Difference In CR Rate Research Articles

Initial Trans-Arterial Chemo-Embolisation (TACE) Is Associated with Similar Survival Outcomes as Compared to Upfront Percutaneous Ablation Allowing for Follow-Up Treatment in Those with Single Hepatocellular Carcinoma (HCC) ≤ 3 cm: Results of a Real-World Propensity-Matched Multi-Centre Australian Cohort Study.

Percutaneous ablation is recommended in Barcelona Clinic Liver Cancer (BCLC) stage 0/A patients with HCC ≤3 cm as a curative treatment modality alongside surgical resection and liver transplantation. However, trans-arterial chemo-embolisation (TACE) is commonly used in the real-world as an initial treatment in patients with single small HCC in contrast to widely accepted clinical practice guidelines which typically describe TACE as a treatment for intermediate-stage HCC. We performed this real-world propensity-matched multi-centre cohort study in patients with single HCC ≤ 3 cm to assess for differences in survival outcomes between those undergoing initial TACE and those receiving upfront ablation. Patients with a new diagnosis of BCLC 0/A HCC with a single tumour ≤3 cm first diagnosed between 1 January 2016 and 31 December 2020 who received initial TACE or ablation were included in the study. A total of 348 patients were included in the study, with 147 patients receiving initial TACE and 201 patients undergoing upfront ablation. After propensity score matching using key covariates, 230 patients were available for analysis with 115 in each group. There were no significant differences in overall survival (log-rank test p = 0.652) or liver-related survival (log-rank test p = 0.495) over a median follow-up of 43 months. While rates of CR were superior after ablation compared to TACE as a first treatment (74% vs. 56%, p < 0.004), there was no significant difference in CR rates when allowing for further subsequent treatments (86% vs. 80% p = 0.219). In those who achieved CR, recurrence-free survival and local recurrence-free survival were similar (log rank test p = 0.355 and p = 0.390, respectively). Our study provides valuable real-world evidence that TACE when offered with appropriate follow-up treatment is a reasonable initial management strategy in very early/early-stage HCC, with similar survival outcomes as compared to those managed with upfront ablation. Further work is needed to better define the role for TACE in BCLC 0/A HCC.

Array CGH + SNP in ALL Enhances Detection of Complex Cytogenetic Profiles and Suggests That PRSS1 Loss May Play a Role in Leukemogenesis

Introduction Cytogenetic alterations are essential prognostic biomarkers in patients (pts) with acute lymphoblastic leukemia/lymphoma (ALL), but are limited by the propensity of leukemic blasts to undergo apoptosis in culture, poor-quality chromosomes, and overgrowth by normal cells. Array CGH + SNP has 10,000-fold higher resolution than conventional cytogenetics and can identify submicroscopic gains, losses and copy number neutral loss of heterozygosity (cnLOH) irrespective of mitotic rate. Few studies outside of clinical trials have investigated microarray findings in adults with ALL or correlated microarray findings with clinical outcomes. Methods We retrospectively reviewed pts with ALL and mixed phenotype acute leukemia (MPAL) aged ≥18 years at diagnosis at our institution between 2017 and 2022. Array analysis was performed on diagnostic bone marrow or peripheral blood samples using high resolution CGH + SNP Genetisure cancer array platform (Agilent). Statistical analysis was done using R software (R core team, 2022). Results Baseline characteristics of included pts (n = 60) are shown in Table 1. CGH + SNP analysis identified 93.3% (56/60) of pts with genomic changes with a mean of 7 (range 0 - 28) aberrations per pt. Among pts with a normal karyotype, 81.8% (9/11) had new genomic abnormalities revealed by CGH + SNP, but significantly fewer aberrations were detected per pt compared to those with abnormal karyotypes (mean 3.09 v. 7.67, p = .008). Pts with Ph-like B-ALL/MPAL had significantly more aberrations on array than pts without Ph-like phenotype (mean 12.0 v. 5.85, p.= .002). Among the 78.3% of pts without complex cytogenetics on chromosome analysis, 44.7% (21/47) were found to have a complex genomic profile (≥5 aberrations) with the addition of CGH + SNP. However, there was no difference in CR rates or OS in pts with &amp;lt;5 or ≥5 microarray aberrations (p = .515 and p = .970, respectively). Quantity of copy number alterations (CNAs) as detected on array was not predictive of achieving end of induction CR/CRi/CRh (mean 6.08 in pts who achieved CR/CRi/CRh v. 7.02 in pts with primary refractory disease, p = .310). Hispanic pts had the same number of CNAs as non-Hispanic pts (mean 6.69 v. 6.94, p = .435). On linear regression analysis, there was no correlation between number of CNAs and age (r 2 = -.01, F = 0.1941, p = .661) or BMI (r 2 = 5.21 x10 -5, F = 0.0029, p = .957). The most frequent focal aberrations were detected in CDKN2A/B (n = 19), IKZF1 (n = 17), PRSS1 (n = 11), PAX5 (n = 8), BTG1 (n = 8) and RB1 (n = 8) (Figure 1). RB1 loss was enriched in pts with T-ALL (45.5% v. 6%, p = .003),and occurred at significantly higher rates than previously reported in T-ALL (Schraders, 2009). Loss of PRSS1 was detected in 18.3% (11/60) of the cohort. Homozygous PRSS1 deletions were identified in 3/11 (27.3%) pts. We identified the minimal overlapping deleted region on 7q34 in all 11 pts, which included the PRSS1 gene within the 124 kb region. Five of 6 pts who had repeat arrays performed at the end of induction had resolution of this aberration. The one pt who retained PRSS1 loss after induction had primary refractory disease, but after further treatment and attainment of CR1, this pt cleared the PRSS1 loss. Asparaginase associated pancreatitis, which has been linked to PRSS1 variations, occurred in only 1 pt with PRSS1 loss. Pts harboring PRSS1 loss were significantly less likely to achieve MRD negativity after induction (50% vs. 82%, P = .041) and had numerically more relapses (37.5% vs. 19%, p = .300), but no OS difference was observed (p = .290). Conclusions In our institutional cohort, the addition of CGH + SNP array reclassified almost half (44.7%) of pts without complex cytogenetics to harbor complex genomic changes (≥5 aberrations). Pts with Ph-like ALL had significantly more aberrations on array than those with Ph-positive or -negative B-ALL. Focal PRSS1 loss was associated with reduced rates of MRD clearance at the end of induction. This aberration resolved upon disease remission, raising the possibility that both homozygous and/or heterozygous deletions of 124 kb from the 7q34 chromosomal region of the PRSS1 gene may potentially have a role in ALL pathogenesis. Further studies with larger cohorts utilizing CGH + SNP analyses at additional time points during treatment are needed to explore the potential integration of microarray data for refined ALL risk stratification as well as to elucidate the functional role of PRSS1 in leukemogenesis.

MDS-110 SELECT-MDS-1 Trial in Progress: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study of Tamibarotene/Azacitidine Versus Placebo/Azacitidine in Newly Diagnosed Adult Patients Selected for RARA-Positive Higher-Risk MDS

A novel genomically defined subset of higher-risk myelodysplastic syndrome (HR-MDS) patients with an actionable target characterized by overexpression of RARA has been identified (McKeown 2017). Approximately 30% of HR-MDS patients are RARA-positive by a blood-based biomarker test (Vigil 2017). Tamibarotene is an oral selective RARα agonist with potential for clinical benefit in RARA-positive HR-MDS patients, irrespective of mutation or cytogenetic risk. Initial clinical data in RARA-positive relapsed/refractory HR-MDS showed myeloid differentiation, improved blood counts, and reduced bone marrow blasts, including one patient who achieved marrow complete remission with hematologic improvement (Jurcic 2017). Tamibarotene/azacitidine led to a CR/CRi rate of 61% with rapid onset of response in RARA-positive newly diagnosed (ND) unfit AML patients, including those with low blast count (≤30%) AML, and a majority of patients achieved or maintained transfusion independence (de Botton 2020). Tamibarotene/azacitidine was generally well tolerated with no increase in myelosuppression compared with azacitidine alone (de Botton 2020). Historical precedent demonstrating similar clinical outcomes in HR-MDS and low blast count AML (Estey 2022) supports further development of tamibarotene/azacitidine in HR-MDS to improve clinical outcomes of standard of care treatment with hypomethylating agents (HMAs). To characterize and compare the CR rate of tamibarotene/azacitidine to placebo/azacitidine in RARA-positive ND HR-MDS patients. Secondary objectives include comparisons of overall response rate, event-free survival, overall survival, transfusion independence, and safety. Global, Phase 3, randomized, double-blind, placebo-controlled trial (NCT04797780). Approximately 190 patients will be randomized 2:1, providing 90% power to detect the difference in CR rates between the experimental and control arms. The included patients will be RARA-positive based on investigational assay and ND with HR-MDS by WHO classification (Arber 2016) with an IPSS-R risk category of very high, high, or intermediate and a blast count >5% at baseline. Patients with prior treatment for MDS with any HMA, chemotherapy, or transplant are excluded. Azacitidine will be administered at 75 mg/m2 IV/SC daily on days 1-7 (or 1-5, 8-9) followed by tamibarotene/placebo at 6 mg BID orally on days 8-28 of each 28-day cycle. Response is assessed per the modified IWG MDS criteria (Cheson 2006).

PB1921: A RANDOMIZED, DOUBLE-BLIND, PHASE 3 STUDY OF TAMIBAROTENE/AZACITIDINE VERSUS PLACEBO/AZACITIDINE IN NEWLY DIAGNOSED ADULT PATIENTS SELECTED FOR RARA-POSITIVE HR-MDS (SELECT-MDS-1)

Background: A novel genomically defined subset of higher-risk MDS (HR-MDS) patients with an actionable target characterized by overexpression of RARA has been identified (McKeown 2017). Approximately 30% of HR-MDS patients are RARA-positive (RARA+) by a blood-based biomarker test (Vigil, 2017). This RARA positivity enables biologically targeted therapy with tamibarotene (formerly SY-1425), an oral selective RARα agonist with potential to provide clinical benefit for HR-MDS patients, irrespective of mutation or cytogenetic risk. Initial Phase 2 clinical data in RARA+ relapsed/refractory HR-MDS patients treated with single agent tamibarotene showed myeloid differentiation, improved blood counts, and reduced bone marrow blasts, including one patient who achieved marrow complete remission with hematologic improvement (Jurcic 2017). Tamibarotene in combination with azacitidine (aza) demonstrated high complete response rates with rapid onset of response in RARA+ newly diagnosed (ND) unfit AML patients, including those with low blast count (≤ 30%) AML, and a majority of patients achieved or maintained transfusion independence (de Botton 2020). Tamibarotene plus aza was generally well tolerated with no increase in myelosuppression compared to single agent aza (de Botton 2020). HR-MDS and AML have common cytogenetic abnormalities and gene mutations present in the blast populations in each condition. The historical precedent demonstrating similar clinical outcomes among patients with HR-MDS and AML, particularly low blast count AML (Estey 2021), supports further development of the combination of tamibarotene plus aza in the HR-MDS population, with the opportunity to improve upon the clinical outcomes of standard of care treatment with hypomethylating agents (HMAs). Aims: This is a global Phase 3, multi-center, randomized, double-blind, placebo-controlled study comparing the activity of tamibarotene plus aza, to placebo plus aza in RARA+ patients with ND HR-MDS. The primary objective is to compare the complete remission rate of tamibarotene plus aza vs. placebo plus aza, with secondary objectives to compare objective response rate, event-free survival, overall survival, transfusion independence rate, time to and duration of initial and complete responses, and safety. Methods: Patients must be RARA+ based on the investigational biomarker test, ND with HR-MDS by WHO classification (Arber 2016), classified by IPSS-R risk category as very high, high, or intermediate risk with a bone marrow blast count > 5% at study entry. Patients suitable for allogeneic HSCT at the time of screening, or who received prior treatment for MDS with any HMA, chemotherapy or allogeneic HSCT are excluded. Aza will be administered at 75 mg/m2 IV/SC daily on days 1-7 (or days 1-5, 8-9) followed by tamibarotene/placebo at 6 mg BID orally days 8-28 of each 28-day cycle. Response will be assessed per the modified IWG MDS criteria (Cheson 2006). Results: Approximately 190 patients will be randomized 2:1 and stratified by IPSS-R risk group and geographic region, providing 90% power to detect the difference in CR rates between the experimental and control arms, respectively, with one-sided alpha of 0.025. Summary/Conclusion: The SELECT-MDS-1 trial opened to enrollment in February 2021, recruitment is ongoing, with sites located in North America, Israel, and Europe (NCT04797780).

Detection of miR3151 Gene Expression in De Novo Adult Acute Myeloid Leukemia and Its Clinical Implication

OBJECTIVE: Acute myeloid leukemia (AML) is a heterogeneous disease, in terms of genetic/molecular abnormalities resulting into marked differences in outcome. We had demonstrated that BAALC expression was of prognostic significance in intermediate-risk AML in the prophase study. MiR-3151 was discovered in intron 1 of BAALC. However, miR-3151 prognostic value has not been examined in Chinese adult de novo AML patients. METHODS: Pretreatment bone marrow samples from 209 adult de novo AML patients were analyzed for miR-3151mRNA expression by real-time reverse transcriptase polymerase chain reaction. Patients were divided into different groups according to miR-3151 level and were compared for clinical outcome. RESULTS: 73 cases of 92 intermediated cytogenetically AML patients got CR after the first block with a CR rate being 79.3% and the CR rate of total group is 72.7%(152/209). However , 29 cases of the CR patients with intermediated cytogenetically AML relapsed with the relapsed rate being 39.7%. Results showed no statistical difference in CR rate (74.0 %vs 71.4 %, P=0. 672),relapse rate (36.4 % vs. 48 . 0 %, P=0.14 6) and OS (35.4 % vs 40 . 0 %,P=0. 919) for 209 AML patients with low miR3151 comparing to those with high miR3151 expression. Patients with low miR3151 had a superior CR rate (88 . 6 %vs 70 . 8 %, P=0.0 35), OS (69.9% vs 11.5% P=0.00 0) and lower relapse rate(28.2 % vs. 5 2. 9 %, P=0.000) than low miR3151 expression in 92 intermediated cytogenetically AML. Conclusion: High expression of miR3151 identifies intermediated cytogenetically AML patients with a unfavorable long-term outcome. DisclosuresNo relevant conflicts of interest to declare.

Rituximab Combined Therapy and Maintenance Eliminate the Follicular Lymphoma with MYC Translocation

Introduction : The WHO classification published in 2016 shows that lymphoma with BCL2 and MYC rearrangement is mostly classified as high-grade B-cell lymphomas. On the other hand, follicular lymphoma with BCL2 and MYC rearrangement (double-hit follicular lymphoma, DH-FL) is rare. In some case-reports described that DH-FL patients frequently transformed to aggressive disease and had resistance to the treatment. However, there is no large study with regard to the rate of DH-FL and the comparison of the prognosis between DH-FL and FL without MYC translocation. In this study, we assessed the frequency of DH-FL and the prognosis of DH-FL.Methods : We retrospectively studied 99 patients diagnosed as FL from 2005 to 2015 in our institution. The pathological diagnosis was performed based on histopathological and cytogenetic analyses. The clinical stage of patients and evaluation of the effect of the therapy were performed using PET-CT scan. The statistical analyses of characteristics of patients were performed by Fisher's exact test. The survivals were calculated by the Kaplan Meier method, and statistical analysis were performed by log rank test using EZR software. The samples for FISH analysis were derived from tumor biopsy or bone marrow aspiration. All cells fixed by carnoy solution, then collected cells by cytospin. The cells prepared to slide, then hybridized with the probe of BCL2 or MYC . After hybridization with each probe, the cells were taken the photo and analyzed using In Cell Analyzer 6000. The cells were counted 100 cells in each sample. By the peripheral blood of five healthy volunteers, we calculated the standard deviation of false positive and evaluated each sample's data. This protocol approved by our institute ethical committee.Results : The averages of positive percentage within five healthy volunteer samples were 0.8% (0-2%) and 1.2% (0-3%), and the standard deviations were 0.74 and 1.3 for BCL2 and MYC, respectively. From these data, we decided to set the cutoff points of ≥3% and ≥5% for BCL2 - and MYC -positive, respectively. Within 98 samples from FL patients, BCL2 -positive were 75 (77%). In these 75 BCL2 -positive FL patients, we assessed the frequency of DH-FL and the prognosis of DH-FL. The characteristics of 75 FL patients were as follows: the median age was 61 years old (range 36-79), and a median follow up was 71 months (range 18-132). FL Grade1 was 45 (60%), Grade2 was 26 (35%) and Grade 3A was 4 (5%). Men was 33 (44%), stages III-IV was 60 (80%), IPI high and high intermediate was 20 (27%) and ECOG PS 0 was 72 (96%) and 1 was 3 (4%). The first treatments were as follows: 52 (69%) were Rituximab(R)-CHOP or R-COP, 6 (8%) were CHOP or COP like regimen without rituximab, 3 (4%) were rituximab monotherapy, 3 (4%) were clinical trial, 5 (7%) were radiation only, 3 (4%) were others (bendamustine with or without rituximab 2, R-fludarabine 1). 3 patients (4%) were watch and waiting. Within 75 FL patients, MYC -positive cases were 6 (8%). MYC-positive level was 6-17% within each 100 cell counts. The median age of DH-FL patients was 61 years old (range 40-75), Men was 2 (33%), all DH-FL patients were stages III-IV, IPI high was 1 (16%). There was no difference in CR rate after first treatment between DH-FL and FL without MYC translocation (83% vs 72%, p=0.581, DH-FL vs FL without MYC translocation, respectively.). Furthermore, there were no differences in OS and PFS between DH-FL patients and the FL patients without MYC translocation (4-year OS: 100% vs 92.8%, p=0.416, 4-year PFS: 55.6% vs 78.0%, p=0.832, DH-FL vs FL without MYC translocation, respectively.). There were also no differences in relapse rate within 2 years (17% vs 11%, p=1.0, DH-FL vs FL without MYC translocation, respectively).In DH-FL patients, five patients got CR after the first chemotherapy. In the 4 patients still maintain CR; they were treated with R-COP and rituximab maintenance. The one patient relapsed after first treatment without rituximab. The other one patient with bulky disease got CR after R-CHOP plus radiation and relapsed after rituximab maintenance.Conclusion and Discussion: In the previous reports, it is considered that patients with DH-FL showed poor prognosis, however, our data suggested that the prognosis of DH-FL patients treated by R-CHOP with rituximab maintenance were not inferior to the FL patients without MYC translocation. Rituximab maintenance therapy might overcome the progression of tumor with MYC translocation in FL. DisclosuresMishima:Chugai Pharmaceutical, Inc: Other: consignment job. Terui:Celgene Corporation: Speakers Bureau; Janssen Pharmaceutical K.K.: Speakers Bureau; Novartis Pharma K.K.: Speakers Bureau; Takeda Pharmaceutical Company Limited.: Speakers Bureau; Bristol-Myers Squibb company: Speakers Bureau. Yokoyama:Chugai Pharmaceutical, Inc: Other: consignment job. Nishimura:Chugai Pharmaceutical, Inc: Other: consignment job. Hatake:AbbVie, Gilead, Celgene, Solasia, Pfizer, Bristol-Myers Squibb, Janssen, Ghugai: Research Funding; Mundipharma K.K.: Honoraria.

Clinical features and prognostic impact of TCF3–PBX1 in childhood acute lymphoblastic leukemia: A single-center retrospective study of 837 patients from China

ObjectivesConflicting data have been published regarding the prognostic impact of the t(1;19)/TCF3-PBX1 translocation in childhood ALL. The objective of this study was to explore the correlation between the TCF3-PBX1 fusion gene and clinical outcome in Chinese children with newly diagnosed ALL. MethodsIn order to address this issue in our setting, we summarized and analyzed the data of 837 Chinese children with ALL diagnosed between 2010 and 2017. All the patients were treated with the National Protocol of Childhood Leukemia in China (NPCLC)-ALL-2008 protocol. Clinical characteristics and prognosis of pediatric ALL patients with or without TCF3-PBX1 rearrangement were analyzed and compared retrospectively. ResultsThe TCF3-PBX1 fusion gene was identified in 48 (5.7%) of 837 children with ALL. Our results showed that TCF3-PBX1 positive patients had higher pretreatment white blood cell counts, higher PB blasts percentages and worse risk classification at diagnosis. No statistically significant differences in CR rates, response to prednisone and relapse rates were found between TCF3-PBX1-positive and -negative patients. The 5-year predicted EFS, RFS, and OS of the TCF3-PBX1 positive group compared with the control group were 86.2%±5.3% vs 85.4%±1.3% (P=0.657), 88.2%±5.1% vs 92.2%±1.0% (P=0.458) and 90.4%±4.6% vs 89.0%±1.1% (P=0.561), respectively. No differences were observed regarding clinical outcome between these two groups. When compared with standard risk, intermediate risk and high risk group patients, the long-term survival of TCF3/PBX1 positive group was approximately similar to that of the intermediate risk group under the same protocol in our single center. ConclusionIn contrast to previous studies, childhood ALL patients with TCF3-PBX1 transcripts do not appear to show a better outcome than their negative counterparts. TCF3/PBX1 positive was a definitive intermediate risk factor with our NPCLC-ALL-2008 protocol.

Effect of CD56 Expression on Prognosis of AML Patients with AML/ETO Mutation

To investigate the expression and prognostic significance of CD56 in the patients suffered from acute myeloid leukemia with AML/ETO mutation. The clinical data of 60 newly diagnosed AML patients with AML/ETO from January 2012 to December 2016 were analyzed retrospectively. The clinical characteristics and outcome between CD56+ and CD56- patients were compared. There were significant differences in CR rate after one course chemotherapy, relapse rate within 1 year and gene mutations between the CD56 positive and negative patients (P＜0.05). The RFS and OS of CD56 positive patients were significantly lower than those of CD56 negative patients (P＜0.05). The expression of CD56 may be an important factor of poor prognosis in AML patients with AML/ETO.

Effect of CD56 Expression on Prognosis of AML Patients with AML/ETO Mutation

To investigate the expression and prognostic significance of CD56 in the patients suffered from acute myeloid leukemia with AML/ETO mutation. The clinical data of 60 newly diagnosed AML patients with AML/ETO from January 2012 to December 2016 were analyzed retrospectively. The clinical characteristics and outcome between CD56+ and CD56- patients were compared. There were significant differences in CR rate after one course chemotherapy, relapse rate within 1 year and gene mutations between the CD56 positive and negative patients (P＜0.05). The RFS and OS of CD56 positive patients were significantly lower than those of CD56 negative patients (P＜0.05). The expression of CD56 may be an important factor of poor prognosis in AML patients with AML/ETO.

Retrospective Comparison between MEC and FLAG-Ida Regimens for Refractory or Relapsed Acute Myeloid Leukemia in Adults

Introduction: There is no consensus regarding the best salvage regimen for refractory or relapsed acute myeloid leukemia (r/rAML), with classic regimens traditionally based on high-dose cytarabine in a changeable combination with anthracyclines, purine analogs, and etoposide. Outcomes of r/rAML patients in developing countries are underreported, even though the same regimens are widely used. Methods: This is a retrospective single-center study, conducted in an academic center in Brazil. Local research ethics committee approved this analysis. All patients above 16 years of age who received MEC (mitoxantrone, etoposide and cytarabine) or FLAG-IDA (fludarabine, cytarabine, filgrastim and idarubicin) as originally reported (Amadori, S. et al. and Steinmetz, H. T. et al.) for r/rAML between December/2009 and January/2019 were included. Only patients with refractory or relapsed disease following standard upfront therapy ("7+3" regimen) were included in this analysis, being divided among refractory (less than partial response after one cycle of "7+3"), early relapsed (relapse within one year from first complete response [CR]) and late relapsed (relapse after one year of CR). Only the first salvage was considered for this study. Results: Sixty patients were included in the final analysis, with a median age of 45 years (range, 17 - 69). There were no cases of therapy-related AML. Four AML cases (7%) were secondary to myeloproliferative neoplasm (MPN) or myelodysplastic syndrome (MDS). All FLT3-ITD positive cases had an associated NPM1 mutation. Two patients had chronic human immunodeficiency virus infection and received antiretroviral therapy. Baseline characteristics of the whole cohort are summarized in Table 1. Three patients had undergone SCT in first CR and were post-SCT relapses. Twenty-eight patients received MEC and 32 received FLAG-IDA. By comparing the baseline characteristics of both groups, no difference statistically significant was found except for the indication for salvage treatment, in which there were more refractory cases in FLAG-IDA group (56 vs. 28%, p=0.029) (Table 2). Overall, 17/60 achieved CR and 12/60 CRi, with a total CR rate (CR+CRi) of 48.3% (95% confidence interval [CI], 35.4 - 61.5). Sixteen patients (27%) early died before a response assessment. By univariate analysis, only age affected the CR rate (p=0.045). No difference in CR rate was found between the two protocols (MEC 53.5 vs. FLAG-IDA 43.7%, p=0.447). Looking into this data, it can be seen that there were more refractory patients in FLAG-IDA arm (37.5 vs. 4%, p=0.02) but more patients early-died in MEC arm (35.7 vs. 18.7%, p=0.137), even though the latter was not statistically significant. After correcting the initial differences between the two groups regarding indication for salvage through a propensity score calculation, a post-matching cohort with 44 subjects was found. In this cohort, no difference in refractoriness rate could be detected (p=0.077). In the whole cohort, 17 patients proceeded to allogeneic SCT - 15 in CR/CRi and 2 with active disease, with no difference in SCT execution rate between the two groups (p=0.470). 4/17 transplanted patients were alive. Median follow-up was 48 months. Median survival for total cohort was 4 months (95% CI, 2.7 - 9.2), with a 3-year OS of 9.7% (95% CI, 4 - 23.7) and a 3-year EFS of 7.5% (95% CI, 2.5 - 22.4). In the univariate analysis for OS, age (p=0.04), FLT3 status (p&amp;lt;0.001) and SCT procedure (p=0.002) were statistically significant. Chosen regimen did not influence OS or EFS as well as the genetic risk, colonization or time of relapse (Figure 1). In a multivariable model for EFS including age, FLT3 status and SCT procedure, only the last two indicators remained significant: FLT3-ITD mutation (Hazard ratio [HR] = 4.6 [95% CI 1.9 - 11.4], p&amp;lt;0.001) and SCT procedure (HR = 0.43 [95% CI 0.22 - 0.82], p=0.01). Conclusion: In this analysis, there was no difference concerning the chosen regimen for r/rAML, even though a possible higher refractoriness rate could be seen in FLAG-IDA arm. High early toxicity was found, emphasizing the role of supportive care and judicious selection of patients to intensive salvage therapy in our setting. FLT3-ITD mutation and SCT remained as significant factors for survival in a multivariable analysis, which is in line with previous studies. Disclosures No relevant conflicts of interest to declare.

One-Day Versus Three-Day Dexamethasone in Combination with Palonosetron for the Prevention of Chemotherapy-Induced Nausea and Vomiting: A Systematic Review and Individual Patient Data-Based Meta-Analysis.

A dexamethasone-sparing regimen consisting of palonosetron plus 1-day dexamethasone for the prevention of chemotherapy-induced nausea and vomiting (CINV) has been studied previously. Here, we evaluate the noninferiority of the dexamethasone-sparing regimen in overall antiemetic control using a meta-analysis based on individual patient data (IPD). We conducted a systematic review for randomized trials reporting CINV outcomes for the comparison of palonosetron plus 1-day dexamethasone (d1 arm) versus the same regimen followed by dexamethasone on days 2-3 after chemotherapy (d3 arm) in chemotherapy-naïve adult patients undergoing either moderately emetogenic chemotherapy (MEC) or anthracycline plus cyclophosphamide (AC)-containing chemotherapy. PubMed and MEDLINE were searched electronically. A manual search was also conducted. The primary endpoint was complete response (CR; no emesis and no rescue medication) in the overall 5-day study period. The noninferiority margin was set at -8.0% (d1 arm-d3 arm). Five studies (n = 1,194) were eligible for analysis and all IPD was collected. In the overall study period, the d1 arm showed noninferiority to the d3 arm for CR as well as complete control (pooled risk difference in CR rate - 1.5%, 95% confidence interval [CI] -7.1 to 4.0%, I2 = 0%; in complete control rate - 2.4%, 95% CI -7.7 to 2.9%, I2 = 0%). There was no significant interaction between dexamethasone regimen and risk factors (type of chemotherapy, sex, age, and alcohol consumption). This IPD meta-analysis indicates that the dexamethasone-sparing regimen is not associated with a significant loss in overall antiemetic control in patients undergoing MEC or AC-containing chemotherapy, irrespective of known risk factors for CINV. Although dexamethasone in combination with other antiemetic agents has been used to prevent chemotherapy-induced nausea and vomiting (CINV), it is of clinical importance to minimize total dose of dexamethasone in patients undergoing multiple cycles of emetogenic chemotherapy. This individual-patient-data meta-analysis from five randomized controlled trials (1,194 patients) demonstrated a noninferiority of the dexamethasone-sparing regimen for complete response and complete control of CINV. The outcomes were comparable across patients with different characteristics. These findings thus help physicians minimize use of the steroid and further reduce the burden of dexamethasone-related side effects in patients undergoing multiple consecutive courses of emetogenic chemotherapy.

Immunofixation (IF) in Urine Is Really Necessary to Define Complete Remission in Multiple Myeloma (MM)? a Subanalysis from the Pethema/GEM2012MENOS65 Phase III Clinical Trial

Immunofixation (IF) in Urine Is Really Necessary to Define Complete Remission in Multiple Myeloma (MM)? a Subanalysis from the Pethema/GEM2012MENOS65 Phase III Clinical Trial

Systematic review and individual patient data based meta-analysis of palonosetron trials for chemotherapy induced nausea and vomiting.

e21688 Background: Several clinical trials have evaluated the need for corticosteroid-containing antiemetic regimens on the days after the first 24 hours to control delayed chemotherapy-induced nausea and vomiting (CINV) during moderate emetogenic chemotherapy (MEC) or anthracycline and/or cyclophosphamide (AC)-containing chemotherapy. Methods:We conducted systematic review using research databases and trial registries for any randomized controlled trials reporting CINV outcomes for a single 1-day-dexamethasone (D1 group) containing antiemetic regimen in chemotherapy-naive adult patients scheduled to receive a MEC or AC-containing chemotherapy, compared with additional dexamethasone on days 2 and 3 (D3 group). We also gathered the individual patient data (IPD) from each study investigator. The primary endpoint was complete response (CR: no vomiting and no rescue antiemetics) in the 5-day study period. Secondary efficacy end points were CR rates in 0–24 h and CR rates in 24–120 h; complete control in the overall, acute, delayed periods. An IPD meta-analysis was conducted to quantify the pooled risk differences between D1 group and D3 group and its interaction with patient characteristics using a fixed effect model. Results: Of 887 articles screened, 5 eligible studies were identified comprising 1194 patients, all enrolled in the meta-analysis. Overall, D1 group was not significantly inferior to D3 group in CR rate as well as CC rate [pooled risk difference in CR rate -1.5%, 95% confidence interval (CI) -7.1–4.0%; in delayed CR rate -2.4%, 95% CI -7.7–2.9%]. There was no significant interaction between dexamethasone regimen and patient characteristics (sex, age category ( &lt; 60 or 60 years), and alcohol consumption). Conclusions: These results strongly suggest that the dexamethasone-sparing regimen is not associated with a significant loss in overall antiemetic control in an adult patient undergoing MEC or AC-containing chemotherapy, irrespective of patient baseline characteristics. These data contribute to simplify antiemetic regimens and spare many patients from the potential side-effects of multiple-day corticosteroids.

Long Term Follow up from the NCRI AML17 Trial of Attenuated Arsenic Trioxide and ATRA Therapy for Newly Diagnosed and Relapsed Acute Promyelocytic Leukaemia

▪Background: Two randomized studies have reported comparison of the "chemo-free" combination of ATO+ATRA with Anthracycline/ ATRA (AIDA) in APL. The GIMEMA-AMLSG-SAL trial, using a daily schedule improved both survival and relapse risk in patients with newly diagnosed, low or intermediate-risk APL. (Lo Coco et al., NEJM 2013; 369: 111-21). The NCRI AML17 trial using an attenuated dosing schedule in all risk groups resulted in a very low risk of relapse, significantly better EFS but no significant survival advantageAims: The NCRI AML17 Trial compared AIDA vs the chemo-free combination of ATO (in an attenuated schedule) + ATRA. Here we present long term survival results for randomized patients and for 24 patients who received the same chemo-free schedule of ATO + ATRA after relapsing from the AIDA arm of the trial.Methods: From May 2009 to October 2013, 235 patients aged >16 who entered the AML17 trial with molecularly confirmed APL were randomized to either ATRA+ATO (8 week induction 0.3mg/kg d1-5 w1, 0.25mg/kgx2/w w2-8, followed by 4 consolidation courses of 0.3mg/kgx2 w1, 0.25mg/kgx2/ w2-4 (63 ATO doses) OR AIDA schedule: Idarubicin (Ida)12mg/m2 d2,4,6,8 + ATRA to d60) (induction) then Ida 5mg/m2 d1-4 + ATRA d1-15 (Course 2); Mitox. 10mg/m2 d1-4 + ATRA d1-15 (course 3); Ida 12mg/m2 d1 + ATRA d1-15 (Course 4). ATRA was 45mg/m2/d. Maintenance was not given. High risk patients could receive Gemtuzumab Ozogamicin (d1,6mg/m2). Another 70 patients were treated in AML17 with AIDA after closure of the randomization. 25/189 patients relapsed post AIDA and 24 were treated with a median of 4 cycles (range 1-5) of ATRA + ATO, 11/24 were later transplanted. Follow-up is complete to 1 January 2016.Results: The median age was 47y (16-77); 57 had WBC>10x109/L (27 AIDA, 30 ATRA+ATO) and 49 (24 AIDA, 25 ATRA+ATO) were >60y. The early results of the randomization for newly diagnosed patients have been reported (Burnett et al. Lancet Oncol. 2015, 16 (13):1295). 91% entered morphological CR with no significant difference in CR rate between the arms (Chemo-free 94%, Chemo 89%; OR 0.54 (0.21-1.34), p= 0.18). The OS at 4 years was 93% (Chemo-free) vs 89% (Chemo), HR 0.60 (0.26-1.42) p= 0.2, but EFS was significantly superior with ATRA+ATO (91% vs 70%, HR 0.35 (0.18-0.68) p=0.002).With a longer median follow-up of 53.4 months 5-year survival is now 93% (chemo-free) v 87% (chemo) (HR 0.61 (0.27-1.35) p=0.2). A significant reduction in relapse (2% vs 16% at 5 years, HR 0.19 (0.09-0.45) p=0.0005) translates to continuing significant RFS benefit for the chemo-free approach (96% vs 82%; HR 0.30 (0.13-0.67) p=0.004). This is seen both in low risk (95% vs 86% HR 0.45 (0.17-1.20) p=0.11) and high risk disease (100% vs 69% HR 0.10 (0.02-0.46) p=0.003), p=0.11 for heterogeneity.25 patients relapsed following AIDA therapy, of whom 1 died in frank relapse before treatment could be initiated and 24 (5 with concomitant CNS involvement) were treated with the attenuated ATO + ATRA schedule. Of these 16 were treated at molecular relapse, reflecting the value of centralised MRD monitoring as part of the trial protocol. All 24 patients achieved molecular CR post ATO +ATRA. Eleven patients were transplanted (8 autograft, 3 allograft) including 4 of the 5 patients with CNS disease. 3 patients have had a second molecular relapse after ATO + ATRA salvage (1 transplanted and 2 not transplanted). The 3-year overall survival post-relapse is 96% with the only other death occurring post-transplant after 37 months.Summary/Conclusion: The combination of ATO + ATRA continues to show a very low risk of relapse irrespective of risk group resulting in significantly better RFS compared to AIDA and excellent survival but no survival benefit has emerged primarily because of effective salvage interventions for AIDA-treated patients with most patients treated at molecular relapse. Molecular monitoring for t(15;17) is therefore essential to optimize therapy with AIDA. For patients treated with frontline ATO+ATRA molecular monitoring is of questionable value once achievement of molecular CR has been documented, but molecular surveillance remains important in those with relapsed disease. The attenuated AML17 ATO dosing approach is effective both upfront and in patients relapsing post AIDA and these results question the role of transplantation as consolidation in patients achieving molecular CR2 with ATO + ATRA who do not have CNS disease at relapse. DisclosuresBurnett:CTI Life Sciences, London: Employment. Hills:TEVA: Honoraria. Grimwade:TEVA: Research Funding.

Outcomes of Ibrutinib Therapy By Age in Patients with CLL/SLL: Analyses from Phase 3 Trial Data (RESONATE and RESONATE-2)

Background: Chronic lymphocytic leukemia (CLL) is primarily a disease of the elderly, with the majority of patients (pts) older than 65 y at diagnosis (US SEER). Historically, younger, more fit pts were eligible for aggressive chemoimmunotherapy treatments, but older age and comorbid conditions can limit options due to tolerability concerns. Ibrutinib (ibr), a first-in-class, oral, once-daily inhibitor of Bruton9s tyrosine kinase, is indicated by the US FDA for the treatment of pts with CLL/small lymphocytic lymphoma (SLL) and allows for treatment without chemotherapy. Results from the phase 3 RESONATE (PCYC-1112) and RESONATE-2 (PCYC-1115) trials established ibr as a standard option in relapsed/refractory (R/R) and treatment-naive (TN) CLL/SLL. This analysis examines safety and efficacy from these studies by age. Methods: RESONATE randomized 391 pts with R/R CLL/SLL to receive ibr (n=195; 420 mg once daily) until progressive disease (PD) or unacceptable toxicity or intravenous ofatumumab (n=196; 300 mg at week 1, 2000 mg weekly for 7 w and then every 4 w for 16 w). RESONATE-2 randomized TN pts aged ≥65 y to receive ibr (n=136; 420 mg once daily) until PD or chlorambucil (clb; n=133; 0.5 mg/kg to a maximum of 0.8 mg/kg) on days 1 and 15 of a 28-day cycle for up to 12 cycles. Pt data from both studies were grouped by age (ibr and comparators [comp]) and analyzed for effect of age on outcome. Results: Ibr group included 136 TN pts: 65 to Conclusions: The PFS rate for TN ibr pts was similar regardless of age subgroup, whereas it was shorter for clb-treated pts ≥75 y compared with those 65 to Disclosures Woyach:Karyopharm: Research Funding; Morphosys: Research Funding; Acerta: Research Funding. Hillmen:Pharmacyclics: Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Abbvie: Research Funding. Brown:Pfizer: Consultancy, Honoraria, Other: travel, accommodations, expenses; Genentech: Consultancy, Honoraria; Roche: Honoraria; Infinity: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Other: travel, accommodations, expenses; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: travel, accommodations, expenses; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria; Sun Biopharma: Honoraria, Other: travel, accommodations, or other expenses. Coutre:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; AbbVie: Research Funding. Barr:AbbVie: Consultancy; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Research Funding. O9Brien:Janssen: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding. Devereux:Janssen: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau; GSK: Consultancy; Roche: Consultancy, Other: Travel, Accommodations, Expenses ; Gilead: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau. Reddy:KITE: Membership on an entity9s Board of Directors or advisory committees; celgene: Membership on an entity9s Board of Directors or advisory committees; GILEAD: Membership on an entity9s Board of Directors or advisory committees; INFINITY: Membership on an entity9s Board of Directors or advisory committees. Mulligan:GSK: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau. Zhou:AbbVie: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment. Ninomoto:AbbVie: Equity Ownership; Amgen: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment. James:Pharmacyclics, LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Burger:Janssen: Consultancy, Other: Travel, Accommodations, Expenses; Portola: Consultancy; Gilead: Research Funding; Pharmacyclics, LLC, an AbbVie Company: Research Funding; Roche: Other: Travel, Accommodations, Expenses.

Genomic Subtypes of Nucleophosmin (NPM1) Mutations Are Associated with Clinical Outcome in AML - a COG and SWOG Intergroup Collaboration

Background: Genomic variations in AML are associated with disease outcome. Frameshift insertions of Nucleophosmin gene (NPM1) are common in AML with significantly higher prevalence in adults compared to childhood AML. NPM1 frameshift mutations are the result of 4 base pair (bp) insertions in exon 12 of the gene that encodes the Nuclear Export Signal (NES) domain, causing a premature truncation, leading to cytoplasmic mis-localization of NPM1 protein. Several genomic subsets of NPM1 insertions have been identified, with the Type A variant (insertion of TCTG) being the most common. Non-Type A NPM1 mutations occur in 25% of adult AML, but occur in >50% of pediatric AML, suggesting possible biologic and functional significance of NPM1genotype in AML. We studied the effect of different NPM1 insertion genotypes on disease characteristics and outcome among children and adults with de novo AML treated on COG and SWOG AML trials.Methods: Genomic profile from 2301 patients treated on recent COG AML trials (CCG 2961, COG 03p1 and COG 0531, N=1915) and SWOG young adult AML trial S0106 (N=396) were studied. In this cohort of 2301 patients, initial NPM1 mutations were detected by fragment length analysis in 266 patients (12%) with prevalence of 9% in the COG Pediatric studies and 27% in the SWOG studies. There was a clear age-associated prevalence of NPM1 mutations with a prevalence of <1% in children younger than 2 years of age, 29% in those 10-18 years and 36% in those 45-60 years (p=0.004). Of the 266 cases with NPM1 mutations, diagnostic DNA was available from 206 patients for NPM1 insertion genotyping. Specific genotype of NPM1 insertion was determined and correlated with disease characteristics and outcome. Chi-square or Exact test was used to test proportion of patients. Mann-Whitney test was used to compare medians between the two groups. Kaplan-Meier methods were used to compare survival estimates of OS, EFS and RFS.Results: Sequencing of exon 12 demonstrated multiple 4 bp insertion subtypes with Type A variant (TCTG) in 128 patients (62%) and non-Type A variants in 78 patients (38%). Those with non-Type A variants included type B in 15.5%, type D in 8.3%, type J in 2.9% and others in 11.2%. In our study, comparison was performed between type A vs. non-type A.Comparison of disease characteristics between those with Type A vs. non-Type A NPM1 mutations demonstrated that Type A variants were more prevalent in older patients (p=0.018) with a clear age-based predominance of non-Type A variants in the younger patients (Figure A). FLT3/ITD prevalence was similar between Type A vs. non-Type A variants (36% vs. 39%, p=0.695). Evaluation of clinical outcome based on NPM1 genotypes showed no difference in CR rate (93% Type A vs. 91% non-Type A, p=0.625). However, those with Type A insertions had a 5 year event-free survival (EFS) of 39% vs. 64% for those with non-Type A variants (p=0.01), with a corresponding 5 year relapse-free survival of 41% vs. 70%, respectively (p=0.002, Figure B). As therapies between pediatric and adult trials differed, we performed a separate analysis for the COG and SWOG studies. In COG trials, 5 year EFS for those with and without Type A variant was 53% vs. 71% (p=0.058). Similar outcome evaluation for the SWOG study showed EFS of 25% vs. 50% (p=0.035) for those with and without Type A variants. Additionally, given significant overlap between FLT3/ITD and NPM1 mutations, we studied the impact of NPM1 mutation genotype in FLT3/ITD positive vs. negative cohorts. In FLT3/ITD positive patients, those with and without type A NPM1 variants had EFS of 27% vs. 57% (P=0.033) and in FLT3/ITD negative cohort, those with and without type A NPM1 variants had EFS of 45% vs. 68% (p=0.012), Figure C. Multivariate Cox regression analysis that included age (SWOG vs. COG) and FLT3/ITD status demonstrated that NPM1genotype was an independent predictor of EFS (HR 1.6, p=0.04) and RFS (HR 2.02, p=0.006) regardless of age or FLT3/ITD status, Figure D.Conclusion: This COG/SWOG collaborative study of over 2300 pediatric and adult patients demonstrates clear functional biology behind age-based variation in NPM1 genotype where those with Type A variants have a significantly inferior outcome compared to non-Type A variants. Upon validation, specific genotype of NPM1 mutations might contribute to more accurate risk-based therapy allocation in AML. [Display omitted] DisclosuresSelim:CTI International Biopharma: Other: Supporting the research. Othus:Celgene: Consultancy; Glycomimetics: Consultancy. Radich:ARIAD: Consultancy; Novartis: Consultancy, Other: laboratory contract; TwinStrand: Consultancy; Pfizer: Consultancy; Bristol-MyersSquibb: Consultancy.

Routine interim disease assessment in patients undergoing induction chemotherapy for acute myeloid leukemia: Can we do better?

The presence of >5% blasts at "day 14" (D14), in patients undergoing induction chemotherapy for acute myeloid leukemia (AML) is problematic. It is unclear if a second course of chemotherapy for early persistent disease will alter outcome in these patients. We conducted a retrospective study of AML patients undergoing induction chemotherapy where diagnostic, interim (around day 14), and recovery (days 21-42) bone marrow (BM) evaluations were available for review. Of the 113 patients included in the final analysis, 99 (87.6%) achieved CR at hematologic recovery. At D14, 90 patients (79.6%) had <5% blasts and of these, 87 (96.7%) ultimately achieved CR. At D14, Twenty-three (20.4%) patients had residual leukemia (>5% blasts). Of these, 11 (47.8%) received a second course of chemotherapy (double induction [DI]) and 12 (52.2%) were observed until count recovery (single induction [SI]). No significant difference in CR rates was observed between these two groups (58.3% DI group vs. 45.5% SI group, P value = 0.684). In our analysis, D14 BM evaluation did not uniformly identify patients with primary induction failure. To unequivocally determine the value of a D14 marrow assessment in AML, prospective studies in the context of large cooperative group trials are required. Considering our findings and similar reports from others, we propose that D14 marrow assessment should be individualized, and that other factors, such as cytogenetics and early peripheral blood blast clearance should be considered, to identify patients most likely to benefit from interim disease assessment during AML induction therapy.

Characteristics and Prognosis of AML Patients with or without a History of Clonal Hematopoiesis

Background: Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the detection of mutations in genes like DNA methyltransferase 3A (DNMT3A) and has recently been described to occur in healthy people and to predispose them to myeloid malignancies. DNMT3A is frequently mutated in acute myeloid leukemia (AML) and mutations have been detected in CD3 positive T-cells of some AML patients. In these patients DNMT3A mutations are early events that are likely to arise from CHIP. It is unknown how a history (hx) of CHIP influences the characteristics of AML patients and their response to therapy. We studied this question on the basis of a large cohort of DNMT3A mutated AML patients.Patients and Methods: 171 DNMT3A mutated AML patients (aged 18-87 years) were included in our study. 127 patients were treated intensively in trials of the AMLSHG and AMLSG. 34 patients received non-intensive therapy and for 10 patients the therapy is unknown. 148 patients carried a mutation at arginine R882. At the time of diagnosis and relapse samples were further sequenced for 54 genes involved in leukemia with next generation sequencing (NGS) on the Illumina platform. Library preparation of diagnostic samples was performed with the TruSight Myeloid sequencing panel (Illumina). T-cells (CD3+ CD11b- CD14- CD33-) were purified by flow cytometry from AML samples at the time of diagnosis. DNMT3A mutational analysis of T-cell samples and of mononuclear cells during remission or at relapse was performed also with ultra-deep sequencing using customized DNMT3A NGS primers. Presence of a DNMT3A mutation in sorted T cell populations was used as an indicator of a hx of CHIP.Results: A total of 40 patients (23%) were found to have the DNMT3A mutation in mononuclear cells and T-cells (hx of CHIP), while 131 patients (77%) had a DNMT3A mutation in mononuclear cells, but not T-cells (control cohort). Comparing these two patient cohorts revealed that significantly more patients in the hx of CHIP cohort had secondary AML (p=0.009), were older (p=0.005) and less likely to receive intensive treatment (p=0.047) while other clinical parameters did not significantly differ. Analysing the mutational profile of 54 genes revealed that the number of mutations per patient between these 2 groups was similar (median 5 vs 4 mutations, p=0.39). Patients with a hx of CHIP were significantly more likely to harbour mutations in TET2 (p=0.006), RUNX1 (p=0.004), SF3B1 (p=0.049), U2AF1 (p=0.015) but less likely to be NPM1 mutated (p=0.005). There was no significant difference in the allelic burden of DNMT3A in the CHIP hx (mean 43.6) vs control group (mean 44.5). The mean variant allele frequencies of DNMT3A, RUNX1 and NPM1 were highest (44, 45 and 43 respectively) as compared to other mutated genes like IDH1, IDH2 and FLT3 (32, 37 and 34). In relapse samples (n=11), the identical DNMT3A mutation could always be identified. However, patients with a hx of CHIP (n=2) had comparable allelic frequencies compared to diagnosis of mutated DNMT3A (<10% difference), but not NPM1 (> 10% difference), while 7 out of 9 patients in the control group had a change in the allelic frequency at the time of relapse (mostly reduction). In all remission samples DNMT3A mutations could be identified with ultra-deep NGS but with variable allelic frequencies (0.13-50.01% in the control group, 0.25-70.14% in the hx of CHIP group). In the cohort of patients with intensive therapy there was no difference in CR rates between hx of CHIP and control groups (82 vs 90%, p=0.31). Overall survival (OS) was not influenced by a hx of CHIP (whole cohort: HR 1.09; 95%CI 0.67-1.79; P=.73; intensively treated cohort: HR 0.72; 95%CI 0.34-1.51; P=.38). Relapse-free survival (RFS) was also not different in the hx of CHIP vs the control group (HR 1.06; 95%CI 0.58-1.93; P=.85; intensively treated cohort only HR 0.91; 95%CI 0.46-1.78; P=.78). However, when looking at the influence of allogeneic stem cell transplantations (HSCT) on outcome in intensively treated patients, patients with a hx of CHIP showed abenefit from HSCT (HR 0.082; 95%CI 0.009-0.75; P= 0.027 Figure 1A) as compared to the control group (HR 0.68; 95%CI 0.39-1.21; P= 0.19, Figure 1B).Conclusion: AML patients with a hx of CHIP, as defined by mutated DNMT3A in T-cells, show a distinct clinical and molecular profile and may benefit from HSCT. [Display omitted] [Display omitted] DisclosuresBug:TEVA Oncology, Astellas: Other: Travel Grant; NordMedica, Boehringer Ingelheim, Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene, Novartis: Research Funding. Fiedler:Pfizer, Amgen, Kolltan: Research Funding; Teva, Amgen, Astellas: Other: Travel Grant; Karyopharm: Research Funding. Schlenk:Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Research Funding; Arog: Honoraria, Research Funding; Teva: Honoraria, Research Funding; Boehringer-Ingelheim: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Research Funding.

Treating Indolent Lymphoma in Older Adults: What Is the Right Way?

Introduction: The treatment of hematological malignancies in older adults is an emerging and important issue due to the aging population trend as well as drug-related toxicities in pts (pts) with comorbidities. Indolent lymphomas constitute a subgroup of incurable non-Hodgkin lymphomas characterized by multiple relapses. Anthracycline containing chemo-immunotherapy regimens (ACR) such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) are very active in indolent lymphomas, resulting in a long progression-free survival (PFS). Due to their high rate of associated toxicities, such regimens are less likely to be given to the elderly population. Currently, there is no consensus regarding the treatment of indolent lymphomas in older adults. The present study assessed overall survival (OS), time to next treatment (TNT) and treatment-associated toxicity in this distinctive subpopulation of pts with indolent lymphoma, aiming to develop an optimal approach to the management of such pts.Methods: This retrospective cohort analysis included pts with indolent lymphoma (histology diagnosis of follicular lymphoma, marginal zone lymphoma, Waldenstrom's macroglobulinaemia and indolent lymphoma not otherwise specified) aged ≥60 at therapy initiation (1st line) treated with either an ACR or a non-ACR at the Rambam Department of Hematology and Bone Marrow Transplantation between the years 2000 and 2012. All regimens included rituximab. OS, TNT and treatment-related toxicity (neutropenic fever and hospital admission due to noninfectious causes during the treatment period) were assessed.Results: Forty three pts treated with an ACR and 55 pts receiving a non-ACR were included in the analysis. Clinical characteristics, response to therapy and treatment modification data are presented in table 1. The median age was 67 years in the ACR group and 73 years in the non-ACR group; median duration of the follow-up was 4.3 years (range 0.1-11.9 years). No difference in terms of high risk co-morbidity score, defined as modified Charlson co-morbidity score ≥5 (Charlson et al, 1987), was found between the ACR group and the non-ACR group. Significantly more pts with follicular lymphoma were treated with ACR compared to non-follicular indolent lymphomas. There was no difference in CR rate between the ACR and non-ACR groups. In a univariate analysis, OS was found to be significantly higher in the ACR group, but in the multivariate analysis, OS appeared to be influenced only by age. The cause of death was disease-related in 8 pts (100% of deaths) in the ACR group and in 7 pts (64%) in the non-ACR group (data on the cause of death were available for 11 out of 18 pts from the non-ACR group). The median TNT was longer in the ACR cohort, but the difference did not reach statistical significance. No difference was found between the ACR and non-ACR groups in terms of major treatment-related toxicities assessed by the number of hospital admissions because of infection or other causes. Dose adjustments and treatment delays were far more frequent in the ACR cohort. This study is limited by its retrospective nature, the small number of patients and a significantly higher number of pts with follicular lymphoma treated in the ACR group.Conclusions: The present analysis of a cohort of older adults with indolent lymphoma treated with chemo-immunotherapy regimens in routine clinical practice has demonstrated that ACR was safe and efficacious. When approaching older adults suffering from indolent lymphoma, the considerations of quality of life (time without the need of further treatment, the minimal number of hospital admissions and minimal number of infections requiring hospitalization) should play a major role in treatment decision-making. In the current study, ACR was not inferior to non-ACR in terms of toxicity. A trend to an improved OS and longer TNT was demonstrated in the ACR group. The patient age should not deter physicians from using ACR in older adults.Table 1ParametersACR N=43Non-ACR N=55P valueAge, median67730.05Pts with modified Charlson comorbidity score ≥5 (%)7 (17)10 (19)0.55Pts with follicular lymphoma (%)33 (77)27 (49)0.007CR rate (%)30 (70)33 (60)0.44-year OS, %8167<0.04Median time to next treatment, months90550.2Dose adjustments65370.008Treatment delays57370.06 DisclosuresNo relevant conflicts of interest to declare.

High-dose cytarabine-mitoxantrone versus hyper-CVAD in adult acute lymphoblastic leukemia and Burkitt’s lymphoma: A single center experience of two induction regimens.

7076 Background: This is a retrospective analysis of 111 newly diagnosed adult ALL patients treated between January 1994 and January 2012 at Westchester Medical Center. Methods: Patients received induction chemotherapy with either high dose mitoxantrone and high-dose Ara-c (HDAM, n=62) or Hyper-CVAD (n=49). The patient characteristics are summarized in the table. OS, CR duration and time to recurrence were estimated using the Kaplan-Meier product estimate methods and comparative study was conducted based on Log-rank test. Differences in CR rates by treatment and by prognostic factors were analyzed using Chi-squared test and Fisher’s exact test. Results: The CR rate was 85% in the HDAM group and 84% in the HyperCVAD group. The median OS was 22.7 months (m), (95% CI 15.3-38.3 m) for the entire cohort, 21.4 m (95% CI 13.3 - 35.5 m) for HDAM arm and 26.8 m (95% CI 11.7 - 63.3 m) for HyperCVAD arm. The OS for patients with Philadelphia chromosome positive or t(4,11) was 13.2 m (95 % CI 9.5 – 26.8 m). In an analysis of the entire cohort for differences in CR rates based on prognostic factors, WBC &lt; 10,000 was the only favorable factor toward CR (p=0.049). Other prognostic factors including cytogenetics, cell type, age, LDH, were not statistically significant. Conclusions: HDAM and Hyper-CVAD appear to be comparable in CR induction and overall survival in this single institution retrospective analysis. These two regimens should be compared in a large multicenter randomized study. [Table: see text]