MRD Monitoring Using Minor-BCR-ABL1 Genomic Breakpoint in Childhood ALL Identifies a Subgroup with Distinct Biology and a Very Poor Prognosis

Abstract Background: The exact role of minimal residual disease (MRD) testing in childhood BCR-ABL1+ ALL is still unclear and MRD levels are used rather for stem cell transplantation (SCT) indication than for frontline treatment stratification. There are two standard targets used for MRD monitoring in these ALLs: Ig/TR rearrangements and the fusion transcript quantification. However, despite similar sensitivity of the methods, we previously showed a poor correlation between them in some patients. Overall, 20% of samples negative by Ig/TR MRD were BCR-ABL1 positive (even at high levels). By demonstrating presence of BCR-ABL1 within the non-lymphoid (Ig/TR-negative) population in the non-correlating samples we showed that multilineage involvement is at least partly responsible for the discrepancy (Zaliova, Leukemia 2009). Here we established MRD monitoring based on the quantification of the patient-specific genomic (intronic) BCR-ABL1 breakpoint sequence, compared MRD levels obtained from different approaches and analyzed their prognostic significance. Methods: Our cohort totals 35 children diagnosed with minor-BCR-ABL1+ ALL. The BCR-ABL1 genomic breakpoint was found using multiplex long distance DNA PCR. The patient-specific intronic fusion sequences were used for MRD quantification by qPCR. We quantified MRD levels in 386 bone marrow (BM) samples. The results of genomic BCR-ABL1 quantification were compared with Ig/TR and BCR-ABL1 transcript levels. Samples with >1 log difference in MRD levels were considered non-correlating. For correlation analysis of methods, double-negative (DN) samples were excluded. Overall survival (OS) rates were calculated according to Kaplan-Meier and compared by log-rank test. Results: Analysis of MRD in BM samples confirmed poor correlation between Ig/TR and BCR-ABL1 mRNA quantification (Spearman correlation coefficient R=0.70; n=166 non-DN samples). Moreover, we also saw poor correlation when comparing the two DNA methods (Ig/TR vs. BCR-ABL1 DNA, R=0.69; n=254 non-DN samples) with 21% of samples positive by BCR-ABL1 (at levels up to 10e-1) while negative by Ig/TR. While in some patients the correlation of the DNA-based methods was very good, others had several subsequent follow-up samples with poor correlation (> 1 log difference) suggesting distinct biology of the disease. MRD levels determined by BCR-ABL1 DNA quantification had the best predictive value for overall survival (the best separation of survival curves was at week 12 of treatment with 10e-3 cut-off: BCR-ABL1 DNA, p=0.0003; Ig/TR, p=0.017; BCR-ABL1 mRNA, not significant). The proportion of samples with BCR-ABL1 DNA levels higher than Ig/TR by more than 1 log increased with time on treatment (day 15: 10% (2/20); day 33: 26% (7/27); week 12: 39% (7/18); week 22: 50% (7/14)). Importantly, presence of samples with this poor correlation was prognostically relevant as patients with BCR-ABL1 levels higher than Ig/TR by more than 1 log at the end of induction treatment (day 33) had significantly worse outcome (2 years OS 84+/-9% (n=21) vs. 28+/-23% (n=6) for correlating and non-correlating patients, respectively; p=0.004). Conclusion: The BCR-ABL1 quantification at genomic level probably provides the most accurate measurement of leukaemic burden. Due to multi-lineage involvement in some Ph+ ALL as well as occasional presence of subclones with different Ig/TR markers, quantification of the BCR-ABL1 gene breakpoint is more reliable than Ig/TR monitoring. Moreover, in contrast to the BCR-ABL1 transcript, measurement of the gene is not influenced by possible variability in expression between cell subtypes or during concurrent treatment. Importantly, the MRD levels determined by BCR-ABL1 DNA-based testing have higher predictive value than Ig/TR DNA or BCR-ABL1 transcript quantification. The poorer outcome observed in the subset of patients in whom BCR-ABL1 DNA-based MRD levels were higher than Ig/TR-based MRD detection possibly reflects multilineage involvement, suggesting, that some cases with minor-BCR-ABL1+ ALL are in fact CML cases identified in a lymphoid blast crisis. In view of their poor outcome, these cases might be candidates for early SCT or alternative treatments. The most reliable method for MRD detection in BCR-ABL1+ ALL needs to be further investigated within a large therapeutic protocol. Support: GAUK 554214; MH CZ-DRO UH Motol 00064203; NHMRC Australia APP1057746. Disclosures Machova Polakova: Bristol Myers-Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding.

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Cladribine in Combination with Standard Daunorubicine and Cytarabine (DAC) as a Remission Induction Treatment Improves the Overall Survival in Untreated Adults with AML Aged < 60 y Contrary to Combination Including Fludarabine (DAF): A Multicenter, Randomized, Phase III PALG AML 1/2004 DAC/DAF/DA Study in 673 Patients-A Final Update.

Blood ◽

10.1182/blood.v114.22.2055.2055 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2055-2055

Author(s):

Jerzy Holowiecki ◽

Sebastian Grosicki ◽

Slawomira Kyrcz-Krzemien ◽

Kazimierz Kuliczkowski ◽

Aleksander B Skotnicki ◽

...

Keyword(s):

Overall Survival ◽

Research Funding ◽

Remission Rate ◽

Randomized Study ◽

Phase Iii ◽

Remission Induction ◽

Induction Treatment ◽

P Value ◽

Who Grade ◽

Free Survival

Abstract Abstract 2055 Poster Board II-32 This trial is a continuation of earlier Polish Adult Leukemia Group (PALG) studies on the use of purine analogues for therapy of AML patients (Leukemia 2004,18:989–97, updated at 7 y: ASH 2006, Abstr.N#2003, Ann Hematol. 2008, 87:361–7). The goal of the present study was to evaluate the efficacy of combination including fludarabine – DAF (daunorubicine 60 mg/m2/d iv, d 1–3; cytarabine (AraC) 200 mg/m2/d ci, d 1–7, and fludarabine 25 mg/m2 iv d 1–5) in untreated adult patients with AML, based on head to head comparison with DAC (DNR, AraC, Cladribine), and standard DA regimens (preliminary results: ASH 2008, abstr.#133). Primary end-points were: complete remission rate (CR) and overall survival (OS); secondary objectives were: toxicity and leukemia-free survival (LFS). Patients achieving CR received two courses of subsequent intensive consolidation: HAM (HD AraC, mitoxantrone) and HD AraC. Reduction of consolidation was accepted in patients treated with early alloBMT. In case of partial remission (PR) after the first induction course the same regimen was repeated. Patients with no remission (NR) or with PR after 2 induction courses were withdrawn from the study. Between 09.2004 and 05.2008, 673 adult untreated AML patients aged 18–60 y, median 47 y, sex: male 49,5%, female 50,5%, treated in 18 co-operating PALG centers were centrally randomized to either DAF (n=225), DAC (n=224) or DA (n=224) arm (1:1:1). PML/RAR alfa positive - FAB M3 cases were excluded. The study groups were well balanced in respect of age, sex, FAB subtype, and WBC. The results are summarized in the table. Outcome DAC (n = 223) DAF (n = 219) DA (n = 210) P Value (DAC vs DA) P Value (DAC vs DAF) CR 68 59 56 .013 .08 CR after 1 cycle 62 55 50,5 .017 16 3-yr OS 46 30 31 02 .02 2-yr LFS 47 40 39 NS NS Both, the entire CR rate and the CR rate after a single induction course were significantly superior in the DAC arm if compared with DA and DAF subgroups. With a median follow-up of 34 months (the longest observation time 5y) the OS rate equaled 46% for the DAC treated subgroup and was higher in comparison to the standard DA arm and the DAF arm. There were no significant differences in the leukemia free survival rates. The early death rates of 8,5–11%. were similar in the studied treatment subgroups. All patients developed WHO grade IV thrombocytopenia and agranulocytosis. The frequency and severity of infections, mucositis, vomiting, diarrhoea, alopecia, polyneuropathy as well as of cardiac, liver or kidney dysfunctions were comparable in particular arms. In conclusion, this updated results of randomized study prove that the incorporation of cladribine to the standard DA induction regimen (DAC) improves CR rate and the overall survival in adults with AML aged up to 60 y, without additional toxicity. This beneficial effect was not observed in patients treated using the DAF protocol with fludarabine added to the standard “DA 3+7” schedule. Disclosures: Robak: Celgene: Consultancy; Roche: Honoraria, Research Funding; Genmab: Research Funding; Cambridge Antibody Technology: Research Funding; GlaxoSmithKline: Honoraria. Warzocha:BMS: Consultancy, Honoraria; Celgene: Consultancy; Roche: Honoraria; Pfizer: Honoraria; Amgen: Honoraria.

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HLA Homozygosity and Haplotype Bias Among Patients with Chronic Lymphocytic Leukemia: Implications for Disease Control by Physiologic Immune Surveillance

Blood ◽

10.1182/blood.v116.21.1370.1370 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1370-1370

Author(s):

Nina Shah ◽

William Decker ◽

Ruth Lapushin ◽

Dongxia Xing ◽

Simon Robinson ◽

...

Keyword(s):

Overall Survival ◽

Clinical Outcome ◽

Patient Population ◽

Research Funding ◽

Advanced Disease ◽

Immune Surveillance ◽

Prognostic Significance ◽

Cancer Center ◽

Cell Transplant ◽

Hla Alleles

Abstract Abstract 1370 Background: Though the cancer immune surveillance hypothesis was first proposed a century ago, there has been limited evidence to support the role of antigen presentation in the detection or suppression of CLL. In this study we evaluated the frequencies of HLA haplotype and homozygosity and subsequent impact on clinical outcome in CLL patients with advanced disease. Methods: We performed a retrospective chart review of 249 CLL patients who were referred for allogeneic stem cell transplant at MD Anderson Cancer Center. We compared HLA allele frequencies of the patient population with those of local, race-matched controls and identified specific HLA alleles which were more frequent in the patient population. We also compared HLA homozygosity between the patient and control population. The Kaplan-Meier method was then used to determine the prognostic significance of the identified HLA alleles and homozygosity on clinical outcome within our patient population. Progression-free survival (PFS) was calculated from the time of first treatment to the time of progression or death. Results: CLL patients with advanced disease were significantly more likely to express HLA-A1 (OR=1.49, 95% CI 1.15–1.94, p=0.0003) or HLA- C7 (OR 1.24, 95% CI 1.00–1.53, p=0.05). In addition, these patients were more likely to be homozygous at any HLA locus than were controls (OR=1.20, 95% CI 0.97–1.48, p=0.04), particularly at HLA-C (OR=1.62, 95% CI 1.13–2.33, p=0.002) and at multiple HLA loci (OR=1.69, 95% CI 1.06–2.70, p=0.006). CLL patients who were HLA-A1+, HLA-A1/C7+ or homozygous at any allele demonstrated worse PFS in comparison with CLL patients without any of these HLA allelic characteristics. Median survival was 23.9 months for HLA-A1+ patients, 13.9 months for HLA-A1/C7+ patients and 25.7 months for patients with homozygosity, in comparison to 31.8 months for the population without any detrimental alleles or homozygosity (p=0.02, p=0.0008, and p=0.007 respectively, Figure 1: A, B, C). Analysis of patients possessing only HLA-C7 as a risk factor demonstrated a trend toward decreased PFS but was not quite statistically significant (p=0.07, data not shown). Conclusions: Patients with advanced CLL appear to express certain HLA alleles and exhibit HLA homozygosity more frequently than normal controls. In addition, these HLA characteristics may predispose CLL patients to a worse outcome. Because HLA allelic variation determines the specificity of antigens presented to the immune system, the data suggest that immune surveillance may play a physiologic role in the control of leukemic disease and provide a theoretical framework for the identification of CLL antigens which could eventually serve as targets for immunotherapy. A. Negative effects of HLA-A1 allele on overall survival of patients with advanced CLL are B. synergistically worsened by the presence of the HLA-C7 allele. C. Homozygosity at any HLA allele also imparted a negative impact upon overall survival. Disclosures: O'Brien: Novartis: Research Funding; BMS: Research Funding.

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Minimal Residual Disease Detection by Four-Color Multidimensional Flow Cytometry Identifies Pediatric AML Patients at High Risk of Relapse.

Blood ◽

10.1182/blood.v110.11.1429.1429 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1429-1429 ◽

Cited By ~ 2

Author(s):

Soheil Meshinchi ◽

Todd Alonzo ◽

Robert B. Gerbing ◽

Jessica A. Pollard ◽

Alan S. Gamis ◽

...

Keyword(s):

Overall Survival ◽

Prognostic Factors ◽

High Risk ◽

Residual Disease ◽

Prognostic Significance ◽

Institutional Setting ◽

Patient Specific ◽

Flow Cytometric Method ◽

Flow Cytometric ◽

Risk Of Relapse

Abstract We previously demonstrated that the presence of residual leukemic blasts (MRD) in patients in morphologic remission was predictive of subsequent leukemic relapse. More recently, we developed a four-color multidimensional flow cytometric method using standardized rather than patient specific panels, distinguishing the abnormal cells based on “difference from normal”. The feasibility of utilizing this method, which does not require a diagnostic specimen and is applicable even if the phenotype of the leukemic clone changes was tested in a blinded study as part of the recently completed COG AML pilot AAML03P1 that enrolled 341 patients. 302/341 patients in the study consented to participate in the biology portion of the study. 223 (74%) had evaluable specimens at the end of induction I, 191 (87%) of which achieved a morphologic CR at the end of induction I. Of the 191 patients in CR at the end of induction I, 48 (25%) had evidence of MRD. The level of MRD ranged from 0.02% to 3% with 70% of patients having an MRD level between 0.1% to 1%. Relapse risk was assessed in those with and without MRD. Those with evidence of MRD were at significantly higher risk of subsequent relapse, with a relapse-free survival (RFS) from end of induction I of 36% for those with MRD compared to 70% for those without MRD (p < 0.001). The corresponding overall survival at 2 years from induction I was 63% and 86% for those with and without MRD (p=0.003). 181 patients who were in morphologic CR at the end of induction II had evaluable samples for MRD analysis. MRD was detected in 36/181 patients (20%) and presence of MRD was associated with a RFS from end of induction II of 34% compared to that of 70% in those without MRD (p<0.001). Corresponding overall survival at 2 years from induction II was 56% and 83% for those with and without MRD (p=0.009). We determined whether MRD positive patients who clear their disease have an improved outcome. There were 16 patients with detectable MRD at the end of course I with undetectable MRD at the end of course II. Relative risk of relapse for these patients was 40% vs. 30% for those who were MRD negative at both time points. Data from end of induction I and Induction II were combined to maximize our ability to identify those at high risk of relapse. This study demonstrates that flow cytometric based MRD can be utilized in a multi-institutional setting to accurately identify those at high risk of relapse. Multivariate analysis of the prognostic significance of MRD in the context of other prognostic factors including cytogenetics (CBF, etc.) and molecular (FLT3/ITD) prognostic factors will be presented.

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Outcome of Elderly Patients with Acute Myeloid Leukemia (AML) Post Hypomethylating Agent (HMA) Failure.

Blood ◽

10.1182/blood.v120.21.2627.2627 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2627-2627 ◽

Cited By ~ 1

Author(s):

Koichi Takahashi ◽

Hagop M. Kantarjian ◽

Hady Ghanem ◽

Farhad Ravandi ◽

Jorge E. Cortes ◽

...

Keyword(s):

Overall Survival ◽

Elderly Patients ◽

Salvage Therapy ◽

Research Funding ◽

Objective Response ◽

Induction Treatment ◽

High Dose ◽

Cell Transplant ◽

Investigational Agents ◽

The Impact

Abstract Abstract 2627 Background and Aims: HMA such as 5-azacitadine or decitabine have been increasingly used as induction therapy in elderly patients with AML. The prognosis of such patients who failed initial HMA and the impact of subsequent chemotherapy on outcome are unknown. Therefore the aims of the current analysis are 1) to evaluate the prognosis of elderly patients with AML post HMA failure and 2) to evaluate the efficacy of using intensive cytarabine-based salvage therapy vs. low intensity investigational therapy. Methods: We analyzed 54 patients older than 60 years old with AML who received induction treatment with HMA using either 5-azacitadine (n=17; 31%) or decitabine (n=37; 69%) under various clinical trials. Result: Median age of the group was 68 years (range; 60–84); 39% patients were female. Forty three patients (77%) had performance status (PS) ≤1 and 11 patients had PS of 2 (23%). Mean initial white blood cell count was 10.9 ± 3.2 (x103/μl), hemoglobin 9.9 ± 0.2 (g/dl), platelet count 77 ± 9 (x103/μl), and bone marrow blast count 44 ± 2.9 (%). Cytogenetic category was classified as intermediate in 30 (55%) patients and poor in 24 (45%) based on the MRC criteria. Six patients (11%) carried FLT3-ITD mutation and 1 carried FLT3 D835 mutation. Complete remission (CR) was achieved in 24 patients (44%) with median numbers of cycles required to achieve CR being 3 (range; 1–6). All patients received further salvage therapies, at the time of failure, with a median of 2.5 (range, 2–5) salvage regimens. As part of the salvage regimen, high-dose cytarabine-based regimen (HDAC) was given to 32 patients (59%). Objective response rate to HDAC was 53%, with 18 pts achieving CR. Median number of courses given was 2 (range, 1–7) with a median duration of response of 3 months. No induction death was reported. Stem cell transplant was performed in total of 9 patients (17%) as a consolidation post HDAC (n=4) or as salvage therapy (n=5). With a median follow-up of 5 months post HMA failure, 5 (9%) patients remained alive receiving therapy. The median overall survival (OS) was 5.4 months (range, 2.3–8.5). The 1-year overall survival rate was 26%. There was no difference in OS between patients who received HDAC versus those who received investigational agents (p=0.25). Conclusion: The outcome of untreated elderly patients with AML who failed HMA is poor with a median survival of 5 months. HDAC based regimen, although active with low treatment related morbidity, yielded no survival improvement compared to investigational agents. Such patients should benefit from more innovative approaches. Disclosures: Ravandi: Celgene: Honoraria, Research Funding; Eisai: Honoraria, Research Funding.

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Impact Of Rituximab Maintenance Schedule On Prognosis In First Line Treatment Of Follicular Lymphoma. Retrospective Analysis From Czech Lymphoma Group (CLG) Database

Blood ◽

10.1182/blood.v122.21.4387.4387 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4387-4387

Author(s):

Andrea Janikova ◽

Zbynek Bortlicek ◽

Vit Campr ◽

Leos Kren ◽

David Belada ◽

...

Keyword(s):

Overall Survival ◽

Follicular Lymphoma ◽

Retrospective Analysis ◽

Research Funding ◽

Statistical Significance ◽

Induction Treatment ◽

Line Treatment ◽

First Line ◽

Rituximab Maintenance ◽

First Line Treatment

Abstract Introduction Results of randomized studies showed benefit of maintenance therapy with monoclonal anti-CD20 antibody (rituximab) in terms of time to progression (PFS) and overall survival (OS) in follicular lymphoma (FL). General recommendation, based on large clinical trial, is to give 2 years of rituximab maintenance á 375mg/m2every 2 months (12 doses) in first line setting. On the other hand, there are various rituximab maintenance schedules; however, the clear comparison of clinical efficacy is missing. Our retrospective analysis compared two different schedule of rituximab maintenance in first-line treatment of FL used in university centers participating on CLG registry. Methods Data were recruited from 1702 FL patients registered in the prospectively maintained multicentric database (Czech Lymphoma Group; CLG). For the analysis, patients with stage II-IV of new diagnosed FL (grade 1-3a) responding (complete or partial remission) to 6-8 cycles first-line RCHOP (rituximab, cyclophosphamide, doxorubicine, vincristine and prednisone) followed with rituximab maintenance (RM) were included. Completed planned maintenance was inclusion criterion. Patients with previous watch and wait or additional first line therapy (radiotherapy, other chemotherapy, transplant therapy) were excluded. Results Totally, 168 evaluable FL patients with median age 57ys (range 28-82) including 70 (41.7%) men treated with RCHOP + RM were found in CLG database. 52/168 patients received totaly 8 doses of rituximab maintenance every 3 months for 2 years (RM8 arm), whereas 47/168 patients were treated with totaly 12 doses (RM12 arm) of rituximab maintenance every 2 months for 2 years. All patients in both subgroups completed planned RM therapy. There was no difference in distribution of age, gender, FLIPI, grade, B-symptoms, bone marrow involvement, performance status, LDH and beta2microglobuline level between both arms. Induction treatment in terms of administered cycles CHOP (6xCHOP in 41/52 and 35/45 pts., for RM8 and RM12 arm) and rituximab doses (8xR in 48/52 and 41/45 pts., for RM8 and RM12 arm) was similar between arms (ns). There were 4/52 (7.7%) and 5/47 (10.6%) relapses in subgroups RM8 and RM12, with no statistical significance. Median PFS was 3.8 (2.1-5.8) years vs. 3.9 (2.4-7.8) years in RM8 and RM12 arms (not significant), and median OS 3.91 (2.2-6.94) years vs. 3.1 (2.48-8.6) years also with no statistical significance. Conclusion Our results show, that rituximab maintenance given every 2 or every 3 months for two years in first line treatment brings similar benefit to the FL patients in terms of remission duration and overall survival. Despite the fact, that presented data are retrospective observation, this is the first report comparing two different rituximab maintenance regimens in FL. Further prospective study and longer follow up are needed to confirm our preliminary data. This work was supported by grant NT/12193-5 and MHCZ-DRO (FNBr 65269705) Disclosures: Mayer: Roche: Consultancy, Research Funding; Glaxo: Consultancy, Research Funding. Trneny:Roche: Honoraria, Research Funding.

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Outcomes of Children, Adolescents, and Young Adults with Acute Lymphoblastic Leukemia Based on Blast Genotype at Diagnosis: A Report from the Children's Oncology Group

Blood ◽

10.1182/blood.v128.22.451.451 ◽

2016 ◽

Vol 128 (22) ◽

pp. 451-451 ◽

Cited By ~ 4

Author(s):

Mignon L. Loh ◽

Elizabeth Raetz ◽

Meenakshi Devidas ◽

Yunfeng Dai ◽

Michael J. Borowitz ◽

...

Keyword(s):

Risk Factors ◽

Overall Survival ◽

Research Funding ◽

Lymphoblastic Leukemia ◽

Prognostic Significance ◽

Multivariable Analysis ◽

Oncology Group ◽

Genetic Groups ◽

Independent Prognostic Significance ◽

Independent Risk Factors

Abstract Survival for childhood acute lymphoblastic leukemia (ALL) now approaches 90% with risk adapted therapy based on National Cancer Institute risk group (NCI RG) at diagnosis, somatic lymphoblast genetics, and early response to therapy as measured by minimal residual disease (MRD). The Children's Oncology Group AALL03B1 ALL Classification trial enrolled 11,145 children, adolescents, and young adults less than 31 years of age with newly diagnosed B- or T-lineage ALL between December 2003 and September 2011. Companion therapeutic trials for B-lineage ALL included AALL0331 (n= 5226) for NCI standard risk (SR-ALL)(age 1-10 years and white blood cell count (WBC) < 50,000/uL) and AALL0232 (n=2907] for NCI high risk (HR) ALL (age > 10 years or presenting WBC > 50,000/uL). Assessing outcome by lymphoblast genetics revealed statistically significant distributions of genotype and NCI RG, as well as differences in event-free and overall-survival (EFS, OS) (Table 1). Not surprisingly, favorable genetic groups of Trisomy 4/10/17 (TT) and ETV6/RUNX1 were significantly more common in NCI SR patients (p< 0.0001 for each) while those with unfavorable characteristics (MLL rearranged [MLLr], intrachromosomal amplification of chromosome 21 [iAMP21], BCR/ABL1 and hypodiploidy [n<44]) occurred more frequently in NCI HR patients (p<0.0001 for each). Event-free and OS were correspondingly poorer in NCI HR patients with the exception of iAMP21, where EFS in those treated on AALL0232 was better than that in NCI SR (Table 1). Surprisingly, NCI SR BCR/ABL1 positive patients (N= 64, 1.2%) had a 5-year EFS of 85±5.0%, although these patients came off study at end induction and likely received imatinib with chemotherapy on a companion ALL trial for Ph+ ALL. Notably, hypodiploidy was associated with the worst EFS and OS regardless of NCI RG, with 5-year EFS and OS of 51.3±5.0% and 58.2±5.0%, respectively, suggesting that these patients continue to fare poorly with salvage therapies. Multivariable analysis demonstrated age, WBC, and day 29 MRD as significant independent risk factors for sustained CR, and the individual genetic groups of TT, ETV6/RUNX1, iAMP21, BCR/ABL1 and hypodiploidy, but notably, not MLLr, all retained independent prognostic significance when added to the model individually. A subset of consecutively enrolled (N=605) AALL0232 NCI HR patients underwent additional genomic interrogation, including assessment of Ph-like status, ABL1 class fusions, CRLF2r, JAK mutations (JAKm), and IKZF1 alterations. Based on sample availability, patients studied were younger (p < 0.0001) and had a higher WBC (p < 0.0001) compared to the remainder of AALL0232. There were 85/605 (14.0%) Ph-like patients defined using PAM clustering algorithms and Ph-like status was significantly associated with an IKZF1 alteration (75%) (p < 0.0001) and day 29 MRD > .01% (p < 0.0001). Five-year EFS for Ph-like versus non Ph-like was 62.3±5.8% vs. 83.9±1.7% (p < 0.0001). Outcomes of Ph-like ALL with or without CRLF2r were similar (60.6±8.3% versus 65.4±8.0%, p =0.86). Similarly, 5-year EFS of Ph-like ALL was no different with or without IKZF1 alterations (61.5±7.0% vs. 64.6 ±11.1%). There were 155 (27.1%) IKZF1 alterations, 60 of which occurred in Ph-like ALL with a trend towards concomitant CRLF2r/JAKm (p=0.055). Five-year EFS for patients with IKZF1 alterations was 66.8±4.0% (p < 0.0001) versus 86.4±1.8% for those without IKZF1 lesions. Multivariable analysis demonstrated age, WBC and day 29 MRD as independent risk factors for sustained CR while only Ph-like status, IKZF1 alteration, BCR/ABL1 and ETV6/RUNX1retained independent prognostic significance when added to the model individually. In summary, somatic sentinel cytogenetic alterations are independently prognostic in childhood ALL and are strongly associated with NCI RG and outcome, supporting continued incorporation into risk stratification algorithms. Notably, >44% of all patients have favorable blast cytogenetics with 5-year overall survival rates approaching 100%. In contrast, NCI HR patients with Ph-like ALL have poor outcomes with currently available therapy and this subtype is associated with CRLF2 r and IKZF1 alterations, which do not confer an inferior EFS within the Ph-like subgroup. Novel therapies for genomicallydefined Ph-like ALL may improve outcomes. Disclosures Loh: Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding. Borowitz:HTG Molecular: Consultancy; Bristol-Myers Squibb: Research Funding; MedImmune: Research Funding; BD Biosciences: Research Funding.

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Prognostic Significance of Somatic Mutations in Treatment of AML in Salvage Setting: A Retrospective Analysis

Blood ◽

10.1182/blood.v126.23.1313.1313 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1313-1313

Author(s):

Birendra KC ◽

Hagop M. Kantarjian ◽

Guillermo Garcia-Manero ◽

Naval Daver ◽

Gautam Borthakur ◽

...

Keyword(s):

Complete Remission ◽

Salvage Therapy ◽

Research Funding ◽

Univariate Analysis ◽

Prognostic Significance ◽

Salvage Treatment ◽

Induction Treatment ◽

Ras Mutations ◽

Cebpa Mutations ◽

New Mutations

Abstract Introduction : Acute myeloid leukemia (AML) is a heterogeneous disease with various cytogenetics and molecular abnormalities that lead to different clinical outcomes. The overall prognostic significance of specific mutations at diagnosis has been described. Some are associated with better prognosis (eg, mutations in the myeloid transcription factor gene CEBPA, mutations in the NPM1 gene in the absence of FLT3-ITD, downregulated HOX expression) and some with an adverse prognosis (eg, FLT3-ITD, high expression of the BAALC gene, overexpression of the ETS-related gene ERG, certain mutations in IDH1 and IDH2). However the impact of these mutations in a salvage setting is not well described. Methods: We retrospectively analyzed the patients with AML who received 1st or 2nd salvage treatment (Salvage 1 & Salvage 2) from September 2012 to June of 2015. All patients included in the study had received induction treatment at MD Anderson. The somatic mutations used in the study were obtained at the time of diagnosis. A total of 108 patients with known mutations who eventually received Salvage 1 were included; these also included the 41 patients who later received Salvage 2. Eight mutations (FLT3, CEBPA, IDH1, IDH2, TP53, NPM1, RAS, and JAK2) were evaluated for their correlation with outcome after salvage therapy, specifically event-free survival (EFS) and overall survival (OS) after salvage 1 and salvage 2. Any new evolving mutation after the treatment was also investigated. Results: Out of 108 patients that received salvage 1 treatment, 27% patients had IDH mutations, 19% had TP53 mutations, 16% had RAS mutations, 15% had FLT3-ITD mutations, 11% had NPM1 mutations, 11% had CEBPA mutations and 6% had JAK2 mutations at the time of diagnosis. Median age was 65 years (range: 19-84), median WBC count 5.9 x 109/L (range: 0.8-250), bone marrow blast 45% (range: 0-93) and peripheral blood blast 15.5% (range: 0-96). Cytogenetic abnormalities according to SWOG/ECOG classification were 5% favorable, 50% intermediate, 41% unfavorable and 12 % indeterminate cytogenetics. Forty-two percent of patients were refractory to induction treatment and 58% had achieved complete remission and relapsed after a median of 7 months (range: 1-22). Complete remission and complete remission with incomplete count recovery (CR/CRi) rate after 1st salvage therapy was 30% (95% CI: 21-39%). Median EFS and OS were 2.2 and 5.0 months, respectively. Among 30 pts with repeat molecular analysis prior to salvage 1, some patients developed new mutations, including 4 that acquired FLT3-ITD, and 1 patient each with new TP53, NPM1 and RAS mutations. Using cox univariate analysis stratified by the cytogenetic risk group, CEBPA (HR: 2.3, 95%CI: 1.1-4.7), TP53 (HR: 2.3, 95%CI: 1.1-4.7), JAK2 (HR: 3.3, 95%CI: 1.3-7.9) mutations were significantly associated with shorter OS after start of salvage 1 (Figure 1&2). Patients with CEBPA and/or TP53 and/or JAK2 mutations had a significantly shorter median OS compared to patients without any of these mutations (2.9 vs 7.6 months, respectively). IDH1, IDH2, FLT3-ITD, NPM1 and RAS mutations were not significantly associated with survival outcome. Among these 108 patients, 41 (38%) later received salvage 2 therapy. After Salvage 1 1 of 5 pts assessed developed a new mutation (TP53) prior to salvage 2. Overall remission (CR/CRi) rate was 29% (95%CI: 16-46%) with 2nd salvage therapy. Median OS was 3.5 months and EFS 1.5 months. Using Cox-univariate analysis stratified by the cytogenetic risk, CEBPA mutation (HR: 8.7, 95%CI: 2.3-33.0) and TP53 mutation (HR: 5.9, 95%CI: 1.3-26.2) were significantly associated with shorter OS. Conclusion: This analysis suggests that CEBPA and TP53 mutations are associated with shorter OS in patients receiving 1st or 2nd salvage therapy after failure of induction therapy. The adverse prognostic influence of CEBPA is particularly notable and requires further study. In addition, occasionally new mutations may arise after treatment failure. Mutation profiling at diagnosis as well as prior to each salvage treatment can thus be used for risk stratification of patients undergoing salvage treatment and to consider for targeted drugs to improve the outcome. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Konopleva: Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding. Cortes:Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Teva: Research Funding; Pfizer: Consultancy, Research Funding; BerGenBio AS: Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy.

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The Prognostic Significance of ASXL1/EZH2 Co-Mutation in Comparison with ASXL1 or EZH2 Mutation Alone in Myelodysplastic Syndromes

Blood ◽

10.1182/blood-2019-132070 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5428-5428

Author(s):

Pukhraz Basra ◽

David Gajzer ◽

Mohammad O Hussaini ◽

Hailing Zhang ◽

Lynn C. Moscinski ◽

...

Keyword(s):

Overall Survival ◽

Myelodysplastic Syndromes ◽

Research Funding ◽

Statistical Power ◽

Molecular Mechanisms ◽

Tp53 Mutation ◽

Survival Curve ◽

Statistical Significance ◽

Prognostic Significance ◽

Driver Mutations

Introduction: Advanced molecular profiling with next generation sequencing (NGS) has greatly improved the diagnostic and prognostic stratification of hematological disorders. Several driver mutations including TP53, RUNX1, ASXL1, and EZH2 mutations are independent predictors of overall survival (OS) in myelodysplastic syndromes (MDS). Frequent co-mutations of ASXL1, EZH2,RUNX1 and/or TET2 have also been described in the entity. However, studies exploring the clinical significance of co-mutations in these adverse genes are limited. Our study assesses mutation profiles and compares clinical outcomes among MDS patients with EZH2 mutation alone, ASXL1 mutation alone, ASXL1/EZH2 co-mutation, and co-mutated ASXL1/EZH2 with additional mutations. Materials and Methods: The retrospective study was approved by the institutional review board. We searched our institutional database (>4000 patients) for patients who were diagnosed with MDS and harbored only ASXL1 or EZH2 mutations, only ASXL1/EZH2 co-mutations, and co-mutated ASXL1/EZH2 plus other genes identified by targeted NGS using a myeloid gene panel (up to 54 genes). Patient demographics, diagnosis, cytogenetic abnormalities, and overall survival times were analyzed. Mann-Whitney U Test was used for statistical analysis of OS and a Kaplan Meier survival curve was generated. Results: Total 140 patients were retrieved: 71 patients with only ASXL1 mutation, 12 patients with only EZH2 mutation, 8 patients with only ASXL1/EZH2 co-mutation and 49 patients with multiple mutations. As shown in Figure 1, patients with ASXL1/EZH2 co-mutation or multiple mutations show worse OS when compared with patients with EZH2 mutation alone or ASXL1 mutation alone. However, only the differences between either the survival of patients with ASXL1 or EZH2 mutations alone vs multiple mutations are approaching statistical significance (p values = 0.0669 and 0.0927 respectively). Interestingly the patients with ASXL1 mutation alone or multiple mutations appeared more likely to harbor good cytogenetics (70.42% and 65.3%) rather than poor cytogenetics (7% and 2%, respectively). Finally, TP53 mutation appears to be mutually exclusive with ASXL1 or EZH2 mutations, occurring only in 1 patient with multiple mutations. Conclusion: In our study, MDS patients with ASXL1/EZH2 co-mutations or combined with other mutations appear to show worse prognosis than patients harboring ASXL1 mutation alone or EZH2 mutation alone, though statistical significance was not reached. This could be due to the fact that both ASXL1 and EZH2 confer such an unfavorable prognosis to the patients that additional mutation(s) will not produce any significant clinical impacts. This could also be due to the limited sample size in our study, thus the limited statistical power. A larger cohort study is needed to further explore the prognostic values of co-mutations in this setting. Similar to other reports, TP53 mutation also appears to be mutually exclusive with ASXL1 and/or EZH2; that is of value to further explore the molecular mechanisms. Figure 1 Disclosures Sallman: Abbvie: Speakers Bureau; Novartis: Speakers Bureau; Jazz: Research Funding; Incyte: Speakers Bureau; Celyad: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding, Speakers Bureau. Komrokji:celgene: Consultancy; pfizer: Consultancy; DSI: Consultancy; Novartis: Speakers Bureau; JAZZ: Speakers Bureau; Incyte: Consultancy; Agios: Consultancy; JAZZ: Consultancy.

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Patient Specific Comorbidities Impact Overall Survival in Myelofibrosis

Blood ◽

10.1182/blood-2019-121513 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2959-2959

Author(s):

Andrew Sochacki ◽

Cosmin Adrian Bejan ◽

Shilin Zhao ◽

Travis Spaulding ◽

Shannon Stockton ◽

...

Keyword(s):

Overall Survival ◽

Renal Failure ◽

Board Of Directors ◽

Research Funding ◽

Patient Specific ◽

Cell Transplant ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Comorbidity Burden ◽

Icd Codes

Background:Treatment decisions in primary myelofibrosis (PMF) are guided by several prognostic systems based on disease-specific risk factors, including complete blood counts and cytogenetics. Patient specific comorbidities, e.g. non-hematopoietic organ dysfunction, are not incorporated into current prognostic models. Likewise, PMF risk stratification has not yet integrated large scale electronic health record (EHR) clinical data to refine these scoring systems. We have identified a PMF cohort within the Synthetic Derivative (SD), a de-identified, research-dedicated mirror of the EHR at Vanderbilt University Medical Center that contains 2.9 million individual records with 148 million ICD codes, and 125 million clinical notes. As a proof of concept, we leveraged the SD to develop a PMF cohort. We then aimed to identify novel patient specific comorbidities that may be associated with reduced overall survival (OS) in PMF via a phenome-wide association (PheWAS) study. Methods:We interrogated the SD for PMF via an algorithm that relied on ICD codes, natural language processing of physician notes, and medication history to identify high probability cases. Confirmation of PMF was based on strict hematologist review using 2016 WHO criteria. To this end, only patients with accessible hematopathology reports and cytogenetics, and more than 1 visit to the institution were enrolled. Patients with transformation to AML at presentation (e.g. within 30 days) were excluded. To evaluate each patient's overall comorbidity burden, we interrogated patient phecodes, which are grouped ICD9 codes shown to better mimic clinical phenotypes (PMID 20335276). Specifically, we extracted all ICD9 codes within 360 days of PMF diagnosis or referral and converted them to phecodes using the map available at https://phewascatalog.org/phecodes. PMF disease-related phecodes or codes that corresponded to DIPSS dependent variables were excluded. We identified 375 phecodes at PMF diagnosis, and conducted a PheWAS study to test the association of each phecode with survival. Survival was calculated as the interval between PMF diagnosis or referral and death or last follow-up (censor); patients who underwent hematopoietic stem cell transplant (HSCT) or transformed to AML were censored at that respective date. Survival from PMF diagnosis was estimated using the Kaplan-Meier method. We utilized the Cox proportional hazards model adjusted for the DIPSS predictors and evaluated the association of each comorbidity with the overall survival and reported those that are statistically significant after multiple testing adjustment (Bonferroni corrected P<0.00013). Results:We identified 193 cases of PMF from 1995-2016 that met strict pathology inclusion criteria. PMF median age of diagnosis was 59 (range 24-87), 42% were female, and 35 patients were referred greater than one year after diagnosis. Median OS was 39 months (range 1-265), with 23 patients developing AML and 40 patients treated with HSCT. Comorbidity analysis adjusted for DIPSS factors revealed five phecodes associated with reduced OS with Bonferroni correction (Figure 1); intracranial hemorrhage (HR 28.7; 95% CI 7-116; P=2.83E-06) invasive fungal infection (HR 41.1; 95% CI 7-235; P=2.90E-05), cerebral degeneration or hydrocephalus (HR 15.1; 95% CI 3-60;P=8.56E-05), encephalopathy or coma (HR 15; 95% CI 3-59; P=0.0001) and renal failure (HR 4; 95% CI 2-8; P=0.0001). Within the renal failure cohort, uric acid levels within 12 months of PMF diagnosis were elevated (N=18, mean 9.3 mg/dl) compared to the remaining PMF cases (N=132; mean 7.6 mg/dl) P=0.016. An additional 21 patient specific comorbidity patterns noted near Bonferroni cutoff (P<0.01), with highlights including pulmonary congestion (HR 6; 95% CI 1.7-21), pulmonary heart disease (HR 5.9; 95% CI 0.6-58), cardiomyopathy (HR 5; 95% CI 1.3-19), congestive heart failure (HR 4.3; 95% CI 1.3-14), and pneumonia (HR 3.3; 95% CI 1.4-7). Summary:We successfully leveraged our PMF cohort to identify potential high risk patient-specific comorbidities not included in current risk models. In addition, we illustrated the capacity to use these techniques to identify potential clinical intervention (e.g. chronic hyperuricemia and its impact on renal function). This study demonstrates the potential to refine prognostication and treatment decisions via EHR data to study large populations of rare myeloid disease. Disclosures Savona: Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Selvita: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Patents & Royalties; AbbVie: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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