Related Myelodysplastic Syndrome Research Articles

TP53 Mutations in Acute Leukemias and Myelodysplastic Syndromes: Insights and Treatment Updates.

TP53 mutations are found in 5%-10% of de novo myelodysplastic syndrome (MDS) and AML cases. By contrast, in therapy related MDS and AML, mutations in TP53 are found in up to 30%-40% of patients. The majority of inactivating mutations observed in MDS and AML are missense mutations localized in a few prevalent hotspots. TP53 missense mutations together with truncating mutations or chromosomal loss of TP53 determine a loss-of-function effect on normal p53 function. Clonal expansion of TP53-mutant clones is observed under the selection pressure of chemotherapy or MDM2 inhibitor therapy. TP53-mutant clones are resistant to current chemotherapy, and when responses to treatment have been observed, they have correlated poorly with overall survival. The most heavily investigated and targeted agent for patients with TP53-mutant MDS and AML has been APR-246 (eprenetapopt) a p53 reactivator, in combination with azacitidine, but also in triplets with venetoclax. Despite positive results in phase II trials, a phase III trial did not confirm superior response or improved survival. Other agents, like magrolimab (anti-CD47 antibody), failed to demonstrate improved activity in TP53-mutant MDS and AML. Agents whose activity is not dependent on a functional apoptosis system like anti-CD123 antibodies or cellular therapies are in development and may hold promises. Delivering prognostic information in a dismal disease like TP53-mutated MDS and AML is particularly challenging. The physician should balance hope and realism, describing the trajectory of possible treatments and at the same time indicating the poor outcome, together with promoting adaptive coping in patients and elaborating on the nature of the disease.

Burden of Chemotherapy-Related Myelodysplastic Syndrome/Acute Myeloid Leukemia in the Chemotherapeutic Armamentarium

Introduction: Therapy related Myelodysplastic Syndrome and Acute Myeloid Leukemia (t-MDS/AML) is a well-established adverse event (AE) associated with conventional chemotherapy drugs and has historically carried a poorer prognosis when compared to de novo disease. Newer chemo medicines like PARP inhibitors have also been implicated in developing this complication. However, comprehensive real-world data is lacking pertaining to the AE burden relative to individual drug classes. Methods: We used the FDA Adverse Events Report System (FAERS) public dashboard to obtain the data. Data was available for the years 1970 - 2023. We retrieved the number of events that were reported as “Myelodysplastic Syndrome” or “Acute Myeloid Leukemia” for individual chemotherapy classes that have historically been known to cause t-MDS/AML. Disproportionality analysis was performed by calculating the reporting odds ratio (ROR) with its 95% confidence interval (CI). Results: The drug class with the highest ROR of MDS/AML was the topoisomerase inhibitors - ROR 2.38 (95% CI 2.27-2.49). Intercalating agents like anthracyclines and mitoxantrone had the next highest ROR of 2.12 (95% CI 2.04 - 2.21). The novel drug class PARP inhibitors had the third most burden of t-MDS/AML with an ROR of 1.57 (95% CI 1.46 - 1.69). Table 1. depicts the individual drug classes and their ROR for associated MDS/AML. Table 1 depicts the individual drug classes and their ROR for associated MDS/AML. Conclusions: From this retrospective analysis, we identified that among all the chemotherapy drug classes, the topoisomerase II inhibitors were associated with the highest burden of t-MDS/AML, followed by intercalating agents and PARP inhibitors. Further data is essential to identify the patient characteristics associated with higher risk of developing this dreaded complication. This could improve patient-counseling prior to treatment initiation, assist with alternate drug choices when applicable, and perhaps also aid in developing strategies for closer monitoring in high-risk patients.

Pathogen and human NDPK-proteins promote AML cell survival via monocyte NLRP3-inflammasome activation.

A history of infection has been linked with increased risk of acute myeloid leukaemia (AML) and related myelodysplastic syndromes (MDS). Furthermore, AML and MDS patients suffer frequent infections because of disease-related impaired immunity. However, the role of infections in the development and progression of AML and MDS remains poorly understood. We and others previously demonstrated that the human nucleoside diphosphate kinase (NDPK) NM23-H1 protein promotes AML blast cell survival by inducing secretion of IL-1β from accessory cells. NDPKs are an evolutionary highly conserved protein family and pathogenic bacteria secrete NDPKs that regulate virulence and host-pathogen interactions. Here, we demonstrate the presence of IgM antibodies against a broad range of pathogen NDPKs and more selective IgG antibody activity against pathogen NDPKs in the blood of AML patients and normal donors, demonstrating that in vivo exposure to NDPKs likely occurs. We also show that pathogen derived NDPK-proteins faithfully mimic the catalytically independent pro-survival activity of NM23-H1 against primary AML cells. Flow cytometry identified that pathogen and human NDPKs selectively bind to monocytes in peripheral blood. We therefore used vitamin D3 differentiated monocytes from wild type and genetically modified THP1 cells as a model to demonstrate that NDPK-mediated IL-1β secretion by monocytes is NLRP3-inflammasome and caspase 1 dependent, but independent of TLR4 signaling. Monocyte stimulation by NDPKs also resulted in activation of NF-κB and IRF pathways but did not include the formation of pyroptosomes or result in pyroptotic cell death which are pivotal features of canonical NLRP3 inflammasome activation. In the context of the growing importance of the NLRP3 inflammasome and IL-1β in AML and MDS, our findings now implicate pathogen NDPKs in the pathogenesis of these diseases.

Sex Disparities in Myelodysplastic Syndromes: Genotype, Phenotype, and Outcomes.

Introduction/Background The impact of biological sex on the clinical phenotype, genotype, and outcomes among patients with MDS is not well characterized. Materials and Methods We retrospectively reviewed the clinical and genomic data from male and female patients included in our institutional MDS database at Moffitt Cancer Center. Results Among 4580 patients with MDS, 2922 (66%) were men and 1658 (34%) were women. Women were younger (mean age 66.5 vs. 69 years for men, P < .001) at diagnosis. There were more Hispanic/black women than men (9% vs. 5%, P =<.001). Women had lower hemoglobin and higher platelet counts than men. More women had del 5q/monosomy 5 abnormalities compared to men (P =<.001). Therapy related MDS were more common in women than men (25% vs.17%, P=<.001). On assessment of molecular profile, SRSF2, U2AF1, ASXL1, and RUNX1 mutations were more frequent in men. The median overall survival (mOS) was 37.5 months (mo) for females compared to 35 monthsfor males, (P=.002). The mOS was significantly prolonged for women in lower-risk MDS, but not in higher-risk MDS. Women were more likely to respond to immunosuppression with ATG/CSA than men (38% vs. 19%, P= 0.04).Conclusion Ongoing research is needed for understanding the impact of sex on phenotype, genotype, and outcomes in patients diagnosed with MDS.

Outcome of Patients Undergoing Hematopoietic Cell Transplantation for TP53-Mutated Acute Leukemias and MDS: Effect of Conditioning and GvHD Prophylaxis Regimens Intensity

TP53 mutations are seen in ~ 5-10% of hematological malignancies and 25-40% of patients with therapy related myelodysplastic syndrome (MDS) or acute leukemias (AML and ALL). Several studies have demonstrated inferior survival outcomes in patients with TP53-mutated AML/MDS with 3-year overall survival (OS) of 10-20% regardless of chemotherapy used. Furthermore, data on treatment outcomes in patients TP53-mutated disease after allogeneic hematopoietic cell transplantation (HCT) is conflicted with some studies reporting no survival benefit with HCT when compared no HCT(HR 0.97) with 3-year OS of 11%; and other studies showing a trend towards longer survival in those who underwent allogeneic HCT (14.5 months vs 7.9 months; p=0.09).This conflicting results may be at least partially due to heterogeneity in conditioning / graft-versus-host disease (GvHD) prophylaxis regimens. Here, we aimed to describe treatment outcomes in TP53-mutated patients who underwent different combinations of conditioning regimen intensity [fludarabine and melphalan (FM) as reduced intensity conditioning (RIC) or radiation-based myeloablative conditioning (MAC)], and GvHD prophylaxis regimens [post-transplant cyclophosphamide (PTCy) or tacrolimus/Sirolimus (T/S)]. We retrospectively studied 99 patients with TP53 mutated acute leukemias (AML 48.5%, ALL 23.2%) or MDS (28.3%) who underwent HCT with mobilized peripheral blood stem cell (PBSC) as graft source between January 2015 and December 2021. TP53 mutations confirmed by deletion of chr17/17p using FISH/cytogenetics or by HopeSeq NGS were included. Table 1 details patient and HCT characteristics. The median age was 61 years (range: 15-77 years), and 62.6% of patients were males, 87.9% had a KPS >80, 63.6% had a high/very high DRI score and 54.5% had a HCT co-morbidity index ≥3. Donors were matched unrelated or matched sibling in 40.4% and 38.4%, respectively. Conditioning regimen was either radiation (RT) based MAC (n=35; 35.4%) or RIC with FM (n=64; 64.6%). GVHD prophylaxis was PTCy-based in (n=27; 27.3%) and T/S-based in (n=72; 72.7%). For the overall group, 1-year OS, and disease-free survival (DFS) were 48.8% (95% CI: 0.37 -0.59), 36.9% (95% CI: 0.26 -0.47), respectively. Cumulative incidence of relapse (CIR), and non-relapse mortality (NRM) were 36.2% (95% CI: 0.26 -0.46) and 27% (95% CI: 0.18 -0.36), respectively. The cumulative incidence of Day 100 grade 2-4 and 3-4 acute GVHD were 37.4% (95% CI: 0.27 -0.47) and 17.6% (95% CI: 0.10 -0.26). CI of 1 year limited and extensive chronic GvHD were 33.8% (95% CI 0.23 -0.44) and 31.2% (95% CI 0.21 -0.41), respectively. On multivariate analysis, intensity of conditioning or GvHD prophylaxis did not affect OS when FM was compared with RT-based conditioning (HR: 1.14; 95%CI: 0.65-2.1, P=0.64) and PTCy was compared to T/S- based GvHD prophylaxis (HR: 1.41; 95%CI: 0.74-2.67, P=0.27). Conditioning regimen or GVHD prophylaxis intensity did not affect RFS, CIR and NRM. Patients with a DRI score <3 had a better OS (HR: 2.33; 95%CI: 1.25-4.36, P=0.005), RFS (HR: 2.02; 95% CI: 1.15-3.54, P=0.01) and NRM (HR: 3.56, 95% CI: 1.22-10.39, P=0.014) without an impact on relapse rate. Complex Karyotype was associated with lower OS (HR: 2.72, 95%CI: 1.17-6.35, P=0.015) and RFS (HR: 2.19, 95%CI: 1.08-4.44, P= 0.024) but did not increase CIR or NRM. KPS >80 was associated with better OS, RFS and NRM but not CIR. Figure 1 depicts comparable 1-year OS and CIR among different combinations of conditioning regimens and GVHD prophylaxis of FM-PTCy (n=13), FM-T/S (n=51), RT-PTCy (n=14) and RT-T/S (n=21); with p value of 0.57 and 0.96, In this large single center study, patients with TP53 mutant acute leukemias or MDS who underwent HCT at our center had 1-year OS of 48.8%. Patients with better KPS and DRI score of < 3 had better OS with no effect on the risk of relapse. Outcomes of TP53-mutated patients undergoing FM-based RIC was comparable to patients with RT-based MAC regimen regardless of GvHD prophylaxis intensity. Our data provide insight on possible strategies for patient selection and optimization of pre-/post-HCT management and indicates that improving transplant outcomes in patients with TP53-mutated acute leukemias or MDS remains an unmet need. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Outcomes of Allogeneic Haematopoietic Stem Cell Transplantation for Therapy-Related Myeloid Neoplasms Following Treatment for Myeloma

Introduction As the outcomes for patients with multiple myeloma continue to improve, therapy-related myeloid neoplasms (t-MN) are increasingly recognised as a treatment complication. The prognosis of tMDS is poor with life expectancy typically less than a year1. There is limited data on the management of t-MN secondary to myeloma therapies. We performed a registry study on the outcomes of patients who underwent an allogeneic haematopoietic stem cell transplant (allo-HCT) for both therapy related myelodysplastic syndrome (t-MDS) and acute myeloid leukemia (t-AML) following treatment for myeloma. Methods The European Society for Blood and Marrow Transplantation (EBMT) registry was used to identify 157 patients with t-MN across 96 centres between 2006-2018. The median age of patients was 62.1 years (57.6-66.7), with 63.7% male and 36.5% female. 100 patients were transplanted for t-AML and 57 for t-MDS with a median time from myeloma diagnosis to time of allo-HCT of 72.6 (46.1-102.9) months. The median time from t-MN diagnosis to allo-HCT was 6.4 (3.9-9.4) months. We examined overall survival (OS), progression free survival (PFS) relapse and non-relapse mortality (NRM) and myeloma recurrence. The median follow-up time was 64.9 months. Results The median survival time for all patients was 14.3 months. OS at 12- and 60 months was 55% and 27% respectively and PFS at 12- and 60 months was 45% and 24% respectively. The incidence of relapse of tMN at 12- and 60 months was 35% and 45% respectively, with NRM 20% and 31% respectively. The commonest cause of death was infection (36.3% n=37) followed by disease relapse/progression (34.3% n=35). With respect to t-MN disease status 59% of patients with t-MN were in a complete remission at time of transplant. Cytogenetic results were available for all patients with 67.6% abnormal, 26.7% normal and failed/not done in 5.7% cases. IPPS-R was available in 58% of cases; Good 17(29.3%), intermediate 13(22.4%), poor 13(22.4%) and very poor 15(25.9%). Data on status of myeloma at time of allo-HCT was available in only 50 patients (CR 38%, VGPR 22%, PR 10%, stable disease 11% and progressive disease 8%). The majority of patients underwent matched unrelated transplant 79%(124) versus sibling allo 21% (n33). The majority had reduced intensity conditioning (RIC 70.3%, standard 29.7%, missing 1.3%). 130 patients had undergone prior autologous transplant (auto) for myeloma with 55.4% having one auto, 21% two autos, 5.1% three autos and 1.3% four autos. With respect to the number of lines of myeloma therapy prior to transplant; 1 line (29.4%), 2 (30.9%), 3 (16.9%), 4 (8.8%) and >4 (14%). 120 patients received chemotherapy for myeloma prior to their t-MN diagnosis, however data was missing in the remainder of patients in this study. Data on myeloma recurrence was available in 31.2% (49 patients), at 12- and 60 months myeloma recurrence was 4% and 12% respectively with myeloma NRM at 12- and 60 months 33% and 57%. Univariate analysis failed to show any statistically significant difference in outcomes with respect to t-MDS vs t-AML, t-MN disease status, Karnofsky performance status, conditioning or donor source. Multivariate analysis was not possible due to the small numbers within this study. Further analysis of this data will be undertaken. Conclusion This study indicates that allo-HCT for t-MN following treatment for myeloma is a viable treatment option. The myeloma recurrence in this study was low and further strategies to reduce t-MN relapse and NRM are needed. References; Bhatia R, Deeg HJ. Treatment-Related Myelodysplastic Syndrome - Molecular Characteristics and Therapy. Curr Opin Hematol.2011;18(2):77-82.

Gasdermin D Mediates Inflammation-Driven Pathogenesis of the Myelodysplastic Syndromes

The myelodysplastic syndromes (MDS) are a group of clonal hematopoietic stem cell diseases characterize by cytopenia(s), dysplasia in one or more of the major myeloid cell lines, ineffective hematopoiesis, and increased risk of development of acute myeloid leukemia (AML). Growing evidence revealed the significance of pyroptotic cell death in the inflammatory bone marrow in MDS. However, the detailed mechanisms of pyroptosis in the pathogenesis and progression of MDS remain unknown.Gasdermin D is a pore-forming protein that is cleaved upon inflammasome assembly by inflammatory caspases at the linker between the N-terminus pore-forming domain and the C-terminus autoinhibitory domain. The activation of gasdermin D results in increased cell permeability, cell pyroptosis, and the release of cytokines including Interleukin 1 (IL-1) family. Binding of these cytokines to the IL-1 receptor triggers the activation and release of other pro-inflammatory cytokines, including IL-6 and tumor necrosis factor (TNF).Our group recently established a Diap1 (encoding mDia1) and miR-146a double knockout (DKO) mouse model phenocopying MDS. These two genes are involved in the innate immune signaling and inflammation. DKO mice develop aging-related anemia and thrombocytopenia with over-secretion of pro-inflammatory cytokines. Many DKO mice progress to acute myeloid leukemia (AML) with monocytic differentiation and bone marrow fibrosis at 12 months of age. We found that gasdermin D is upregulated and activated (cleaved) in the bone marrow and spleens of the DKO mice. To study the role of gasdermin D in MDS, we crossed DKO mice with gasdermin D knock out mice to generate gasdermin D, mDia1, miR-146a triple knock out (TKO) mice. Gasdermin D knock out in the background of DKO significantly antagonized the increase of leukocyte count, especially the monocyte count, in the aging mice, and partially rescued the anemia. We transplanted bone marrow from 5-month-old TKO, DKO, and wildtype mice to 5-month-old lethally irradiated mice, respectively, to investigate whether the rescue effect of gasdermin D knock out was hematopoietic cell intrinsic. As expected, TKO bone marrow transplanted (BMT) mice had significantly less leukocyte count compared with DKO BMT mice, the anemia was also ameliorated in TKO BMT mice. More importantly, gasdermin D depletion in hematopoietic cells significantly extended the survival of DKO mice and reverted the progression to AML, suggesting a critical role of GSDMD in the pathogenesis of MDS.These findings indicate that gasdermin D plays a pivotal role in inflammation related MDS development and progression. This is further supported by the evidence that gasdermin D is highly upregulated in patients with MDS in our preliminary immunohistochemical studies in the bone marrow from patients with different types of MDS. Therefore, targeting gasdermin D could be a novel therapeutic approach in the management of MDS. DisclosuresNo relevant conflicts of interest to declare.

A Phase I Study of the Combination of Venetoclax and Azacitidine in Relapse/Refractory Higher Risk Myelodysplastic Syndrome (MDS)

A Phase I Study of the Combination of Venetoclax and Azacitidine in Relapse/Refractory Higher Risk Myelodysplastic Syndrome (MDS)

Overview of myelodysplastic syndrome in Baghdad, Iraq- clinical picture and outcome

Background: Myelodysplastic syndromes (MDS) can represent a challenge in diagnosis and treatment because of heterogeneous presentation, unpredictable response to variable measures with propensity for leukemic transformation. Aim of study: To review MDS Iraqi patients in term of presentation, risk stratification and treatment options and to assess outcome of different treatment options in term of response criteria, quality of life and progression. Patients and method: a hospital based study conducted over a period of 21 months from January 2018 till October 2019 in different hematology centers in Baghdad. Any patient with primary or therapy related MDS diagnosed were enrolled in this study. Each patient stratified into different risk groups when applying cytogenetic versus non cytogenetic scoring systems, the therapeutic options for every patient. They observed for their response to different therapeutic modalities and any evidence of progression. Results: Mean age at diagnosis for MDS was 58.7± Anemia was the most common presenting symptom representing 68.4% of patients. MDS with excess blasts-II is forming 28.8%. Majority of patients categorized as intermediate risk group. Hypomethylating agents used for 50% of MDS patients while 32.1% received best available therapy. Those on HMA achieve partial remission in 7.1%, 25.2% reached to stable disease, hematological improvement in 25.2%. Death outcome in 21.6 with a mean survival is 7.7 months. Disease progression in 10.8%, 7.2% showed leukemic transformation. Conclusion: Iraqi MDS patients present at younger age with advanced manifestation that needs standard risk stratification. The non-cytogenetic score systems can't be of equivalent application even low resources circumstances.

Presence of Rare Germline Variants in Fanconi Anaemia Pathway Genes Confers a Poor Prognosis Comparable to TP53 Mutations in Therapy-Related Myeloid Neoplasms

Introduction: T-MN inclusive of therapy related myelodysplastic syndrome (T-MDS) and acute myeloid leukemia (T-AML) are aggressive neoplasms occurring after exposure to chemo (CT) and/or radiotherapy (RT) and are characterized by high frequency of complex cytogenetics and poor prognosis. TP53 and other genes involved in DNA repair such as Fanconi Anaemia(FANC) pathway are critical in maintaining genomic stability. TP53 mutations are associated with complex karyotype and poor prognosis in myeloid malignancies. Further, variants in the FANC pathway are a risk factor for malignancies, but remain less well studied in T-MN. Churpek et al . (Cancer 2016) reported germline mutations in BRCA1, BRCA2, TP53, CHEK2 and PALB2 in 8/43 (19%) treated breast cancer patients who developed T-MN. However, their interaction with TP53 mutations and impact on survival is unknown. Here we investigate the genomic architecture of T-MN patients from the South Australian Myelodysplastic Syndrome (SA-MDS) registry.Methods: Demographic, clinical and laboratory data including cytogenetic profile of 147 T-MN patients were analysed. Targeted Massively Parallel Sequencing of a custom panel of 63 genes (43 myeloid neoplasms associated genes & 20 FANC; all coding regions) was performed on diagnosis bone marrow samples from 101 T-MN samples. Rare FANC variants were selected based ExAC MAF <0.2% and variants only with VAL ≥20% were selected for further analysis. FANC variants were called deleterious if predicted to be deleterious by atleast two in-silico prediction model (e.g. CADD, SIFT, POLYPHEN and Mutation taster) and/or reported in COSMIC, gene specific databases or in literature.Results: Median age of T-MN was 71 (20-91) years and the most frequent primary neoplasms were lymphoproliferative neoplasms (n=56, 38%) and prostate cancer (n=22, 15%). Sixty-three (43%), 34 (23%) and 48(33%) patients received CT, RT and CT plus RT respectively. The T-MN group consisted of 104 T-MDS (71%) and 43 T-AML (29%). Poor risk cytogenetics were more frequent in T-MN cases following CT than after RT alone.Somatic mutations in myeloid genes were detected in 95/101 (94%) of T-MN cases. Notably, all normal karyotype T-MN (29/29, 100%) were mutated. Mutations were most frequently seen in transcriptional factors (35%), TP53 (32%) and splicing factors (26%). Significantly higher proportion of TP53mut T-MN patients had complex karyotype (22/32, 84%) compared to TP53wt (5/69; 7%, p<0.0001).Examination of 20 FANC pathway genes identified 38 rare variants in 31(31%) T-MN at a variant allele frequency (VAF) of ≥20% and most of the variants were missense (35/38; 92%). These were mostly seen in BRCA1, FANCA, FANCM, BRCA2, FANCL and SLX4 genes. Of patients with FANC variants, 42% (13/31) had concomitant TP53 mutations. The median VAF was 49% (range 20-100%) with no significant difference between the deleterious (n=13; 34%) and non-deleterious variants (n=25). Out of 13 deleterious variants (including 2 BRCA1 variants previously reported pathogenic on BIC database), ten variants were seen in nine TP53wt patients. We compared the disease characteristics, prior chemotherapy and survival outcome in patients with TP53mut (n=32), TP53wt harbouring predicted deleterious FANC variants (TP53wt /FANCdel var; n=9), TP53wt harbouring predicted non-deleterious FANC variants (TP53wt /FANCnon-del var; n=9) and TP53wt /FANCwt (n=51). There was no difference in bone marrow blast %, type of prior malignancy, prior therapy (CT vs RT vs combination), proportion of T-AML and treatment for T-MN between the groups. Interestingly, median number of mutations were significantly lower in TP53mut group (1; range 0-11) compared to TP53wt /FANCdel var, TP53wt /FANCnon-del var (both groups - 3; range 0-6) and TP53wt /FANCwt (3; range 0-9) (p=0.0005). Importantly, median OS of TP53wt /FANCdel var and TP53wt /FANCnon-del var groups was identical and significantly shorter than TP53wt /FANCwt (9.7 vs. 9.9 vs. 19.1 months; p=0.00485), and similar to TP53mut group (8.9 months).Conclusions: In our cohort, somatic mutations were seen in 90% of T-MN patients, comparable to primary MDS, contrary to previously published literature. Somatic TP53 mutations and FANC variants are seen in 32% and 31% of cases respectively and 13% harboring both. This study demonstrating that rare FANC variants are associated with significantly poor survival comparable to TP53 mutated T-MN patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Chronic Lymphocytic Leukemia with Deletion 13q: Prognostic Predictors and Outcome after Treatment with Fludarabine, Cyclophosphamide and Rituximab (FCR)

INTRODUCTIONChronic lymphocytic leukemia (CLL) with deletion 13q (del13q) has historically better outcome after chemotherapy. However a sizeable number of such patients do progress with a decreased progression free survival (PFS) and overall survival (OS). We analyzed this group of patients treated with FCR to characterize the relationship between clinico-biological parameters and outcome. METHODSWe retrospectively analyzed 134 CLL patients with del(13q) treated with FCR from March 2004 to August 2014 in our institution. The association between base line characteristics, 12 month minimal residual disease (MRD) status as detected by flow cytometry with PFS and OS was assessed using univariate Cox proportional hazards model on all patients. RESULTSOf 134 patients 63% (n=84) were male and 37% (n=50) female, and median age was 60 (range 35-83) yrs. Median follow up was 70.3 mths (5.9 yrs). Median WBC was 39.3 K/μL (3.2-666.5) and Hb 13.6 (g/dL) (7.1-16.4). Seventy three (54%) were IGVH mutated and 51(38%) unmutated. Eighty nine (66%) had beta-2 microglobulin (β2M) <4 and 44 (33%) > 4 μg/mL. Karyotype was diploid in 107 (80%) patients and abnormal in 16 (12%) patients. By fluorescence in situ hybridization (FISH), %age of cells having del(13q) ranged from 8-98% with median of 55.75%. One locus was involved in 110 (82%) and both loci in 20 (15%) patients. Splenomegaly was present in 55 (41%) and absent in 76 (57%). Ninety six percent (n=129) patients had non bulky disease and only 4 (3%) had bulky disease. After FCR therapy, 83 patients (62%) achieved complete response (CR), 26 (20%) nodular partial response (nPR), 21 (16%) partial response (PR) and 4 (3%) treatment failure. Overall 38% (n=51) patients experienced disease progression. Thirteen percent (n=17) patients died after FCR treatment, of which 8 had progressed and 9 had not progressed. There were 12 malignancies detected after diagnosis of CLL: 4 basal cell carcinomas, 4 squamous cell carcinomas, 1 breast carcinoma, 1 colon carcinoma, 1 small bowel carcinoma, 1 therapy related acute myeloid leukemia, 1 therapy related myelodysplastic syndrome, 1 B-acute lymphoblastic leukemia. Median PFS was 83.1 mths (6.9 years), OS at 5 years was 89.9%, and at 10 years was 79.1%. Median OS was not reached. Of 51 patients who experienced disease progression, there were 8 observed deaths. Due to small number of observed events, estimated survival rates could not be ascertained meaningfully. β2M >4 (HR 1.85, p=0.02), high WBC count (HR 1.55, p<0.01), Hb <10 gm/dL (p=0.01), unmated IGVH (HR 2.78, p=0.001), abnormal karyotype (HR 2.01, p=0.04), splenomegaly (HR 2.45, p=0.001), MRD positivity at 12 months (HR 2.87, p=0.01) had a significant negative impact on PFS. Platelet count <50,000/μl, bi-allelic del(13q) while showing a negative impact on PFS was not statistically significant. Percentage of del(13q) >50% had no impact on PFS. Except for Hb <10 gm/dl (p=0.001), none of other parameters had statistically significant impact on OS. This could be explained by the limited statistical power for detecting OS due to small number of observed patient deaths. CONCLUSIONIn CLL with del(13q), a subset of patients progress after FCR therapy and have poor PFS. β2M, WBC count, Hb, unmated IGVH, abnormal karyotype, splenomegaly, MRD positivity at 12 months have a significant impact on PFS. [Display omitted] DisclosuresKantarjian:Pfizer: Research Funding; Amgen: Research Funding; Bristol-Meyers Squibb: Research Funding; ARIAD: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding. Wierda:The University of Texas MD Anderson Cancer Center: Employment; Sanofi: Consultancy, Honoraria; Kite: Research Funding; Karyopharm: Research Funding; Emergent: Consultancy, Honoraria, Research Funding; Janssen: Research Funding; Genentech/Roche: Consultancy, Honoraria, Research Funding; GSK/Novartis: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Acerta: Research Funding; Merck: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Juno: Research Funding. Burger:Novartis: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Gilead: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding. Jain:Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Research Funding; Celgene: Research Funding; BMS: Research Funding; Abbvie: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Clonal Hematopoiesis of Indeterminate Potential — Associated Mutations and Risk of Comorbidities in Patients with Myelodysplastic Syndrome

Introduction:Comorbidities have a significant impact on the prognosis and survival of patients with myelodysplastic syndrome (MDS) (Naqvi et al, JCO. 2011). Recent studies have indicated the role of clonal hematopoiesis of indeterminate potential (CHIP) - associated mutations (TET2, ASXL1, DNMT3A and JAK2) and atherosclerotic cardiovascular disease (Ebert et al. NEJM. 2017). The objective of this study was to evaluate the association of these CHIP - associated mutations as well as TP53 mutations and comorbidities in patients with MDS.Methods:We conducted a retrospective study of 566 consecutive patients with MDS who presented to MD Anderson Cancer Center from August 2013 to December 2016. The Adult Comorbidity Evaluation-27 (ACE-27) scale, a validated 27-item comorbidity index for cancer patients was used to assess the severity of comorbid conditions. We used next-generation sequencing to detect the presence of CHIP mutations in the bone marrow samples. Data on demographics, international prognostic scoring system (IPSS) were collected. Wilcoxon's rank-sum test and chi-squared test were used to determine the association between genes and comorbidities.Results:Of the 566 patients included in this study, 66% were male, and 82% white; median age at presentation was 69 years (range: 22-93). A total of 350 (62%) patients had an IPSS of Intermediate-1 and low; complex karyotype was noted in 128 (23%) patients. The ACE-27 comorbidity scores were as follows: none, 101 (18%); mild, 214 (38%); moderate, 146 (26%); and severe, 105 (19%). Mutations in DNMT3A, ASXL1, TET2, JAK2 and TP53 were noted in 9%, 18%, 20%, 2% and 21% patients respectively. One hundred and seventy (30%) patients had no mutations. With respect to the cardiovascular system, patients harboring DNMT3A were noted to have a higher incidence of myocardial infarction than those without DNMT3A mutation (14% vs 6%; p= 0.03). As expected, patients with a JAK2 mutation had higher number of venous thromboembolic events (18% vs 4%; p= 0.013). TET2, ASXL1 and TP53 mutationshowever were not associated with increased cardiovascular events in our patients. TP53 mutations were highly associated with history of prior malignancy: solid tumors, 44% vs 21%; p= <0.001; myeloma, 9% vs 3%; p= 0.003; lymphoma, 17% vs 3%; p= <0.001. Patients with renal disease and diabetes mellitus were also noted to most likely harbor TP53 mutations: 16% vs 9%; p= 0.016 and 27% vs 16%; p= 0.009 respectively. Patients with ASXL1 were less likely to have prior malignancy (18% vs 27%; p= 0.057). Additionally, IDH1, IDH2 and RUNX1 mutations were also noted in 3%, 6% and 9% of the patients respectively but without any association with the comorbidities. A trend towards higher ACE-27 comorbidity scores and increased number of mutations was noted (p= 0.075).Conclusion:CHIP associated mutations namely DNMT3A was noted to be associated with higher number of cardiovascular events. Contrary to what is previously reported, we didn't find this association with TET2. TP53 mutations were highly prevalent in patients with therapy related MDS. Further work is ongoing studying the variant allele frequency of these mutations and impact on comorbidities. DisclosuresJabbour:Bristol-Myers Squibb: Consultancy. Daver:Karyopharm: Consultancy, Research Funding; Pfizer Inc.: Consultancy, Research Funding; Daiichi-Sankyo: Research Funding; Otsuka America Pharmaceutical, Inc.: Consultancy; Sunesis Pharmaceuticals, Inc.: Consultancy, Research Funding; Incyte Corporation: Honoraria, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Immunogen: Research Funding; Jazz: Consultancy; Kiromic: Research Funding; Bristol-Myers Squibb Company: Consultancy, Research Funding. DiNardo:Daiichi-Sankyo: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy. Jain:Abbvie: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Verastem: Research Funding; Celgene: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Pemmaraju:Novartis: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria; Cellectis: Research Funding; Stemline: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria, Research Funding. Kantarjian:Bristol-Meyers Squibb: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; ARIAD: Research Funding; Amgen: Research Funding; Delta-Fly Pharma: Research Funding.

Leukemia Cutis in a Patient with Metastatic Pancreatic Cancer: A Case Report

Background: Leukemia cutis is an extramedullary manifestation of leukemia with infiltration of neoplastic leukocytes into the epidermis, dermis, or subcutaneous tissues. Most often it is associated with myelodysplastic syndrome or acute myelogenous leukemia. Case History: Here we present a patient with new-onset, multiple, non-tender red papules, that were initially concerning for skin metastases of her previously diagnosed pancreatic ductal adenocarcinoma. She was previously diagnosed with pancreatic cancer six years prior and was in remission until one year prior when she was found to have pulmonary metastases. The metastatic pulmonary nodules were successfully treated with radiotherapy, and the patient was in surveillance prior to presenting with a two month history of rapidly growing pink nodules on her skin. Results: Skin biopsies initially indicated this was likely not metastatic pancreatic adenocarcinoma but rather a hematologic malignancy with monocytic blast dermal infiltration. A subsequent bone-marrow biopsy and staining indicated a second primary hematologic malignancy, acute myelogenous leukemia. With the patient’s previous chemotherapy history, this new malignancy could have been treatment related. However, genetic analysis revealed this was not likely as it did not harbor known phenotypes or markers of treatment related myelodysplastic syndrome or acute myelogenous leukemia including myelomonocytic leukemia with eosinophils (FAB M4EO) or an inversion in chromosome 16 (p13q22). Instead, cytogenetics and next-generation sequencing showed trisomy 8 and a gain of function missense mutation in U2AF1. Conclusion: Maintaining a broad differential and utilizing sequential diagnostic testing confirmed a blast phase de novo acute myelogenous leukemia, presenting as leukemia cutis. She was treated with decitabine and venetoclax and within a few days of initiation, her skin nodules had already begun to recede.

SF3B1 Splicing Mutation in the Context of Therapy Related MDS

Background: Therapy related myelodysplastic syndromes (t-MDS) account for 10-20% of all myelodysplastic syndromes (MDS). They are associated with poor outcome namely driven by high occurrence of poor risk cytogenetics and TP53 mutations. Acquired SF3B1 splicing mutation is the sole somatic mutation (SM) associated with favorable outcome in de novo MDS and is described among 80% of patients with ring sideroblasts (RS) subytpe. The prognostic value of SF3B1 SM in the context of t-MDS has not been reported. We aimed to compare the outcomes of patients with SF3B1 mutation (mut) between t-MDS and de novo MDS, and the outcome among t-MDS patients harboring SF3B1 mut to those with SF3B1 wild type t-MDS. Patients and Methods: Patients with myelodysplastic syndrome seen at Moffitt Cancer Center between 2013 and 2019 were evaluated and included for analysis. SF3B1 mutational status was assessed via next generation sequencing. We included patients with known SF3B1 status. These patients were further stratified into de novo MDS and those with t-MDS. Further, outcomes of t-MDS patients were evaluated based on SF3B1-mut vs SF3B1-WT. Baseline characteristics were compared by chi square (categorical variables) and t- test (continuous variables). Survival estimates were calculated using the Kaplan-Meier method from date of diagnosis and groups were compared using log-rank test. Multivariate survival analysis performed by means of Cox proportional hazards regression. Results: In a large cohort of patients with myelodysplastic syndrome, 320 patients were identified with SF3B1 SM who were classified as de novo MDS (n=289) and t-MDS (n=31). Baseline characteristics were similar among both groups with t-MDS patients being slightly older and harboring high risk cytogenetics. Mutational distribution was also similar except for CBL which was more observed in t-MDS compared to de novo (10% vs 1%, p-value =.002). AML, transformation rate was 12.5% vs 12.9% for de novo MDS and t-MDS respectively, p-value .943. Median overall survival (OS) in those with de novo MDS SF3B1-mut vs t-MDS SF3B1-mut was 103 months vs 59 months, p-value .001. t-MDS patients were then stratified by wild type SF3B1 (SF3B1-WT) and SF3B1-mut. Of the 272 t-MDS in our database with known SF3B1 status, 31 were SF3B1-mut (11%). Of those with SF3B1-mut, 60% were classified as MDS-RS compared to 4.1% of those SF3B1-wt with t-MDS. Complex cytogenetics were seen in 37.4% vs 10.3% of patients with SF3B1-WT vs SF3B1-mut, p-value .009. TP53 mutation was seen in 36.1% SF3B1-WT vs 10% SF3B1-mut, p-value .004. AML transformation rate was 34.4% in SF3B1-WT compared to 12.9% SF3B1-mut, p-value .016. Median overall survival was17 months in SF3B1-WT vs 43 months in SF3B1-mut, p-value .004. Conclusion: In our study, SF3B1 mutations are more commonly seen in de novo than in therapy related MDS. De novo MDS SF3B1-mut had better outcomes compared to t-MDS SF3B1-mut although rate of AML transformation was similar. In patients with therapy related MDS, those with SF3B1-mut had better outcomes than those with SF3B1-WT. Additionally complex cytogenetics, TP53 mutation, and transformation to AML occurred more with SF3B1-WT than with SF3B1-mut. In the absence of SF3B1 mut, t-MDS with ring sideroblasts has been reported to have higher rate of TP53 mut compared to de novo MDS-RS. To our knowledge, our data is first to suggest that among t-MDS patients, SF3B1-mut may portend a better prognosis. Disclosures Padron: BMS: Research Funding; Novartis: Honoraria; Kura: Research Funding; Incyte: Research Funding. Sallman:Celgene, Jazz Pharma: Research Funding; Agios, Bristol Myers Squibb, Celyad Oncology, Incyte, Intellia Therapeutics, Kite Pharma, Novartis, Syndax: Consultancy. Komrokji:Acceleron: Honoraria; Geron: Honoraria; Agios: Honoraria, Speakers Bureau; AbbVie: Honoraria; JAZZ: Honoraria, Speakers Bureau; Incyte: Honoraria; Novartis: Honoraria; BMS: Honoraria, Speakers Bureau.

Clinical Features of Myelodisplastic Syndromes in a Colombian Population: Retrospective Analysis of Two Large Referral Centers

Introduction: Myelodysplastic syndromes (MDS) comprise a varied group of clonal myeloid neoplasms characterized by cytopenias and an increased risk of progression to acute myeloid leukemia. Prognosis is variable, but little is known about the clinical features of MDS in the Colombian population. The diverseness of the disease and changes in standardized diagnostic criteria throughout the years have hinder accurate case detection and epidemiologic evaluation of MDS in our population. Objective: The aim of the present study was to determine the clinical characteristics and evaluate the overall survival (OS) of patients with MDS treated at two large referral centers in Colombia. Methods: An observational, retrospective study was conducted at two tertiary care centers in Colombia. Patients diagnosed with MDS at Clinica FOSCAL and Hospital San Jose between June 2013 and June 2019 were selected. Descriptive statistics were used to analyze baseline demographic characteristics and clinical data such as disease classification, risk stratification, and treatment. The Kaplan-Meier method was used to assess overall (OS) at 1, 3 and 5 years. Results: A total of 96 patients were included. Median age at diagnosis was 75 years (range 31-104). Fifty-two (54.2%) patients were male. According to the 2016 World Health Organization classification of MDS, the most commonly diagnosed subtype was MDS with multilineage dysplasia (31.2%), followed by MDS with excess blasts (13.5%); however, 35.4% of patients had an unclassifiable MDS sub-type. Twenty-nine (31.2%) patients were screened for cytogenetic abnormalities, the most common chromosomal abnormalities were deletion in the long arm of chromosome 5 (4.2%) and deletion of 7q (2.1%). Therapy related MDS was diagnosed in 13 (13.5%) patients and secondary MDS associated to pesticides exposure in 2 (2.1%) patients. After stratifying patients by the International Prognostic Scoring System (IPSS), the majority of patients were in the intermediate risk group, with 21 (34.4%) and 16 (26.2%) patients in the intermediate-1 and intermediate-2 categories respectively. Almost 80% of the patients presented one or more comorbidities, the most common was cardiac disease (30.5%). Supportive care with erythropoiesis-stimulating agents was the most common first-line treatment (61.4%), followed by iron chelation therapy (6.2%). Forty-eight (50%) patients were treated with hypomethylating agents (HMA), 43.7% receiving azacytidine and 6.3% decitabine. Among HMA-treated patients, 49.6% were in the intermediate-2 and high-risk IPSS groups. Two patients underwent allogeneic hematopoietic stem cell transplantation. Only patients treated with HMA and cytarabine/idarubicin chemotherapy achieved a complete response (11.5%). OS at one- and five-years post-diagnosis was 73.4% and 40.7% (95%CI 62.4-81.6 and 27.1-53.9) respectively. Patients in the intermediate-2 and high-risk IPSS groups had lower survival rates compared to those in the low and intermediate-1 risk groups. The OS for patients treated with azacytidine was 77.2% (95%CI 60.7-87.5%) at one-year, 43.2% (95%CI 23.9-61.1%) at three-years, and 37.8% (95%CI 19.0-56.5) at five-years after diagnosis. The most common cause of death was infection (51.3%), followed by disease progression (24.3%). Conclusions: The OS of patients with MDS in our study is similar to the reported in the existing literature. Knowing the epidemiology, clinical characteristics, risk stratification, and disease outcomes of MDS patients in our population is crucial to decide the best treatment strategies and improve the clinical outcomes of our patients. Disclosures Sossa: Roche: Honoraria; Astellas: Honoraria; Takeda: Honoraria; Novo: Honoraria. Abello:Dr. Reddy's: Consultancy, Research Funding; Takeda: Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Novartis: Consultancy, Honoraria; Abbvie: Consultancy, Research Funding. Peña:Roche: Honoraria. Salazar:Novartis: Honoraria; Janssen: Honoraria. Sandoval-Sus:Celgene: Speakers Bureau; Massive Bio: Consultancy; Janssen: Consultancy; MorphoSys US: Consultancy.

Allogeneic Hematopoietic Stem Cell Transplantation in Therapy Related Acute Leukemia.

Therapy related acute leukemia consists of a unique subset of acute leukemia with an increased frequency of high risk cytogenetic and molecular abnormalities, dismal response to therapy, higher relapse rates and poor overall survival. Therapy related acute myeloid leukemia (t-AML) is a better defined disease entity than therapy related acute lymphoid leukemia (t-ALL). However, in recent times, t-ALL is also being increasingly recognized and extensively studied. Therapy related acute myeloid leukemia is usually classified together with therapy related myelodysplastic syndrome. However, the management of these two diseases maybe different regarding needs of induction chemotherapy and eligibility for upfront allogeneic hematopoietic stem cell transplantation (Allo HSCT). There is also evidence regarding differences in prognosis and outcomes between these two entities. Allo HSCT offers a potential for cure in t-AML and t-ALL. However, existing literature on the same is confounded by inclusion of t-MDS and secondary acute leukemias. Here we review the current evidence on the outcomes and predictors of outcomes of Allo HSCT in the management of therapy related acute leukemias. We also shed light into the under-representation of therapy related leukemias in clinical trials. This stresses the need for prospective trials incorporating measurable residual disease monitoring and sequential next generation sequencing based genomic data for accurate prognostication and management of therapy related acute leukemia.

Predictors of Outcomes in Adult Patients with Therapy Related Acute Myeloid Leukemia Undergoing Allogeneic Hematopoietic Stem Cell Transplantation - Twenty Year Experience from a Tertiary Care Centre

Background Therapy related acute myeloid leukemia (t-AML) constitutes a subset of AML that has an increased proportion of high risk cytogenetic and molecular features, poor response to therapy, higher relapse, and decreased overall survival. The incidence ranges from 10-20% across various studies. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) offers a potential cure in t-AML, with disease free survival reported up to 30% at 2 years. Most studies on HSCT in t-AML have limited number of patients and are confounded by the inclusion of patients with secondary AML and therapy related myelodysplastic syndromes (t-MDS). We aim to report our 20-year experience of allo-HSCT in t-AML and identify predictors of survival. Patients and Methods We retrospectively reviewed all cases of t-AML who underwent allo-HSCT at our centre from June 1999 to July 2019. We collected data for demographic characteristics, prior malignancy and treatment, latent period before AML, cytogenetic and molecular characteristics of AML, induction treatment received, transplant details (donor details, conditioning regimens, GVHD prophylaxis) as well as post-transplant complications (transplant related mortality, occurrence and severity of acute and chronic GVHD, CMV and EBV reactivations). Primary outcome evaluated was overall survival and secondary outcomes were relapse rate and relapse free survival (RFS). Cox-proportional hazards regression model was used to identify predictors of survival. Results Fifty-two patients underwent allo-HSCT for t-AML during the study period. 58% were male (n=30). Median age at HSCT was 55.5 years (Range 18-70). Baseline characteristics are summarized in Table 1. Complex cytogenetics were present in 23.2% (n=12) patients, while 11q23 rearrangement (MLL-KMT2A), monosomy 7, monosomy 5, and 17p deletion were present in 15.4% (n = 8), 15.4% (n= 8), 7.7% (n = 4) and 7.7% (n=4) patients respectively. Based on the ELN 2017 risk stratification schema, 13.5% (n=7) patients could be considered favorable risk based on cytogenetic and molecular profiles, 36.5% (n=19) intermediate risk, and 57.7% (n=30) in poor risk category. Performance status prior to transplant was ECOG 0/1 in 71.2% (n=37) patients, and 2 in 28.8% (n=15) patients. Myeloablative conditioning was used in 30.8% (n=16) patients, and reduced intensity conditioning in 69.2% (n=36). GVHD prophylaxis was CyclosporineA(CSA)/Methotrexate in 23.1% (n=12), Alemtuzumab/CSA in 21.2% (n=11), ATG/CSA/PTCy in 28.8% (n=15), and other regimens in 26.9% (n=14) patients. Transplant related mortality (death before day+100) was 21.1% (n=11). Acute and chronic GVHD (any grade) occurred in 61.5% (n = 32) and 28.8% (n=15) patients respectively. Eleven patients (21.2%) relapsed with a median RFS of 8 months (Range 0.17-158). Median OS of the whole cohort was 8.9 months (0.17-158 months). No patient had a relapse of their primary malignancy during follow up. RFS at 12 and 24 months were 46% and 28% while OS at 1 and 2 years was 46% and 30%, respectively. Significant predictors of reduced OS (Figure 1a,b,c) after day+100 of HSCT by Cox-regression were ECOG performance status 2 (Hazard ratio - 6.1; p value 0.003), GVHD prophylaxis with CSA/methotrexate (HR - 4.5; p value 0.01), and haploidentical donor transplantation (HR - 34; p value - 0.002). Cytogenetics were a predictor of OS in univariate analysis but not in multivariate regression analysis. No difference in OS was found between patients who underwent HSCT 2010 or prior versus after 2010. Conclusions Patients with favorable cytogenetic profile, better performance status, and an HLA matched donor may have better outcomes after allo-HSCT in therapy related AML. Patients with unfavorable cytogenetic risk profiles may require more intense therapy or post-transplant maintenance therapy to prevent relapse. Disclosures Michelis: CSL Behring: Other: Financial Support. Mattsson:Gilead: Honoraria; Celgene: Honoraria; Therakos: Honoraria.

Somatic Mutations Improve Risk Classification By Cytogenetic Abnormalities in Patients with Myelodysplastic Syndrome after Hematopoietic Stem Cell Transplantation

Somatic Mutations Improve Risk Classification By Cytogenetic Abnormalities in Patients with Myelodysplastic Syndrome after Hematopoietic Stem Cell Transplantation

History of Autoimmune Disease Is Associated with Increased Risk for Myelodysplastic Syndromes

Background With the exception of therapy related MDS due to treatment with alkylating agents and/or radiation or with a topoisomerase II inhibitor, little is known about the etiology of myelodysplastic syndromes (MDS). A few studies have evaluated pre-existing medical conditions as risk factors for MDS, with evidence suggesting that autoimmune disease is associated with an increased risk of MDS. Here, we evaluated associations between history of autoimmune disease, overall and by individual disease subtype, and risk of MDS in a population-based case control study. Methods MDS cases were identified by rapid case ascertainment through the population-based Minnesota Cancer Surveillance System (MCSS). Participants were recruited if they were diagnosed with MDS between April 1, 2010 and October 31, 2014. Eligibility criteria included residence in Minnesota, age at diagnosis between 20 and 85 years, and ability to understand English or Spanish. Centralized pathology and cytogenetics review were conducted to confirm diagnosis and classify by subtypes. Controls were identified through the Minnesota State driver's license/identification card list. History of autoimmune disease was reported using a self-administered questionnaire; proxy interviews were not conducted. Unconditional logistic regression with adjustment for age, sex and confounders (education, NSAID use, benzene exposure, BMI) was used to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CI) for autoimmune disease and MDS. Results A total of 399 cases with a confirmed diagnosis of MDS and 1399 controls were included. Cases were significantly more likely to report a diagnosis of any autoimmune disease when compared with controls (OR=1.49, 95% CI 1.13-1.97). As illustrated in Figure 1, specific associations were observed for hypothyroidism (OR=2.07, 95% CI 1.39-3.08), ulcerative colitis (OR=2.26, 95% CI 1.09-4.69), Crohn's disease (OR=3.88, 95% CI 1.23-12.2), and systemic lupus erythematosus (SLE; OR=7.52, 95% CI 1.98-28.6). Autoimmune conditions were more commonly reported in both female cases and female controls when compared with males; however, associations for hypothyroidism and ulcerative colitis were significantly associated with MDS in males in an analysis stratified by sex. Associations between autoimmune disease and MDS remained statistically significant after exclusion of therapy-related MDS cases. Discussion Our results validate previous findings of an association between autoimmune disease and MDS risk from population-based registry studies and case-control studies. In addition, our results provide additional evidence to suggest that this association is largely driven by hypothyroidism, inflammatory bowel disease, and SLE. This increased MDS risk following a diagnosis for an autoimmune condition is hypothesized to be due to shared genetic or environmental risk factors, treatment for autoimmune diseases, altered immune surveillance or damage to the bone marrow caused by the autoimmune condition. Further studies are required to confirm which of these is the most plausible explanation. Disclosures No relevant conflicts of interest to declare.

Activity of Venetoclax-Based Therapy in Myelodysplastic Syndrome (MDS)

Activity of Venetoclax-Based Therapy in Myelodysplastic Syndrome (MDS)