A Phase II Single-Arm Open-Labeled Study Evaluating Combination of Quizartinib and Omacetaxine Mepesuccinate (QUIZOM) in Newly Diagnosed or Relapsed/Refractory AML Carrying FlT3-ITD

Objectives: Acute myeloid leukemia (AML) carrying internal tandem duplication (ITD) of Fms-Like Tyrosine Kinase 3 (FLT3) is associated with high relapse risk and adverse outcome. This single-arm, phase 2 study evaluated efficacy and safety of combination treatment with FLT3 inhibitor quizartinib and protein translation inhibitor omacetaxine mepesuccinate (OME), referred herein QUIZOM - in elderly patients with newly diagnosed FLT3-ITD AML or young patients with relapsed/refractory (R/R) diseases, whose outcome is hitherto dismal. Methods: R/R FLT3-ITD AML patients ≥ 18 years old or newly diagnosed patients ≥ 65 years old were recruited. Treatment comprised quizartinib 30 mg daily and OME [2 mg daily for 7 (first course) or 5 days (second course onwards) every 21-28 days] until disease progression or allogeneic hematopoietic stem cell transplantation (HSCT). Quizartinib was given as post HSCT maintenance after engraftment at doses ranging from 30 mg twice weekly to 30 mg daily, depending on blood counts. Primary endpoint was composite complete remission (CRc) defined by CR+CRi (CR with incomplete haematological recovery). Secondary endpoints were leukaemia-free (LFS) and overall survival (OS). Molecular responses were evaluated by FLT3-ITD based on PCR and NPM1 variant allele frequency (VAF) based on digital PCR (ddPCR). Mutation profiling was performed by MiSeq Next Generation Sequencing (NGS) based on IDT xGen Lockdown probes custom panel of 67 genes or TruSight myeloid panel of 54 genes. Results: Twenty-nine patients (R/R case=22; newly diagnosed case=7) were recruited between November 2017 and July 2019. Their clinicopathologic characteristics were shown in Table 1. Twenty-seven patients completed at least one course of QUIZOM (median= 2 courses, range: 1-20 courses) of whom 22 (R/R=19; newly diagnosed=3) achieved CR/CRi [CR=2 (7%); CRi=20 (74%), CRc=22 (81%)], 3 patients showed partial remission (PR) and 2 patients did not respond. All 6 patients who had prior FLT3 inhibitors (sorafenib or midostaurin) achieved CR/CRi. Median LFS and OS of CR/CRi group were 5.2 and 11.07 months (Figure 1). Seven patients received allogeneic HSCT of whom all have remained in remission post HSCT as of 31 July 2019 (OS 6.43 to 19.8 months) (Figure 1). Deep molecular responses (DMR) as defined by FLT3-ITD VAF ≤0.1% and NPM1 VAF ≤ 0.001% could be accomplished in 78% and 27% patients. Adverse effects associated with QUIZOM were primarily haematological and non-haematologic adverse effects were scarce. Two patients succumbed before commencement and on day 1 of QUIZOM due to pneumonia and intracranial haemorrhage. None of recurrently mutated genes was significantly associated with treatment responses in this cohort. Conclusion: QUIZOM is effective and safe for newly diagnosed and R/R FLT3-ITD AML. Acknowledgements: Li Shu Fan Medical Foundation, S.K. Yee Medical Foundation, Croucher Foundation, LKS Faculty of Medicine, University of Hong Kong, Daiichi Sankyo Inc. Disclosures No relevant conflicts of interest to declare.

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Randomized Phase II Study of Two Schedules of Flavopiridol (Alvocidib, F) Given as Timed Sequential Therapy (TST) Wtih Ara-C and Mitoxantrone (FLAM) for Adults with Newly Diagnosed, Poor-Risk Acute Myelogenous Leukemia (AML)

Blood ◽

10.1182/blood.v116.21.186.186 ◽

2010 ◽

Vol 116 (21) ◽

pp. 186-186 ◽

Cited By ~ 1

Author(s):

Judith E. Karp ◽

John M. Pagel ◽

B. Douglas Smith ◽

Jacqueline M Greer ◽

D. Michelle Drye ◽

...

Keyword(s):

Phase Ii ◽

Kinase Inhibitor ◽

Conflicts Of Interest ◽

Disease Free Survival ◽

Sequential Therapy ◽

Myelogenous Leukemia ◽

Newly Diagnosed ◽

Hematopoietic Stem ◽

Cyclin Dependent Kinase Inhibitor ◽

Poor Risk

Abstract Abstract 186 Acute Myeloid Leukemia - Therapy, excluding Transplantation: Pediatric and Adult AML Therapy F is a protein bound, cytotoxic, cyclin dependent kinase inhibitor. A prior Phase II trial of TST with FLAM, with F given by one hour bolus daily × 3 for adults with newly-diagnosed AML with poor-risk features demonstrated that the complete remission (CR) rate was 30/45 (67%) with median overall survival (OS) and disease-free survival (DFS) for CR patients being 12.6 and 13.3 months, respectively. We now compare FLAM using bolus F (50 mg/m2 daily × 3; Arm A) vs. FLAM using F given by pharmacologically-derived “hybrid” schedule (30 mg/m2 bolus over 30 min followed by 40 mg/m2 in a 4 hr infusion daily × 3; Arm B) in 70 newly-diagnosed AML patients (pts) with poor-risk features. Results: Pt demographics are presented below. Age # < 50 Secondary AML Adverse Genetics MDS/MPD t-AML Single Complex Flt3 ARM A (n = 36) 59ü(24–78) 3 19 5 6 13 3 Total 24/36 = 67% Total 22/36 = 61% ARM B (n = 34) 58ü(20–73) 5 16 9 8 10 5 Total 25/34 = 74% Total 23/34 = 68% Grade > 3 tumor lysis occurred in 4/70 (6%) with 1 death (A), 1 transient hemodialysis (A), 1 transient hyperkalemia (B), and 1 discontinuation of therapy (B). Four pts (6%) died from regimen toxicity before day 60 (1 A, 3 B). Median time for ANC >500/uL was Day 33 (range 22–71), and platelets > 50,000/uL Day 30 (21-80) for both arms. CR rate in Arm A is 23/36 (64%) including 16/24 (67%) with prior MDS and 13/19 (68%) with adverse cytogenetics and 3/3 (100%) with FLT3-ITD. CR rate in Arm B is 24/34 (71%) including 16/24 (67%) with prior MDS, 12/18 (67%) with adverse cytogenetics, and 4/5 (80%) with FLT3-ITD. As of 7/1/10, 20/23 Arm A CR pts have received chemotherapy and/or allogeneic hematopoietic stem cell transplantation (HCT) in CR: 15/23 (65%) of these pts remain alive and in continuous CR for up to 14+ months, 2 relapsed 4 months post-HCT, and 2 died (1 FLAM consolidation, 1 HCT). Similarly, 20/24 Arm B CR pts have received chemotherapy and/or HCT in CR: 12/20 (60%) remain alive and in continuous CR for up to 18+ months. Of Arm B pts receiving FLAM consolidation, 1 relapsed at 2 months, 1 died at 8 months of cardiac failure, and 2 died during therapy. Three were unable to receive a second cycle and 1 refused. Overall, 51/70 (73%) of all pts and 40/47 (85%) of CR pts are alive 2+ - 19+ months after FLAM. Conclusions: TST with FLAM induces CR in >60% of newly diagnosed, poor-risk AML pts, including those with prior MDS and adverse genetics. There does not appear to be major difference in toxicity or responses between the two F schedules (bolus vs. “hybrid” bolus-infusion). Thus far, allogeneic HCT has been successfully undertaken in 21/47 (45%) of first CR patients, median age 57 (20-64), with 2 early relapses and 1 death from GVHD. Bolus F may be easier to administer than hybrid F and is therefore recommended for further study in newly diagnosed AML pts. These salutary results of FLAM in poor-risk pts will now be evaluated broadly in adults with AML and compared to traditional cytotoxic chemotherapy induction regimens. Disclosures: No relevant conflicts of interest to declare.

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Family History Of Hematologic Malignancies and Disorders In a Population Based Study Of Myelodysplastic Syndromes (MDS)

Blood ◽

10.1182/blood.v122.21.1541.1541 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1541-1541

Author(s):

Angela R. Smith ◽

Erica D. Warlick ◽

Rachel K. Fonstad ◽

Michelle A. Roesler ◽

Jenny N. Poynter ◽

...

Keyword(s):

Family History ◽

Conflicts Of Interest ◽

Positive Family History ◽

Hematologic Malignancies ◽

Population Based ◽

Newly Diagnosed ◽

Population Based Study ◽

Hematopoietic Stem ◽

Increased Risk ◽

History Of

Abstract Background MDS is a clonal hematopoietic stem cell disorder characterized by dysplastic changes in the bone marrow, ineffective hematopoiesis and an increased risk for developing acute myeloid leukemia (AML). The majority of MDS cases are sporadic, but rare familial cases have been described and are often ascertained through clinic-based referrals. To our knowledge, no population based study of MDS has examined the frequency of family history of hematologic malignancies and disorders in patients, nor associations with disease characteristics and outcomes. Methods Newly diagnosed MDS cases are being identified by rapid case ascertainment by the Minnesota Cancer Surveillance System (MCSS), a population-based cancer registry in Minnesota. Eligibility criteria include all newly diagnosed cases of MDS during the period April 1, 2010-October 31, 2014, between 20-85 years, Minnesota resident, and ability to understand English or Spanish. Proxy interviews are not being conducted. Medical records and biologic samples are obtained and questionnaires are filled out by participants. Centralized pathology and cytogenetics review confirm diagnosis and classify by subtype and risk score including the Revised International Prognostic Scoring System (IPSS-R). Since 2010, information on family history has been obtained through questionnaire responses and/or medical record review on 353 MDS patients. Cases were considered to have a positive family history if they reported a first degree relative with MDS, leukemia, lymphoma or other hematologic condition (multiple myeloma [n=4], Waldenstrom’s macroglobulinemia [n=1] and idiopathic thrombocytopenic purpura [n=1]). Treatment related MDS cases were excluded leaving 330 MDS patients for analysis. Unconditional logistic regression was used to calculate crude odds ratios (ORs) and 95% confidence intervals (CI) overall and by sex. Results A total of 61/330 (18.5%) cases reported a family history of a hematologic condition. The mean age at diagnosis was 71.3 years in those with a family history compared to 72.2 years in those without a family history (p=0.53). There was no difference in the sex distribution between the two groups. Though not statistically significant, the odds of having abnormal cytogenetics or an IPSS-R of High/Very High was lower for those having a positive family history (OR 0.57 [CI 0.25-1.33, p=0.19 and 0.67 [CI 0.24-1.84, p=0.29], respectively). The odds of survival at one year after diagnosis was significantly higher in those with a family history (OR 2.79 [CI 1.04-7.51, p=0.04]) compared to those without (Table). Further stratification by sex revealed that this association was strongest for males (OR=4.23, [CI 0.94-19.0, p=0.06] compared to females (OR=1.84 [CI=0.47-7.19, p=0.38]). Discussion In this population based study of adults with MDS, the prevalence of MDS cases having a positive family history was higher than previous reports. Additionally, cases reporting a family history of hematologic malignancies and disorders appear to experience lower risk disease and have significantly improved overall survival, especially males. It is possible that patients with a family history of hematologic conditions are diagnosed earlier in the course of their disease secondary to increased awareness about blood disorders and/or more active screening within the family. Our analysis is limited by relatively small numbers, but enrollment is ongoing so subsequent analyses with larger numbers of subjects may be more revealing. Additionally, a prospective study to examine these families further, including detailed medical histories and collection of biospecimens (saliva, blood, skin) for genetic analyses is underway in order to identify potential mechanisms and mutations involved in the development of MDS and progression to AML. Disclosures: No relevant conflicts of interest to declare.

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Multiple Copies of MLL Is The Most Commonly Detected Cytogenetic Abnormality In Newly Diagnosed Multiple Myeloma and May Modify Disease Risk

Blood ◽

10.1182/blood.v122.21.1910.1910 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1910-1910 ◽

Cited By ~ 2

Author(s):

Chrystal Landry ◽

Dory Londono ◽

Sean M. Devlin ◽

Alex Lesokhin ◽

Nikoletta Lendvai ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Overall Survival ◽

Disease Risk ◽

Conflicts Of Interest ◽

Prognostic Significance ◽

Protein Translation ◽

Response To Therapy ◽

Cytogenetic Abnormality ◽

Newly Diagnosed

Abstract Background Multiple myeloma (MM) is a heterogeneous condition with variable disease course, response to therapy, and survival outcome. Cytogenetics and fluorescent in-situ hybridization (FISH) have identified several recurrent chromosomal aberrations in MM and play important and independent roles in risk stratification (Munshi et al. Blood 2011). However, the pathogenesis of the disorder remains poorly understood. Next-generation sequencing has recently identified that MM involves mutations of genes with roles in protein translation, histone methylation, and blood coagulation (Chapman et al. Nature 2011). Based on the observation that extra copies of MLL, a histone methyltransferase known to regulate the homeotic transcription factor HOXA9 that is highly expressed in MM, is frequently detected in MM, we sought to define the incidence and prognostic significance of excess MLL in MM patients. Methods We identified 188 patients with newly diagnosed MM who had cytogenetics and/or FISH performed on initial, pre-treatment bone marrow specimens at Memorial Sloan-Kettering Cancer Center between January 2009 and December 2012. Standard karyotype and FISH were performed as previously described (Cigudosa et al. Blood 1998, Gerritsen et al. Blood 1992). Probes included LSI IgH/FGF3, LSI IgH/CCND1, LSI IgH/MAF, LSI MLL, LSI p53/cep17, LSI13q14.3/13q34, LSI ETV6, LSI CBFB, LSI 1p36/1q25, and LSI 5,9,15 from Abbott Molecular. Fisher's exact test evaluated the association between MLL and selected abnormalities. Kaplan-Meier methodology estimated overall survival from the date of BM evaluation, and survival was compared using a logrank test. Results In unselected bone marrow specimens, abnormalities were detected by karyotype in 17% (27/156) and FISH in 47% (87/186) of patients tested. Hyperdiploidy, which has been associated with longer survival, was identified in 23% (43/187) of patients, while the unfavorable risk abnormalities, including loss of p53, deletion 13q (by karyotype), translocation (4;14) and excess 1q were seen in 8% (15/179), 8% (12/156), 4% (7/176) and 16% (29/178) of patients, respectively. Translocation (11;14) was seen in 4 patients; translocation (14;16) was not identified in any patient. 28% (51/183) of patients had extra copies of MLL, which was the most frequent genetic abnormality identified. Unexpectedly, this abnormality was significantly associated with both favorable (hyperdiploidy, P = <0.001) and unfavorable (deletion 13q, P = 0.043; excess 1q P = 0.001) risk genetics. While having excess MLL had no impact on the overall survival of standard-risk patients, defined as neither hyperdiploid nor with unfavorable genetics (N = 100), patients with poor-risk genetics (N = 46) and extra copies of MLL had a trend toward better survival, P = 0.06 (Figure 1). Conclusions Karyotype and FISH studies identified excess MLL as the most frequent cytogenetic abnormality in a large cohort of newly diagnosed MM patients. In patients with MM and unfavorable cytogenetics, the presence of excess MLL may ameliorate some of the adverse impact of associated with these abnormalities. Understanding the functional significance of excess MLL, perhaps as it relates to frequently dysregulated HOXA9 in MM, may provide insight into disease pathogenesis and/or identify drugable targets. Disclosures: No relevant conflicts of interest to declare.

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Eltrombopag Combined with G-CSF and Cyclosporine Could Effect for Severe Acquired Aplastic Anemia

Blood ◽

10.1182/blood-2018-99-115779 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5110-5110 ◽

Cited By ~ 1

Author(s):

Bingyi Wu ◽

Jiahui Cai ◽

Li Yingshi ◽

Dong Ruihong

Keyword(s):

Bone Marrow ◽

Aplastic Anemia ◽

Median Time ◽

Antithymocyte Globulin ◽

Complete Blood Count ◽

Conflicts Of Interest ◽

Fungal Infections ◽

Young Patients ◽

Severe Adverse Effect ◽

Hematopoietic Stem

Abstract Backgroud Acquired aplastic anemia (AA) is a potential life-threatening hematopoietic stem cell (HSC) disorder resulting in cytopenia. The first line therapy for AA is HSC transplantation for young patients who have suitable donors and immunosuppressive therapy (IST) with antithymocyte globulin and cyclosporine for the remaining patients. However, about 30% of patients are refractory to IST or relapse after IST. IST with antithymocyte globulin and cyclosporine result in severe complication and mortality infection. To reduce the mortality infection and increase the response of IST for AA is still problem. Eltrombopag, a thrombopoietin mimetic, demonstrated efficacy in restoring trilineage hematopoiesis, has recently emerged as an encouraging and promising agent for patients with refractory AA. To explore the effect of eltrombopag for severe acquired aplastic anemia, we treated seven severe AA patients with eltrombopag combined with cyclosporine and G-CSF. Herein we report initial results of the eltrombopag combined with cyclosporine and G-CSF for severe AA. Methods The diagnostic of AA patient consisted of a complete blood count, a bone marrow biopsy, bone marrow karyotype analysis and assessment of a paroxysmal nocturnal hemoglobinuria (PNH) clone. Patients with SAA aged ≥18 years old who without suitable donors received eltrombopag 75mg/d, cyclosporine 6mg/kg by oral, and G-CSF 300ug/d by subcutaneous injection from diagnosis. Red blood was infused to maintained HB more than 60g/L. Platelet were infused to maintained PLT more than 20x109/L. G-CSF was administered until neutrophil count more than 1.0x109/L. Vale concentration of cyclosporine were maintained more than 100ug/ml in blood plasm and maintained two years. Eltrombopag was taper down when platelet was more than 100x109/L. Eltrombopag was given at least three months. Antibacterial was administered when patient was high fever. Posaconazole were given for fungal infections prophylaxsis. Hematologic improvements were assessed by the National Institutes of Health (NIH) response criteria for AA. Results The median age of 7 patients with SAA was 44 years old (range 19-68 yr). Full hematologic improvements were achieved in 3 patients. All patients achieved platelet and RBC infusion independence. The median time from the first eltrombopag therapy to platelet infusion independence was 35 days (range 33-46d). The median time from the first eltrombopag therapy to RBC infusion independence was 40 days (range 30-50d). Median 6 units (1200ml) (range 3-10U, 600ml -2000ml) RBC and 7 units (2.5x109/unit) platelet were infused. With median 8 months follow-up (3-12 months),3 patients are still full hematologic improvements and 4 platelet and RBC infusion independence. No severe fugual infection was observed in this group patients. ALT slightly elevate in one patient. No other severe adverse effect was observed. Conclusions Treatment of SAA patients with G-CSF、cyclosporine combined with eltrombopag is feasible and effect. Our results deserve further research and confirmation in larger samples. Disclosures No relevant conflicts of interest to declare.

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Response Rate, Event-Free Survival (EFS), and Overall Survival (OS) in Newly-Diagnosed Acute Myeloid Leukemia (AML): U.S. Food and Drug Administration (FDA) Trial-Level and Patient-Level Analyses

Blood ◽

10.1182/blood-2018-99-119678 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2670-2670

Author(s):

Kelly J. Norsworthy ◽

Xin Gao ◽

Chia-Wen Ko ◽

Jiaxi Zhou ◽

Yutao Gong ◽

...

Keyword(s):

Response Rate ◽

Conflicts Of Interest ◽

Strong Association ◽

Least Square ◽

Coefficient Of Determination ◽

Newly Diagnosed ◽

Hematopoietic Stem ◽

Platelet Recovery ◽

Patient Level ◽

Responder Analysis

Abstract Background: Several novel therapeutics are being developed for AML with demonstrable effects on response rates (e.g. complete remission [CR], CR with incomplete hematologic recovery [CRi], CR with incomplete platelet recovery [CRp], overall response rate [ORR = CR+CRi/CRp]), and EFS. Improvement in EFS recently served as the basis of approval of gemtuzumab ozogamicin (GO) for the treatment of newly-diagnosed CD33-positive AML in adults (Jen et al. Clin Cancer Res 2018). The relationship between response rate, EFS, and OS in newly-diagnosed AML has not been conclusively established. Therefore, we conducted trial-level and patient-level meta-analyses of newly-diagnosed AML trials submitted to the FDA. Methods: We searched for trials submitted with Biologics License or New Drug Applications for treatment of newly-diagnosed AML between 2007 and 2017. Criteria for inclusion were randomized, active-controlled, multicenter trials of intensive AML induction and consolidation chemotherapy. The estimated odd ratios (OR - ratio of odds of response in treatment to odds of response in controls) of CR and ORR and hazard ratios (HR - ratio of hazard of treatment versus control) for EFS and OS were calculated for each study. EFS was defined as time from randomization to treatment failure (defined as date of randomization for patients who failed to achieve CR following induction), disease relapse following CR, or death. Associations between treatment effects at the trial-level were evaluated using weighted least square (WLS) regression analyses on the log-scale (weighted by sample size of each randomized comparison). Coefficient of determination (R2) and 95% confidence interval (CI) were calculated to measure the strength of associations. Individual patient data for OS were plotted against EFS to explore their relationship. An exploratory patient-level responder analysis was performed to compare OS between responders and non-responders, regardless of treatment assignment in the pooled dataset. We estimated HRs of OS from Cox proportional hazards models. OS estimates by response were obtained based on the Kaplan-Meier method. Results: We identified 8 trials with a total of 4482 patients and 3 experimental agents (GO, n=5; [daunorubicin and cytarabine] liposome injection, n=2; midostaurin, n=1) for treatment of newly-diagnosed AML. Two trials tested therapy in defined patient populations (FLT3 mutant = 1 and secondary AML = 1). The association between OS HR and CR OR at the trial-level was moderate (R2 = 0.67, 95% CI: 0.16 - 0.94; Figure 1), whereas the association between OS HR and ORR OR was weak (R2 = 0.43, 95% CI: 0.03 - 0.98). For the OS vs. EFS HR analysis, a weaker than expected association was observed (data to be presented at the meeting). Individual patient level data scatter plots suggested that one possible reason for the lack of a strong association between EFS and OS was that early failures and relapses did not always result in worse OS (Figure 2). In the patient-level responder analysis, patients who achieved a CR response had better OS compared with CRi+CRp response and no response (Figure 3). Conclusions: On a trial level, the meta-analysis of randomized, active-controlled trials in newly-diagnosed AML suggests a moderate association between OS and CR rate, but not ORR. A strong association between EFS and OS is not established and may be confounded by improvements in salvage therapy, supportive care, hematopoietic stem cell transplantation, and/or differing censoring across trials. A patient-level responder analysis showed that CR responders have better OS compared with CRi+CRp responders and nonresponders. While our results are limited by the number of trials, they suggest that CR remains the response endpoint associated with greatest long-term benefit and that EFS, while clinically meaningful, is not a surrogate for OS. Disclosures No relevant conflicts of interest to declare.

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Early Normalization of Serum Free Light Chain (FLC) Assays Correlates with Profound and Prolonged Responses in Newly Diagnosed Multiple Myeloma (MM)

Blood ◽

10.1182/blood-2018-99-116475 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1897-1897

Author(s):

Mercedes Gironella ◽

Alicia Senín ◽

Karla Vallejo ◽

Pamela Arenas ◽

Priyanka Raheja ◽

...

Keyword(s):

Conflicts Of Interest ◽

Autologous Transplantation ◽

University Hospital ◽

Rank Test ◽

Induction Treatment ◽

Early Prediction ◽

Newly Diagnosed ◽

Chemotherapy Treatment ◽

Hematopoietic Stem ◽

Prolonged Response

Abstract FLC is a recognized biomarker used for monitoring response and outcome of patients with amyloidosis and oligosecretory and non-secretory MM. Nevertheless, the role of FLC in the early prediction of response to the treatment in patients with gammopathies has not been fully ascertained. Against this background, we have evaluated the relationship between early FLC detection and the achievement of a deep and prolonged response after the end of the treatment in a series of patients diagnosed with MM and homogeneously treated in a single institution. Eighty-six newly diagnosed patients with MM between 2011 and January 2018 at the University Hospital Vall d'Hebron treated front-line with a bortezomib-based scheme were retrospectively analyzed. All patients had FLC levels measured by the Freelite® nephelometric assay at diagnosis, after the 2nd cycle of therapy, and at the end of treatment. Different parameters related to the FLC measurement were evaluated: normalization of the involved FLC (iFLC), ratio of involved/uninvolved FLCs (R_FLC)<10, reduction of R_FLC>95% compared to the baseline, and normalization of the ratio Kappa/lambda FLC (R_K/L). The predictive value of these parameters on the response after chemotherapy treatment was evaluated by using the Pearson´s exact test, and their impact on outcomes was analyzed by Kaplan Meier method using the long rank test for comparisons. The median age of the series at diagnosis was 69 years old (45-89). Forty-seven patients (55%) were considered candidate for autologous hematopoietic stem cell transplantation, therefore receiving induction treatment with the VTD combination (bortezomib-talidomide-dexametasone). In contrast, 39 patients (45%) were not candidate for autologous transplantation and were treated with MPV (melfalan-prednisone-bortezomib). The involved Ig was IgG in 54.7% of cases, IgA in 18.6%, IgD in 1.2% and IgM in 1.2%. Twenty-four percent of patients were diagnosed with MM of light chains (12% kappa and 12% lambda), whereas only 3 patients were diagnosed as having a oligosecretory MM. Twenty-nine percent of the cases were ISS III, 33% had increased serum LDH levels, and 79% showed immunoparesis. The kappa FLC mean at diagnosis was 1603.61 mg/dL (0.06 -36100 mg/dL) and lambda FLC was 1104 mg/dL (0.05-26500 mg/dL). Kappa FLC mean after 2nd cicle was of 192.14 mg/dL (1,61-6430 mg/dL) and lambda FLC was 61.41 mg/dL (0.05-1434 mg/dL). Thrirty-seven percent of patients obtained a profound response (≥VGPR) after the 2nd cycle of therapy, being this percentage increased to 63% of patients at the end of the chemotherapy treatment. Alongside this, the normalization of the iFLC was observed after the 2nd cycle of treatment in 44% of patients, the normalization of the R_K/L in 42%, R_FLC<10 in 70% of patients, and a reduction of R_FLs>95% was observed in 57% of patients. The great majority (80-87%) of patients attaining the normalization of any of these parameters after the 2nd cycle experienced a response ≥VGPR at the end of the treatment (table 1). With a median follow-up of 28.2 months (7-84 months), the overall PFS of the series was of 26.7 months. Of note, median PFS was of 40.3 months for patients who achieved the normalization of the iFLC after the 2nd cycle vs. 24.6 months for those who did not (p=0.047) (figure 1). Moreover, PFS was 27.3 months for those who had R_FLC<10 vs. 23 months for those with R_FLC≥10 (p=0.042). Finally, patients with reduction of R_FLC>95% exhibited a trend for a longer PFS (40.3 vs. 23.5 months) (p=0.09), as those patients with normalization of R_K/L who presented a PFS of 40.3 vs. 26.5 months (p=0.099). In conclusion, patients with normalization of different parameters related to FLC at 2 months of the onset of treatment exhibit a deeper and prolonged response to bortezomib-based chemotherapies, suggesting that this assessment could be of paramount interest in the early prediction of outcomes in patients with MM receiving treatment. Therefore, early FLC determinations should be incorporated into prospective clinical trials to validate these observations. Disclosures No relevant conflicts of interest to declare.

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Mutant nucleophosmin1 (NPM1) Links Protein Translation with Oncogenic Metabolism in Leukemia

Blood ◽

10.1182/blood.v128.22.2727.2727 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2727-2727

Author(s):

Marisa Juntilla ◽

Alina Garbuzov ◽

Natalie Ortiz ◽

Julia Eberhard ◽

Caitlin Roake ◽

...

Keyword(s):

Cell Size ◽

Cell Lines ◽

Conflicts Of Interest ◽

Aerobic Glycolysis ◽

Leukemia Cell ◽

Lactate Production ◽

Protein Translation ◽

Metabolic Reprogramming ◽

Wild Type ◽

Hematopoietic Stem

Abstract Nucleophosmin 1 (NPM1) is the most common gene mutated in acute myeloid leukemia (AML). Several putative mechanisms for the role of NPM1 in the generation of AML have been proposed, including acting as a tumor suppressor by promoting the degradation of p53 and sequestration of wild-type NPM1. However, the specificity of the mutation- most commonly a 4 base pair duplication in the C-terminus- suggests that it may be a gain- of- function mutation conferring an unidentified pro-leukemic effect. Using a novel set of leukemia cell lines generated with CRISPR/Cas9 technology in combination with studies in primary hematopoietic cells, we show that mutant NPM1 may promote leukemia by deregulating protein translation with downstream effects on cellular metabolism. Thus, mutant NPM1 may serve as a critical lynchpin to match metabolic precursors and cellular energetics to ribosomal output. The implications of our results suggest that combined metabolic and protein translation inhibition may be a previously unidentified vulnerability in AML with mutated NPM1. CRISPR/Cas9 technology was used to generate a set of isogenic cell lines derived from the heterozygous OCI-AML3 line. Transcriptomic analysis of clones with either parental allele configuration (wild-type and mutant, WTAM) vs. inactivation of the mutant allele (wild-type only, WTO) confirmed that mutant NPM1 regulates HOX genes, as shown in both mouse models and patient samples. Next, the effects of mutant NPM1 on ribosome biogenesis and protein translation were assayed with pulse- chase and static experiments and showed both ribosomal RNA and protein translation were increased in WTAM clones vs. WTO clones. During these investigations, cell size was noted to be increased in WTAM cells. Cell size can be a consequence of the metabolic activity of a cell. Analysis of the rate of glucose consumption and lactate production showed that WTAM cells have increased aerobic glycolysis compared with WTO cells. To test if mutant NPM1 is sufficient to drive both protein translation and aerobic glycolysis in a normal cell, these studies were replicated in normal human hematopoietic stem cells stably expressing either wild-type NPM1 or mutant NPM1. In summary, our results suggest that mutant NPM1 acts through dysregulation of protein translation and participates in metabolic reprogramming required to drive oncogenic transformation. Disclosures No relevant conflicts of interest to declare.

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Predictable Recurrence by Regular Monitoring Minimal Residual Disease with Flowcytometry In the Patients with Both AML and ALL: A Single-Center Study of 158 Cases.

Blood ◽

10.1182/blood.v116.21.1661.1661 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1661-1661 ◽

Cited By ~ 1

Author(s):

Chunrong Tong ◽

Junfang Yang ◽

Yuehui Lin ◽

Xinhong Fei ◽

Jie Zhao ◽

...

Keyword(s):

High Risk ◽

Minimal Residual Disease ◽

Conflicts Of Interest ◽

Residual Disease ◽

Newly Diagnosed ◽

Aberrant Expression ◽

Hematopoietic Stem ◽

The Difference ◽

Almost All ◽

Minimal Residual

Abstract Abstract 1661 Minimal residual disease (MRD) is the most important factor to predict the prognosis after chemotherapy in the patients with acute leukemia(AL). Among the techniques for MRD detection, flowcytometry (FCM) is both sensitive and feasible tool, which can be used in almost all patients no matter with or without cytogenetic or molecular marker. It has been widely recognized that the MRD by FCM can predict the prognosis of the patients with ALL after several cycles of chemotherapy, but there are few reports on the value of MRD by FCM in AML. To investigate the clinical prognostic value of monitoring MRD regularly with FCM, the correlation of MRD and leukemia-free survival (LFS) in patients with AL without initial high risk factors was studied. From April 2005 to July 2009, 119 newly diagnosed patients (AML 85, ALL 34) and 39 treated cases (AML 19, ALL 20) were included. Those treated patients had attained the first complete remission (CR1) for more than 1 year after chemotherapy in other hospital and then were transferred to our hospital and detected MRD by FCM regularly since then. MRD in bone marrow (BM) was detected every 1 to 3 months in the first year after CR1, and every 2 to 6 months thereafter until hematological or extramedullary relapse or by July 2010. The special antibody combinations were employed for each patient according to aberrant expression of leukemia cells detected by the primary immune phenotype, or antigen drift in the follow-up. MRD was analyzed by the same doctor and assessed according to some abnormal characteristics, including antigen over-expression, antigen low-expression or even loss, co-expression of different lineages or different stage antigens on a single cell, and abnormal patterns in light scatters. MRD+ was defined as the aberrant cells more than 0.01% in BM at the twelfth month for AML and the fifth month for ALL. Among 85 newly diagnosed AML, 33 cases were MRD+ with the median ages 29(4-73)years old, 52 cases were MRD- with the median ages 35(9-68)years old. A total of 2/33 patients in MRD+ group and 40/52 patients in MRD- group remained in LFS. The probability of LFS at 12 months and 24 months was 56% and 16% in MRD+ group, 100% and 84% in MRD- group, respectively (see Figure 1), the difference between MRD+ and MRD- groups was significant statistically (p<0.001). Among 34 newly diagnosed ALL, 13 cases were MRD+ with the median ages 20(12-45)years old, 21 cases were MRD- with the median ages 17(6-35)years old . A total of 1/13 patients in MRD+ and 19/21 patients in MRD- remained in LFS. The probability of LFS at 12 months and 24 months was 46% and 38% in MRD+ group, 95% and 95% in MRD- group(see Figure 2), the difference between MRD+ and MRD- groups was significant statistically (p<0.001). Similar pattern was seen in treated patients. Among 19 treated AML, 0/6 in MRD+ group and 11/13 in MRD- group remained in LFS. Among 20 treated B-ALL, 0/5 in MRD+ group and 14/15 in MRD- group remained LFS. In conclusion, our data indicate that MRD monitored by FCM in both AML and B-ALL correlates to LFS very well. It is important to monitor MRD regularly with FCM in the patients with AL after remission in order to earlier identify high-risk patients for relapse who need intensified treatment, such as allogeneic hematopoietic stem cell transplantation. Disclosures: No relevant conflicts of interest to declare.

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Results of a Phase I Open-Label Study of Decitabine in Combination with Midostaurin (PKC412) for Elderly (Age ≥ 60) Newly Diagnosed or Relapsed/Refractory Adult Patients with Acute Myeloid Leukemia,

Blood ◽

10.1182/blood.v118.21.3610.3610 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3610-3610

Author(s):

Casey B Williams ◽

Suman Kambhampati ◽

Siddhartha Ganguly ◽

Omar S. Aljitawi ◽

Ruben Reyes ◽

...

Keyword(s):

Phase I ◽

Conflicts Of Interest ◽

Complete Response ◽

Pharmacokinetic Analysis ◽

Clinical Activity ◽

Cell Transplant ◽

Newly Diagnosed ◽

Elderly Age ◽

Open Label ◽

Hematopoietic Stem

Abstract Abstract 3610 The activated FMS-like tyrosine kinase 3 (FLT3) receptor promotes proliferation, survival and differentiation of primitive hematopoietic progenitor cells, with downstream targets including the Raf/MEK/ERK pathway. Methylation-associated silencing inactivates certain tumor suppressor genes as effectively as some mutations potentially acting as one of the cancer predisposing hits of the two-hit = leukemogenesis hypothesis. Methods: We present data from a phase I, single-center study designed to determine the MTD and recommended Phase II dose of midostaurin (PKC412), a FLT3 inhibitor, combined either sequentially (days 8–21) or concurrently (days 1–28) with decitabine 20 mg/m2 days 1–5 in AML patients. Additional endpoints: tolerability; exploratory activity assessments. Adult AML patients with relapsed or refractory (R/R) disease or elderly (≥ 60 years) patients unable to receive standard induction chemotherapy, with ECOG PS ≤2, were eligible and received treatment for 3 cycles or until disease progression. Previous hypomethylating agents were allowed. Results: Enrollment is complete with 16 patients (Table 1) with 15 evaluable for safety (1 pt withdrew prior to receiving any midostaurin). One patient in cohort 1 remains on study in cycle 14. Median number of cycles completed was 2 with 5 patients receiving 3 or more cycles. Median age was 68 years (range 48–81) with 9 males. The number of newly diagnosed and R/R patients was evenly split at 8 each. Of note, 3 of 8 patients (38%) with R/R disease had relapsed subsequent to allogeneic hematopoietic stem cell transplant (HSCT). Only 2 of 16 patients (13%) had FLT3 ITD mutations and no patient had KIT mutations. Additionally, 44% of patients had received prior therapy with either azacitidine or decitabine. Safety profile: All patients whom received treatment (15) experienced adverse events (AE), the majority of which were Grade 1/2 in severity and included fatigue, nausea, mouth sores, and insomnia. Most AEs were hematologic, including anemia, thrombocytopenia, and neutropenia as expected in this population. Three patients developed dose limiting toxicities: 2 patients in cohort 3 developed pulmonary edema requiring mechanical ventilation and 1 patient in cohort 2 developed a prolonged QTc > 500 msec. All but two of 15 patients required admission for neutropenic fever. Three patients developed fungal (2) or viral pneumonia (1) and expired. However, most study treatments were given in the clinic allowing patients to spend a majority of the time as an outpatient. Response: Of twelve patients evaluable for response, 10 (83%) achieved stable disease (SD) or better while on trial. Three of the 12 patients (25%) had a complete response (CR or CRi) after 1 cycle (28 days) and 2 of these patients were able to undergo allogeneic HSCT. Of the two patients with FLT3 ITD mutations, one patient was evaluable for response and achieved a CR (cohort 2). Pharmacokinetic analysis is ongoing. Conclusion: These data indicate that the combination of decitabine with sequential midostaurin is possible without significant unexpected toxicity. The MTD for this combination was determined to be decitabine 20mg/m2 IV daily × 5 days (days 1–5) followed by midostaurin 50mg po bid days 8–21 given every 4 weeks. In addition, the combination shows promising clinical activity in R/R and untreated AML in elderly patients. Disclosures: No relevant conflicts of interest to declare.

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Iron Overload Occurs Very Early In Newly-Diagnosed Patients With Congenital, Transfusion-Dependent Anemias

Blood ◽

10.1182/blood.v122.21.4704.4704 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4704-4704

Author(s):

Antonios Kattamis ◽

Polyxeni Delaporta ◽

Ioannis Papassotiriou ◽

Dimitra Kyriakopoulou ◽

Natalia Tourkantoni ◽

...

Keyword(s):

Iron Overload ◽

Chelation Therapy ◽

Conflicts Of Interest ◽

Initial Period ◽

Transferrin Saturation ◽

Young Patients ◽

Beta Thalassemia ◽

Newly Diagnosed ◽

Transfusion Therapy ◽

Transfusion History

Systematic transfusions are lifesaving for patients with severe congenital anemias, but they eventually lead to iron overload and the indispensable necessity of iron chelation therapy. Current official guidelines for the starting time of chelation therapy derives from data obtained with the use of desferrioxamine, which has been shown to have significant toxicity in very young patients, especially when used in low iron burden. No data exist on the use of the oral iron chelators in this setting. The purpose of this study was to evaluate the changes of iron parameters at the initial period of transfusion therapy in newly diagnosed patients with congenital anemias Methods Nine patients participated in this study. One patient was diagnosed with Diamond-Blackfan anemia, one patient with severe alpha-thalassemia, while 7 had beta-thalassemia. Three of the beta-thalassemia started transfusions at 1.5, 2 and 5 years, respectively. All others started transfusions between 2-4 months of age. Iron, transferrin saturation, ferritin levels. serum transferrin receptors (sTfR), were estimated by standard methods, while labile plasma iron (LPI) by the FeROS LPI kit (Aferrix, Ltd, Israel). The main results of the study show that: 1) transferrin saturation increases rapidly with transfusions (mean levels after 4 transfusions 49.2% (range: 23.8-90.5%), mean after 6 transfusions 69.1% (range: 39.5-112%)), though it has significant diversity in between patients, as indicated also by one patient that continued to have transferrin saturation at 65% even after 12 sessions. Transferrin saturation significantly correlates with ferritin levels (r=0.763, p<0.0001), with the number of previous transfusions (r=0.486, p=0.002) and with the levels of sTfR, which is also an index of the degree of erythropoiesis (r=0.550, p<0.001). The increase of ferritin correlates also with the sTfR levels (r=0.697, p<0.0001), while the rate of increasing transferrin saturation per transfusion correlates to sTfR levels (r=0.486, p=0.002). LPI levels appears early in the transfusion history and correlates with transfusion saturation. Discussion The results of the study indicate that iron overload starts early in the transfusion history of young patients with transfusion-dependent anemias. These findings dispute current guidelines suggesting starting chelation therapy, when the patients have already received 10 transfusions or when ferritin levels reach more than 1000ug/dl. Disclosures: No relevant conflicts of interest to declare.

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