Risk AML Research Articles

Mini‐consolidations or intermediate‐dose cytarabine for the post‐remission therapy of AML patients over 60. A retrospective study from the DATAML and SAL registries

AbstractAccording to current recommendations, older AML patients in first complete remission (CR) after induction chemotherapy should receive consolidation with intermediate‐dose cytarabine (IDAC). However, no study has demonstrated the superiority of IDAC over other regimen. In this retrospective study, we compared the efficacy of mini‐consolidations (idarubicin 8 mg/m2 day 1, cytarabine 50 mg/m2/12 h, day 1–5) and IDAC. Inclusion criteria were newly diagnosed AML, age > 60 years, first CR after induction and at least 1 cycle of consolidation. Of the 796 included patients, 322 patients received mini‐consolidations and 474 patients received IDAC. Mini‐consolidation patients were older, and more often, they had de novo AML and unfavorable risk. The rate of allogeneic transplantation was higher in the IDAC group. The median number of cycles was higher in the mini‐consolidation group (4 vs. 2; p < .0001). Median relapse‐free survival was 18 months with mini‐consolidations and 12 months with IDAC (p = .0064). In multivariate analysis, the risk of relapse or death was significantly higher in the IDAC group (p = .004). Median OS was 36 versus 31 months with mini‐consolidations or IDAC, respectively (p = .46). In multivariate analysis, the consolidation regimen had no significant influence on OS (p = .43). In older AML patients, post‐remission therapy with mini‐consolidations represents an alternative to IDAC.

Glutamine metabolism-related genes predict the prognostic risk of acute myeloid leukemia and stratify patients by subtype analysis

BackgroundAcute myeloid leukemia (AML) is a genetically heterogeneous disease in which glutamine (Gln) contributes to AML progression. Therefore, this study aimed to identify potential prognostic biomarkers for AML based on Gln metabolism-related genes.MethodsGln-related genes that were differentially expressed between Cancer Genome Atlas-based AML and normal samples were analyzed using the limma package. Univariate, least absolute shrinkage, selection operators, and stepwise Cox regression analyses were used to identify prognostic signatures. Risk score-based prognostic and nomogram models were constructed to predict the prognostic risk of AML. Subsequently, consistent cluster analysis was performed to stratify patients into different subtypes, and subtype-related module genes were screened using weighted gene co-expression network analysis.ResultsThrough a series of regression analyses, HGF, ANGPTL3, MB, F2, CALR, EIF4EBP1, EPHX1, and PDHA1 were identified as potential prognostic biomarkers of AML. Prognostic and nomogram models constructed based on these genes could significantly differentiate between high- and low-risk AML with high predictive accuracy. The eight-signature also stratified patients with AML into two subtypes, among which Cluster 2 was prone to a high risk of AML prognosis. These two clusters exhibited different immune profiles. Of the subtype-related module genes, the HOXA and HOXB family genes may be genetic features of AML subtypes.ConclusionEight Gln metabolism-related genes were identified as potential biomarkers of AML to predict prognostic risk. The molecular subtypes clustered by these genes enabled prognostic risk stratification.

A brief look at genetic and environmental risk factors of leukemia and its preventions and treatment

Leukemia, the most diagnosed cancer in children and adolescents, is the malignancy of white blood cells that begins in hematopoietic stem cells in the bone marrow and brings severe impact to the lymphatic system in which ALL, AML, CML, and CLL are diagnosed most commonly. Risk factors of leukemia is highly evaluated in recent studies and treatments for leukemia have shown great advance too. However, the knowledge to public about leukemia, its risk factors, and its treatments is still limited. This article aims to introduce different types of leukemia including ALL, AML, CLL, CML, analyze genetic and environmental risk factors of leukemia, and describe some of its treatments such as chemotherapy, radiation therapy, and bone marrow transplantation in detail. To avoid and address mechanisms of resistance that arise during leukemia therapy, it is crucial to adopt a comprehensive strategy to the combination of medicine, to manage risk factors to the public, to make lifestyle interventions, to develop more advanced therapies, and to gain a deeper understanding of mechanism of resistance.

Tyrosine Kinase Inhibitors with Intensive Chemotherapy in AML with t(9;22)(q34.1;q11.2)/ BCR::ABL1: Time to Reconsider Prognostic Risk? a Study from the Dataml Registry

Introduction De novo AML with t(9;22)(q34.1;q11.2)/ BCR::ABL1 is now a distinct entity of the ICC and WHO 2022 classifications within the group of AML with defining genetic abnormalities. This entity is distinguished from cases with history of chronic myeloid leukemia (CML) and ≥ 20% blasts, which are classified as CML in myeloid blast phase (CML-BP), although the distinction between both entities could be challenging. In the 2022 ELN classification, AML with BCR::ABL1 belong to the adverse risk group. However, this entity is very rare and generally excluded from clinical trials. Thus, there is little data on outcome especially since the era of BCR::ABL1 inhibitors (Orsmark-Pietras C et al.). In this study, we thought to describe treatments and outcome of patients (pts) with de novo AML with t(9;22)(q34.1;q11.2)/ BCR::ABL1 in comparison with CML-BP and ELN 2017 intermediate (Int) or adverse (Adv) risk AML. Methods Inclusion criteria were: pts aged ≥ 18y, included in the DATAML registry between 2000 and 2021, with either de novo BCR::ABL1 AML defined as no previous history of CML, no previous treatment with TKI and ≥ 20% blasts in bone marrow/blood or CML-BP defined as the occurrence of ≥ 20% blasts following the diagnosis of CML in chronic phase. Outcomes of pts with de novo BCR::ABL1 AML were compared with those of CML-BP pts and AML with ELN 2017 Int (n=643) or Adv (n=863) risk treated with intensive chemotherapy (IC) over the same period. A 50-gene NGS panel was retrospectively performed on available samples. Results We identified 20 pts with de novo BCR::ABL1 AML among 5819 AML (0.3%). We only studied the 18 pts who received IC. Their main characteristics were: female to male ratio (55.6%), median age (54y), extramedullary disease (47%) including splenomegaly (35%); high WBC at diagnosis; isolated t(9;22) (67%); p210 isotype (78%), mutations in ASXL1, RUNX1, NPM1, TET2, BCOR, BCORL1, DNMT3A, EZH2, IDH1, KDM6A, NF1, SMC1A, SRSF2, WT1. Comparisons with the 24 pts CML-BP who were treated with IC are shown in the Table. The main differences between both groups was a higher WBC and the presence of NPM1 mutation in de novo pts whereas ABL1 mutations were found in CML-BP only. Induction chemotherapy was mainly cytarabine and daunorubicin (45-90 mg/m²) combined with imatinib (median dose 600 mg, range 400-800). Only 2 patients did not receive imatinib because the drug was not available in 2000-2003. Those 2 pts achieved complete remission (CR) but subsequently relapsed and died from progression. Overall, 17 pts (94.4%) achieved CR or CR with incomplete hematologic recovery (CRi) after one or two induction cycles, one pt failed and there was no early death. Consolidation was mainly high dose cytarabine with imatinib and 12 pts received an allogeneic hematopoietic cell transplantation (alloHCT) in first CR/CRi with myeloablative or reduced intensity conditioning in 7 and 5 pts, respectively. Five pts received maintenance therapy with imatinib (n=4) or nilotinib (n=1). Of note, 4 of the 5 CR/CRi pts who were not transplanted in CR1 did not relapse. With a median follow-up of 76.3 months, median RFS was not reached and 2y-RFS was 82.4% (95%CI, 55-94). Median OS was not reached and 2-y OS was 77.4% (95%CI, 50.3-90.9). Of note, there were 3 late deaths at 48, 60 and 84 months unrelated to AML (1 lung cancer, 1 pancreatic cancer, 1 infection). CR/CRi rate was significantly higher in pts with de novo BCR::ABL1 AML(94.4%) compared with CML-BP (79.2%), AML with ELN 2017 Int (83.4%) or Adv (68.5%) risk (P<0.0001). RFS (median, CML-BP: 100.5 months, IQR 19.7-NR; ELN-Int: 20.6 months, IQR 7.2-115.3; ELN-Adv: 10.3 months, IQR 4.4-48.1; P<0.0001) and OS (median, CML-BP: 33.9 months, IQR 14.6-NR; ELN-Int: 26.9 months, IQR 10.3-117.3; ELN-Adv: 11.8 months, IQR 4.7-40.0; P<0.0001) were also significantly improved. 2-y OS was 77.4%, 57.0%, 53.7% and 33.4% in de novo BCR::ABL1 AML, CML-BP, AML with ELN2017 Int and Adv, respectively (P<0.0001) (Figure). Conclusion De novo AML with t(9;22)(q34.1;q11.2)/ BCR::ABL1 is a very rare event in AML classifications (<1%) with particular features. Pts treated with IC and imatinib have a high rate of CR, very low incidence of relapse and a remarkable OS rate that do not support the ELN2022 risk classification . Pts may have prolonged RFS and OS without alloHCT. Further studies are needed to confirm these results and reclassify these AMLs in the intermediate or even favorable group of the ELN 2022 classification.

Dynamic Changes in Pre- and 3 Months Post-Transplant NGS MRD Status May Predict the Allogeneic Stem Cell Transplant Outcome of Patients with AML

Introduction: To deal with the high propensity for relapse and substantial genetic heterogeneity of AML, monitoring measurable residual disease (MRD) has become an effective approach to evaluate the response to chemotherapy and to predict relapse. However, the clinical implications of NGS MRD change after allogeneic hematopoietic cell transplantation (alloHCT) are still under investigation. The aims of this retrospective study are to verify whether alloHCT improved the outcome of AML patients with NGS MRD positive status in pre-transplant and to investigate how pre- and post-transplant NGS MRD status changes affect the outcome of patients with AML. Methods: This study analyzed patients of age more than 18 years who underwent alloHCT between 2018 and 2022 at single center. NGS mutation test was obtained at diagnosis, and every 3 months after stem cell transplant for 2 years with synchronized peripheral blood chimerism tests. Requirement for inclusion in this retrospective cohort study was availability of NGS mutation results at pre-transplant and at 3 months, as well as donor chimerism results after alloHCT. Patients with no mutations by NGS at diagnosis and at pre-transplant were excluded. Patients were classified by the NGS MRD status in pre-transplant and at 3 months post-transplant: Positive MRD to Positive MRD (Group A), Positive MRD to Negative MRD (Group B), Negative MRD to Positive MRD (Group C), and Negative MRD to Negative MRD (Group D). Patient characteristics are in Table 1. The Kaplan-Meier method and log-rank tests were used to estimate the survival and to compare the differences in survival. Statistical analyses were performed with GraphPad Prism version 9.1.0 (Prism Inc), Microsoft Excel (Microsoft Corporation). Results: Median follow-up was 21 months (range, 3-66). One hundred sixty-five patients met inclusion criteria. Among these, 104 (63.0%) were MRD positive, and 61 (37.0%) were MRD negative by NGS at pre-alloHCT. Fifty-one of the MRD positive patients (49%) became MRD negative by NGS at 3 months after alloHCT. The conversion rate to MRD negative from positive by NGS was not different by conditioning regimen (myeloablative (MA) 54.3% versus reduced intensity (RIC) 49.2%, p=0.67), or by AML risk group (intermediate 48.9% versus adverse 44.7%, p=0.84). Four years cumulative incidence of relapse (CIR) of each group was statistically different between Group A and the others (Group A 47.3%, Group B 17.7%, Group C 25.9%, and Group D 10.9%, p<0.001), but not different between Group B, C and D (p>0.5). Median OS was 17 months for Group A, 27 months for Group C, but the other groups did not reach. Four-year OS of each group was statistically different between Group A, Group B, and Group D (Group A 21.1% (95% CI: 2.0 - 53.8), Group B 55.2% (95% CI: 38.7 - 68.9), Group C 50.0% (95% CI: 20.8 - 73.6), and Group D 79.3% (95% CI: 63.7 - 94.9), respectively, p< 0.05). Among 12 patients who were MRD positive by NGS in post-alloHCT, but not in pre-alloHCT (Group C), 3 had clinical relapse, at 4 months, 6 months, and 26 months, respectively. Five patients had NGS mutations different from the initial diagnosis. They did not show clinical relapse and maintained 100% peripheral blood lymphoid (CD3) donor chimerism throughout the observation. Conclusion: This study showed alloHCT could convert 49% of pre-transplant MRD positive patients to MRD negative by NGS. However, there were no differences in conversion rate by intensity of conditioning regimen or by AML risk group. Combining pre- and 3 months post-transplant MRD status by NGS could discriminate prognostic subgroups in post-transplant MRD positive and negative group each and may be useful in designing post-alloHCT therapies.

STAG2 and PHF6: Comparison of 2 X-Linked Gene Mutations in Myeloid Neoplasms

INTRODUCTION: The Stromal Antigen 2 ( STAG2), on Xq25, is the most common cohesin complex gene mutated in myeloid neoplasms (MN) (5-10%). STAG2 mutations ( STAG2m) were incorporated in the ELN2022 as AML-MDS defining genetic mutations inferring poor prognosis and is a genetic marker in IPSS-M risk stratification. The PHD-finger protein 6 ( PHF6) gene, on Xq26.3, is a tumor suppressor gene, mutated in 3% of MN, and is more common in T-ALL. PHF6m is believed to be a late event in MN with little data on its prognostic implications in MN. Both STAG2m and PHF6m are more prevalent in males, but their implications on the clinical presentation of MN have not been compared prior. METHOD: Our study is a multicenter study at Mayo Clinic (Rochester, Florida, Arizona). After IRB approval, we retrospectively analyzed charts of 7935 patients who had NGS between 2016-2022. STAG2m was found in 96 patients, and PHF6m in 116 (including 3 with concurrent STAG2m and PHF6m). We excluded 4 PHF6m patients who had T-ALL. Data was captured at time of NGS. MDS risk stratification was by IPSS-M and AML by ELN2022. Overall survival (OS) was calculated from date of NGS to date of last follow-up. BlueSky Software was used for statistical analysis. RESULTS: Characteristics: We compared 96 STAG2m vs 112 PHF6m MN patients. Of STAG2m cases, 78% were male vs 76% in PHF6m MN. Median age was 72 vs 73 years, respectively. Diagnoses included AML (29% of STAG2m vs 34% of PHF6m MN), MDS (54% vs 28%), MDS/MPN (10% vs 21%) and MPN (3% vs 9%). MDS was more common among STAG2m MN (p<.001) while MDS/MPN was more common among PHF6m MN (=.05). MDS-IB was the most common subtype in both (69% vs 52% in STAG2m vs PHF6m MDS). MDS-LB and 5q subtypes were only found in PHF6m MDS, and there was more PHF6m MDS-RS (13% vs 2%). Median IPSS-M score was 0.9 vs 0.8 in STAG2m vs PHF6m MDS (both high-risk). Majority of STAG2m AML were adverse risk (96%) while PHF6m AML were intermediate (79%) (p<.001). AML cases included 43% vs 30% secondary AML (sAML) in STAG2m vs PHF6m AML. Among STAG2m and PHF6m MN, 17% of each were tMN. Cytogenetic abnormalities were more common in PHF6m MN (50% vs 31%, p=.005). The median bone marrow (BM) blasts count among STAG2m MN was 7% vs 4% in PHF6m MN (p=.03). Genetic characteristics: STAG2m were nonsense, frameshift and splice site (54%, 36% and 11%). PHF6m were nonsense, frameshift, splice site, missense and start loss variant mutations (44%, 33%, 12%, 10% and 1%). The median variant allele frequency (VAF) of STAG2m MN was 50% compared to 32% in PHF6m MN (p=.008). Co-mutations: The median number of co-mutations was 3 in STAG2m and 4 in PHF6m MN (p=.04). The most common were TET2m (37% in STAG2m MN vs 45% in PHF6m MN), RUNX1m (31% in both), SRSF2m (39% vs 20%), ASXL1m (66% vs 38%), BCORm (19% vs 6%), U2AF1m (13% vs 14%) and IDH2m (18% vs 7%). ASXL1m, SRSF2m, BCORm, IDH2m and SF3B1m were more common among STAG2m MN (p=<.001, .003, .006, .02, .09). JAK2m, IDH1m are more common among PHF6m MN (p=.02, .06). Survival: Of STAG2m and PHF6m MN, 70% and 72% of patients received treatment. HSCT was performed in 23 (24%) and 23 (21%) of STAG2m and PHF6m patients, including AML (n=9, n=10), MDS (n=12, n=8), MDS/MPN (n=2, n=2). OS among STAG2m and PHF6m MN was 20.5 and 22.1 months, respectively. OS among AML cases was 13.5 vs 21 months (p=.6) in STAG2m vs PHF6m, was NR vs 22 months (p=.4) in MDS, 11.7 vs 17.6 months in MDS/MPN (p=.4), and 10.4 vs 27.4 months (p=.5) in MPN. There was no difference between males and females in either STAG2m or PHF6m MN. HSCT led to longer OS among both STAG2m (NR vs 19.9 months, p=.01) and PHF6m MN patients (NR vs 17.6 months, p=.07). Among AML patients, HSCT did not significantly impact OS (18 vs 9.6 months, p=.3 and 25.1 vs 21 months, p=.2, in STAG2m and PHF6m). HSCT improved OS in STAG2m MDS (NR vs 20.5 months, p=.03). In PHF6m MDS, OS was 22.1 vs 13.1 months in HSCT vs non-HSCT (p=.3). CONCLUSION: STAG2m and PHF6m are 2 X-linked mutations that occur in MN. Both commonly occur in elderly males. MDS was the most common diagnosis in STAG2m MN. STAG2m co-occurred particularly with SRSF2m ASXL1m and BCORm, which are associated with poor prognosis. In our cohort, STAG2m AML carried a poorer prognosis than PHF6m AML. Our study confirms the ELN2022 AML risk stratification. MDS risk classification and OS did not differ between STAG2m and PHF6m in our cohort. A larger cohort is required to confirm our findings and may provide stronger validation.

NFTs and the virtual yet concrete art of money laundering

While much has been said regarding the anti-money laundering treatment of crypto-assets, NFTs seem to have remained on the sidelines of such a debate. Collectible NFTs, however, present a distinct AML risk. Eminently, they mix the risk-factor connected with crypto-assets and fine art. As the first, they are global, pseudonymous, and immaterial. As the second, they have a highly subjective price. In the absence of clear regulation, the risk is for this market to become a criminal haven. The present contribution analyses the relation between collectible NFTs and AML regulation. We pursue our analysis with a view at analyzing the compatibility of NFTs with their two connected categories: crypto-assets and fine art.

Refining risk stratification in CMML: A comprehensive assessment of the IPSS-M and other molecularly informed models.

7020 Background: Multiple molecularly-informed models have been designed in hopes of improving prognostication in CMML. More recently the IPSS-M was introduced for MDS and showed improved prognostic accuracy over the IPSS-R. Here we aimed to analyze whether the applicability of the IPSS-M extends to CMML and provide a definitive comparison between all major molecularly-informed models. Methods: A total of 367 pts with CMML treated at Moffitt Cancer Center with annotated clinical and molecular data were analyzed. The mean IPSS-M score was used as reference. Correlative analysis between CPSS-Mol, Mayo Molecular (MMM), GFM and IPSS-M was performed. Time-to-event analyses were estimated using Kaplan–Meier. We used Cox regression for survival endpoints. Model discrimination was evaluated using Harrell’s C concordance index. Results: We identified 987 driver point mutations involving 21 genes across 367 pts. We identified at least 1 mutation in 96% of pts (n = 352). Median follow-up was 4.4 yrs (3.8-5.0). The most prevalent mts were TET2, SRSF2, ASXL1, RUNX1 and NRAS. Using the IPSS-M schema, pts were classified as very low (7%, n = 26), low (29%, n = 108), moderate low (21%, n = 76), moderate high (16%, n = 58), high (18%, n = 65) and very high-risk (9%, n = 34). The IPSS-M identified 6 risk categories with mOS of 5.0, 5.1, 3.9, 2.6, 1.7 and 1.1 yrs, ranging from VL to VH (p < .05) and a 4-yr cumulative incidence of AML evolution of 2%, 14%, 17%, 18%, 25% and 14% respectively (p < .05) CPSS-Mol and IPSS-M equally showed improved OS discrimination over the MMM and GFM as demonstrated by an 11% and 6% increase in c-index respectively (0.71 vs 0.60 and 0.65). Similarly, CPSS-Mol outperformed CPSS by 3% (0.71 vs 0.68), as did IPSS-M relative to IPSS-R (6%, 0.71 vs 0.65) A 4-to-4 mapping between CPSS-Mol and IPSS-M risk groups (by merging VL/L and H/VH into LR and HR), resulted in the restratification of 57% of pts (n = 202). 22% (n = 15) of LR CPSS-Mol pts were upstaged. 30% (n = 23) of HR pts were downstaged 87 pts (23.7%) developed AML: 34 by 1 (9.2%), 60 by 2 (16.3%) and 79 by 4 yrs (21.5%). There was significant segregation between IPSS-M and CPSS-Mol groups and AML risk (p < .05), but not MMM (p = .191). CPSS-Mol showed the highest accuracy, followed by IPSS-M, MMM and GFM (0.66 vs 0.63 vs 0.57 vs 0.52) We then analyzed the predictive value of the models in pts receiving frontline HMA (n = 146). IPSS-M retained its prognostic accuracy with significant segregation between strata (p < .01), as did CPSS-Mol (p < .01) and MMM (p = .01). Conclusions: The IPSS-M can be used reliably in pts with CMML and shows comparable prognostic accuracy to the CPSS-Mol. Both outperformed MMM and GFM. All models retained its predictive value in pts receiving frontline HMA. This carries particular importance in community settings where CMML tends to be misdiagnosed as MDS. In such instances use of the IPSS-M is unlikely to adversely impact outcomes when used to guide treatment decisions.

Secondary primary malignancy risk by ER, PR, and HER-2 status in post-menopausal women with breast cancer: A population-based analysis.

1050 Background: Breast cancer is the most commonly diagnosed cancer and second leading cause of death due to cancer in women in the United States. We aimed to determine site specific incidence of SPMs in post-menopausal women with primary BC using data from the US Surveillance, Epidemiology, and End Results (SEER-17) cancer registries. Methods: We retrospectively analyzed post-menopausal women aged 45 or older with a first primary breast cancer diagnosis between 2000 and 2019, excluding those aged 45 or younger or with non-breast cancers as their first malignancy. We defined SPMs as second malignancies occurring at least 6 months after the initial breast cancer diagnosis and calculated standardized incidence ratios (SIRs) and absolute excess risk (AER) using SEER*Stat. Statistical significance was determined using p-values <0.05 and a 95% CI assuming a Poisson distribution of SPM incidence. Results: Among 774,965 post-menopausal women ≥45 years old with primary breast cancer, 10.8% developed SPMs, with significantly increased risk compared to the general population (SIR=1.14, 95% CI=1.13-1.15, p<0.05), particularly for solid tumors (SIR=1.16, 95% CI=1.15-1.16, p<0.05) and certain malignancies including salivary gland (SIR=1.77), thyroid (SIR=1.56), endocrine system (SIR=1.56), and hematological malignancies such as ALL, ANLL, and AML (SIR>1.70). Women aged 45-59 and Black women had the highest risk for all malignancies. PR receptor-positive women had higher risk for thyroid SPMs, while PR-negative women had higher risk for SPMs in female genitalia, bones and joints, and hematological malignancies. HER-positive and triple-positive (HER ER PR) women had higher risk for thyroid and hematological SPMs, while triple-negative women had higher risk for ALL, ANLL, and AML. Conclusions: This study found that 11% of post-menopausal women with primary BC develop SPMs, with thyroid cancer being the most common. Black and older women (45-59 years) had a higher risk of developing SPMs. [Table: see text]

Validation and refinement of the 2022 European LeukemiaNet genetic risk stratification of acute myeloid leukemia

The revised 2022 European LeukemiaNet (ELN) AML risk stratification system requires validation in large, homogeneously treated cohorts. We studied 1118 newly diagnosed AML patients (median age, 58 years; range, 18–86 years) who received cytarabine-based induction chemotherapy between 1999 and 2012 and compared ELN-2022 to the previous ELN-2017 risk classification. Key findings were validated in a cohort of 1160 mostly younger patients. ELN-2022 reclassified 15% of patients, 3% into more favorable, and 12% into more adverse risk groups. This was mainly driven by patients reclassified from intermediate- to adverse-risk based on additional myelodysplasia-related mutations being included as adverse-risk markers. These patients (n = 79) had significantly better outcomes than patients with other adverse-risk genotypes (5-year OS, 26% vs. 12%) and resembled the remaining intermediate-risk group. Overall, time-dependent ROC curves and Harrel’s C-index controlling for age, sex, and AML type (de novo vs. sAML/tAML) show slightly worse prognostic discrimination of ELN-2022 compared to ELN-2017 for OS. Further refinement of ELN-2022 without including additional genetic markers is possible, in particular by recognizing TP53-mutated patients with complex karyotypes as “very adverse”. In summary, the ELN-2022 risk classification identifies a larger group of adverse-risk patients at the cost of slightly reduced prognostic accuracy compared to ELN-2017.

SPECTRUM OF CYTOGENETIC ABNORMALITIES IN PEDIATRIC PATIENTS WITH ACUTE MYELOID LEUKEMIA

Objective: To determine the frequency and types of cytogenetic abnormalities in pediatric Acute Myeloid Leukemia. Material and Methods: This cross-sectional study was conducted from January 2021 to October 2021 in Hematology department of the CHUGHTAI Institute of Pathology in Lahore Pakistan. Total 60 patients who were newly diagnosed with Acute myeloid leukemia in CHUGHTAI Institute of Pathology and were also referred from Children Hospital Lahore were included. Patients under the age of 16 years and from both gender were included. Informed consent was taken from patient’s guardian/parents. Patients had their bone marrow aspirates processed for standard G-banding and their karyotypes were examined using a cyto-vision system, where the number of chromosomes was counted and examined for any changes, such as damaged, missing, rearranged, or additional copies of chromosomes. Morphology, immunophenotyping of aspirate, and trephine biopsy are used to make the diagnosis of AML. Data was entered in SPSS version 23.0. Result: There were total 60 patients included in the study. The mean age was 10.2+ 3.2 years. There were n=32(53.3%) males and n=28(46.6%) female. Normal karyotype was observed in n=36(60%) patients, abnormal were seen in n=14(23.3%) and unsuccessful was shown in n=10(16.6%) patients. Favorable cytogenetic results were seen in n=6 (10%), intermediate in n=41 (68.3%), and unfavorable in n=4 (6.6%) cases. t(8;21) (q22:q22) and t(15;17)(q24;q21) were found in 8.3% and 1.6% of our study population respectively which have favorable prognosis . One of our patients had complex cytogenetic abnormalities, including [del5p, del7q, del11q-17+] which shows poor prognosis. Conclusion: The study discovered that 14 (23.3%) of the total pediatric patients with acute myeloid leukemia showed aberrant cytogenetic abnormalities. Chromosomal abnormalities should be identified as early as possible since they can be used for AML risk stratification and prediction of prognosis. Keywords: Acute myeloid leukemia, Complex cytogenetic, Cyto-vision, Karyotype, Morphology, Pediatric

Understanding What Matters to Myelodysplastic Syndrome Patients - a Study of Preferences for Treatments with Hypomethylating Agents

Introduction/Background: Hypomethylating agents (HMAs) are the standard of care for the treatment of myelodysplastic syndrome (MDS). Understanding how patients with MDS perceive and value different HMA characteristics provides critical treatment selection insight for healthcare providers. Objectives: To understand HMA preferences for United States (US) and Canadian patients with MDS. Given HMAs’ treatments’ similar efficacy and safety profiles, we also investigated how HMA administration burden can play a role in patients’ preferences when all other factors are equal. Materials and Methods: We used the discrete-choice experiment (DCE) method to conduct a preference study in collaboration with patient organizations in the US and Canada (i.e., MDS Foundation, the Aplastic Anemia and MDS International Foundation, and the Aplastic Anemia and Myelodysplasia Association of Canada). The study was comprised of two Phases: (1) a qualitative Phase (i.e., DCE survey design) and (2) a quantitative Phase (i.e., DCE survey implementation). In Phase 1, literature review, interviews with clinician, patient and caregiver, and input from the patient organizations informed the DCE survey design. Qualitative interviews were analyzed through content analysis. In Phase 2, survey participants answered a series of DCE choice tasks to indicate their preference between different hypothetical HMA profiles that varied in characteristics (i.e., attributes). Respondents were also asked to indicate their preferences by choosing between HMA profiles mirroring real-life options, all associated with the same risk of AML transformation and level of fatigue but differing in mode of and frequency administration: IV HMAs requiring 5 days or 7 days of treatment session each month, SC HMA with 5 sessions each month, oral HMA and no treatment. Survey results were analyzed using random parameter logit models. The relative importance of attributes (RAI) was calculated, which is the contribution (expressed in percentages) of each attributes relative to all attributes in patient preferences. A larger RAI percentage score shows that the attribute has a larger effect on how the respondents make their decisions. All patient respondents were recruited through the patient organizations’ networks. Results: 16 Phase 1 respondents completed the interview and 184 Phase 2 respondents (including 158 patients and 26 caregivers serving as patient proxies) completed the DCE survey. Interview respondents in Phase 1 valued efficacy attributes (i.e., risk of AML transformation and fatigue) and expressed the treatment burdens associated with injectable treatments (such as injection site reaction, stressful experience of damaged veins, burden of travelling to clinic, etc.). The Phase 2 survey participants had a mean age of 67.2 years old and 88% were from the US. About one-third of the survey participants did not know their MDS risk, 35% were low risk and 31% were high risk. Most (56%) participants were currently receiving treatment, while 24% had received treatment but discontinued and the remaining 20% had not received treatment. The attributes’ importance rankings (via RAI) were risk of AML transformation (40%), fatigue level (33%), number of visits (12%), mode of administration (6%), visit duration (5%), and administration frequency (4%). When HMA treatments were assumed to be associated with the same risk of AML and level of fatigue but to differ in terms of mode and frequency administration, 77% of respondents were predicted to switch to an oral pill if available to them. When considering real-life profiles, 77% and 88% of participants considered the oral option to be the best choice and no treatment to be the worst one, respectively. Conclusion: MDS patients demonstrated strong preferences for HMA with lesser treatment burden (i.e., oral pill) when such agents are with similar treatment efficacy and safety profiles. Understanding patients’ treatment preferences can facilitate shared decision making towards optimal management of MDS.

Racial and Ethnic Disparities in Acute Myeloid Leukemia: 15-Year Experience at a Safety-Net Health System

Background Significant disparities in AML have been reported in the non-Hispanic black (NHB) population compared to Caucasians. Much less is known about the disparities seen in Hispanics (H), who face unique barriers to healthcare access and treatment. Recent reports suggest that Hispanics have decreased overall survival (OS) compared to non-Hispanic whites (NHW) despite higher prevalence of favorable cytogenetics, younger age at diagnosis and similar rates of chemotherapy. We conducted a single center study investigating the outcomes of AML patients treated at a non-transplant safety net hospital in Texas where the majority of the population is Hispanic. Our primary goal was to compare the impact of race/ethnicity on outcomes and further evaluate the underlying genomic differences between these groups. Methods We reviewed the medical records of 162 adult AML patients treated at Parkland Health (Dallas, TX) from January 2007 to June 2022. Demographics, baseline disease characteristics including cytogenetics and genomic profile, and AML directed therapies were collected. Patients were grouped based on race/ethnicity into H, NHW and NHB populations. Cytogenetic risk was classified as favorable, normal, complex or other, per the 2017 European Leukemia Net (ELN) risk classification. Genomic testing was performed using the FoundationOne Heme panel. Overall AML risk was classified per 2017 ELN stratification. Response was assessed using the IWG criteria. Categorical and continuous variables were compared using Chi square test and Kruskal-Wallis one-way analysis of variance. OS plots were calculated using Kaplan Meier method, and groups were compared using log rank testing. Multivariable Cox proportional hazard model was used for survival analysis. Results In our cohort of 162 patients, 82 (50.6%) were Hispanic (H), 36 (22.2%) were NHB and 44 (27.2%) were NHW. Hispanics were diagnosed at a significantly younger age compared to NHB (42.5 years (y) vs 49 y) and NHW (42.5 y vs 52.5 y, p=.02). Hispanics were found to have higher rates of complex cytogenetics (20.3% for H vs 11.8% for NHB vs 9.5% for NHW), similar rates of favorable cytogenetics (20.3% vs 20.6% vs 19.0%) and lower rates of normal cytogenetics (29.1% vs 44.1% vs 40.5%). Hispanic patients had a lower frequency of NPM1 mutations (p=.058) and higher frequency of CEBPA, NRAS, MLL, WT1, RUNX1 and TET2 mutations. Per ELN risk classification, Hispanics were less likely to have favorable risk AML (23.2% vs 36.1% vs 29.5%) and more likely to have intermediate (53.7% vs 44.4% vs 50.0%) or high-risk disease (23.2% vs 19.4% vs 20.5%) than NHB and NHW. Hispanics were less likely to receive intensive induction chemotherapy with 7+3 (85.4% vs 97.2% vs 90.9%), despite their overall younger age of presentation, but achieved similar remission rates post frontline therapy (78.0% vs 86.1% vs 75.0%). Hispanics had a numerically longer OS compared to NHB and NHW (mOS 43 months (m) vs 17 m, vs 14 m), although differences were not statistically significant (p=.20) likely due to the small size of the cohort. When Hispanics were compared against a combined cohort of NHB/NHW, they had longer OS in the high-risk group (p=.03). In a multivariate Cox regression analysis, OS was negatively associated with age at diagnosis (HR 1.022, p=.0063) and intermediate or high ELN risk (HR 3.431, p=.0002 and HR 4.689, p=3.84 x 10-05 respectively) and positively associated with Hispanics (HR .614, p=.0259). In our cohort, only 14 patients (8.6%), 3 of which had high risk disease, were able to proceed to transplant. Conclusion Our study of underserved patients with AML demonstrate a younger age at presentation for Hispanics but suggest that, contradictory to previously reported results, Hispanics have improved overall survival, particularly in the high-risk group, compared to NHB/NHW in the non-transplant setting. Our results may suggest that when healthcare access is not a barrier to treatment, Hispanic patients with AML can have similar, if not improved, outcomes to other populations. However, access to transplant remains a major barrier that needs to be further addressed to improve outcomes for this patient population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Metabolic Dysfunctions Driven By PRPF8 Explain Cases with Ring Sideroblasts without SF3B1 Mutations: Similarity/ Differences of Genotype/ Phenotype Association

SF3B1 mutations (SF3B1MT) mostly identify a group of MDS with ringed sideroblasts (RS), isolated erythroid dysplasia and favorable prognosis. Besides SF3B1, we and others have demonstrated that other genes might be involved in RS formation either due to convergent metabolic pathways or erythroid driver genes. MDS subtypes characterized by multilineage dysplasia lacking SF3B1MT and presenting with RS are paradigmatic examples of such a possibility. In addition, RS in AML is often unrecognized by hematopathologists due to the focus on the presence of blasts as a predominant feature and/ or the reduction of erythroid precursors inherent to blast infiltration. However, when we previously studied defects in PRPF81, a central but unappreciated target of somatic lesions in MDS, we found a correlation with the RS phenotype. To follow up on this initial finding, we compiled a well-annotated cohort of patients seen at the Cleveland Clinic to assess phenotype/ genotype association of PRPF8MT and RS. NGS results including PRPF8 mutational status of 3,545 cases with myeloid neoplasia were reviewed. Calls were retained after assessment of pathogenicity by the ACMG and VarSome classifiers. Excluding cases with concomitant SF3B1MT, we found PRPF8MT (median VAF 38% [3-79]) in 78 (2%) patients. In total, 83% of the mutations were missense, whereas 15% were truncating. Homology sequence between yeast and humans denoted that hotspots mapped to highly conserved amino acids. D1598 and C1594, localizing in the U6-snRNA interacting domain (1442-1601), were mutated in 14% and 5% of the patients, respectively. T418S mapped in a central domain of several SFs (PROCN) and was found in 9% of the cases, whereas the F1099fs alteration was detected in 5% of our cohort. Prussian blue stain showed the presence of RS in 25% of PRPF8MT. Since PRPF8 maps to the proximal regions of 17p, we also noticed that three informative cases carried somatic PRPF8MT and 17p11.2 deletion or loss of chr.17 (1/2), all showing the presence of RS. We thus screened a more complete cohort of chr.17 abnormalities (88% in the context of a complex karyotype) to investigate their contribution to RS formation. While 66% had RS, the high blast count may have concealed their presence in cases lacking this feature because of their predominant AML or high risk MDS. Notably, we also found 8 additional patients in whom SNP-A showed cryptic losses such as del17p11.2 and 17p13.1 (n=7) or UPD (n=2) containing elevated RS. In this cohort, TP53 was the most commonly mutated gene (49%) followed by ASXL1 and DNMT3A (10% each), BCOR/L1 and TET2 (7.5%). In regard to other SFMT, no patient had SRSF2MT, three had U2AF1S34/Q157, two carried somatic DDX41c.139-5C>T/A225D (with -5/del5q) and one patient had a LUC7L2G48* without -7/del7p. While the coincidental presence of marrow RS in TP53MT lacking SF3B1MT has been previously demonstrated2, no study has investigated whether RS might be a result of shared metabolic feedback mechanisms common to SFMT. We thus analyzed RNA splicing and gene expression (GE)3 of patients with single PRPF8MT (n=34) and SF3B1MT (n=281) finding overlapping splicing features in the a-hemoglobin synthesis HBA2 gene. Upregulation of HBA2 has been described in SF3B1MT patients4,5 to correlate with impaired erythrocyte maturation and its accumulation in early erythrocytes. Interestingly enough, given our data on chr.17 abnormalities, we also found that cases with single TP53MT (n=52) displayed high covariance features for HBA2, a possible culprit in cases carrying RS but unmutated for SF3B1 and PRPF8. Indeed by applying gene-set overrepresentation analysis to PRPF8MT and TP53MT GE profiles, we clustered the top 5 categories (FDR< .001) in erythrocytes differentiation (KLF1, EPB42), homeostasis and development (ALAS2, GATA1, RHAG, SLC4A1) suggesting that these genes might inversely correlate with HBA2 expression and be responsible for the formation of RS. Our study demonstrates that PRPF8MT is another molecular lesion phenocopying SF3B1MT via a compensatory metabolic mechanism responsible for the failure of terminal erythroid differentiation. In analogy, given the proximal genomic location of PRPF8 and TP53 we do not exclude that this commonality might be involved in TP53MT with RS as well. These likely phenocopying mechanisms may enable therapeutic opportunities (luspatercept) in cases lacking SF3B1MT presenting with RS and transfusion-dependent anemia.

A Mixed Methods Study to Examine the Influence of Structural Racism on Treatment in Acute Myeloid Leukemia

Background Multiple cancer registries including SEER and NCDB have repeatedly demonstrated increased mortality in non-white AML patients, with the survival disparity widening over the past 2 decades. A recent mediation analysis conducted in our newly created Chicago AML registry suggests that the Black-White and Hispanic-White survival disparity is significantly mediated by census tract variables (tract affluence, disadvantage and segregation) and these serve as surrogates for structural racism (Abraham et al. Blood 2022). In the current study we try to operationalize the mechanisms of structural racism contributing to disparities in myeloid malignancies Methods A prospective mixed-methods approach using quantitative (questionnaires) and qualitative (semi-structured interviews) methods is employed to uncover the complex interrelationship between individual, neighborhood/built environment and community level factors (Fig. 1A) that can influence treatment outcomes. Patients are enrolled 30-90 days from diagnosis and will be followed for two years. Validated questionnaires evaluate: patients' neighborhood and environmental living conditions (AHC HRSN), health literacy (CHLT-6), financial toxicity (COST-FACIT), medication affordability/adherence (ARMS), and mental health (PHQ-4). This is complemented by qualitative data from semi-structured interviews. The transcripts are processed and coded, using a qualitative data management software, and emerging themes noted (Fig. 1B). Results Data collection is ongoing and completed on 18 patients with aggressive hematologic malignancies, majority with AML and high risk MDS. The median age is 56 years with 50% self-declaring as NHW, the remainder NHB, Hispanic and Asian. Only 25% received a college education, 50% reported a median household income below $50,000, and the patient was the primary or sole financial provider for the family in one-half of cases. While most patients did not report struggles with insurance coverage and out of pocket costs on the questionnaire, they did express worry about long-term consequences such as job security and financial well-being. Financial toxicity was highest and health literacy lowest in the NHB patients. 62% reported access to internet and 50% had smartphones. Patients did not endorse concerns about housing or neighborhood conditions influencing their health care. Medication affordability/adherence was adequate across groups. Most patients felt sufficiently supported by family for transportation but 25% reported that they could use more help with ADLs. One-half of patients reported feeling loneliness and stress on the PHQ-4 questionnaire, and detailed the consequences of a long hospitalization (isolation, missing family events) in interviews. Adolescent and young adult (AYA) patients also discussed grappling with their newfound cancer identity. Notably, 25% of patients reported >5 alcoholic drinks /day for men or >4/day for women. Medical mistrust was not reported, most patients expressed trust/confidence in their treatment team which was improved by regular communication and responsiveness. Discussion The mixed methods approach offers an ample source of data from both questionnaires and interviews for a fuller understanding of factors that can influence inequity in the delivery of leukemia care. The unique perspectives of an understudied population at a minority serving cancer identified targetable barriers to care. There is broad need for additional assistance at home for ADLs, mental health concerns as well as significant levels of alcohol use which have not been previously explored. A third of patients lacked access to regular internet, an important source of education and communication that could widen health inequities. Patients expressed unique challenges specific to AML including the prolonged hospitalizations resulting isolation, and difficulty coping with the cancer identity reported by the AYA population. Regular communication with a responsive medical team contributed positively to patient-provider relationships. Ongoing work includes i) expanding the current cohort across a broader socioeconomic spectrum to further enrich the data ii) prospectively linking this data to treatment complications and outcomes. The results of this study can guide future strategies for targeting resources and interventions to narrow leukemia outcome disparities. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Risk of Therapy-Related Acute Myeloid Leukemia (t-AML) in Cancer Patients Treated with Chemotherapy with or without Radiotherapy: A National Population-Based Cohort Study Using SEER Registry

Background: Therapy-related AML (t-AML) is a rare and fatal complication in cancer patients (pts) previously treated with chemotherapy (CTX) and radiotherapy (RT). The risk of t-AML has evolved over time mostly due to advances in cancer therapeutics. In this study, we provide a comprehensive analysis on the risk of t-AML over a 40-year period in cancer patients treated with CTX with or without RT in the US. Methods: Eligible pts for this study were identified from nine Surveillance, Epidemiology, and End Results Program (SEER 9) registries and included those between the ages of 18 and 84 years who were diagnosed with any first primary malignancy (other than CML) between 1975-2018 and received initial course of treatment with CTX. All AML cases that occurred at least one year after the first diagnosis of a primary malignancy were included as t-AML as per the World Health Organization classification. All malignancies were identified based on International Classification of Disease for Oncology, 3rd edition (ICD-O-3) morphology and topography codes. Subjects were followed until t-AML diagnosis, attained age of 85 years, death, loss to follow up, or end of study (December 31, 2018). Standardized incidence ratios (SIRs) were calculated as the ratio of the observed-to-expected (O/E) number of AML using SEER*Stat. The expected number of AML was computed from age-, race-, sex-, and calendar year-specific incidence rates of AML from the general SEER population, multiplied by the appropriate person-years at risk. We calculated exact 95% confidence intervals (CI) about the SIRs. We also computed the excess absolute risk (EAR) to estimate the number of excess cancers beyond that expected per 10,000 persons per year. We conducted Poisson regression analyses comparing excess relative risks (ERR) with initial RT, using CTX alone as the reference. Results: Among 1,030,380 pts initially treated with CTX for first primary malignancy, we identified 2,081 t-AML cases with a 4.76 fold increased risk of AML (SIR; 95% CI, 4.55-4.96) compared to the general population and an excess of 3.94 cases per 10,000 person-years (Table 1). We focused our analysis on first primary malignancies with at least 100 t-AML cases, which included cancers of the lung, breast, ovaries, Hodgkin Lymphoma (HL), Non-Hodgkin Lymphoma (NHL), and myeloma. t-AML risks were particularly high (six- to twenty-fold higher than general population) in the first 5 years following these primary cancer diagnoses, then declined substantially with increasing latency. Long-term risk (≥10 years) of t-AML remained significantly elevated in pts with all these primary cancers except for lung cancer and the risk was highest in pts with myeloma (SIR = 13.74; 95% CI, 8.27-21.46). Additionally, we assessed the risk of t-AML with and without RT in addition to CTX (Table 2). Pts were more likely to develop t-AML if they were treated with both RT and CTX for lung cancer (ERR 1.85, 95%CI, 1.24-2.78), breast cancer (ERR 1.36, 95%CI, 1.13-1.65), and ovarian cancer (ERR 1.70, 95%CI, 0.83-3.47) compared to pts who were treated with CTX alone. When analyzed by different calendar periods of diagnosis, the risk of t-AML in pts with HL, NHL and myeloma was lower following combined modality compared to chemotherapy alone in recent time periods (1997-2007, 2008-2018) compared to earlier years of diagnosis. We also identified trends of t-AML risk over time, displayed in 11-year intervals from 1975-2018 (Table 2). Ptrend was calculated using annual SIRs over the study period. In patients who received CTX for their first primary malignancy, irrespective of RT, we found that t-AML risk has significantly declined after CTX for lung cancer (Ptrend < 0.001), HL (Ptrend = 0.003), and myeloma (Ptrend = 0.001). Over the same period, the risk of t-AML increased in breast cancer (Ptrend < 0.001) and NHL (Ptrend < 0.001). Conclusions: In our study spanning the past 40 years, we observed the risk of t-AML trending down for lung cancer, HL, and myeloma while increasing for breast cancer and NHL. A notable finding was increasing risk of t-AML with increasing latency in myeloma. Of interest, the risk of t-AML with combined modality regimens (CTX and RT) in recent time periods is lower than chemotherapy alone for HL, NHL and myeloma. Based on these observations, it is imperative to analyze the impact of newer therapies on the risk of t-AML, which will greatly benefit risk-benefit counseling of pts at individual level. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Comparison of fragment analysis and PCR electrophoresis methods for the detection of FLT3‑ITD mutations in patients with acute myeloid leukemia

Background. The presence of the FLT3-ITD mutations in patients with AML serves as a marker of poor prognosis, which is included in the ELN 2017 risk stratification guideline. The main criterion for dividing patients into groups according to the predicted outcomes was the allelic ratio (AR) with a cutoff of 0.5: an AR value &lt;0.5 is considered low, and ≥0.5 is considered high. At the same time, if the importance of AR determination is beyond doubt, the value of information about the length of the repeat and localization is still controversial. There are two common approaches for FLT3-ITD screening. The first, more accessible and cheaper method is the method of pCR electrophoresis and the second, more expensive and requiring special equipment, is the fragment analysis method, which allows not only to detect a mutation and determine the repeat length, but also to quantify or calculate AR.Aim. To compare fragment analysis and pCR electrophoresis in the search for the FLT3-ITD mutations in dNA samples from AML patients.Materials and methods. for the period of 2020–2022 fragment analysis and pCR electrophoresis were used to analyze blood and/or bone marrow samples taken from 45 patients with a confirmed diagnosis of AML who were treated at the Regional Clinical Hospital (Krasnoyarsk). Confirmation and identification of the FLT3-ITD mutations was performed by means of Sanger sequencing.Results. both methods revealed the FLT3-ITD mutations in 11 (24.45 %) patients among the 45 patients studied. According to the results of fragment analysis, the median repeat length was 42.70 base pairs (range 26.01–99.84 base pairs), AR was 0.532 (0.027–3.328), and the allelic frequency (Af) was 34.71 (2.67–76.90) %. Three different ITds were identified in one sample. Sanger sequencing identified mutations in 9 of 11 patients.Conclusion. fragment analysis and pCR electrophoresis showed similar results when analyzing samples with different ITd lengths and with different allelic ratios. but it can be assumed that in the case of a small ITd and low AR and Af values, when using pCR electrophoresis, the mutant allele will not be visualized, which can lead to a false negative result. The disadvantage of using the pCR electrophoresis method is also that without the use of special programs that allow determining the size and intensity of the band corresponding to the mutant allele, it is impossible to determine the AR value, which is important for AML risk stratification. Thus, for detection of the FLT3-ITD we recommend using the fragment analysis method.

Evaluation of miR-143 rs4705342 and miR-222 rs2858060 genetic variants in patients with acute myeloid leukemia

Background and aimConsidering the importance of miR-143 and miR-222 in carcinogenicity and the importance of miRSNPs in acute myeloid leukemia, this research was done to investigate the association of miR-143 rs4705342 and miR-222 rs2858060 polymorphisms with AML. Methods and materialsIn this investigation, 150 AML patients and 150 healthy subjects participated. Genotyping of selected polymorphisms was detected by T-ARMS-PCR technique, and data was analyzed using the SPSS (version 24) software. ResultsOur findings showed that the miR-143 rs4705342 TC genotype and C allele increase the susceptibility to AML (P < 0.001). Moreover, the miR-222 rs2858060 CC genotype (P = 0.019) increases the risk of AML, and the C allele in this polymorphism showed an increased risk for AML in the dominant mode (P = 0.022). Haplotypes CC (OR:8.78, P < 0.001), CT (OR:0.42, P < 0.001) and GT (OR:0.61, P = 0.003) showed significant association with AML. ConclusionWe reported for the first time, miR-143 rs4705342 and miR-222 rs2858060 polymorphisms are associated with increased AML risk in Iranian subjects.

Patient Preferences for Benefits, Risks, and Administration Route of Hypomethylating Agents in Myelodysplastic Syndromes.

Therapy with infused or injected hypomethylating agents (HMAs) may lead to higher treatment administration burden (ie, local reaction, visit frequency and duration) vs. oral HMAs. OBJECTIVES: To reveal preferences of US and Canadian patients with myelodysplastic syndromes (MDS) for HMAs' benefits, risks, and administration burden through an online discrete-choice experiment (DCE). Choice of DCE attributes and survey development were informed by literature review and interviews with clinicians, MDS patients, and caregivers serving as patient proxies, and patient advocacy groups (PAGs) representatives, including from AAMAC, AAMDS, and MDSF. DCE choice tasks were analyzed using random parameter logit models. Survey patients were recruited by the PAGs via their networks. To understand key preference drivers and how much patients were willing to trade between attributes, we calculated each attribute's relative attribute importance (RAI) and marginal rates of substitution. One hundred eighty-four respondents (including 158 patients; mean age, 67.2 years; male, 50.5%; White, 50.5%; US residents, 88%) completed the survey. MDS risk was low (34.8%), high (30.9%), or unknown (34.2%). RAI (in decreasing order) was as follows: risk of AML (40%), fatigue level (33%), number of visits (12%), mode of administration (6%), visit duration (5%), and administration frequency (4%). Assuming the same risk of AML transformation or level of fatigue, most respondents (76.6%) were predicted to switch to an oral pill if it were available to them. Given equivalent effectiveness across HMAs, patients' preferences for HMA administration method should be considered in treatment decision-making to minimize burden and facilitate adherence.

GENETIC POLYMORHISM OF CASPASE 8 AND 9 IN IRAQ

This study examined the potential association between polymorphisms of Caspase 9 −293del (rs4645982) and Caspase8−652 6N ins / del (rs3834129) and the danger of acute and chronic myeloid leukaemia in Iraqi population. This case-control study was conducted as 128 (62 acute, and 66 chronic) myeloid leukaemia patient and 65 healthy individuals not infected with cancer. A conventional PCR method was used for detection in this study. The results showed that the Caspase9 −293del (rs4645982) in homozygous and heterozygous deletion genotypes were associated significantly with CML risk ( p= 0.001 and 0.005 ,respectively ) and in homozygous insertion and deletion genotypes of Caspase 8 -652 6N were also associated significantly with CML risk (p= 0.004 and p= 0.00, respectively), while there were non significant association between Caspase9 −293del (rs4645982) and Caspase8 −652 6N (rs3834129) with AML risk in all genotypes of them p &gt; 0.05. These findings suggest that polymorphisms in the Caspase-9 and Caspase-8 genes might be useful markers for determining genetic susceptibility to CML and AML. The results of this study suggest that Caspase9-293 is associated with increased risk of CML in case of homozygous of deletion, and insertion in case of AML, while in Caspase8-652 6N insertion polymorphism are associated with increased risk of both CML and AML in a sample of Iraqi populations.