High MYC Protein Expression in MDS Is Associated with Early Transformation to AML

Acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MRC) is shown to be associated with dismal clinical outcomes and there remains a pressing need for new therapeutic strategies to improve survival outcomes. It is also important to identify targetable markers that could predict an earlier AML transformation from preexisting MDS. Our recent studies demonstrated that high expression level of MYC oncoprotein is associated inferior survival outcome in AML-MRC patients and that MYC plays an oncogenic role by epigenetic regulation of hydroxylation of 5-methylcytosine. However, the role of MYC in MDS to AML progression remain to be answered. Here, we investigated MYC protein expression levels in bone marrow (BM) specimens of patients with preexisting MDS and their subsequent AML-MRC specimens to determine whether increased MYC expression is associated with early AML progression. We retrospectively identified 32 patients with histologically confirmed AML-MRC evolving from MDS and evaluated MYC protein levels in BM biopsy specimens at the time of initial MDS diagnosis and at the time of disease transformation to AML-MRC, respectively. Clinical data including age at diagnosis, gender, CBC with differential count, cytogenetics, somatic mutations common in myeloid disease, blasts count, and IPSS were extracted at the time of MDS and AML-MRC diagnosis. MYC expression was assessed by immunohistochemistry on 4-5µm tissue sections. Deparaffinized slides were stained with anti-MYC antibody (clone Y69, Roche Diagnostics) using a Ventana Benchmark automated system. MYC expression was scored independently by two hematopathologists and categorized as low vs. high as previously described. The cut-off for high MYC expression is ≥5% positive cells. The MDS-to-AML progression free survival (PFS) and overall survival (OS) were calculated from the date of MDS diagnosis and outcomes were estimated with the Kaplan-Meier method and compared using the log-rank test. All statistical analyses were performed using SPSS v24.0. Among 32 patients, 69% (n=22) and 31% (n=10) patients had low and high MYC expression at MDS diagnosis (Table 1). The median age was 67.9 (33.5-78.7) and 61.1 (38.9-73.4) and the % of MYC positive blasts were 1% (range, 0-4.5) and 17.5% (range, 5-27.5) in low and high MYC groups, respectively, at the time of MDS diagnosis. There was no statistical difference in BM blast counts between low vs. high MYC groups (median 5% vs. 7.5%, p=0.4951). IPSS risk assessment in a total of 26 patients (19 in low MYC and 7 in high MYC) showed that 9% (n=2), 27% (n=6), 32% (n=7), and 18% (n=4) in low MYC group and 0% (n=0), 20% (n=2), 20% (n=2), and 30% (n=3) in high MYC groups had low, intermediate-I, intermediate-II, and high risk at the time of MDS diagnosis (Table 1). A total of 84% (86% [n=19] in low MYC and 80% [n=8] in high MYC) patients received treatments for MDS; ESA in 16% (n=5), hypomethylating agents in 81% (n=26), and Revlimid in 16% (n=5) (Table 1). Allogeneic stem cell transplant (allo-SCT) was performed in 12.5% (n=4) patients (n=3, low MYC; n=1, high MYC). Following AML progression, a total of 91% (n=29) patients received treatment for AML including induction chemotherapy (n=18), hypomethylating agents (n=7), and other therapies including trial (n=4) (Table 1). In the univariate analyses, patients with low MYC expression had significantly longer MDS-to-AML PFS (median 15.8 vs. 7.25 months, HR=0.1745, 95%CI=0.0591-0.5157, p=0.0016) (Figure 1), however, there was no OS difference between two groups (4.32 vs. 2.35 years, HR=0.5131, 95%CI=0.1064-2.475, p=0.6909). In a multivariate Cox model (adjusting for IPSS, age, front-line therapy, gender, allo-SCT, and MYC level), high MYC expression (HR=3.939, 95%CI=1.107-14.012, p=0.034) and IPSS risk (HR=1.903, 95%CI=1.139-3.181, p=0.014) were significant factor for MDS-to-AML PFS. In conclusion, high MYC expression at the MDS stage was associated with shorter time to AML progression, indicating that MYC plays an oncogenic role in MDS to AML transformation. Although our findings need further validation by prospective studies with greater sample size, our results support a combination treatment of hypomethylating agents with novel agents targeting MYC or/and its downstream pathways and warrant further study to identify underlying mechanisms of MYC-driven MDS to AML progression. Disclosures Talati: Pfizer: Honoraria; Astellas: Speakers Bureau; Jazz: Speakers Bureau; BMS: Honoraria; AbbVie: Honoraria. Kuykendall:Blueprint Medicines: Research Funding; BMS: Research Funding; Incyte: Research Funding; Novartis: Research Funding. Padron:Novartis: Honoraria; Incyte: Research Funding; Kura: Research Funding; BMS: Research Funding. Komrokji:JAZZ: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Honoraria; Incyte: Honoraria; Acceleron: Honoraria; Geron: Honoraria; AbbVie: Honoraria; Agios: Honoraria, Speakers Bureau. Lancet:Abbvie: Consultancy; Agios Pharmaceuticals: Consultancy, Honoraria; Astellas Pharma: Consultancy; Celgene: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; ElevateBio Management: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy. Sallman:Celgene, Jazz Pharma: Research Funding; Agios, Bristol Myers Squibb, Celyad Oncology, Incyte, Intellia Therapeutics, Kite Pharma, Novartis, Syndax: Consultancy.

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Outcome of Hodgkin Lymphoma after Progression Following Autologous Stem Cell Transplantation

Blood ◽

10.1182/blood.v128.22.2994.2994 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2994-2994

Author(s):

Joseph M. Connors ◽

Alina S Gerrie ◽

Maryse M Power ◽

Kerry J Savage

Keyword(s):

Stem Cell ◽

Hodgkin Lymphoma ◽

Research Funding ◽

Single Agent ◽

Progression Free Survival ◽

Brentuximab Vedotin ◽

Primary Objective ◽

Initial Diagnosis ◽

Cell Transplant ◽

Free Survival

Abstract Background Clinical trials have demonstrated a high level of effectiveness for brentuximab vedotin (BV) for patients with relapsed or refractory classical Hodgkin lymphoma (HL); however, how patients fare in routine clinical practice if their HL recurs after autologous stem cell transplant (ASCT) is less clear. Our primary objective was to characterize overall survival (OS) and progression-free survival (PFS) among a cohort of real-world patients treated with BV after ASCT. The secondary objective was to characterize the outcome of treatment after failure of ASCT or ASCT and BV. Methods We screened the population-based British Columbia Cancer Agency (BCCA) Lymphoid Cancer Database to identify patients with classical HL (excluding lymphocyte predominant HL) who were aged >16 years at initial diagnosis, staged and treated in BC, had primary treatment with ABVD or equivalent chemotherapy, underwent ASCT as part of first treatment for refractory or relapsed disease and relapsed again after ASCT. We excluded patients who have been treated at any time with a checkpoint inhibitor. We determined Kaplan-Meier estimates of overall (OS) and progression free survival (PFS) from the date of the progression that occurred after ASCT and, for those treated with the agent, after subsequent BV. Therapies given in sequence without a pause between therapies were considered part of the same line of therapy. Results Between 1986 and 2015 93 patients experienced recurrence of HL after ASCT. Their median age at initial diagnosis was 30 years and 51% were male. After failure of ASCT 23 (25%) received radiation monotherapy and 61 received chemotherapy (66%), either as a single agent or in various combinations and of these 9 (10%) also received radiation; 6 (6%) received a second transplant (5 allogeneic and 1 repeat ASCT); and 5 refused or were too frail for treatment other than with corticosteroids. The median PFS and OS from the time of relapse after ASCT for these 93 patients were 7.1 (range 0.2-352) and 16.2 months (range 0.2-352), respectively. Of those 93, 17 patients received BV alone or BV+bendamustine at some point following ASCT. The median age of BV-treated patients was 33 years at the time of their original diagnosis and 29% were male. Among those 17 patients, 9 received single agent BV and 8, BV+bendamustine as part of a clinical trial. The median time from ASCT to the start of BV was 27.5 months. Counting ASCT as 2nd line treatment, 10 individuals received BV as 3rd line, 6 as 4th line and 1 as 5th line therapy. For all 17 patients the subsequent median PFS and OS from the time of BV initiation were 5.1 (range 1.5-34.6) and 18.8 months (range 2.4-40.5), respectively. 12 of these patients relapsed again and their subsequent median PFS and OS were 0.6 (range 0.5-29) and 3 (range 0.5-30) months, respectively. All 9 patients who received single agent BV relapsed again at a median of 2 months (range 1.2-9.7); 5 of the 8 patients treated with BV+bendamustine remain in remission 6 to 36 months later. Conclusions These data highlight the poor prognosis for patients with relapsed or refractory cHL, particularly for those whose lymphoma recurs after brentuximab vedotin as well as the highly individualized management of patients whose lymphoma has recurred after ASCT. Future therapies that prevent or significantly delay relapse will help in alleviate the substantial clinical burden due to relapsed and refractory Hodgkin lymphoma. Disclosures Connors: Millennium Takeda: Research Funding; Seattle Genetics: Research Funding; NanoString Technologies: Research Funding; F Hoffmann-La Roche: Research Funding; Bristol Myers Squib: Research Funding.

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Characterization of BCL-2 alternative proteins and outcome in patients with peripheral T-cell lymphoma (PTCL).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e19531 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e19531-e19531

Author(s):

Mario L. Marques-Piubelli ◽

Luisa Maren Solis ◽

Luis Malpica ◽

Sushant Gouni ◽

Ranjit Nair ◽

...

Keyword(s):

Treatment Strategies ◽

Stage Iv ◽

Progression Free Survival ◽

Response To Therapy ◽

Rank Test ◽

Cell Transplant ◽

Functional Studies ◽

Tissue Biopsy ◽

Previously Treated

e19531 Background: The outcome of patients with PTCL, NOS is generally very poor, and the identification of biologically rational targets, which may translate into effective and non-toxic treatment strategies, is a high priority. The pro-survival BCL-2 family members BCL-2, BCL-XL (BCL2L1), BCL-W (BCL2L2), BCL2A1 and MCL-1 contribute to tumor maintenance, progression, and chemo-resistance across a range of cancers, but their contributions in PTCL, NOS are poorly understood. Methods: Patients with PTCL, NOS treated between 09/2000 and 09/2019 and with available tissue biopsy were included in the study. Diagnosis was retrospectively confirmed by two expert hematopathologists. BCL-2, BCL-XL, BCL-W, BCL2A1 and MCL-1 expression was assessed by immunohistochemistry (IHC), and the percentage of positive tumor cells assessed by standard microscopy. The 2014 Lugano Classification was used to define response to therapy. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method, and were compared using log-rank test between patient groups. Results: Twenty-seven patients were included in the study: 67% were male, 52% ≥ 65 year old, and 48% had stage IV disease; 59% were previously treated and 41% received > 2 lines of therapy, including stem cell transplant (SCT) in 19%. The median expression of BCL-2, BCL-XL, BCL-W, BCL2A1 and MCL-1 by IHC was: 30% (range: 0-100%), 10% (range: 0-90%), 100% (range: 40-100%), 20% (range: 0-90%), and 70% (range: 1-100%), respectively. BCL-2A1 was significantly higher in previously treated patients (35% vs 5%, p = 0.02), and in those who had previously received > 2 lines of therapy (40% vs 5%, p = 0.02). Twenty-four (89%) patients were treated after tissue biopsy, 17 (63%) with chemotherapy, 7 (26%) with biological therapy, and 6 (22%) received subsequent SCT. Five (24%) patients achieved complete remission (CR); only BCL-W associated with response, a higher expression (quartiles 3 and 4) being observed among patients not achieving CR (median 100% vs 90%, p = 0.07). After a median follow-up of 28 months (95% CI, 14-42 months), 22 (81%) patients progressed or died, and median PFS was 4 months (95% CI, 2-6 months); only BCL-W associated with PFS, a shorter median PFS being observed for patients with higher expression (3 months vs 7 months, p = 0.001). At most recent follow-up, 17 (63%) patients died, and median OS was 6 months (95% CI, 1-12 months). only BCL-W associated with OS, a shorter median OS being observed for patients with higher expression (4 months vs not reached, p = 0.004). Conclusions: High expression of BCL-W associates with significantly worse outcome in patients with PTCL, NOS. While clinical trials investigating the safety and efficacy of BCL-2 inhibition in PTCL, NOS are ongoing, these results suggest that concomitant BCL-W inhibition may be beneficial, and functional studies aimed at confirming these findings are highly needed.

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Correlation of PKM2 and CD44 Protein Expression with Poor Prognosis in Platinum-Treated Epithelial Ovarian Cancer: A Retrospective Study

Cancers ◽

10.3390/cancers12041013 ◽

2020 ◽

Vol 12 (4) ◽

pp. 1013

Author(s):

Chara Papadaki ◽

Stavroula Manolakou ◽

Eleni Lagoudaki ◽

Spyros Pontikakis ◽

Despo Ierodiakonou ◽

...

Keyword(s):

Ovarian Cancer ◽

Overall Survival ◽

Prognostic Factor ◽

Protein Expression ◽

Epithelial Ovarian Cancer ◽

Cancer Cells ◽

Progression Free Survival ◽

Free Survival ◽

Protein Levels ◽

Low Expression

CD44, a surface marker for cancer stem cells, interacts with PKM2, a key regulator of aerobic glycolysis, and enhances the glycolytic phenotype of cancer cells leading to antioxidant protection and macromolecules’ synthesis. To clarify the clinical importance of this “cross-talk” as a mechanism of drug resistance, we assessed the expression both of PKM2 and of CD44 in cancer cells of patients with epithelial ovarian cancer (EOC) treated with platinum-based treatment. One hundred and seventy-one patients with EOC were assessed for PKM2mRNA expression and PKM2 and CD44 proteins detection. Associations with progression-free survival (PFS) and overall survival (OS) were assessed with Kaplan–Meier and adjusted Cox regression models. PKM2mRNA and protein as well as CD44 protein were detectable in the majority of patients. Positive correlation between PKM2 and CD44 protein expression was observed (Spearman rho = 0.2, p = 0.015). When we used the median to group patients into high versus low expression, high PKM2mRNA and protein levels were significantly associated with lower progression-free survival (PFS; p = 0.003 and p = 0.002, respectively) and shorter overall survival (OS; p ≤ 0.001 and p = 0.001, respectively). However, high CD44 protein expression was significantly correlated only with shorter OS (p = 0.004). Moreover, patients with both high PKM2 and CD44 protein levels experienced shorter PFS and OS (p = 0.007 and p = 0.003, respectively) compared to patients with low expression of both proteins. Finally, higher PKM2mRNA and protein expression as well as CD44 protein expression (HR: 2.16; HR: 1.82; HR: 1.01, respectively) were independent prognostic factors for decreased median OS (mOS), whereas only PKM2 protein expression (HR: 1.95) was an independent prognostic factor for decreased median PFS (mPFS). In conclusion, PKM2 expression is a negative prognostic factor in EOC patients, but the interaction between CD44 and PKM2 that may be implicated in EOC platinum-resistance needs further investigation.

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Impact of Molecular Mutations on Treatment Response to Hypomethylating Agents in MDS

Blood ◽

10.1182/blood.v118.21.461.461 ◽

2011 ◽

Vol 118 (21) ◽

pp. 461-461 ◽

Cited By ~ 5

Author(s):

Fabiola Traina ◽

Anna M Jankowska ◽

Valeria Visconte ◽

Yuka Sugimoto ◽

Hadrian Szpurka ◽

...

Keyword(s):

Treatment Response ◽

Predictive Value ◽

Research Funding ◽

Myeloproliferative Neoplasms ◽

Progression Free Survival ◽

Predictive Biomarker ◽

Median Number ◽

Categorical Variables ◽

Hypomethylating Agents ◽

Significant Difference

Abstract Abstract 461 Aberrant DNA methylation is a hallmark of myelodysplastic syndromes (MDS), MDS/myeloproliferative neoplasms (MDS/MPN) and secondary acute myeloid leukemia (sAML). It provides a rationale for treating these malignancies with hypomethylating agents like 5-azacitidine (AZA) and decitabine (DAC). However, treatment outcomes remain limited and heavily weighed on morphologic/cytogenetic results. The discovery of novel mutations has provided important insight into the pathogenesis of MDS and related disorders. Genes implicated in epigenetic regulation, including DNMT3A, TET2, IDH1/IDH2, EZH2, ASXL1 and UTX have been found mutated in MDS, while others have also been implicated in MDS pathogenesis. There is limited data on the predictive value of these genetic defects for treatment response and disease outcome. We hypothesized that these defects are important biomarkers predictive of response to hypomethylating agents. We studied 88 patients with MDS (RCUD=2, RARS=6, RCMD=11, MDS-U=3, RAEB-1/2=29, CMML1/2=16, MDS/MPN-U=5, RARS-T=5, AML from MDS=11) who received hypomethylating agents (AZA=53, DAC=24, both=11). The median number of cycles was 7 [range 1–35], median age was 69 years (range 42–82) and median follow-up was 18 months (range 0–76). Responses were scored according to IWG criteria. DNMT3A, TET2, IDH1/2, EZH2, ASXL1, UTX, KRAS, NRAS, CBL, RUNX1, TP53 and SF3B1 were sequenced using standard techniques. Categorical variables were analyzed using Chi-square statistics. Overall survival (OS) was analyzed using Kaplan-Meier; p-values ≤ 0.05 were considered statistically significant. Mutated patients were older than wild type (WT) cases (72 vs. 68 years, p=.01) but were well matched for marrow blast %, cytogenetic risk group and cycles of hypomethylating agents received. We found mutations in 40/88 (45%) patients. Mutations were most frequent in SF3B1 (6/11; 55%), ASXL1 (13/50; 26%), TET2 (18/88; 20%), KRAS (3/34; 9%), and DNMT3A (7/88; 8%). Less common were mutations in EZH2 (2/43; 5%), TP53 (1/23; 4%), IDH1 (4/88; 5%), IDH2 (3/88; 3%), and UTX (1/36;3%). No mutations were found in CBL, NRAS or RUNX1. Based on single mutations, overall response rate (ORR) was higher in mutated vs WT patients for DNMT3A (6/7 [86%] vs 33/81 [41%]; p=.02), ASXL1 (11/13 [85%] vs 14/37 [38%]; p=.003), and TET2 (12/18 [67%] vs. 27/70 [39%]; p=.03). All heterozygous DNMT3A mutants responded to hypomethylating agents. Differences remained significant when stratified to AZA treatment alone for DNMT3A (6/7 [86%] vs 21/56 [38%]; p=.01) and ASXL1 (9/11 [82%] vs 12/29 [41%]; p=.02) but not TET2 (6/10 [60%] vs 21/53 [40%]; p=0.22). The predictive value of combined mutations were analyzed for DNMT3A, TET2 and/or IDH1/2, showing better response to hypomethylating therapy in patients who had a mutation; ORR (mutated: 18/28 (64%) vs WT: 21/60 (35%); p=.01). This difference remained significant in patients receiving only AZA (n=53); ORR was 11/18 (61%) in mutant and 11/35 (31%) in WT patients (p=.03). No differences in ORR were noted for KRAS, EZH2 and IDH1/2 mutant and WT patients. No SF3B1 mutants responded to treatment while both patients with UTX and TP53 mutations responded. The frequency of AML evolution was also analyzed and showed no difference between mutant and WT cases for TET2 (7/18 [39%] vs 22/70 [31%];p=.52), ASXL1 (4/10 [40%] vs 11/35 [31%]; p=.61), and DNMT3A (3/7 [43%] vs 26/81 [32%];p=.56). No differences in OS and progression free survival (PFS) were noted between responders and non-responders to hypomethylating therapy (28 vs 17 mos, p=.25; 16 vs 8 mos, p=.54). Comparison of survival outcomes for mutant and WT patients showed no significant difference for DNMT3A (OS: 30 vs 21 mos, p=0.43; PFS: 20 vs 11, p=.53), ASXL1 (OS: 28 vs 22, p=.68; PFS: 16 vs 10, p=.88), and TET2 (OS: 30 vs 20 mos, p=.30). PFS was better in TET2 mutants compared to WT (19 vs 9, p=.03). No survival differences were noted between mutant and WT cases who responded to hypomethylating agents for DNMT3A (OS: 25 vs 28,p=.84; PFS: 14 vs 16, p=.78), ASXL1 (OS: 10 vs 18, p=.48; PFS: 10 vs 6, p=.76) TET2 (OS: 27 vs 16, p=.79; PFS: 18 vs10, p=.19). In conclusion, DNMT3A, ASXL1 and TET2 mutations were independently associated with a better response to hypomethylating drugs. Moreover, combined mutations in DNMT3A/TET2/IDH1/IDH2 may influence the response to hypomethylating agents, especially AZA supporting its role as a predictive biomarker in MDS treatment. Disclosures: Maciejewski: Celgene and Eisai, NIH, AA&MDS Foundation: Research Funding. Tiu:MDS Foundation Young Investigator Award: Research Funding.

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Do Elderly Myeloma Patients Benefit From High Dose Therapy (HDT) and Autologous Stem Cell Transplant (ASCT)?: A Comparative Survival Analysis using SEER Registry

Blood ◽

10.1182/blood.v120.21.2072.2072 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2072-2072 ◽

Cited By ~ 1

Author(s):

Eden Hailemichael ◽

Jonathan L. Kaufman ◽

Christopher R. Flowers ◽

Edmund K. Waller ◽

Mary Jo Lechowicz ◽

...

Keyword(s):

Overall Survival ◽

Elderly Patients ◽

Research Funding ◽

Selection Process ◽

Progression Free Survival ◽

The Elderly ◽

Autologous Stem Cell Transplant ◽

High Dose ◽

Cell Transplant ◽

Significant Survival

Abstract Abstract 2072 Introduction: Many randomized control trials demonstrated that HDT-ASCT is superior to conventional therapies in myeloma patients and prolongs progression free survival (PFS) and overall survival (OS) (Attal M, 1996, Childs JA, 2003). However, in treating a malignancy with a median age of diagnosis of 69 years, the majority of the patients will not be eligible for this beneficial approach if a nominal numerical age cut-off (<65 years) is followed based on the assumption that elderly patients cannot tolerate HDT-ASCT; nor will they be eligible for clinical trials involving HDT-ASCT if stringent age-restricted inclusion criteria are incorporated. Therefore, we have evaluated if the elderly patients benefit from HDT-ASCT. Methods: We used the Surveillance, Epidemiology, and End Results (SEER) 18 registry data (www.seer.cancer.gov) as our comparator (reflects 28% of the US population);to provide information on incidence, prevalence and survival from 1973–2009. The data from an institutional cohort (IC) is obtained from the records of patients that underwent HDT-ASCT from January 2000 to January 2012. We used IBM SPSS version 20 to generate the Kaplan-Meier survival curves. Results: Of the 6,571,117 malignant cases listed in SEER registry, a total of 74,826 cases (1.1%) of multiple myeloma (ICD-03 code 9732) were identified (39735 males and 35091 females). Median age of the patients is 70 years. Among these patients 48,988 patients (65%) are over the age of 65. A total of 901 myeloma patients underwent HDT-ASCT from IC during the evaluable period and 167 patients (19%) were over the age of 65. The median survival for each subset is listed in Table 1. Both male and female WCI-ASCT myeloma patientshad prolonged OS compared to the SEER myeloma patients, despite the difference in magnitude of advantage in IC-ASCT male patients vs. female patients. Both white and black patients, as well as patients undergoing HDT-ASCT across all age subgroups had a significant survival advantage. Conclusions: In each subgroup, by the decade of diagnosis, gender, race, age subsets we have consistently demonstrated a significant survival benefit for IC transplant patients ≥age 65 compared to SEER myeloma patients ≥age 65 if offered HDT-ASCT. Selection-bias prevails in the groups showing improved overall survival. Hence, a careful selection process considering physiologic age as a determinant for transplant eligibility would result in better outcomes, and not preclude the elderly from the survival benefits of HDT-ASCT. Disclosures: Kaufman: Millenium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Onyx: Consultancy. Flowers:Celgene: Consultancy; Prescription Solutions: Consultancy; Seattle Genetics: Consultancy; Millennium: Research Funding, Unpaid consultancy, Unpaid consultancy Other; Genentech: Unpaid consultancy, Unpaid consultancy Other; Gilead: Research Funding; Spectrum: Research Funding; Janssen lymphoma research foundation: Membership on an entity's Board of Directors or advisory committees. Waller:Outsuka: Research Funding.

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Treatment with Hypomethylating Agents before Allogeneic Stem Cell Transplant Improves Survival for Patients with Chronic Myelomonocytic Leukemia

Blood ◽

10.1182/blood.v126.23.4347.4347 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4347-4347 ◽

Cited By ~ 1

Author(s):

Piyanuch Kongtim ◽

Uday R. Popat ◽

Antonio M. Jimenez ◽

Sameh Gabella ◽

Riad O. El Fakih ◽

...

Keyword(s):

Acute Gvhd ◽

Chronic Gvhd ◽

Progression Free Survival ◽

Cell Transplant ◽

Hypomethylating Agents ◽

Hematopoietic Stem ◽

Free Survival ◽

Unrelated Donors ◽

Conditioning Regimens

Abstract Introduction Allogeneic hematopoietic stem cell transplant (allo-SCT) is the only curative treatment modality for patients with CMML. Here we retrospectively reviewed the data for patients with CMML who received an all-SCT at our institution to identify factors associated with improved survival and determine whether treatment with hypomethylating agents (HMA) before transplant improves survival for these patients. Methods All 83 patients 18 years of age or older with a diagnosis of CMML confirmed at The University of Texas MD Anderson Cancer Center who underwent allo-SCT between April 1991 and December 2013 were identified through review of the institutionÕs medical records and included in this analysis. Forty, 7, and 36 patients had CMML-1, CMML-2 and CMML that had progressed to AML (CMML/AML) respectively. The median age was 57 years. CMML specific cytogenetic risk at diagnosis (Such E, hematologica, 2011) was good, intermediate, and high risk in 46, 19, and 18 patients respectively. Seventy-eight patients received induction treatment before transplant, 37 receiving HMA (either 5-azacytidine or decitabine) for at least 3 courses and 41 receiving 1-2 courses of cytotoxic chemotherapy. Among the patients who received induction therapy, 15 patients in HMA group and 9 patients in convention chemotherapy group achieved a complete remission before transplant. Thirty, 47 and 6 patients received transplants from matched related donors (MRD), matched unrelated donors (MUD), and mismatched related or unrelated donors (MMD), respectively. The sources of hematopoietic stem cells were peripheral blood for 48 patients (57.8%) and bone marrow for 35 patients (42.2%). Conditioning regimens varied; most patients received either fludarabine in combination with busulfan or fludarabine combined with melphalan. Sixty-four patients received myeloablative and 19 patients received reduced intensity conditioning regimens. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and methotrexate. Patient and transplant characteristics did not significantly differ between the patients treated with HMA and the patients treated with conventional chemotherapy or given supportive care alone. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival (OS), Treatment related mortality (TRM), relapse incidence through last follow-up and incidences of acute GVHD and chronic GVHD. All of these outcomes were measured from the time of allo-SCT. Results Median follow up duration for 29 survivors was 48 months. Seventy-five patients engrafted (90.4%) with median time to neutrophil and platelet engraftment of 13 and 15 days respectively. Patients treated with a HMA had a significantly lower cumulative incidence (CI) of relapse at 3 years post-transplant (22%) than those treated with other agents (35%; p=0.03), whereas TRM at 1 year post-transplantdid not significantly differ between the groups (27% and 30%, respectively; p=0.84). Acute GVHD all grades and grade 2-4 were seen in 28.2% versus 35.8% (p=0.05) and 12.8% versus 11.3% (p=0.72) in patients who received a HMA compared to those who treated with other agents respectively. CI of chronic GVHD was 35% in patients treated with a HMA versus 19.2% in those treated with other agents (p=0.36) while CI of chronic extensive GVHD was seen in only 26.7% versus 19.2% respectively (p=0.64). The lower relapse rate resulted in a significantly higher 3-year PFS rate in patients treated with a HMA (43%) than in those who received other treatments (27%; p=0.04) (Figure 1). However, therapy with HMA before transplant did not significantly influence the 3-year OS rate (45% in those treated with HMA and 39% in those treated with other agents; p=0.22). The independent prognostic factors for PFS were a blast count of < 5% before transplant (HR 0.36, 95%CI 0.14-0.78), treatment with a HMA (HR 0.44, 95% CI 0.23-0.86), a transplant from an MRD (HR 0.41, 95% CI 0.22-0.94), development of grade 2-4 acute GVHD (HR 2.7, 95% CI 1.27-5.77), and development of chronic GVHD (HR 0.15, 95% CI 0.05-0.45). Conclusion We conclude that treatment with hypomethylating agents before allo-SCT may improve survival in patients with CMML. Figure 1. Progression free survival Figure 1. Progression free survival Disclosures Alousi: Therakos, Inc: Research Funding. Andersson:Otsuka Research and Development, Inc.: Consultancy.

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In the Era of Bortezomib-Based Chemotherapy the Presence of Minimal Residual Disease Predicts Progression Free Survival after Autologous Hematopoietic Cell Transplant

Blood ◽

10.1182/blood.v126.23.5493.5493 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5493-5493

Author(s):

Robert F Cornell ◽

Jade E Jones ◽

Claudio A. Mosse ◽

Heidi Chen ◽

Laura Dugger ◽

...

Keyword(s):

Induction Chemotherapy ◽

Induction Therapy ◽

Research Funding ◽

Residual Disease ◽

Progression Free Survival ◽

Cell Transplant ◽

Hematopoietic Cell Transplant ◽

Free Survival ◽

Kaplan Meier ◽

Minimal Residual

Abstract Background: Retrospective studies have shown that achieving minimal residual disease (MRD) by multi-parameter flow cytometry (MFC) is predictive of outcomes in multiple myeloma (MM). Modern induction therapies including bortezomib (V), lenalidomide (R) followed by autologous hematopoietic cell transplant (AHCT) have resulted in substantial improvements in progression free survival (PFS) and overall survival (OS). The impact of bortezomib-based therapy on end of induction chemotherapy MRD status and post-AHCT MRD status is not well defined. We designed a prospective clinical trial (NCT01215344) to study the incidence of MRD negativity at end of induction and following AHCT, and its association with PFS and OS. Patients and Methods: Twenty patients with newly diagnosed, symptomatic MM were enrolled. They received four cycles of VRd induction therapy followed by AHCT. Dose modifications of VRd were controlled during the clinical trial. MRD status by MFC was evaluated at the end of induction chemotherapy and at day 100 post-AHCT. The MFC cut-off to determine MRD negativity was defined as 10-4. Outcomes analyzed included MM disease status, PFS and OS. Results: Three cohorts of patients were identified; patients achieving MRD negative status at the end of induction (cohort 1, 50%), those achieving MRD negative status only after AHCT (cohort 2, 15%) and patients never achieving MRD negative status (cohort 3, 35%). All patients achieving MRD negative status at the end of induction remained MRD negative post-AHCT. There were no significant differences in median age, renal function, disease stage, cytogenetic risk and maintenance chemotherapy post-AHCT between cohorts. The table summarizes characteristics of these cohorts. Patients who never achieved MRD negative status after AHCT had significantly shorter PFS (cohort 3) compared with patients who achieved MRD negative status (cohorts 1 and 2, p=0.008) (figure). The median PFS for cohort 3 was 2.64 years and not yet reached for the other cohorts. There were no significant differences in OS. Median follow-up for survivors was 2.53 years (range, 0.73-4.04). Conclusions: In this study, bortezomib-based therapy resulted in half of patients achieving MRD negative status with induction chemotherapy alone. AHCT improved the depth of response with 30% of patients who were MRD positive after induction therapy converting to MRD negativity following AHCT. Achieving a negative MRD state, pre- and at D100 post-AHCT resulted in improved PFS. These findings were independent of molecular cytogenetics or ISS stage. MRD positive status at day 100 post-AHCT is highly predictive of earlier disease progression, and may help identify patients for alternative management approaches. Delay of AHCT may be considered as a potential management option for patients with MRD negative status at the end of induction therapy, as being studied in the IFM DFCI study (NCT01208662). As some patients with MRD positive disease at the end of induction therapy become MRD negative with AHCT, these patients may benefit from AHCT and this population warrants further investigation. Table. Descriptive analysis Cohort 1 MRD -/- (%) (n=10) Cohort 2 MRD +/- (%) (n=3) Cohort 3 MRD +/+ (%) (n=7) Test Statistic Median Age 55 54 60 0.31 ISS Stage III 40 33 14 0.52 DS Stage III 89 67 60 0.14 Median Serum creatinine 0.90 0.60 0.88 0.10 Serum M-spike 2.0 1.9 2.1 0.80 Bone marrow plasma cells 14 44 14 0.18 Cytogenetics 0.37 Standard risk 40 0 57 Intermediate risk 50 67 43 High risk 10 33 0 Figure 1. Kaplan-Meier curve of progression-free survival comparing patients achieving MRD negative disease with MRD positive disease. Figure 1. Kaplan-Meier curve of progression-free survival comparing patients achieving MRD negative disease with MRD positive disease. Disclosures Cornell: Prothena: Research Funding. Jagasia:Takeda Inc: Research Funding.

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An international, randomized, placebo-controlled, double-blind phase III study (MONET1) of motesanib plus carboplatin/paclitaxel (C/P) in patients with advanced nonsquamous non-small cell lung cancer (NSCLC).

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.18_suppl.lba7512 ◽

2011 ◽

Vol 29 (18_suppl) ◽

pp. LBA7512-LBA7512 ◽

Cited By ~ 9

Author(s):

G. Scagliotti ◽

I. Vynnychenko ◽

Y. Ichinose ◽

K. Park ◽

K. Kubota ◽

...

Keyword(s):

Cox Model ◽

Objective Response ◽

Stage Iv ◽

Progression Free Survival ◽

High Rate ◽

Phase Iii ◽

Rank Test ◽

Double Blind ◽

Grade 3 ◽

Nonsquamous Nsclc

LBA7512 Background: This study evaluated whether motesanib (a selective oral inhibitor of VEGFR 1, 2 and 3; PDGFR and Kit) plus C/P improved overall survival (OS) compared with placebo + C/P in patients (pts) with nonsquamous NSCLC and in a subset of pts with adenocarcinoma. Methods: Pts had stage IIIB/IV or recurrent nonsquamous NSCLC and no prior systemic therapy for advanced NSCLC. The study initially enrolled all histologies but was amended to exclude pts with squamous NSCLC owing to a high rate of hemoptysis. Pts were randomized 1:1 to receive up to six 3-wk cycles of C (AUC 6 mg/mL·min) and P (200 mg/m2) with either motesanib 125 mg QD (Arm A) or placebo QD (Arm B) orally continuously. The primary endpoint was OS; secondary endpoints included progression-free survival (PFS), adverse events (AEs), objective response rate (ORR) and association between placental growth factor (PLGF) change and OS. OS was evaluated using a stratified Cox model and 2-sided log-rank test (α=0.03 for nonsquamous pts and α=0.02 for adenocarcinoma pts). Results: 1090 pts with nonsquamous NSCLC were randomized (Arm A/B, n=541/549); 890 had adenocarcinoma (n=448/442). 61% were men; median age was 60 years (range 21–87); 83% had stage IV disease. At the time of analysis, 753 pts had died (608 pts with adenocarcinoma). Median follow-up was 10.6 mo. OS was not significantly improved in Arm A compared with Arm B (Table). In Arm A, PLGF analysis did not show an association with OS. The incidence of grade ≥3 AEs in Arms A/B was 73/59%. Grade ≥3 AEs occurring more frequently in Arm A than B included neutropenia (22/15%), diarrhea (9/1%), hypertension (7/1%) and cholecystitis (3/0%). The incidence of grade 5 AEs was 14/9% in Arms A/B. Conclusions: In pts with advanced nonsquamous NSCLC, treatment with motesanib + C/P did not significantly improve OS compared with C/P alone. [Table: see text]

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Factors influencing survival in inflammatory breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.26_suppl.136 ◽

2014 ◽

Vol 32 (26_suppl) ◽

pp. 136-136

Author(s):

Julie A. Cupp ◽

Diane Liu ◽

Yu Shen ◽

Naoto T. Ueno ◽

Ricardo H. Alvarez ◽

...

Keyword(s):

Breast Cancer ◽

Inflammatory Breast Cancer ◽

Poor Prognosis ◽

Cox Model ◽

Univariate Analysis ◽

Progression Free Survival ◽

Rank Test ◽

Rapid Progression ◽

Progression Of Disease ◽

Delay In Treatment

136 Background: Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer associated with poor prognosis, characterized by rapidly growing mass, skin changes, and regional adenopathy. The objective of this study was to determine if delay in treatment influenced survival in IBC patients. Methods: A prospective IBC database identified 93 women with stage III IBC who received care at MD Anderson from 2007 - 2012 and were retrospectively reviewed. All patients received neoadjuvant chemotherapy followed by surgery, unless progression of disease was noted, and postmastectomy radiation. Impact of time from onset of symptoms to chemotherapy or to surgery on overall survival (OS) and progression free survival (PFS) were evaluated after adjusting for the baseline covariates in the Cox model. Results: A majority of patients were white (77.4%) with an average age of 54 years. Average days from onset of symptoms to first chemo is 95 (range 16 – 387) and to surgery is 283 (range 184 – 585). Four patients had progression while on chemo. There were 14 deaths with median follow up of 2.6 years from diagnosis. In univariate analysis, delay in treatment, > 90 days from onset of symptoms to chemo, did not affect OS or PFS. Obtaining negative margins was statistically significant for OS and PFS measured from first chemo (p=0.005 and p=0.007). Positive HER-2 status was associated with longer PFS time from chemo (p=0.02, log-rank test) and from surgery (p=0.009). Positive progesterone receptor (PR) was found to be statistically significantly associated with longer OS time from chemo (p=0.01) and from surgery (p=0.03). Clinical and imaging response to chemo were associated with better OS (p=0.007 and p=0.005) and pathologic response was marginally associated with improved OS and PFS (p=0.07 and p=0.06), both measured from surgery. In multivariate Cox model, adjusting for PR or HER2, days from onset of symptoms to chemo or surgery did not have significant impact on OS or PFS. Conclusions: While traditionally delay diagnosis and treatment is considered one of the factors associated with poor prognosis, our study suggests otherwise. However, due to such rapid progression of disease, early diagnosis is still important in the overall management of patients diagnosed with IBC.

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VEGFR2 cytoplasmic expression (VEGFR2ce) in relation to survival in metastatic breast cancer (MBC) patients (pts) treated with bevacizumab (Bev).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.11523 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 11523-11523

Author(s):

Roseana Melo Borba ◽

Tiago Cordeiro Felismino ◽

Alexandre Andre B. A. Da Costa ◽

Vladmir C. Lima ◽

Marcelo Corassa ◽

...

Keyword(s):

Breast Cancer ◽

Multivariate Analysis ◽

Cox Model ◽

Breast Cancer Subtype ◽

Antiangiogenic Therapy ◽

Metastatic Breast ◽

Progression Free Survival ◽

Rank Test ◽

Predictive Tool ◽

Tumor Subtypes

11523 Background: Bev is a monoclonal antibody that binds to VEGFA that demonstrated improved progression free survival (PFS) in MBC clinical trials. VEGFR2, NOTCH1, Integrin a1b2 and ILK are angiogenesis-related proteins possibly related with Bev efficacy. The correlation of these proteins expression and Bev survival variables was evaluated. Methods: We retrospectively analyzed 1st line chemotherapy in two HER2 negative MBC cohorts. Pts were treated between May-07 and July-14. Cohort 1 (C1) was treated with paclitaxel and Cohort 2 (C2) with paclitaxel and Bev. Expression of biomarkers was determined by immunohistochemistry. Tumor samples were arranged on a tissue microarray. Survival curves were calculated by Kaplan-Meier method and log-rank test. Cox model was used in multivariate analysis. Results: C1 had 42 pts. Median age was 63y. Tumor subtypes were divided in luminal (92.9%) and triple negative (TN) (7.1%). Visceral metastasis (mets) were present in 71.4%. Median follow-up (mFUP) time was 32.1m. mPFS was 8.0m and mOS was 33.5m. C2 had 29 pts. Median age was 57y. Luminal 79.3%; TN 20.7%; Visceral mets 79.3%; mFUP 38m. mPFS was 10.5m and mOS was 47m. In C2, high VEGFR2ce was correlated with improved PFS (high VEGFR2 16.5m x low VEGFR2 6.8m, p = 0.025). Breast cancer subtype, metastasis pattern and VEGFR2 expression were included in the multivariate analysis for PFS. VEGFR2 remained as independent factor (HR 0.35; IC95% 0.14 – 0.85, p = 0.021). In C1, VEGFR2 was not correlated with improved PFS (high VEGFR2 8.6m x low VEGFR2 8.0m, p = 0.24). Other markers were not associated with PFS. Conclusions: High VEGFR2ce was associated with increased PFS in patients treated with Bev. In MBC VEGFR2 may have a role as a predictive tool on benefit of antiangiogenic therapy.

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