GM-CSF Signaling Abnormalities in Chronic Myelomonocytic Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1713-1713 ◽  
Author(s):  
Eric Padron ◽  
Jeffrey S. Painter ◽  
Adam W Mailloux ◽  
Jessica M. McDaniel ◽  
Christopher Bebbington ◽  
...  
Keyword(s):  
Scoring System ◽  
Who Classification ◽  
Chronic Myelomonocytic Leukemia ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Serum Free ◽  
Gm Csf ◽  
Equity Ownership ◽  
Md Anderson ◽  
Myelomonocytic Leukemia

Abstract Abstract 1713 Background: Chronic Myelomonocytic Leukemia (CMML) and Juvenile Myelomonocytic leukemia (JMML) are classified as MDS/MPN in the WHO classification system. Despite sharing clinical and histological features, CMML is characterized by a heterogeneous collection of molecular lesions while JMML is defined by well-established molecular aberrations clustered along the RAS pathway leading directly to GM-CSF hypersensitivity; a pathognomonic characteristic of JMML. Here we test whether a molecular signature for GM-CSF hypersensitivity in JMML, determined by the pSTAT5 activation assay, is also present in CMML and whether this signature clusters within a specific CMML subgroup. Methods: Cryopreserved bone marrow aspirates from 24 patients with newly diagnosed or relapsed CMML were obtained from the Moffitt Cancer Center Tissue Repository. Cells were thawed and rested in Stem Span H3000 with 10% FBS for 2 hours and then either starved for one hour in serum-free media, serum free group (n=12), or rested in Stem Span for an additional hour, serum group (n=12), prior to stimulation with G-CSF, IL-3, or GM-CSF for 15 minutes and then fixed and permeabilized with formaldehyde and methanol, as previously described. Samples were stained with an anti-pSTAT5(Y-694) antibody and analyzed by flow cytometry (Kotecha, Cancer Cell. 2009). Cells stained with isotype-control antibody were used to establish the threshold for basal STAT5 phosphorylation. Because STAT5 was constitutively phosphorylated in serum, and to a lesser extent in serum-free conditions, inducible cytokine activation was defined as the percentage of pSTAT5 positive cells above untreated samples in both CMML and healthy controls. A retrospective chart review was performed to obtain clinical variables including age, sex, WHO classification, Dusseldorf scoring system, MD Anderson scoring system, WBC, peripheral monocyte count, blast percentage, anemia, platelet count, splenomegaly, and metaphase cytogenetics. Results: The percentage of pSTAT5 responsive cells after G-CSF stimulation with doses up to 10 ng/ml was similar in cases and normal BM controls (p=0.14), whereas, a statistically significant increase in the percentage of inducible pSTAT5 positive cells was observed with GM-CSF 0.1 ng/ml (p=0.04), GM-CSF 1 ng/ml (p=0.02), and GM-CSF 10 ng/ml (p=0.01) in CMML BM cells compared to healthy donor BM cells, as shown in Figure 1. Using one standard deviation below the mean as a cut point, only 5 patients failed to show GM-CSF hypersensitivity in the serum (n=3) and serum-free groups (n=2), respectively. IL-3 and GM-CSF play similar roles in hematopoietic growth through the activation of JAK2/STAT5 and share a common beta-chain required for signaling. Signaling mediated by GM-CSF and IL3 converge to activate RAS and other downstream intermediates that regulate DNA synthesis, cell-cycle progression and suppression of apoptosis. The concentration of IL3 required to induce STAT5 phosphorylation was 10-fold greater than GM-CSF in CMML cells, but the percentage of cells responsive to IL3 was greater in CMML cases compared to controls at 10 ng/ml (p=0.02). Analysis of the percentage of GM-CSF hypersensitive cells and clinical parameters revealed no associations with age at onset, WHO classification, Dusseldorf scoring system, MD Anderson scoring system, blast percentage, anemia, platelet count, splenomegaly, or karyotype. The percentage of pSTAT5 positive cells with GM-CSF 0.1 ng/ml positively correlated with the total leukocyte (p=0.03) and total monocyte (p=0.02) count indicating that the JAK2/STAT5 signaling response is indicative of disease burden. Conclusions: Based on the threshold for cytokine stimulation and percentage of cells that display pSTAT5 induction, CMML appears to preferentially utilize GM-CSF for survival and/or expansion. Although RAS mutations were not assessed, CMML cells were preferentially sensitive to GM-CSF in newly diagnosed cases independent of cytogenetic abnormalities suggesting that JMML and CMML share biological features of GM-CSF hypersensitivity. Disclosures: Padron: KaloBios Pharmaceuticals, Inc.: Research Funding. Bebbington:KaloBios Pharmaceuticals, Inc.: Employment, Equity Ownership. Baer:KaloBios Pharmaceuticals, Inc.: Employment, Equity Ownership.

Validation of Alternative Chronic Myelomonocytic Leukemia (CMML)-Specific Prognostic Scoring (CPSS) System in UT MD Anderson Cancer Center Cohort

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3278-3278
Author(s):  
Priyanka Priyanka ◽  
Janhavi Raut ◽  
Patricia S Fox ◽  
Francesco Stingo ◽  
Tariq Muzzafar
Keyword(s):  
Overall Survival ◽  
Scoring System ◽  
Risk Groups ◽  
Risk Classification ◽  
Chronic Myelomonocytic Leukemia ◽  
Cancer Center ◽  
Newly Diagnosed ◽  
Md Anderson ◽  
Myelomonocytic Leukemia

Abstract INTRODUCTION: Chronic myelomonocytic leukemia (CMML) is a myeloid neoplasm that belongs to the category of myelodysplastic syndrome / myeloproliferative neoplasms (MDS / MPN). The International Prognostic Scoring System for Myelodysplastic Syndromes (IPSS) classification and its revised version (IPSS-R) addressed patients with newly diagnosed, untreated MDS and excluded CMML. While numerous investigators have attempted to devise a prognostic risk scoring system for CMML, no system has been generally accepted for this entity. A CMML-specific prognostic scoring (CPSS) system proposed by Such, et al [Blood. 2013; 11;121(15):3005-15] defines 4 different prognostic risk categories for estimating both overall survival (OS) and risk for AML transformation; the alternative version replaces RBC transfusion dependency with hemoglobin levels. AIM: The aim of the study is to validate the alternative CPSS scoring system on the CMML patient cohort at UT MD Anderson Cancer Center (UTMDACC). METHODS: The databases of the Department of Hematopathology at UTMDACC were searched for patients diagnosed with CMML presenting from 2005 to 2012. Cases were classified by WHO 2008 criteria. Inclusion criteria were: confirmed diagnosis of CMML, age > 18 years, persistent absolute monocyte count >1 × 109/L, marrow blasts < 20%, peripheral blood blasts < 20%. The alternative CPSS score was calculated as a function of WHO subtype, FAB subtype, CMML-specific cytogenetic risk classification, and hemoglobin score. Cox proportional hazards regression was used to model overall survival and time to AML progression from date of diagnosis. For time to AML progression, patients who did not experience AML progression were censored at their date of death or last follow-up. Kaplan-Meier curves were used to estimate survival and the log-rank test was used to test for significant differences by CPSS score. All statistical analyses were performed using SAS 9.3 for Windows. RESULTS: Two hundred and three patients with newly diagnosed, untreated CMML were identified in the clinical databases. These included 132 males and 71 females; median age was 70 (range 55-80) years. 149 had CMML-1 and 54 had CMML-2. A total of 107 deaths and 38 progressions were observed. The median (range) follow-up time for all patients was 1.9 (2 days-10.8) years. The variables that compose the alternative CPSS (WHO subtype, FAB subtype, CMML-specific cytogenetic risk classification, hemoglobin) as well as a description of how the score is calculated are given in Tables 1-2. In univariate Cox models, the alternative CPSS score was a significant predictor of both OS and time to AML progression (Type III p-values <.0001 and 0.0037, respectively). Median survival times for OS were 4.07, 3.32, 2.14, and 1.23 years in the low, intermediate-1, intermediate-2, and high risk groups, respectively. Since less than half the patients progressed, the median time to AML progression could not be estimated for all groups but was 6.40 and 1.60 in the intermediate-2 and high risk groups, respectively. Overall, the alternative CPSS score was highly predictive of both OS and progression free survival (PFS) and clearly delineated the patient risk groups in this sample. CONCLUSIONS: These data reinforce the validity of the alternative CPSS and serve as an additional validation cohort. Table 1. Alternative CMML-specific prognostic scoring system (CPSS) score criteria Variable Each level assigned the following value(sum to get the composite CPSS score): 0 1 2 WHO subtype CMML-1 blasts (including promonocytes) <5% in the PB and <10% in the BM CMML-2 blasts (including promonocytes) from 5% to 19% in the PB and from 10% to 19% in the BM, or when Auer rods are present irrespective of blast count — FAB subtype CMML-MD (WBC <13 × 109/L) CMML-MP (WBC ≥13 × 109/L) — CMML-specific cytogenetic risk classification* Low Intermediate High Hemoglobin ≥10 g/dL <10/dL WBC: white blood cell * CMML-specific cytogenetic risk classification; low: normal and isolated –Y; intermediate: other abnormalities; and high: trisomy 8, complex karyotype (≥3 abnormalities), chromosome 7 abnormalities Table 2. Alternative CPSS: scores used for predicting likelihood of survival and leukemic evolution in individual patient with CMML Risk group Overall CPSS score Low 0 Intermediate-1 1 Intermediate-2 2-3 High 4-5 Figure 1 Overall Survival by alternative CPSS Score Figure 1. Overall Survival by alternative CPSS Score Figure 2 Time to AML Progression by alternative CPSS Score Figure 2. Time to AML Progression by alternative CPSS Score Disclosures No relevant conflicts of interest to declare.

Analyses of 81 Chronic Myelomonocytic Leukemia (CMML) for EZH2, TET2, ASXL1, CBL, KRAS, NRAS, RUNX1, IDH1, IDH2, and NPM1 Revealed Mutations In 86.4% of All Patients with TET2 and EZH2 Being of High Prognostic Relevance

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 296-296 ◽  
Author(s):  
Vera Grossmann ◽  
Alexander Kohlmann ◽  
Christiane Eder ◽  
Nicholas C.P. Cross ◽  
Claudia Haferlach ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Chronic Myelomonocytic Leukemia ◽  
Molecular Heterogeneity ◽  
Cell Renewal ◽  
Wild Type ◽  
Employment Equity ◽  
Ras Pathway ◽  
Equity Ownership ◽  
Exon 4 ◽  
Myelomonocytic Leukemia

Abstract Abstract 296 Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic malignancy that is characterized by features of both a myeloproliferative neoplasm and a myelodysplastic syndrome. Recently, we investigated 81 CMML cases (45 CMML-1, 36 CMML-2) diagnosed between 10/2005 - 9/2008, which had been characterized by chromosome banding analysis and mutation analysis in 6 candidate genes: Mutations were detected in TET2 (44.4%), CBL (22.2%), NRAS (22.2%), KRAS (12.3%), JAK2 (9.8%), RUNX1 (8.7%) (Kohlmann et al., J Clin Oncol. 2010 Jul 19). We now applied amplicon-based deep-sequencing using the small volume Titanium chemistry assay (454 Life Sciences, Branford, CT) to investigate additional 4 candidate genes: IDH1 (exon 4), IDH2 (exon 4) and NPM1 (exon 12) (at known mutational hotspot regions) and the complete coding region of EZH2. EZH2 encodes a catalytic subunit of the polycomb repressive complex 2, a highly conserved histone H3 lysine 27 methyltransferase that influences stem cell renewal. Mutations in EZH2 were recently described to play a role in MPN/MDS. The sequencing library preparation for IDH1, IDH2, NPM1, and EZH2, in total 22 amplicons, was performed using 48.48 Access Array technology (Fluidigm, South San Francisco, CA) to cope with the number of amplicons. In median, 498 reads per amplicon were obtained, thus yielding sufficient coverage for detection of mutations with high sensitivity. After excluding polymorphisms and silent mutations aberrations were detected in IDH1 (1/81; 1.2%), IDH2 (3/81; 3.7%), NPM1 (1/81; 1.2%), and EZH2 (10/81; 12.3%). Another gene recently described in hematological diseases is ASXL1 (additional sex combs like 1) on chromosome 20q11.1. Therefore, the hotspot region of ASXL1 exon 12 was additionally investigated by Sanger sequencing in those 20 cases, in which no mutation had been observed thus far. Nine of these 20 cases (45%) harbored a mutation in ASXL1, thus only 11 cases (13.6%) remained in this cohort in which no mutation was detected. Summarizing this data, 86.4% of these CMMLs harbored at least one molecular aberration with a median of two genes mutated (range 1–4). In more detail, we observed 11 novel distinct EZH2 mutations in ten patients: 7 missense, 3 frameshifts (2 deletions, 1 insertion), and one splice site mutation. EZH2 mutations were found to be heterogeneous and were spread over several exons, predominantly located in the four conserved regions (6/11 in the conserved SET domain; e.g. H680R, N659S). No case revealed a Tyr641 of EZH2 mutation as described for follicular and diffuse large B-cell lymphomas. In median, the burden of EZH2 mutations was 42.5% of sequencing reads per patient (range 1.4–98%). Similarly, a high mutation burden was detected in RUNX1 (median 46.7%), TET2 (median 44.6%), and CBL (median 42.5%) whereas the burden was low in RAS pathway alterations, i.e. NRAS (median 11.1%), KRAS (median 27%), or JAK2 V617F mutations (median 6.9%). With respect to associations of distinct mutations no specific pattern was observed, i.e. EZH2 mutations were concomitantly detected with TET2 (4/10), RUNX1 (3/10), CBL (3/10), JAK2 (3/10), NRAS (2/10), KRAS (1/10), and IDH2 (1/10), respectively. Further, EZH2 mutations were associated neither with morphologic CMML subtype or dysplastic or myeloproliferative characteristics nor with age, white blood cell count, thrombocytes count, or hemoglobin. However, with respect to clinical data a very poor outcome was observed for patients that carried EZH2 mutations compared to EZH2 wild-type cases (median OS 4.3 vs. 130.4 months; p<0.001). In contrast, a significantly better outcome was seen for patients who carried TET2 mutations compared to TET2 wild-type cases (median OS 130.4 vs. 53.6 months, p=0.013). Subsequently, we performed a survival analysis taking both EZH2 and TET2 mutations into account. Here, the cohort was significantly separated into three distinct prognostic groups, i.e. EZH2-mutated with a poor median OS of 4.3 months, EZH2/TET2 wild-type with a median OS of 90 months and TET2-mutated cases with a median OS of 130.4 months (p<0.001). In conclusion, our study revealed molecular mutations in 86.4% of 81 CMML patients providing new insights into the molecular heterogeneity of this disease. Besides alterations in TET2, CBL, ASXL1, and the RAS pathway, EZH2 is targeted by various types of frameshift and point mutations and is a novel biomarker with unfavorable prognosis and clinical utility. Disclosures: Grossmann: MLL Munich Leukemia Laboratory: Employment. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Eder:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership, Research Funding. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

SRSF2 is Mutated in 47.2% (77/163) of Chronic Myelomonocytic Leukemia (CMML) and Prognostically Favorable in Cases with Concomitant RUNX1 mutations

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 274-274 ◽  
Author(s):  
Susanne Schnittger ◽  
Manja Meggendorfer ◽  
Alexander Kohlmann ◽  
Vera Grossmann ◽  
Kenichi Yoshida ◽  
...  
Keyword(s):  
Hot Spot ◽  
Myeloproliferative Neoplasm ◽  
Gene Mutations ◽  
Chronic Myelomonocytic Leukemia ◽  
Structural Basis ◽  
Employment Equity ◽  
Cell Counts ◽  
Number Of Genes ◽  
Equity Ownership ◽  
Myelomonocytic Leukemia

Abstract Abstract 274 Introduction: Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic malignancy characterized by features of both a myeloproliferative neoplasm and a myelodysplastic syndrome. We previously investigated 81 CMML cases and detected a number of genes frequently mutated (TET2 44.4%, CBL 22.2%, NRAS 22.2%, KRAS 12.3%, JAK2 9.8%, RUNX1 8.7%, EZH2 12.3% (Kohlmann et al., JCO, 2010; Grossmann et al., Leukemia, 2011). Recently, we detected a new candidate gene, SRSF2 (serine/arginine-rich splicing factor 2, also known as SC35) that is a component of the RNA splicing machinery and found it to be frequently mutated in MDS. Aim: As CMML has been increasingly characterized by a growing number of genes during the last years we here analyzed both the frequency of SRSF2 mutations in this entity and the relevance in the context of other previously described gene mutations, as well as to look for a potential prognostic implication. Patients and Methods: In total, 163 cases with CMML (CMML-1 n=105, CMML-2 n=58) were included. The cohort comprised 115 males and 48 females with a median age of 72.8 yrs (range: 21.9 – 88.8 yrs) including all 81 pts that have been published previously. 112 cases (69%) had a normal karyotype and 51 (31%) showed aberrant karyotypes. The mutational hot spot region of SRSF2 around Proline codon 95 (P95) was analyzed by Sanger sequencing in all cases. Data on further mutations were available in respective subcohorts: ASXL1 (n=128), CBL (n=162), EZH2 (n=134), JAK2V617F (n=162), KRAS (n=140), NRAS (n=79), RUNX1 (n=156), TET2 (n=143), TP53 (n=80). Results:SRSF2 mutations of P95 were detected in 77/163 (47.2%) of all cases (49/105, 46.7% in CMML-1, and 28/58, 48.3% in CMML-2). In detail, 74 cases had a missense mutation leading to a change of P95 to P95H (n=33), P95L (n=24), P95R (n=16) or P95A (n=1). In further 3 cases a newly described 24 bp (8 amino acids) deletion starting at P95 was observed. All cases had a mutation load of approximately 50%. The mutations were correlated with higher age (73.3 yrs vs 68.7 yrs in the SRSF2wt cases, p=0.010) and higher hemoglobin levels (11.4 vs 10.5 g/dl in the SRSF2wt cases, p=0.019) whereas white blood cell counts were not different. Further, SRSF2 mutations were mutually exclusive of EZH2 mutations (0/12, 0% vs. 66/122, 54.1% in the EZH2wt, p<0.001) whereas a high coincidence occurred with RUNX1 mutations (22/35, 62.9% vs 52/121, 43% in the RUNX1wt, p=0.054) and TET2 mutations (50/82, 61% vs 18/61, 29.5% in the TET2wt, p<0.001). With respect to associations with all other gene mutations investigated and karyotype no specific pattern was observed. In the total cohort no impact of SRSF2 on survival was observed. Because of the high coincidence of SRSF2mut with RUNX1mut and TET2mut, we performed an analysis in these specific subcohorts. No impact of SRSF2mut in the TET2mut subcohort was found. Whereas in the RUNX1mut subcohort SRSF2mut had a favorable impact on overall survival compared to SRSF2wt (median OS: 108.0 months vs 41.8 months, p=0.05). Conclusions:SRSF2 has recently been described as a new marker in CMML and demonstrated to be useful to delineate further the genetic defects of this disease. This very frequent new mutation is characterized by higher age, higher hemoglobin levels and a high coincidence with TET2 and RUNX1 mutations. It is mutually exclusive of EZH2 mutations. In the subset of RUNX1 mutated CMML SRSF2 mutations demonstrated a favorable impact on outcome. Furthermore, for the first time a 24 bp deletion was observed in three cases that may provide further insight into the structural basis for the abnormal function of SRSF2. Disclosures: Schnittger: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Grossmann:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

Refined MD Anderson Prognostic Scoring System (MDAPS-R) for Chronic Myelomonocytic Leukemia (CMML)

2013 ◽  
Vol 13 ◽  
pp. S373 ◽  
Author(s):  
Koichi Takahashi ◽  
Naveen Pemmaraju ◽  
Hagop Kantarjian ◽  
Miloslav Beran ◽  
Alfonso Quintas-Cardama ◽  
...  
Keyword(s):  
Scoring System ◽  
Chronic Myelomonocytic Leukemia ◽  
Md Anderson ◽  
Myelomonocytic Leukemia

scholarly journals Treatment Patterns and Outcomes in Elderly Patients with Newly Diagnosed Multiple Myeloma: Results from the Connect® MM Registry

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3129-3129
Author(s):  
Hans C. Lee ◽  
Sikander Ailawadhi ◽  
Cristina Gasparetto ◽  
Sundar Jagannath ◽  
Robert M. Rifkin ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Causes Of Death ◽  
Age Groups ◽  
Treatment Patterns ◽  
Age Group ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Background: Multiple myeloma (MM) is common among the elderly, with 35% of patients (pts) diagnosed being aged ≥75 years (y). With increasing overall life expectancy, the incidence and prevalence of newly diagnosed and previously treated MM patients ≥80 y is expected to increase over time. Because elderly pts are often excluded from clinical trials, data focused on their treatment patterns and clinical outcomes are lacking. The Connect® MM Registry (NCT01081028) is a large, US, multicenter, prospective observational cohort study of pts with newly diagnosed MM (NDMM) designed to examine real-world diagnostic patterns, treatment patterns, clinical outcomes, and health-related quality of life patient-reported outcomes. This analysis reviews treatment patterns and outcomes in elderly pts from the Connect MM Registry. Methods: Pts enrolled in the Connect MM registry at 250 community, academic, and government sites were included in this analysis. Eligible pts were adults aged ≥18 y with symptomatic MM diagnosed ≤2 months before enrollment, as defined by International Myeloma Working Group criteria; no exclusion criteria were applied. For this analysis, pts were categorized into 4 age groups: <65, 65 to 74, 75 to 84, and ≥85 y. Pts were followed from time of enrollment to the earliest of disease progression (or death), loss to follow-up, or data cutoff date of February 7, 2019. Descriptive statistics were used for baseline characteristics and treatment regimens. Survival outcomes were analyzed using Cox regression. Time to progression (TTP) analysis excluded causes of death not related to MM. Results: Of 3011 pts enrolled (median age 67 y), 132 (4%) were aged ≥85 y, and 615 (20%) were aged 75-84 y at baseline. More pts aged ≥85 y had poor prognostic factors such as ISS stage III disease and reduced hemoglobin (<10 g/dL or >2 g/dL <LLN) compared with other age groups, although no notable differences between creatinine and calcium levels were observed across age groups (Table). A lower proportion of elderly pts (75-84 and ≥85 y) received triplet regimens as frontline therapy. More elderly pts received a single novel agent, whereas use of 2 novel agents was more common in younger pts (Table). The most common frontline regimens among elderly pts were bortezomib (V) + dexamethasone (D), followed by lenalidomide (R) + D, whereas those among younger pts included RVD, followed by VD and CyBorD (Table). No pt aged ≥85 y, and 4% of pts aged 75-84 y received high-dose chemotherapy and autologous stem cell transplant (vs 61% in the <65 y and 37% in the 65-74 y age group). The most common maintenance therapy was RD in pts ≥85 y (although the use was low) and R alone in other age groups (Table). In the ≥85 y group, 27%, 10%, and 4% of pts entered 2L, 3L, and 4L treatments respectively, vs 43%, 23%, and 13% in the <65 y group. Progression-free survival was significantly shorter in the ≥85 y age group vs the 75-84 y age group (P=0.003), 65-74 y age group (P<0.001), and <65 y age group (P<0.001; Fig.1). TTP was significantly shorter in the ≥85 y group vs the <65 y group (P=0.020); however, TTP was similar among the 65-74 y, 75-84 y, and ≥85 y cohorts (Fig. 2). Overall survival was significantly shorter in the ≥85 y group vs the 75-84 y, 65-74 y, and <65 y groups (all P<0.001; Fig. 3). The mortality rate was lowest (46%) during first-line treatment (1L) in pts aged ≥85 y (mainly attributed to MM progression) and increased in 2L and 3L (47% and 54%, respectively); a similar trend was observed in the younger age groups. The main cause of death was MM progression (29% in the ≥85 y vs 16% in the <65 y group). Other notable causes of death in the ≥85 y group included cardiac failure (5% vs 2% in <65 y group) and pneumonia (5% vs 1% in <65 y group). Conclusions: In this analysis, elderly pts received similar types of frontline and maintenance regimens as younger pts, although proportions varied with decreased use of triplet regimens with age. Considering similarities in TTP across the 65-74 y, 75-84 y, and ≥85 y cohorts, these real-world data support active treatment and aggressive supportive care of elderly symptomatic pts, including with novel agents. Additionally, further clinical studies specific to elderly patients with MM should be explored. Disclosures Lee: Amgen: Consultancy, Research Funding; GlaxoSmithKline plc: Research Funding; Sanofi: Consultancy; Daiichi Sankyo: Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Ailawadhi:Janssen: Consultancy, Research Funding; Takeda: Consultancy; Pharmacyclics: Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy; Cellectar: Research Funding. Gasparetto:Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Jagannath:AbbVie: Consultancy; Merck & Co.: Consultancy; Bristol-Myers Squibb: Consultancy; Karyopharm Therapeutics: Consultancy; Celgene Corporation: Consultancy; Janssen Pharmaceuticals: Consultancy. Rifkin:Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy. Narang:Celgene: Speakers Bureau. Terebelo:Celgene: Honoraria; Jannsen: Speakers Bureau; Newland Medical Asociates: Employment. Toomey:Celgene: Consultancy. Hardin:Celgene: Membership on an entity's Board of Directors or advisory committees. Wagner:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; American Cancer Society: Other: Section editor, Cancer journal. Omel:Celgene, Takeda, Janssen: Other: Patient Advisory Committees. Srinivasan:Celgene: Employment, Equity Ownership. Liu:TechData: Consultancy. Dhalla:Celgene: Employment. Agarwal:Celgene Corporation: Employment, Equity Ownership. Abonour:BMS: Consultancy; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.

scholarly journals Astarabine, a Novel Leukemia-Targeted Cytarabine Composition Allows, for the First Time, the Delivery of High Cytarabine Doses for Older or Unfit Patients with Acute Leukemia. Results of an Ongoing Phase I/IIa Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1650-1650
Author(s):  
Tsila Zuckerman ◽  
Stela Gengrinovitch ◽  
Ruth Ben-Yakar ◽  
Ron Hoffman ◽  
Israel Henig ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
De Novo ◽  
Intensive Therapy ◽  
High Dose ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Unfit Patients ◽  
Equity Ownership ◽  
High Doses

Abstract Introduction: Therapy of acute myeloid leukemia (AML) has not changed significantly during several decades. High-dose cytarabine, although used as the first-line treatment for AML since 1970s and as a second-line treatment for acute lymphoblastic leukemia (ALL), is associated with severe side effects, such as cerebellar toxicity and bone marrow suppression. Hence, while the incidence of AML increases with age, doses of cytarabine are significantly attenuated or the drug is entirely excluded from the regimen used in older adults due to its potential toxicities, particularly in individuals with hepatic or renal dysfunction. Astarabine is a new composition of cytarabine covalently bound to asparagine. It is designed to target cytarabine to leukemic blasts, thus avoiding extramedullary toxicity. Leukemic cells, which are dependent on an external source of amino acids in general and asparagine in particular, due to their high metabolic rate, have a relatively increased uptake of Astarabine. Inside the blasts, Astarabine is cleaved to cytarabine, enabling targeted killing and relative sparing of normal hematopoiesis. As such, Astarabine may serve as an ideal therapy for leukemia, particularly for delivering high doses of cytarabine to medically unfit or older adults who otherwise can be given supportive therapy only. The aim of this study was to evaluate the safety and optimal dose of Astarabine in refractory/relapsed or medically unfit patients with acute leukemia. Methods: This Phase I/IIa prospective open label study enrolled patients aged ≥18 years with relapsed/refractory or newly-diagnosed acute leukemia unfit for intensive therapy, as judged by the treating physician. The study was approved by the Rambam IRB (approval #0384-11). Patients were enrolled into 6 Astarabine escalating-dose cohorts, each composed of 3-6 patients. Treatment was administered as a 1-hour single daily infusion for 6 days. For cohorts 1-4, Astarabine doses for each infusion were 0.5g/m2, 1.5g/m2, 3g/m2 and 4.5g/m2. The doses were reduced by 50% for patients >50 years. Since dose limiting toxicity (DLT) was not reached in cohorts 1-4, the study was extended to include cohorts 5 and 6 with daily Astarabine doses of 4.5g/m2 and 6g/m2, respectively, with no dose reduction for patients >50 years old. Results: The outcome of 15 patients is reported herein. Six patients with a median age of 64 years (range 27-81) had refractory/relapsed AML, 9 patients with a median age of 80 years (range 70-90) were newly diagnosed (secondary AML - 6, de-novo AML - 2, de-novo ALL - 1) and unfit for intensive therapy. Astarabine treatment was well-tolerated. Two patients died (one from pneumonia and one from sudden death 2 weeks from end of treatment) before completing 30 days post-treatment and hence were excluded from the outcome analysis. Response to the treatment was observed in the bone marrow of 6 of the 7 newly-diagnosed patients for whom bone marrow analysis was available, 3 of whom had a continuous complete remission (CR) for 4 (ongoing), 8, and 10 months post-treatment, and 3 had a continuous partial remission (PR) for 3,7, and 7 (ongoing) months. The median overall survival (OS) of the patients with CR/PR is 7 months to date (table 1). No significant response was observed in the relapsed/refractory patients, with a median OS of 2.5 months. Twelve patients died from disease progression. Conclusions: Astarabine, a new composition of leukemia-targeted cytarabine, is safe and very well tolerated, even in patients over 80 years of age, resulting in response in 6 of 7 newly diagnosed patients with acute leukemia. To the best of our knowledge, this is the first report permitting high-dose of cytarabine, considered a cornerstone of leukemia therapy, to be given to a population of patients that heretofore did not have this option. Further dose escalation studies are currently ongoing at a cytarabine-equivalent dose of 4.5 and 6 g/m2/day. A phase II study is planned to confirm these encouraging results and define the use of Astarabine for patients otherwise unable to receive high doses of cytarabine. Disclosures Zuckerman: BioSight Ltd: Consultancy, Research Funding. Gengrinovitch:BioSight Ltd: Employment, Equity Ownership, Patents & Royalties: Inventor all of the patents. Ben-Yakar:BioSight Ltd: Consultancy, Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Inventor of all patents.

scholarly journals GM-CSF–dependent pSTAT5 sensitivity is a feature with therapeutic potential in chronic myelomonocytic leukemia

Blood ◽  
2013 ◽  
Vol 121 (25) ◽  
pp. 5068-5077 ◽  
Author(s):  
Eric Padron ◽  
Jeffrey S. Painter ◽  
Sateesh Kunigal ◽  
Adam W. Mailloux ◽  
Kathy McGraw ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Neutralizing Antibody ◽  
Chronic Myelomonocytic Leukemia ◽  
Gm Csf ◽  
Key Points ◽  
Myelomonocytic Leukemia ◽  
Jak2 Inhibitors

Key Points GM-CSF–dependent STAT5 hypersensitivity is detected in 90% of CMML samples and is enhanced by signaling mutations. Treatment with a GM-CSF–neutralizing antibody and JAK2 inhibitors reveals therapeutic potential.

scholarly journals Phase 1 study of lenzilumab, a recombinant anti–human GM-CSF antibody, for chronic myelomonocytic leukemia

Blood ◽  
2020 ◽  
Vol 136 (7) ◽  
pp. 909-913 ◽  
Author(s):  
Mrinal M. Patnaik ◽  
David A. Sallman ◽  
Abhishek A. Mangaonkar ◽  
Rachel Heuer ◽  
Jeffery Hirvela ◽  
...  
Keyword(s):  
Preliminary Data ◽  
Phase 1 ◽  
Chronic Myelomonocytic Leukemia ◽  
Colony Stimulating Factor ◽  
Phase 1 Study ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Myelomonocytic Leukemia ◽  
Stimulating Factor

In this phase 1 trial, inhibition of granulocyte-macrophage colony-stimulating factor (GM-CSF) was associated with clinically meaningful responses in 5 of 15 patients with relapsed or refractory chronic myelomonocytic leukemia (CMML). Preliminary data suggest that this approach may be tractable in CMML bearing activating NRAS mutations.

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