Suboptimal response rates to hypomethylating agent therapy in chronic myelomonocytic leukemia; a single institutional study of 121 patients

Hypomethylating agents (HMA) are currently the only FDA approved therapy for patients with chronic myelomonocytic leukemia (CMML). In the current retrospective study, we assessed response rates as adjudicated by the IWG (International Working Group) MDS (myelodysplastic syndrome) and MDS/MPN myeloproliferative neoplasm overlap syndrome response criteria, in 121 CMML patients treated with Azacitidine (AZA, n = 56) and Decitabine (DAC, n = 65). The overall response rates were 41% by the IWG MDS (AZA- 45%, DAC-39%), and 56% by the IWG MDS/MPN (AZA-56%, DAC-58%) response criteria, with CR (complete remission) rates of <20% for both agents, by both criteria. There were no significant differences in response rates between proliferative and dysplastic CMML. Moreover, 29% of CMML patients in a CR with HMA progressed to AML (blast transformation), underscoring the limited impact of these agents on disease biology. Progression after HMA response was associated with a median overall-survival (OS) of 8 months, while median OS in patients with primary HMA failure was 4 months. Lower serum LDH levels (<250 Units/L) were associated with HMA responses by both criteria; while ASXL1 and TET2 mutational status had no impact. HMA treated patients had a longer median OS (31 vs 18 months; P = .01), in comparison to those treated with conventional care regimens (excluding observation only patients), without any differences between AZA vs DAC (P = .37). In conclusion, this study highlights the inadequacies of HMA therapy in CMML, retrospectively validates the IWG MDS/MPN response criteria and underscores the need for newer, rationally derived therapies.     

20+ Years and alive with primary myelofibrosis: Phenotypic signature of very long-lived patients

In the last decade, several prognostic models for primary myelofibrosis (PMF) have been introduced and shown to be effective in predicting overall survival. The main objective for this study was to identify clinical and genetic markers of very long (20+ years) survival in PMF. A total of 1282 patients with PMF were considered (median age 65 years, range 19-92; 63% males); 26 (2%) patients (median age 51 years, range 28-71; 38% males) survived their disease for at least 20 years (long-lived patients) and 626 (49%) patients (median age 68 years, range 27-92; 66% males) died within 5 years of their diagnosis (short-lived patients). Multivariable logistic regression analysis identified 7 variables that were associated with survival beyond 20 years: age ≤ 70 years (P = .002); female sex (P = .03); hemoglobin level ≥ 10 g/dL for women and ≥ 11 g/dL for men (P = .03), leukocyte count ≤25 × 10⁹/L (P = .009), platelet count ≥100 × 10⁹/L (P = .002), circulating blasts <2% (P = .03) and absence of constitutional symptoms (P = .04). Five-year mortality was independently predicted by high-molecular risk mutations (P < .001); unfavorable or very high risk karyotype (P < .001); absence of type 1/like CALR mutation (P < .001); age > 70 years (P < .001); constitutional symptoms (P < .001); hemoglobin level < 10 g/dL for women and < 11 g/dL for men (P < .001); leukocyte count >25 × 10⁹/L (P = .004); and circulating blasts ≥2% (P = .001). This study suggests that genetic risk factors in PMF are associated with early mortality while survival beyond 20 years could be predicted by easily accessible clinical variables, including age, sex, blood counts, and symptoms.     

3023 Mayo Clinic Patients With Myeloproliferative Neoplasms: Risk-Stratified Comparison of Survival and Outcomes Data Among Disease Subgroups

Objective

To document the Mayo Clinic decades-long experience with myeloproliferative neoplasms (MPNs) and provide mature risk-stratified survival data and disease complication estimates.

Association Between Renal Cell Carcinoma and Myelodysplastic Syndromes: Epigenetic Underpinning?

Background

Renal cell carcinoma (RCC) and certain myeloid malignancies are both characterized by widespread aberrant DNA hypermethylation. After clinical observations of patients with a personal history of both malignancies, we sought to explore a potential association, and to describe the clinical characteristics of these patients.

Acute esophageal necrosis and liver pathology, a rare combination

Acute esophageal necrosis (AEN) or “black esophagus“ is a clinical condition found at endoscopy. It is a rare entity the exact etiology of which remains unknown. We describe a case of ‘black esophagus‘, first of its kind, in the setting of liver cirrhosis and hepatic encephalopathy.     

Therapy related‐chronic myelomonocytic leukemia (CMML): Molecular,cytogenetic, and clinical distinctions from de novo CMML

Therapy related myeloid neoplasms (t‐MN) including therapy related myelodysplastic syndromes (t‐MDS) and acute myeloid leukemia (t‐AML) are associated with aggressive disease biologies and poor outcomes. In this large (n = 497) and informative (inclusive of molecular and cytogenetic information) chronic myelomonocytic leukemia (CMML) patient cohort, we demonstrate key biological insights and an independent prognostic impact for t‐CMML. T‐CMML was diagnosed in 9% of patients and occurred approximately 7 years after exposure to prior chemotherapy and/or radiation therapy. In comparison to de novo CMML, t‐CMML patients had higher LDH levels, higher frequency of karyotypic abnormalities and had higher risk cytogenetic stratification. There were no differences in the distribution of gene mutations and unlike t‐MDS/AML, balanced chromosomal translocations, abnormalities of chromosome 11q23 (1%) and Tp53 mutations (<2%) were uncommon. Molecularly integrated CMML prognostic models were not effective in risk stratifying t‐CMML patients and responses to hypomethylating agents were dismal with no complete responses. Median overall (OS) and leukemia free survival (LFS) was shorter for t‐CMML in comparison to d‐CMML (Median OS 10.9 vs 26 months and median LFS 50 vs 127 months) and t‐CMML independently and adversely impacted OS (P = .0001 HR 2.1 95% CI 1.4‐3.0). This prognostic impact was retained in the context of the Mayo Molecular Model (P = .001, HR 2.4, 95% CI 1.5‐3.7) and the GFM prognostic model (P < .0001, HR 2.15, 95% CI 1.5‐3.7). In summary, we highlight the unique genetics and independent prognostic impact of t‐CMML, warranting its inclusion as a separate entity in the classification schema for both CMML and t‐MN.     

Decreased survival and increased rate of fibrotic progression in essential thrombocythemia chronicled after the FDA approval date of anagrelide

First-line cytoreductive drug of choice in high risk essential thrombocythemia (ET) is currently hydroxyurea, a practice based on the results of a randomized study; second-line drugs of choice include pegylated interferon-α, busulfan and anagrelide. Anagrelide clinical trials were pioneered by the late Murray N. Silverstein (1928-1998) of the Mayo Clinic whose studies led to FDA approval in March 1997. The current study represents a retrospective examination of the potential impact of anagrelide therapy on survival and disease complications in ET. 1076 patients with ET were considered (median age 58 years; females 63%); risk distribution, according to the international prognostic score for ET (IPSET), was 28% high, 42% intermediate, and 30% low. Overall (OS), myelofibrosis-free (MFFS) and thrombosis-free survival data were compared for ET patients diagnosed before and after the 1997 FDA approval date for anagrelide; a significant difference was apparent in OS (P = .006; HR 1.4, 95% CI 1.1-1.7) and MFFS (P < .001; HR 4.2, 95% CI 2.7-6.5), in favor of patients diagnosed prior to 1997; the difference was sustained during multivariable analysis that included IPSET. Similarly stratified survival data in polycythemia vera (n = 665) and primary myelofibrosis (n = 1282) showed no similar impact on survival (P = .3 and .17, respectively). The current study represents a retrospective analysis and suggests significantly decreased OS and MFFS in ET patients diagnosed after the FDA approval date of anagrelide. Whether or not anagrelide therapy was to blame for the worsening of OS and MFFS over time cannot be assumed and requires validation in a prospective study.