Zblewski, Darci

AbstractHypomethylating 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.

e18560 Background: Myelodysplastic syndromes (MDS) are rare hematological neoplasms typically seen in the elderly. Young MDS (yMDS) patients ( < 50 years old) have been reported to comprise between 3-6% in the Surveillance, Epidemiology and End Results (Ma X et al, Cancer 2007; Rollison R et al, Blood 2008) with a better overall survival (OS). Methods: 1012 MDS patients from 1993 to 2015 were found after IRB approval was obtained. All cases had their bone marrow slides reviewed at our institution. yMDS Patients were included as cohort 1, while the rest as cohort 2. Survival estimates were calculated using Kaplan-Meier curves and univariate and multivariate analyses was based on log-rank testing using JMP software version 10. Results: We found 68 (7%) yMDS patients with a median age of 42 years (range, 18-49). Female gender was more common (43% vs 31%, p = 0.05) while platelets were lower in yMDS (61 vs 102, p < 0.0001). Therapy related MDS (t-MDS) was more frequent (33% vs 17%, p = 0.005), as was transformation to acute myeloid leukemia (AML) in yMDS (28 % vs 11%, p = 0.0004). Allogenic hematopoietic cell transplantation (HCT) was more frequent in yMDS (42% vs 4%, p < 0.0001). Survival outcome: Median OS was longer for cohort 1 vs cohort 2 but did not reach statistical significance (43 vs 21 months, p = 0.1). Median progression free survival (PFS) was shorter for cohort 1 vs cohort 2 but also did not reach statistical significance (8 vs 12 months, p = 0.3). Median OS for cohort 1 based on R-IPSS was 44, 105, 40, 18, and 12 months for very low, low, intermediate, high and very high risk groups, respectively (p = 0.09). Median OS was shorter in t-MDS vs de novo MDS in yMDS (13 vs 47 months, p = 0.04). yMDS patients who transformed to AML had worse median OS (18 vs 93 months, p = 0.001). On multivariate analysis neither t-MDS nor R-IPSS had a statistically significant impact on OS. Conclusions: MDS is rarely diagnosed under the age of 50 with IPSS-R being less powerful in detecting mOS. Among yMDS patients, there was a higher proportion of t-MDS compared to older patients with subsequent higher rates of AML transformation and higher rates of allogeneic HCT. In our study, we did not find an improved OS for yMDS patients compared to older patients.

e18559 Background: Myelodysplastic syndromes (MDS) are a group of myeloid neoplasms defined by ineffective hematopoiesis, dysplastic morphologic features, and variable risks of progression to acute myeloid leukemia (AML). Refractory anemia with ring sideroblasts (RARS) is a subtype of MDS defined by < 5% basts and > 15% ring sideroblasts (per 2008 WHO). Because RARS is a lower risk disease which does not frequently require HMA therapy, very little is known about the effects of HMA on RARS. Methods: A total of 1325 MDS patients’ data from 1993-2016 at Mayo Clinic were reviewed after appropriate IRB approval was obtained. All cases had their bone marrow slides reviewed at our center. Patients were considered for our study if they received HMA for their RARS. Response was identified based on MDS IWG 2006 criteria. Prognostic factors were analyzed by univariate and multivariate analyses. Survival estimates were calculated using Kaplan-Meier curves. Results: 168 of the initial 1325 patient were RARS (14%); only 14 (8%) were treated with HMA. Median age was 72 years (range, 51-85); half were males, with median overall survival of 91.3 months. The median number of ring sideroblasts (RS) at diagnosis was 40% (range 10-85%). Of the 14 patients, 11 (79%) received azacitidine (AZA), 2 (14%) decitabine (DAC) and one received both (7%). The median number of cycles for AZA was 6.5 (range, 2-28) vs 6 cycles for DAC (range, 1-24). Of the 14 patients receiving HMA, only 3 responded (21%) achieving hematologic improvement. All 3 responders received AZA. 6 of the 14 RARS patients (43%) had their bone marrow biopsy repeated after HMA therapy, 3 of whom were among the responders to AZA therapy and 3 were non-responders. In 5 patients, ring sideroblasts decreased after HMA therapy by a median of 15% (range 0-80); they remained the same in 1 patient; one patient who had developed AML had a decrease in RS from 85% to 5%. Conclusions: RARS is a low-risk subtype of MDS that is infrequently treated with HMA (8% in our study). Response rate to HMA (21%) was inferior to known rates in MDS. HMA therapy seems to decrease the number of ring sideroblasts irrespective of response. RARS patients should be treated on clinical trials if available.

e18556 Background: RARS is a subtype of myelodysplastic syndromes (MDS) defined by < 5% blasts and ≥15% ring sideroblasts (WHO 2008). Hereditary hemochromatosis is a disorder characterized by dysregulations in iron absorption, largely associated with C282Y and H63D mutations of the HFE gene. Iron levels are elevated in both disorders and pathophysiologic correlations were suggested. HFE gene mutations were previously found higher in MDS compared to controls (50% vs 36%) ( Nearman et al, Am J Hematol 2007). Methods: A total of 168 RARS patients’ data from 1994 to 2015 at Mayo Clinic were reviewed after appropriate IRB approval was obtained. All cases had their bone marrow slides reviewed at our center. We searched patients’ records retrospectively to Identify those tested for HFE gene (C282Y, H62D, S65C) mutations, done inside or outside our institution. Survival estimates were calculated using Kaplan-Meier curves. Results: Out of the 168 RARS patients, only 17 (10%) were tested for HFE gene mutations. Out of the 17 tested, 11 (65%) were found to have mutations; 2 of which (18%) had homozygous H63D mutation, 1 patient (9%) had double heterozygous H63D and C282Y mutations, 5 (45%) had only one H36D heterozygous mutation vs 3 patients (27%) with only one C282Y heterozygous mutation. Only one patient was tested for the additional S65C mutation and it was not detected. H63D mutation was present in a total of 8 patients (73%) vs C282Y mutation which was present in 4 patients (36%). Bone marrow iron stores were increased in all 17 tested patients, except one who had decreased stores, this patient had one heterozygous C282Y mutation. Median overall survival (mOS) was 117 months in the HFE mutated patients vs 75 months in the non-mutated (p = 0.6). Conclusions: Our study found the HFE gene, when tested, to be mutated in higher frequencies among patients with RARS compared to that reported in the general population (65% vs 36%), with H63D mutation in almost three quarters of all mutated patients. Although it did not reach statistical significance, the longer survival observed among HFE mutated patients compared to the wild-type raises the question whether testing for HFE gene mutations among patients with MDS-RARS should be further explored.

7058 Background: The 2016 WHO classification includes myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN-U), as an MDS/MPN overlap syndrome not meeting criteria for well-defined entities such as CMML. No standard prognostication or treatment guidelines exist for such patients. Methods: We retrospectively identified MDS/MPN-U cases from 1990-2016 through our myeloid malignancies database. All bone marrow reports were reviewed to ensure compliance with 2016 WHO criteria. Clinical & cytogenetic parameters at diagnosis were assessed & compared with treatment outcomes. Results: Eighty nine patients met study criteria, with a median age of 69 years (range: 37-93); 58 (65%) males. Median follow-up was 22.2 months (range: 0-172), with 41 (46%) deaths & 13 (15%) leukemic transformations. Median OS was 24.8 months (range: 0-172). 43 (53%) patients had an abnormal karyotype, with common abnormalities being trisomy 8 (12%), complex karyotype (9%) & del (20q) (6%). Given the fewer types of abnormalities identified, the IPSS cytogenetic stratification was more effective than IPSS-R, with risk categorization including; 45 good (55%), 20 intermediate (25%) & 16 high risk (20%) respectively (8 unavailable). On univariate analysis, increased age (p = 0.05), decreased hemoglobin (p = 0.02), higher ANC (p = 0.03), circulating immature myeloid cells (p = 0.02), higher LDH (p = 0.009), absence of bone marrow ring sideroblasts (p = 0.001) & higher risk (intermediate & high) IPSS cytogenetic categories (p = 0.01) adversely impacted OS. In a multivariate model that included the aforementioned variables, higher risk IPSS cytogenetics retained a negative prognostic impact (p = 0.04). 28 patients received a median of 6 cycles (range: 1-21) of hypomethylating agent therapy (HMA), with an overall response rate of 18% (CR-3, PR-2). All responders had an abnormal karyotype (p = 0.01). However, HMA did not affect either OS or LFS. Conclusions: Intermediate & high risk IPSS cytogenetic categories independently & adversely impact survival in WHO defined MDS/MPN-U patients. HMA use did not impact OS; however, patients with abnormal karyotypes were more likely to respond.

AbstractTrabectedin is an FDA‐approved DNA minor groove binder that has activity against translocation‐associated sarcomas. Lurbinectedin is a next‐generation minor groove binder with preclinical activity against myeloid leukemia cells. A dose‐finding phase 1 clinical trial was performed in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with further assessment of safety and tolerability. Forty‐two patients with relapsed/refractory AML/MDS received lurbinectedin administered as a 1‐hour intravenous infusion in a 3 + 3 study design. Two dosing schedules were used: 3.5, 5, 7, or 6 mg on days 1 and 8 or 2, 3, 1, or 1.5 mg for 3 consecutive days on days 1 to 3. Three patients experienced dose‐limiting toxicities of rhabdomyolysis (grade 4), hyperbilirubinemia (grade 3), and oral herpes (grade 3) with the day 1 and 8 schedule. Otherwise, adverse events mainly consisted of gastrointestinal manifestations (n = 11), febrile neutropenia/infections (n = 4), pulmonary toxicity (n = 2), and renal failure (n = 2). The most common laboratory abnormalities observed were an increase in creatinine (93%) and anemia, neutropenia, and thrombocytopenia (100%). Overall, 33 of 42 patients (79%) had reduction in blasts in peripheral blood or bone marrow. One patient achieved a partial response and 2 patients a morphologic leukemia‐free state. Most (n = 30, 71%) were discontinued due to progressive disease. Early deaths occurred from disease‐related causes that were not attributable to lurbinectedin. Four patients with a chromosome 11q21‐23 abnormality had significantly greater bone marrow blast reduction than those without such abnormality, with decrease of 31 ± 14% (n = 4) vs 8 ± 8% (n = 16), respectively (P = .04). Overall, lurbinectedin was safe and tolerated using the schedules and dose levels tested. While no sustained remissions were observed, single‐agent lurbinectedin was transiently leukemia suppressive for some patients.