analyzed. APL was diagnosed by RT-PCR method for detection of PML-RARa and all patients were available with cytogenetic results. All except 5 with normal karyotype was identified with t(15;17)(q22;q21) and 33 (28.2%) showed combination of additional chromosomal abnormalities. Our treatment protocol was based on LPA99 trial using ATRA and idarubicin monotherapy (Sanz et al., Blood, 2004). In relapsed patients, we applied ATO and some high-risk patients were treated with HCT (n=3). PML-RARa and WT1 expression in the BM samples were quantified by RQ-PCR method, and we used WT1 ProfileQuant¢â kit (Ipsogen) for WT1 monitoring. We measured RQ-PCR levels at diagnosis, post-induction and each of the 3 post-consolidation chemotherapies, and 3 months interval after starting maintenance therapy. FLT3- ITD/TKD mutation was evaluated by multiplex allele-specific PCR and concomitantly analyzed. Significant cut-off level of PML-RARa and WT1 expression was calculated by ROC curve analysis. According to the level, we calculated OS, disease free survival (DFS), and cumulative incidence of relapse (CIR).Results: Hematological complete remission (CR) was identified in 117 (100.0%) patients but complete molecular remission (CMR) was identified in 68 (42.7%) after induction. Among 49 patients who failed to achieve CMR, 44 patients achieved CMR after 1st consolidation and 5 patients after 2nd consolidation. Three-year OS and EFS was 92.5% and 82.0%, and CIR rate was 14.7% (n=13). Three patients showed clonal evolution to therapy-related AML and 1 patient died in CR due to lung cancer. FLT3 -TKD and FLT3 -ITD mutation was identified in 6 (5.1%) and 25 (21.4%) patients, and PML-RARa BCR3 and BCR1 subtype was identified in 32 (27.4%) and 85 (72.6%) patients, respectively. For relapse prediction, we analyzed WT1 expression at several time points in association with CMR after induction, FLT3 -ITD/TKD mutation, BCR subtype, and hyperleukocytosis at diagnosis and during first chemotherapy. High WT1 expression (>120 copies/104ABL1) in early period (3 months) after maintenance therapy significantly predicted subsequent relapse. All paired PML-RARa RQ-PCR was not detected except one sample with early relapse after 3rd consolidation. Patients with high post-maintenance WT1 expression (n=40) showed significantly higher CIR rate (30.7% vs. 4.2%, p=0.0003) and inferior 3-year OS (86.1% vs. 97.9%, p =.0103) and DFS (62.8% vs. 94.1%, p<.0001). Multivariate analysis revealed high leukocyte counts [HR=9.2, 95%CI=2.2-38.5, p =.002], WT1 at 3 months post-maintenance [HR=8.7, 95%CI=1.9-38.9, p =.0051], and FLT3 mutation [HR=5.4, 95%CI=1.5-19.4, p =.0092] were significant factors for relapse prediction. However, even in the BCR3 or FLT3 -positive subgroup (n=48), low WT1 at post-maintenance 3 months was associated with lower CIR rate (13.4% vs. 50.8%, p<.0001) and better DFS (95.2% vs. 49.2%, p<.0001).Conclusion: High post-remission WT1 expression was a reliable marker for the prediction of subsequent relapse in APL, even when PML-RARa was not detected at 3 months post-maintenance. In this high-risk group, early intervention with ATRA±ATO, WT1 vaccination or WT1 -specific cytotoxic cell therapy may be used for relapse prevention. The role of WT1 expression needs to be validated by prospective studies in a large cohort. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Long Term Clinical Outcome of Hematopoietic Cell Transplantation for Intermediate to High-Risk Adult AML in Complete Remission; Can We Enhance the Survival Outcome Using Alternative Donor Types?

Background: Standard therapy for intermediate to high-risk acute myeloid leukemia (AML) consists of several hematopoietic cell transplantation (HCT) strategies including autologous-HCT (AUTO), allogeneic-HCT from matched-sibling donor (MSD) or well-matched unrelated donor (WM-URD). When a conventional donor is not available, HCT from partially-matched unrelated donor (PM-URD) or familial mismatched/haploidentical transplantation (FMMT) or umbilical cord blood transplantation is also considered for an alternative choice. Although HCT outcomes of those alternative strategies are advancing with optimization of pre-conditioning regimens with immunosuppressive agents, there are still subjects to debate. We tried to analyze the long-term HCT outcomes according to the donor types including FMMT and PM-URD as an alternative choice.Methods: We enrolled 561 AML patients (median 41 years old, range: 16-68) in complete remission (CR) who were transplanted in Catholic BMT Center in Korea from 2002 to 2013. Patients in at least second CR were excluded. All patients presented intermediate to high-risk karyotype according to the NCCN guidelines, and all of the patients received standard 3+7 chemotherapy followed by consolidation chemotherapy. In the absence of MSD and WM-URD, we allocated PM-URD or AUTO as an alternative choice first, and then FMMT was considered. We divided patients according to the 5 donor types (i.e. MSD (n=252), WM-URD (n=112), PM-URD (n=41), AUTO (n=104), and FMMT (n=52)), and survival outcomes with the cumulative incidence of relapse (CIR), non-relapse mortality (NRM), acute/chronic GVHD and CMV reactivation were analyzed.Results: Engraftment was successful and showed similar recovery pattern in all donor types. Our data showed mismatch in ABO, sex, and certain HLA locus was not influential, and stem cell source and conditioning-intensity were not also influential for survival outcome and incidence of GVHD. After median follow-up of 54.3 month (range: 6.6-145.6), MSD, WM-URD and FMMT showed similar 5-year OS around 62% except for AUTO at 47.4% and PM-URD at 36.7%. DFS at 5-years was 59% for MSD, 56% for WM-URD, 62% for FMMT, 44.3% for AUTO, and 33.5% for PM-URD. Five-year CIR rate was highest in AUTO (50.3%) followed by PM-URD (33.1%) and WM-URD (29.8%). Lower CIR-rate was identified in MSD (22.4%) and FMMT (21.4%), and the lowest NRM rate was identified in AUTO subgroup (5.1%) followed by WM-URD (11.4%), FMMT (15.6%) and MSD (18.0%). PM-URD showed the highest NRM rate (33.3%) with higher incidence (26.7%) of Gr°Ã3 acute GVHD compared to 9.3% of MSD. Incidence of chronic GVHD was not significantly different. In adverse-risk subgroup, 5-year OS of MSD, WM-URD, and FMMT was 46%, 47%, and 58% respectively, while AUTO and PM-URD was 11% and 0%, which was caused by significantly higher CIR rate of 79.7% and 83.5%, respectively, compared to 31.1% of MSD. In intermediate-risk subgroup, 5-year OS of AUTO (55.2%) was not inferior to that of MSD (67.2%, p =0.330) or FMMT (64.9%, p =0.451), which showed the highest CIR rate (42.8%) and the lowest NRM (5.4%). PM-URD also showed highest NRM (39.4%) with high incidence (27.3%) of Gr°Ã3 acute GVHD.Conclusions: FMMT should be considered prior to PM-URD in intermediate to adverse-risk AML and GVHD prophylaxis should be intensified when we have to use PM-URD. AUTO might be considered in intermediate-risk AML in selected patients and prospective study should validate the utility of FMMT or AUTO in addition to the conventional donor types. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Patients over Age 40 with Ph-Negative Acute Lymphoblastic Leukemia Do Not Benefit from Allogeneic Transplant in First Remission. Retrospective Analysis from a Large Tertiary Center

Background: Survival of adult patients with Ph-negative acute lymphoblastic leukemia (ALL) with conventional therapeutic approaches remains poor. Given the ability to safely perform allogeneic stem-cell transplant (alloSCT) in this age cohort, older patients with ALL in first complete remission (CR1) are increasingly offered consolidation with this modality. We asked whether alloSCT in CR1 offers a survival advantage in older patients with ALL as compared to post remission chemotherapy.Methods: One hundred and seven patients ≥40 years were treated at the Dana Farber Cancer Institute for Ph-negative ALL from 1/1/2006 to 12/31/2013; of the 99 patients treated with curative intent, 80 patients (age 54.5 years; range 41-83) achieved first remission (81%; CR and CRi). Baseline characteristics of the chemotherapy and alloSCT post remission groups were compared using the Fisher exact and Wilcoxon rank-sum tests for categorical and continuous variables, respectively. The comparison of outcomes between the alloSCT and chemotherapy cohorts was made using a modified Mantel-Byar test to account for the waiting time to transplant. For graphical comparisons, the method of left-truncation was used to adjust for the time of wait from first CR/CRi to transplant. In Cox modeling of overall survival (OS) and disease free survival (DFS), treatment was included as a time-dependent variable. The cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were calculated and compared between groups from the time of CR/CRi to the time of the event with each considered as competing events. Retrospectively determining the reason for choosing one post remission approach over the other was not always possible. Furthermore, MRD status was available in a minority of patients. The effect and relation of these factors to patient selection and outcome therefore could not be assessed.Results: Eighty patients in first CR/CRi were analyzed. B-cell ALL was diagnosed in 86% of patients and T-cell origin was identified in 14% of patients; 6% of patients had therapy-related ALL. Median WBC, platelet and Hb levels at diagnosis were 5.3X109/L, 61X109/L and 9.6mg/dL, respectively. Cytogenetics were available for 63 patients (cytogenetics were not reported for referred patients (n=11) or were unsuccessful (n=6)) and were diploid (52%), near hyperploid (25%), hyperploid (11%), near hypoploid (5%) and hypoploid (2%). MLL rearrangement was identified in 12.5% of patients. Most patients had an ECOG performance status of 0-1; the median modified Charlson co-morbidity index score was 2 (range 0-10) and 56% of patients had ≥1 co-morbidities.In the alloSCT group, myeloablative and reduced-intensity conditioning were used in 55% and 45% of patients, respectively. Matched related and matched unrelated donors were used in 40% and 48% of patients, respectively, with the remainder receiving alternative donor sources.Forty patients received alloSCT in first remission and 40 patients were treated with chemotherapy only. Baseline characteristics did not significantly differ between the 2 groups except for lower Hb in the alloSCT group (p=0.028). Nine of 10 patients with MLL rearrangement were allocated to the alloSCT group.The median follow-up in the alloSCT and chemotherapy groups was 3.7 and 2.6 years, respectively. OS (Figure 1) and DFS did not differ between the groups at 3 years; the significantly higher CIR rate in the chemotherapy group was offset by the higher NRM in the alloSCT group (Table 1).Univariate Cox Modeling of 13 patient, disease and treatment-related factors including post remission modality were analyzed, none of which were shown to affect OS or DFS. WBC at diagnosis (≥20K vs. <20K) achieved borderline significance for DFS (p=0.053). The type of conditioning and donor source did not affect survival within the alloSCT group.Conclusion: AlloSCT in first CR is associated with a lower CIR but this benefit is offset by higher NRM as compared to chemotherapy. Although this should be confirmed in larger cohorts, these data suggest that alloSCT does not confer a survival benefit in patients ≥40 years with Ph-negative ALL.Table 1Outcome by CohortsOutcomeChemotherapy in CR1 (n=40)AlloSCT in CR1 (n=40)P-valueMedian Follow-up (years)2.6 (0.2, 8.2)3.7 (1.2, 7.0)0.223-yr % OS [95% CI]46 [31-68]39 [26-59]0.353-yr % DFS [95% CI]31 [18-52]40 [27-59]0.983-yr CIR %61 [41-76]28 [15-43]0.0113-yr NRM %9 [2-21]32 [17-47]0.014 [Display omitted] DisclosuresSteensma:Incyte: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Onconova: Consultancy. Stone:Agios: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; AROG: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; Juno: Consultancy; Novartis: Research Funding; Abbvie: Consultancy; Celator: Consultancy; Roche/Genetech: Consultancy; Amgen: Consultancy; Karyopharm: Consultancy; Merck: Consultancy.

Clinical Impact of Additional Cytogenetic Aberrations, cKIT and RAS Mutations, and Treatment Elements in Pediatric t(8;21)-AML: Results From an International Retrospective Study by the International Berlin-Frankfurt-Münster Study Group.

This retrospective cohort study aimed to determine the predictive relevance of clinical characteristics, additional cytogenetic aberrations, and cKIT and RAS mutations, as well as to evaluate whether specific treatment elements were associated with outcomes in pediatric t(8;21)-positive patients with acute myeloid leukemia (AML). Karyotypes of 916 pediatric patients with t(8;21)-AML were reviewed for the presence of additional cytogenetic aberrations, and 228 samples were screened for presence of cKIT and RAS mutations. Multivariable regression models were used to assess the relevance of anthracyclines, cytarabine, and etoposide during induction and overall treatment. End points were the probability of achieving complete remission, cumulative incidence of relapse (CIR), probability of event-free survival, and probability of overall survival. Of 838 patients included in final analyses, 92% achieved complete remission. The 5-year overall survival, event-free survival, and CIR were 74%, 58%, and 26%, respectively. cKIT mutations and RAS mutations were not significantly associated with outcome. Patients with deletions of chromosome arm 9q [del(9q); n = 104] had a lower probability of complete remission (P = .01). Gain of chromosome 4 (+4; n = 21) was associated with inferior CIR and survival (P < .01). Anthracycline doses greater than 150 mg/m(2) and etoposide doses greater than 500 mg/m(2) in the first induction course and high-dose cytarabine 3 g/m(2) during induction were associated with better outcomes on various end points. Cumulative doses of cytarabine greater than 30 g/m(2) and etoposide greater than 1,500 mg/m(2) were associated with lower CIR rates and better probability of event-free survival. Pediatric patients with t(8;21)-AML and additional del(9q) or additional +4 might not be considered at good risk. Patients with t(8;21)-AML likely benefit from protocols that have high doses of anthracyclines, etoposide, and cytarabine during induction, as well as from protocols comprising cumulative high doses of cytarabine and etoposide.

Minimal residual disease negativity in elderly patients with acute myeloid leukemia may indicate different postremission strategies than in younger patients.

In the present analysis, we evaluated whether in elderly acute myeloid leukemia (AML) patients (>60years), minimal residual disease (MRD) assessed by flow cytometry may have a role in guiding choice of postremission strategies. We analyzed 149 young and 61 elderly adults who achieved morphological CR after induction course of EORTC/GIMEMA protocols. Elderly patients reached a postconsolidation MRD negative status less frequently than younger ones (11 vs 28%, p = 0.009). MRD negativity resulted in a longer 5-year disease-free survival (DFS) both in elderly (57 vs 13%, p = 0.0197) and in younger patients (56 vs 31%, p = 0.0017). Accordingly, 5-year cumulative incidence of relapse (CIR) of both elderly (83 vs 42%, p = 0.045) and younger patients (59 vs 24% p = NS) who were MRD positive doubled that of MRD negative ones. Nevertheless, CIR of MRD negative elderly patients was twofold higher than that of younger MRD negative ones (42 vs 24%, p = NS). In conclusion, elderly patients in whom chemotherapy yields a MRD negative CR have duration of DFS and rate of CIR significantly better than those who remain MRD positive. Nonetheless, the high CIR rate observed in the elderly suggests that MRD negativity might have different therapeutic implications in this population than in the younger counterpart.

Clinical Impact of Additional Cytogenetic Aberrations, cKIT- and RAS Mutations and Other Factors in Pediatric t(8;21)-AML

IntroductionWhilst pediatric t(8;21)-positive AML has an overall survival rate of up to 80-90%, the relapse rate at 30-40% remains unacceptably high. Factors that reliably discriminate between patients with t(8;21) who do or do not relapse have been poorly described. The prognostic impact of additional cytogenetic aberrations and of cKIT or RAS mutations in this subgroup remains unclear. In this large retrospective cohort study, supported by the International-BFM study group, we aimed firstly to determine outcome in relation to these aberrations and, secondly to identify any treatments associated with outcome.MethodsData on diagnostics, treatment, response, relapse or other events and follow-up were collected from 19 childhood cancer study groups, who provided data from 916 pediatric AML-patients positive for t(8;21) and/or AML1-ETO fusion gene. Karyotypes were reviewed and classified (CH&BB). Aberrations occurring in at least 10 patients were considered for analyses and involved loss of sex chromosome, deletions of chromosome 9q (del9(q)), abnormalities of chromosome 7q, gain of chromosome 4 (+4) and gain of chromosome 8. A total of 228 samples could be evaluated for cKIT and/or RAS mutations. Significant characteristics in explorative analysis were used in 2 multivariate Cox proportional-hazard regression models for assessing effects of induction and overall treatment elements. Induction was defined as first two courses of chemotherapy. Endpoints were probabilities of achieving complete remission (pCR), of event free survival (pEFS), and of overall survival (pOS) and cumulative incidence of relapse (CIR). Only results of multivariate analyses are shown.ResultsIn final analyses 838 patients with a full karyotype were included. CR was achieved in 92% of the patients. Five-year pOS was 74% (SE 1.5%), five-year pEFS 58% (SE 1.7%) and five-year CIR 26% (SE 1.5%). WBC count >20 x109/L was associated with poorer outcome for all endpoints (p<0.01). CNS involvement at presentation led to higher CIR (p<0.01). Twenty five percent of the patients had cKIT mutation(s). No differences in clinical or leukemic characteristics between mutated and wild-type patients were identified. Seven out of 10 patients with +4 had cKIT mutation(s) (p<0.01). Patients with RAS mutations (13%) had higher WBC counts (p=0.03). No clinical differences between N-RAS (n=17) and K-RAS (n=5) mutated patients were found. No associations between other additional aberrations and cKIT- or RAS mutations were identified. Patients with del(9)(q) (n=104) had lower pCR (p=0.01), without influencing pEFS or pOS. Additional +4 (n=21) was strongly associated with higher CIR (p<0.01) and poorer survival rates (5ypEFS 18% versus 59%, plogrank<0.01 and 5ypOS 33% versus 75%, plogrank<0.01). Presence of other cytogenetic aberrations including complex karyotype or cKIT or RAS mutations did not affect outcome.Anthracyclines >150mg/m2 used in first induction course was associated with higher pCR (p=0.04) and higher pOS (p=0.03). Etoposide >500mg/m2 used in first course was associated with higher pEFS (p=0.01) and pOS (p=0.02). The use of HD-AraC 3g/m2 during induction was associated with higher pCR (p=0.02). When including consolidation therapy, cumulative dosages of cytarabine >30g/m2 and etoposide >1500mg/m2 were associated with lower CIR (p=0.02 and p<0.01 respectively).ConclusionThis study identifies novel negative prognostic factors in pediatric t(8;21)-AML patients - del(9q) associated with an inferior pCR, and +4 significantly associated with an increased relapse rate and inferior survival. This challenges the favorable classification of patients with t(8;21) and +4. The presence of del(9q) may indicate the need for intensified induction therapy in view of the lower pCR. Although cKIT or RAS mutations did not influence outcome in conventionally treated t(8;21)-patients in this study, mutated patients may benefit further from treatment with tyrosine kinase inhibitors.This study suggests benefit from protocols containing high-dose anthracyclines, etoposide and HD-AraC 3g/m2 during induction, and the use of cumulative dosages of cytarabine >30g/m2 and of etoposide >1500mg/m2 in pediatric t(8;21)-positive AML. Optimal dosages and combinations of these agents should be established in prospective randomized trials. DisclosuresNo relevant conflicts of interest to declare.