Chronic Myelomonocytic Leukemia Is Associated with More Frequent and More Rapid Progression to Acute Myeloid Leukemia and Shorter Survival Than Myelodysplastic Syndrome, but Is Less Frequently Treated: Analysis of Surveillance Epidemiology and End Results Data Linked to Medicare Enrollment Claims

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2784-2784
Author(s):  
Dan Zandberg ◽  
Ting-Ying Huang ◽  
Xuehua Ke ◽  
Maria R. Baer ◽  
Steven D. Gore ◽  
...  

Abstract Abstract 2784 Chronic myelomonocytic leukemia (CMML) is a clonal stem cell disorder that displays features of both a myelodysplastic syndrome (MDS) and a myeloproliferative neoplasm (MPN). Originally classified as an MDS subtype in the French-American-British (FAB) classification system, it was reclassified as an MDS/MPN in the World Health Organization (WHO) system. Based on SEER and NAACCR data, CMML is associated with shorter survival than MDS and MPN, but no other population-based data have been available to date. We used the Surveillance Epidemiology and End Results (SEER) dataset linked to Medicare enrollment and claims data to compare patient demographics, baseline characteristics, treatments received, progression to acute myeloid leukemia (AML) and survival between CMML and MDS. The sample included 792 CMML and 6,588 MDS patients diagnosed from 2001 through 2005. MDS cases were 34.6% low-risk [RA, RARS, RCMD, del (5q)], 13.7% high-risk (RAEB), 1.4% therapy-related and 50.4% not otherwise specified. CMML and MDS patients did not differ in age (peak proportion at 80–84 years in both) or race distribution (90% and 88% white non-Hispanic, respectively). Male predominance was greater in CMML than in MDS (59.2% vs. 53.8%; p =.004). Baseline renal disease was more common among CMML patients (13.0% vs. 7.4%; p <.0001), while CHF/ischemic heart disease (37.4% vs. 44.6%; p =.000) and liver disease (2.8% vs.4.3%; p=.041) were more common in MDS. There was no difference in the proportion with poor performance status, diagnosis of other cancers within 5 years of CMML/MDS diagnosis, health care use prior to diagnosis or median household income. More CMML than MDS patients received no treatment (25.25% vs. 15.7%; p <.0001). Among patients who were treated, fewer CMML patients received blood transfusions (59.5% vs. 70.4%; p <.0001), erythropoiesis-stimulating agents (46.3% vs. 62.4; p <.0001) and granulocyte colony-stimulating factor (7.32% vs. 16.9%; p <.0001), while more CMML patients were treated with cytarabine (2.02 vs. 0.87; p =.002), etoposide (1.01 vs. 0.36%; p = 0.009) and bone marrow transplantation (1.14% vs. 0.47%; p =.016). There was no difference in treatment with hypomethylating agents between CMML and MDS patients (5.81% vs. 7.64%; p =.064). A higher percentage of CMML patients progressed to AML (42.6% vs. 16.3%; p < .0001) and progression occurred earlier (median 8 vs. 33 weeks; p < .0001). CMML patients had a lower survival probability at 1 year (51% vs. 66%; p <.0001) and at 3 years (19% vs. 37%; p <.0001), and a shorter median survival (13.3 vs. 24 months; p <.0001). Survival remained significantly lower across gender, age and race groups. In this population-based study, we have demonstrated that CMML patients less frequently receive therapeutic interventions, in relation to MDS patients, but in fact have a higher rate of progression to AML, more rapid progression to AML and shorter survival. The percentages of patients receiving hypomethylating agents for both diseases was low in our dataset and has likely increased following FDA approval of azacitidine in 2004 and decitabine in 2006. Our data support early application of disease-modifying therapies in CMML, and also support the need for clinical trials focused on this disease entity. Disclosures: Gore: Celgene: Consultancy, Equity Ownership, Research Funding. Davidoff:Cellgene: Equity Ownership, Research Funding.

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1424-1424
Author(s):  
Naveen Pemmaraju ◽  
Dhaval Shah ◽  
Hagop M Kantarjian ◽  
Verena Wagner ◽  
Robert Z. Orlowski ◽  
...  

Abstract Background There has been a significant improvement in the outcome for patients (pts) with MM over the last decade, mainly due to the availability of immunomodulatory (IMiD) drugs and proteasome inhibitors (PI). The improvement in survival has also increased the risk of second primary malignancies (SPM), such as therapy-related myelodysplastic syndrome (t-MDS), therapy-related chronic myelomonocytic leukemia (t-CMML) or therapy-related acute myeloid leukemia (t-AML). However, little is known about the characteristics and outcomes of pts with t-MDS, t-CMML or t-AML. Methods We aimed to study the characteristics and outcome of pts who developed t-MDS, t-AML and t-CMML as SPM after the treatment of MM. We reviewed our database of pts with MM who were treated at our institution between 1993 and 2011. We identified 49 pts who were diagnosed to have t-MDS, t-CMML, or t-AML. The primary objective of this study was to evaluate the time to develop t-MDS, t-AML and t-CMML, their response to treatment and overall survival. Results Median age of pts at diagnosis of MM was 61 years. Forty-seven (96%) pts had symptomatic MM, while 2 (4%) had asymptomatic myeloma. Forty-seven (95%) pts with symptomatic myeloma received systemic therapy. Eleven (22%) pts were treated with IMiD or PI: lenalidomide 3, thalidomide 6 and bortezomib 2. Thirty-eight (78%) pts were treated with various conventional chemotherapeutic agents including melphalan, cyclophosphamide, doxorubicin, vincristine, etoposide, cisplatin, idarubicin, thiotepa, busulfan, carmustine and cytarabine. Fourteen (28%) pts also received radiation therapy to the affected areas. Twenty (41%) pts underwent high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HCT). Fourteen pts received maintenance therapy after auto-HCT with either thalidomide, lenalidomide, dexamethasone or bortezomib. Median time from the diagnosis of MM to t-MDS, t-CMML or t-AML was 6 years [0 – 24]. Thirty-four (69 %) pts developed t-MDS, 12 (24%) t-AML, and 3 (6%) t-CMML. Median age at diagnosis of t-MDS, t- CMML, or t-AML was 65 years. Twenty-seven (79%) pts with t-MDS and all 12 pts with t-AML had complex/high risk cytogenetics. Most common cytogenetic abnormalities involved chromosome 5 and 7. Thirty four (69%) pts received at least 1 cycle of induction chemotherapy either with conventional chemotherapeutic agents or investigational drugs. Only 9 pts (26%) achieved complete remission (CR). Median duration of CR in these pts was 4 months [1 – 62]. Median overall survival (OS) of pts who received induction therapy was 6.0 months [0-30]. Five (11%) pts received an allogeneic stem cell transplant with three achieving CR. Median OS in this subgroup of pts was 18 months [9 – 23]. Median OS for all 49 pts after diagnosis of t-MDS, t-CMML or t-AML was 6.0 months [0 – 30] Conclusion Development of t-MDS, t-CMML, or t-AML in pts with MM is associated with a poor outcome. These pts in general have complex cytogenetic abnormalities, chemo-resistant disease, a short CR and OS. A better understanding of disease biology and novel therapeutic approaches are warranted. Disclosures: Orlowski: Bristol-Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millennium: The Takeda Oncology Company: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Resverlogix: Research Funding; Array Biopharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Merck: Membership on an entity’s Board of Directors or advisory committees. Qazilbash:Otsuka: Research Funding; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millennium Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity’s Board of Directors or advisory committees.


Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1528-1528
Author(s):  
Sebastian Stasik ◽  
Jan Moritz Middeke ◽  
Michael Kramer ◽  
Christoph Rollig ◽  
Alwin Krämer ◽  
...  

Abstract Purpose: The enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and key epigenetic regulator involved in transcriptional repression and embryonic development. Loss of EZH2 activity by inactivating mutations is associated with poor prognosis in myeloid malignancies such as MDS. More recently, EZH2 inactivation was shown to induce chemoresistance in acute myeloid leukemia (AML) (Göllner et al., 2017). Data on the frequency and prognostic role of EZH2-mutations in AML are rare and mostly confined to smaller cohorts. To investigate the prevalence and prognostic impact of this alteration in more detail, we analyzed a large cohort of AML patients (n = 1604) for EZH2 mutations. Patients and Methods: All patients analyzed had newly diagnosed AML, were registered in clinical protocols of the Study Alliance Leukemia (SAL) (AML96, AML2003 or AML60+, SORAML) and had available material at diagnosis. Screening for EZH2 mutations and associated alterations was done using Next-Generation Sequencing (NGS) (TruSight Myeloid Sequencing Panel, Illumina) on an Illumina MiSeq-system using bone marrow or peripheral blood. Detection was conducted with a defined cut-off of 5% variant allele frequency (VAF). All samples below the predefined threshold were classified as EZH2 wild type (wt). Patient clinical characteristics and co-mutations were analyzed according to the mutational status. Furthermore, multivariate analysis was used to identify the impact of EZH2 mutations on outcome. Results: EZH2-mutations were found in 63 of 1604 (4%) patients, with a median VAF of 44% (range 6-97%; median coverage 3077x). Mutations were detected within several exons (2-6; 8-12; 14-20) with highest frequencies in exons 17 and 18 (29%). The majority of detected mutations (71% missense and 29% nonsense/frameshift) were single nucleotide variants (SNVs) (87%), followed by small indel mutations. Descriptive statistics of clinical parameters and associated co-mutations revealed significant differences between EZH2-mut and -wt patients. At diagnosis, patients with EZH2 mutations were significantly older (median age 59 yrs) than EZH2-wt patients (median 56 yrs; p=0.044). In addition, significantly fewer EZH2-mut patients (71%) were diagnosed with de novo AML compared to EZH2-wt patients (84%; p=0.036). Accordingly, EZH2-mut patients had a higher rate of secondary acute myeloid leukemia (sAML) (21%), evolving from prior MDS or after prior chemotherapy (tAML) (8%; p=0.036). Also, bone marrow (and blood) blast counts differed between the two groups (EZH2-mut patients had significantly lower BM and PB blast counts; p=0.013). In contrast, no differences were observed for WBC counts, karyotype, ECOG performance status and ELN-2017 risk category compared to EZH2-wt patients. Based on cytogenetics according to the 2017 ELN criteria, 35% of EZH2-mut patients were categorized with favorable risk, 28% had intermediate and 37% adverse risk. No association was seen with -7/7q-. In the group of EZH2-mut AML patients, significantly higher rates of co-mutations were detected in RUNX1 (25%), ASXL1 (22%) and NRAS (25%) compared to EZH2-wt patients (with 10%; 8% and 15%, respectively). Vice versa, concomitant mutations in NPM1 were (non-significantly) more common in EZH2-wt patients (33%) vs EZH2-mut patients (21%). For other frequently mutated genes in AML there was no major difference between EZH2-mut and -wt patients, e.g. FLT3ITD (13%), FLT3TKD (10%) and CEBPA (24%), as well as genes encoding epigenetic modifiers, namely, DNMT3A (21%), IDH1/2 (11/14%), and TET2 (21%). The correlation of EZH2 mutational status with clinical outcomes showed no effect of EZH2 mutations on the rate of complete remission (CR), relapse free survival (RFS) and overall survival (OS) (with a median OS of 18.4 and 17.1 months for EZH2-mut and -wt patients, respectively) in the univariate analyses. Likewise, the multivariate analysis with clinical variable such as age, cytogenetics and WBC using Cox proportional hazard regression, revealed that EZH2 mutations were not an independent risk factor for OS or RFS. Conclusion EZH mutations are recurrent alterations in patients with AML. The association with certain clinical factors and typical mutations such as RUNX1 and ASXL1 points to the fact that these mutations are associated with secondary AML. Our data do not indicate that EZH2 mutations represent an independent prognostic factor. Disclosures Middeke: Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Rollig:Bayer: Research Funding; Janssen: Research Funding. Scholl:Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Abbivie: Other: Travel support; Alexion: Other: Travel support; MDS: Other: Travel support; Novartis: Other: Travel support; Deutsche Krebshilfe: Research Funding; Carreras Foundation: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Hochhaus:Pfizer: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Takeda: Research Funding. Brümmendorf:Janssen: Consultancy; Takeda: Consultancy; Novartis: Consultancy, Research Funding; Merck: Consultancy; Pfizer: Consultancy, Research Funding. Burchert:AOP Orphan: Honoraria, Research Funding; Bayer: Research Funding; Pfizer: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Research Funding. Krause:Novartis: Research Funding. Hänel:Amgen: Honoraria; Roche: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Platzbecker:Celgene: Research Funding. Mayer:Eisai: Research Funding; Novartis: Research Funding; Roche: Research Funding; Johnson & Johnson: Research Funding; Affimed: Research Funding. Serve:Bayer: Research Funding. Ehninger:Cellex Gesellschaft fuer Zellgewinnung mbH: Employment, Equity Ownership; Bayer: Research Funding; GEMoaB Monoclonals GmbH: Employment, Equity Ownership. Thiede:AgenDix: Other: Ownership; Novartis: Honoraria, Research Funding.


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