History Of Myelodysplastic Syndrome Research Articles

Spontaneous Splenic Rupture in a Patient with Myelodysplastic Syndrome

Introduction: Myelodysplastic syndrome (MDS) is a clonal hematopoietic disorder with a risk of progression to acute myeloid leukaemia. This case report discusses a rare instance of spontaneous splenic rupture in a patient with MDS. Case Report: A 76-year-old male with a history of MDS presented with acute abdominal pain and was found to have a splenic rupture. Despite declining chemotherapy, the patient underwent an emergency splenectomy after a CT scan revealed hemoperitoneum. Post-surgery, the patient experienced hypovolemic shock, necessitating a second operation. Discussion: Splenic rupture in MDS is uncommon and its pathogenesis is not fully understood. Management of MDS is complex, often requiring a multidisciplinary approach. This case emphasizes the importance of considering patient preferences in treatment decisions and highlights the role of next-generation sequencing in understanding MDS pathogenesis. Conclusion: The case underscores the need for vigilance in managing MDS due to potential complications like splenic rupture. It also illustrates the importance of personalized care and advances in genetic profiling in predicting prognosis and guiding treatment in MDS.

First-in-human, phase 1/2 study of GSK4524101, an oral DNApolymerase theta inhibitor (POLQi), alone or combined with the poly(ADP-ribose) polymerase (PARP) inhibitor (PARPi) niraparib in adults with solid tumors.

TPS3174 Background: Double-stranded DNA breaks (DSBs) in human cells are typically repaired via nonhomologous end joining (NHEJ) or homologous recombination (HR). Deficiency of HR-mediated DNA repair plays a role in the initiation and progression of many tumor types. In tumors with HR deficiency, PARP inhibition leads to generation of DSBs that cannot be effectively repaired because of the HR defect, resulting in synthetic lethality. This finding has led to the clinical development and approval of several PARPi for the treatment of various tumors including certain ovarian, breast, prostate, and pancreatic cancers that are prone to display HR deficiency (HRd). DNA polymerase theta (encoded by POLQ) mediates an alternative DNA repair mechanism, microhomology-mediated end joining (MMEJ). DNA polymerase theta is generally not detectable in normal tissues but is upregulated in many tumor types. In preclinical studies, POLQi plus PARPi treatment demonstrated superior efficacy to PARPi alone in preventing the growth of HRd tumors. To evaluate the clinical potential of combining POLQi and PARPi, this first-in-human study investigates treatment with GSK4524101, an investigational POLQi, with or without the PARPi niraparib, in patients with solid tumors. Methods: This open-label, multicenter, phase 1/2 study (NCT06077877) opened in October 2023 and comprises dose-finding (part 1, including a food-effect cohort) and dose-expansion (part 2) parts. This trial aims to assess the maximum-tolerated dose, pharmacokinetics, safety, and preliminary antitumor activity of oral GSK4524101 with or without niraparib. The primary endpoints are safety (part 1) and confirmed objective response rate (part 2). Secondary endpoints include pharmacokinetics, safety, progression-free survival (part 2), and response duration (part 2). Up to 135 patients may be enrolled. To be eligible, patients must be aged ≥18 years; have an advanced or metastatic solid tumor, an Eastern Cooperative Oncology Group performance status score of 0–2, and a life expectancy of ≥3 months; and have exhausted all standard treatment options. Individuals are ineligible if they have not recovered from chemotherapy-associated adverse events or have symptomatic uncontrolled brain or leptomeningeal metastases, a history of myelodysplastic syndrome or acute myeloid leukemia, uncontrolled hypertension, or a second malignancy that has progressed or required active treatment in the previous 2 years. The study is actively recruiting in the US and Canada; as of January 1, 2024, 1 patient has been dosed. Patients enrolled in part 1 will receive GSK4524101 alone or GSK4524101 plus niraparib; patients enrolled in part 2 will be randomized to either GSK4524101 plus niraparib or niraparib alone. Part 1 of this study is expected to complete in 2025. Data presented on behalf of the original authors with their permission. Presented at the American Association for Cancer Research (AACR) Annual Meeting 2024; April 5-10, 2024; San Diego, CA. Final publication number: 9686. Reused with permission. Clinical trial information: NCT06077877 .

Abstract CT169: First-in-human, phase 1/2 study of GSK4524101, an oral DNA polymerase theta inhibitor (POLQi), alone or combined with the poly(ADP-ribose) polymerase (PARP) inhibitor (PARPi) niraparib in adults with solid tumors

Abstract Background: Double-stranded DNA breaks (DSBs) in human cells are typically repaired via nonhomologous end joining (NHEJ) or homologous recombination (HR). Deficiency of HR-mediated DNA repair plays a role in the initiation and progression of many tumor types. In tumors with HR deficiency, PARP inhibition leads to generation of DSBs that cannot be effectively repaired because of the HR defect, resulting in synthetic lethality. This finding has led to the clinical development and approval of several PARPi for the treatment of various tumors including certain ovarian, breast, prostate, and pancreatic cancers that are prone to display HR deficiency (HRd). DNA polymerase theta (encoded by POLQ) mediates an alternative DNA repair mechanism, microhomology-mediated end joining (MMEJ). DNA polymerase theta is generally not detectable in normal tissues but is upregulated in many tumor types. In preclinical studies, POLQi plus PARPi treatment demonstrated superior efficacy to PARPi alone in preventing the growth of HRd tumors. To evaluate the clinical potential of combining POLQi and PARPi, this first-in-human study investigates treatment with GSK4524101, an investigational POLQi, with or without the PARPi niraparib, in patients with solid tumors. Methods: This open-label, multicenter, phase 1/2 study (NCT06077877) opened in October 2023 and comprises dose-finding (part 1, including a food-effect cohort) and dose-expansion (part 2) parts. This trial aims to assess the maximum-tolerated dose, pharmacokinetics, safety, and preliminary antitumor activity of oral GSK4524101 with or without niraparib. The primary endpoints are safety (part 1) and confirmed objective response rate (part 2). Secondary endpoints include pharmacokinetics, safety, progression-free survival (part 2), and response duration (part 2). Up to 135 patients may be enrolled. To be eligible, patients must be aged ≥18 years; have an advanced or metastatic solid tumor, an Eastern Cooperative Oncology Group performance status score of 0-2, and a life expectancy of ≥3 months; and have exhausted all standard treatment options. Individuals are ineligible if they have not recovered from chemotherapy-associated adverse events or have symptomatic uncontrolled brain or leptomeningeal metastases, a history of myelodysplastic syndrome or acute myeloid leukemia, uncontrolled hypertension, or a second malignancy that has progressed or required active treatment in the previous 2 years. The study is actively recruiting in the US and Canada; as of January 1, 2024, 1 patient has been dosed. Patients enrolled in part 1 will receive GSK4524101 alone or GSK4524101 plus niraparib; patients enrolled in part 2 will be randomized to either GSK4524101 plus niraparib or niraparib alone. Part 1 of this study is expected to complete in 2025. Citation Format: Vivek Samnotra, Veronica Moroz, Luda Shtessel, Mita Kuchimanchi, Patrick Hanafin, Malar Pannirselvam, Aishwarya Bhaskar, Andrew Liu, Haluk Yuzugullu, Minal Barve, David Sommerhalder, Timothy Yap, Michele Sanicola-Nadel. First-in-human, phase 1/2 study of GSK4524101, an oral DNA polymerase theta inhibitor (POLQi), alone or combined with the poly(ADP-ribose) polymerase (PARP) inhibitor (PARPi) niraparib in adults with solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT169.

Ocular and orbital manifestations in VEXAS syndrome

BackgroundVEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) is a hematoinflammatory disease that typically affects adults. It results from a somatic mutation of the E1 ubiquitin conjugating enzyme encoded by the UBA1 gene. VEXAS is frequently accompanied by myelodysplastic syndrome (MDS). The purpose of this study is to describe the ocular and orbital manifestations of VEXAS patients in a case series in our medical centre.MethodsA retrospective chart review was performed for all patients who were diagnosed with VEXAS syndrome in a tertiary medical centre over two years.ResultsEight patients were identified with VEXAS. In six patients, the diagnosis was confirmed by genomic sequencing. Two patients were identified based on their phenotype. All patients were males. The mean age at diagnosis was 78.7 years. In two patients, the ocular manifestation was the presenting symptom for VEXAS. Seven patients (87.5%) had history of MDS. Systemic inflammation manifestations include: skin rash (n = 5), recurrent fevers (n = 2), relapsing polychondritis (n = 2), pleuritis and pleural effusion (n = 2), poly arteritis nodosa- PAN (n = 1) and thrombophlebitis (n = 1). Seven (87%) patients were presented with periorbital oedema. Three patients showed orbital inflammation. Dacryoadenitis was observed in two patients, and extraocular muscle (EOM) myositis was detected in two patients. Four patients demonstrated ocular inflammation such as: episcleritis, scleritis and anterior uveitis.Conclusionocular manifestations in VEXAS include orbital inflammation, dacryoadenitis, myositis, uveitis, scleritis, episcleritis and periorbital oedema. We recommend that in old male patients, with history of haematological disorder, presenting with ocular symptom, VEXAS investigation should be taken into consideration.

A Phase 2 Study of the Fully Oral Combination of ASTX727 (Decitabine/Cedazuridine) Plus Venetoclax for Older and/or Unfit Patients with Acute Myeloid Leukemia

Background: The combination of a hypomethylating agent (HMA) plus venetoclax is the standard of care for patients (pts) with acute myeloid leukemia (AML) who are older (age ≥ 75 yrs) and/or unfit for intensive chemotherapy. ASTX727 (oral decitabine/cedazuridine) is an oral formulation of decitabine with pharmacokinetic AUC equivalent exposures to IV decitabine. We performed a phase 2 study to evaluate the efficacy and safety of ASTX727 plus venetoclax in the frontline (FL) and relapsed-refractory (R/R) settings. Methods: Pts ≥ 18 yrs with WHO 2016-defined AML were eligible. The FL cohort enrolled newly diagnosed pts with ECOG ≤ 3 who were either ≥ 75 yrs or ineligible for intensive chemotherapy due to comorbidities. Pts ≥ 18 yrs and ECOG ≤ 2 were eligible for the R/R cohort. Pts with a history of myelodysplastic syndrome (MDS), including previously treated MDS, were eligible. Treatment consisted of ASTX727 (decitabine/cedazuridine) 35/100 mg PO daily x 5 days and venetoclax 400 mg PO daily (adjusted for azoles) for 28 days during induction (held if blast clearance on day 21 bone marrow examination) and 21 days in consolidation. Dose reductions were permitted for toxicity/tolerability. Therapy was administered in 28-day cycles for up to 24 cycles. Risk stratification and responses were determined per ELN 2022. This study was registered on ClinicalTrials.gov (NCT04746235). Results: 52 pts have been enrolled (42 in the FL and 10 in the R/R cohorts). In the FL cohort, the median age was 79 yrs (range 50-92). 17/42 (40%) pts had antecedent MDS (including 8 [19%] with treated secondary AML) and 6/42 (14%) had therapy-related AML (t-AML). By ELN 2022, 6 (14%) were favorable, 3 (7%) were intermediate, and 33 (79%) were adverse. 9/42 (21%) had complex cytogenetics and 6 (14%) had TP53 mutations. In the R/R cohort (n=10), the median age was 71 yrs (46-75). 2 (20%) pts had antecedent MDS and 2 (20%) had t-AML. By ELN 2022, 3 (30%) were intermediate and 7 (70%) were adverse. 5/10 (50%) had complex cytogenetics and 2/10 (20%) had TP53 mutations. The median prior lines of therapy in the R/R cohort was 2 (1-4), with 5 (50%) pts with 2 or more prior lines of therapy. The median number of cycles given was 3 (1-12). In the FL cohort, the ORR was 67% (28/42 pts: 15 [36%] CR, 11 [26%] CRi, 2 [5%] MLFS). In responding FL pts, measurable residual disease (MRD) by flow cytometry became undetectable in 7/22 (32%) pts with adequate samples. In the R/R cohort, the ORR was 50% (5/10 pts: 3 [30%] CR, 2 [20%] CRi). The median number of cycles to first and best response were 1 (1-4) and 1 (1-7), respectively. At a median follow-up of 12.8 months, the median OS was 12.7 months in the FL cohort and 7.6 months in the R/R cohort (figure A). In pts achieving CR/CRi (n=26 FL and 5 RR), the median RFS was 9.8 months in the FL and 4.6 months in the R/R cohort (figure B). The median DOR was 13.2 and 4.6 months the FL and R/R settings, respectively. 2 (4%) pts (1 FL and 1 R/R) went off protocol to undergo stem cell transplantation. We then stratified the FL pts into 3 genetic groups (group 1: TP53 wt, K/NRAS wt, no FLT3-ITD; group 2: TP53 wt, K/NRAS mut or FLT3-ITD positive; group 3: TP53 mut) as previously described (Döhner, ASH 2022). The median OS in group 1 (n=24), group 2 (n=12), and group 3 (n=6) was 16.2, 9.1, and 1.4 months, respectively. In FL pts achieving CR/CRi, the median RFS in group 1 (n=17), group 2 (n=7), and group 3 (n=2) was 13.2, 8.1, and 9.8 months, respectively. OS in the FL cohort was similar between the pts under 80 yrs (n=21, median 12.7 months) vs those 80+ yrs (n=21, median 14.8 months), p=0.98. The most common grade 3/4 adverse events were neutropenic fever (23%), pneumonia (13%), bacteremia (8%), cellulitis (6%), sepsis (6%), and respiratory failure (6%). 4-wk and 8-wk mortality were 10% and 15%, respectively. The median time to cycle 2 was 38 days (26-70). In pts who experienced count recovery during cycle 1, the median time to platelets > 50 x 10 9/L and absolute neutrophil count > 1.0 x 10 9/L was 23 (18-55) and 42 (28-69) days, respectively. Cycle 2 dose reductions occurred in 27/42 (64%) pts (21 venetoclax dose reductions, 6 both drugs reduced). Of the 29 observed deaths, 15 (52%) occurred in non-responders, 11 (38%) following AML relapse, and only 3 (10%) in pts with ongoing response (1 sepsis, 1 GI hemorrhage, and 1 electing to pursue hospice). Conclusions: In this older and very high-risk population of pts with AML, an entirely oral regimen consisting of ASTX727 and venetoclax was effective and tolerable.

Selinexor in Combination with Venetoclax and Azacitidine for Newly Diagnosed (ND) Unfit Acute Myeloid Leukemia (AML): A Multicenter, Open-Label Prospective Study

Introduction: Acute myeloid leukemia (AML) predominantly affects the elderly, with a median age at diagnosis around 68 years (Bhansali, 2023). Due to existing or potential comorbidities and frailty, many patients are unable to undergo conventional intensive chemotherapy at the time of diagnosis. The combination of venetoclax with azacytidine has shown improved clinical response rates of 64% with a median overall survival of 14.7 months (DiNardo, 2020). However, subgroup data demonstrated no significant benefits in the Chinese population, in pts with poor risk, or in those with TP53 mutations. Therefore, managing AML in elderly or unfit pts remains a significant challenge. Selinexor has shown promising tolerability and clinical activity in AML through various phase 1/2 trials. The triple regimen of selinexor, venetoclax, and azacytidine (SAV) has demonstrated favorable results in AML pts with severe co-morbidities in real-world settings. To further evaluate its efficacy and safety, we have designed a prospective study (NCT05736965) to assess the SAV regimen for ND AML pts who are ineligible for intensive therapy. Methods: To report the efficacy and safety of ND AML pts ineligible for intensive chemotherapy, treated with a triple regimen from 6 sites. The study enrolled pts who were unfit for intensive chemotherapy, ≥75 years, had significant comorbidities, an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of ≥3, organ dysfunction, or had abandoned intensive chemotherapy. The primary study objectives were the complete response (CR)/complete response with incomplete count recovery (CRi) rate and overall response rate (ORR). Responses were assessed according to the ELN2022 criteria. Pts received the following treatment regimen: Selinexor 60mg on days 3, 10, and 17; Azacitidine 75mg/m2 on days 1-3, 8-9, and 15-16; Venetoclax 100mg on day 1, 200mg on day 2, and 400mg on days 3 to 14. Each treatment cycle lasted for 28 days. Pts who achieved CR, CRh, or CRi, as per the center's treatment guidelines, were eligible for transplantation at any time point. Remaining pts continued to receive the SAV regimen until disease progression or intolerable toxicity. Results: From March 2023 to the data cutoff on June 10, 2023, a total of 20 pts were enrolled in the study, of which 16 had de novo or therapy-related AML, and 4 had secondary AML with a history of myelodysplastic syndrome. Table 1 displays the baseline characteristics and responses of the newly diagnosed AML pts. The median age of the 20 pts was 64 years (range: 28-80), and the majority of them had high-risk disease: 12/20 (60%) had intermediate-risk, and 8/20 (40%) had adverse-risk according to the ELN 2022 criteria. Additionally, 4/20 (20%) of the pts had therapy-related AML, 6/20 (30%) were aged ≥75 years, 12/20 (60%) had ≥2 high-risk molecular mutations, and a significant proportion had high blast counts. All pts completed at least 1 cycle of treatment (range: 1-4). Specifically, 1patient completed 4 cycles, 2pts completed 3 cycles, and 7pts completed 2 cycles. The remaining 10pts have just completed their first cycle of treatment and evaluation. With the exception of one patient with disease progression (PD), all other pts are still undergoing treatment. As the treatment duration extends, the depth of remission in pts may further deepen. The CR/CRi rates and ORR across the ELN 2022 risk groups for all pts, intermediate-risk group, and adverse-risk group were as follows: 80% (16/20) and 90% (18/20), 75% (9/12) and 91.7% (11/12), 87.5% (7/8) and 87.5% (7/8), respectively. In comparison, the VIALE-A data showed a CR/CRi rate of 52.9% for adverse-risk pts, indicating a higher remission rate observed in this study. As of now, 3 pts were MRD-negative. The reported adverse events of grade 3 or higher occurring in ≥10% of pts in the triple regimen were thrombocytopenia (35%), neutropenia (35%), and infections (15%). The most frequently reported adverse events of Grade 1-2 included anemia, nausea, fatigue, anorexia, and hyponatremia. All adverse events could be managed and improved through dose adjustments and supportive treatment. Conclusions: The SAV regimen has been found to be safe and effective, with encouraging complete response (CR) rates in newly diagnosed AML pts, especially in adverse risk patients. Further trial enrollment and correlative analysis are currently underway to thoroughly observe the efficacy and safety of the SAV regimen.

Defining Primary Vs Secondary AML: Correlation between Pathology and NGS/FISH

Introduction: The treatment of acute myelogenous leukemia (AML) is often determined by factors that include an antecedent dysplasia. At presentation it is often unknown whether a patient has had dysplastic bone marrow features or not. We opted to look back at our leukemia patients to determine the frequency of antecedent dysplasia and to determine if next generation sequencing (NGS) or Florescent in situ hybridization (FISH) findings correlate with the pathologic review. Methods: We chart reviewed 43 charts from a period of 9/21/2021 to current from Orlando Health records. We focused on 29 charts that we could gather complete information from. We reviewed initial bone marrow biopsies and NGS/ FISH findings. We determined if a patient had a known history of myelodysplasia from previous records. If there was no known history of myelodysplastic syndrome (MDS) but dysplasia was seen on the bone marrow biopsy, we looked at NGS/FISH. While there can be overlap with AML, findings that suggest MDS are as follows: NGS: TET2, NRAS, U2AF1, RUNX1, TP53, SF3B1 FISH: 5q-, -5 (5p15, 5q31, 5q33), 7q-, -7 (Cen 7, 7q22, 7q31), Trisomy 8 (Cen 8), MLL (11q23), 20q- (20q12, 20qter) We then examined what treatments were used based on these findings. Results: Overall: 11/29 patients had dysplasia mentioned in their initial pathology report. 4/11 had a known preexistent dysplasia. Of the 7 who didn't have known dysplasia, 6/7 had an NGS or FISH suggesting MDS. Age: Of the patient who had dysplastic findings as well as NGS/FISH to support those findings, the patients had an average age of 57. The one patient without MDS/FISH findings has an age of 69. The average age of all patients with dysplastic findings on their bone marrow was 60. Of the patients who did not have any dysplastic findings on the bone marrow, the average age was 58. Treatment: Vyexos (liposomal daunorubicin and cytarabine), a therapy generally used for secondary leukemias was only used in two patients. Age and performance status was cited as a reason to use alternative therapy. Although one patient did receive 7+3 (idarubicin and cytarabine) instead of Vyxeos. One patient also had severe COVID pneumonia at diagnosis as the reason for not getting induction with Vyexos and instead getting venetoclax/azacitidine. Four patients were either treated with hypomethylating agent of either azacitidine or decitabine, again this was normally chosen due to performance status, age, or active COVID pneumonia as above. Conclusion: These results show that pathology findings of underlying dysplastic changes seem to correlate with NGS or FISH findings. Of the 7 patients with these bone marrow changes but no known MDS, 6 of them had NGS or FISH to support an underlying disease. Factors such as age did not help to predict antecedent MDS. Based on this information it may be appropriate to start with induction therapies such as Vyxeos when dysplastic changes are seen on the bone marrow while FISH and NGS are still pending, if their performance status and age allow to do so. Further larger retrospective studies to compare underlying dysplastic findings versus FISH/NGS findings should be done to further support this concept.

Treatment Patterns and Outcomes of Patients with Primary or Secondary Acute Myeloid Leukemia By Type of Site (Academic or Community/Government): A CONNECT® Myeloid Registry Study

Introduction Up to 30% of acute myeloid leukemias (AML) evolve from prior hematologic disorders and are classified as secondary AML. Secondary AML is traditionally associated with worse prognosis than de novo, or primary, AML, resulting in inferior response rates and poorer survival. The treatment landscape for AML has evolved recently with the introduction of venetoclax (VEN) and the availability of targeted agents. To better understand evolution of the management of secondary AML, we evaluated treatment patterns and outcomes in patients (pts) with primary AML vs secondary AML treated in real-world clinical practice and enrolled in the CONNECT® Myeloid Disease Registry (NCT01688011) by type of site (academic or community/government). Methods Pts were classified as having either primary or secondary AML based on history of myelodysplastic syndrome (MDS) or progression from MDS to AML. Overall survival (OS) from the date of AML diagnosis, estimated by the Kaplan-Meier method, was evaluated in each group according to type of site (academic or community/government), utilization of allogeneic hematopoietic stem cell transplantation (alloHSCT), and tumor protein p53 (TP53) mutational status. Time to adoption of a VEN-based therapy, defined as first use of VEN-based therapy following Food and Drug Administration (FDA) approval in this setting, was evaluated using a Cox model with factors for age (< 75 and ≥ 75 y), type of site, and geographic region. Results A total of 891 pts in the Registry with a diagnosis of AML were assessed (primary AML, n = 676; secondary AML, n = 215). Median (range) ages were 70 (55-97) y in the primary AML group and 74 (19-93) y in the secondary AML group. Most pts were male (primary AML, 61.6%; secondary AML, 61.5%) and most were treated at community or government centers (primary AML, 60.2%; secondary AML, 66.0%). Pts with primary AML had significantly longer survival than pts with secondary AML; median OS (95% confidence interval [CI]) was 15.6 (13.6-17.4) mo and 5.1 (3.6-6.7) mo, respectively (P < 0.001). Median OS for pts with primary AML and secondary AML treated at academic centers was 17.0 mo and 5.6 mo, respectively (hazard ratio [HR] [95% CI], 0.41 [0.30-0.54], P < 0.001) and in community/government centers was 14.1 mo and 5.2 mo, respectively (HR [95% CI], 0.53 [0.43-0.66], P < 0.001). There was no significant difference in median OS in pts treated at academic centers compared with pts treated at community/government centers for both primary AML (academic vs community/government centers: 17.0 mo [95% CI, 14.7-20.7] vs 14.1 mo [11.0-16.9]; Figure 1A) and secondary AML (5.0 mo [95% CI, 3.0-7.2] vs 5.1 mo [3.7-7.3]; Figure 1B). Significantly longer median OS in pts with primary AML vs secondary AML was observed regardless of alloHSCT status (no alloHSCT: 11.7 mo vs 4.5 mo; HR [95% CI], 0.53 [0.44-0.64], P < 0.001; with alloHSCT: 64.3 mo [35.8-NC] vs 24.9 mo [6.8-48.9], P = 0.002]. Longer median OS was observed among pts who received alloHSCT compared with those without alloHSCT: primary AML, 41.1 mo vs 12.8 mo; secondary AML, 24.9 mo vs 4.4 mo; additional analyses are warranted to account for immortal time bias. Regardless of TP53 mutation status, pts with primary AML had significantly longer median OS than pts with secondary AML (no mutation: 22.0 mo [17.6-26.1] vs 6.2 mo [2.5-12.6], P < 0.001; with mutation: 8.8 mo [3.9-14.2] vs 3.8 mo [1.4-6.8], P = 0.014). VEN-based therapies were adopted more quickly by pts aged ≥ 75 y vs < 75 y (P < 0.001) and those treated at community or government centers vs academic centers (P = 0.045); no association between geographic region and time to adoption of VEN-based therapies was observed. Conclusions Overall, outcomes of pts with AML in the CONNECT® Myeloid Disease Registry are consistent with previously reported outcomes. Median OS is longer in primary AML vs secondary AML regardless of whether pts receive alloHSCT or have mutations in TP53. This analysis suggests that contrary to commonly held perceptions, site of care does not affect overall pt outcome and that VEN adoption occurs sooner at community centers. The clinically meaningful increase in OS in pts receiving alloHSCT, when compared with pts without alloHSCT, regardless of primary or secondary AML further emphasizes the importance of providing pts with the opportunity for transplant. These observations merit further study into potential differences in treatment patterns and outcomes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

P411: SF3B1 MUTATIONS IN AML ARE STRONGLY ASSOCIATED WITH MECOM REARRANGEMENTS AND MAY BE INDICATIVE OF AN MDS PRE-PHASE

Background: Mutations in the splicing factor gene SF3B1 are most frequent in myelodysplastic syndrome (MDS) or myelodysplastic/myeloproliferative neoplasm (MDS/MPN) but are also recurrently found in acute myeloid leukemia (AML). Splicing factor mutations have been suggested to have additive value if incorporated into the current risk classification of AML (van der Werf et al., Blood Advances 2021). Aims: Explore the genetic landscape of SF3B1 mutated AML and determine the prognostic impact of SF3B1 mutations. Methods: We analyzed 735 patients diagnosed with AML based on cytomorphology, cytogenetics, and molecular genetics according to WHO classification 2017. Reads from amplification-free whole genome sequencing (WGS, median coverage 103x, Illumina, San Diego, CA) were aligned to the human reference genome (GRCh37, Ensembl annotation, Isaac aligner) and variants were called using Strelka Somatic Variant Caller v2.4.7. Results: We identified SF3B1 mutations in 41 of 735 (6%) AML patients. SF3B1 mutations were found in AML with recurrent genetic abnormalities (24/471; 5%), AML with myelodysplasia-related changes (MRC; 11/158; 7%) and AML not otherwise specified (NOS; 6/106; 6%). When focussing on SF3B1mut cases, AML-MRC (11/41; 27%) and AML with GATA2::MECOM (10/41; 24%) were most frequent. 9 additional cases showed another MECOM rearrangement (-rear) resulting in 46% (19/41) of patients with SF3B1 mutations accompanied by a MECOM-rear. A prior history of MDS or MDS/MPN was documented in 20% (8/41) of SF3B1mut patients. Thereof, 63% (5/8) harbored a MECOM rearrangement and 25% RUNX1mut. On average, SF3B1mut patients harbored 2.85 mutations (including SF3B1). The most frequent additional mutations of SF3B1mut patients were RUNX1 (9/41; 22%) and NRAS (8/41; 20%), and NPM1, TET2, or DNMT3A mutations or FLT3-ITD were detected in 15% (6/41) each. SF3B1 showed an average variant allelic frequency (VAF) of 41%. Notably, the VAF of SF3B1 in AML with NPM1 or RUNX1 was higher than the VAFs of NPM1 or RUNX1 in 9/11 (82%) cases, suggesting that SF3B1 preceded these mutations. In 16/41 (39%) cases molecular follow-up data was available. The SF3B1 mutation persisted during the entire disease course in 8 cases (including 1 with relapse). In particular, in two of these AML patients with mutated NPM1, the SF3B1 mutation remained detectable by NGS, despite complete hematologic remission and undetectable NPM1 mutation by high-sensitive qPCR. In all 5 cases with relapse the SF3B1 mutation re-occurred at relapse. In 4 patients, the VAF of SF3B1 decreased, similar to accompanying mutations. In contrast to MDS, SF3B1 mutations did not affect the overall survival (median OS: 16.9 months in SF3B1mut; 5.7 months in unmutated group; p=0.822) in the total AML cohort. When stratified for AML sub-entities, the prognosis of the SF3B1mut AML seems to be dominated by the sub-entity. Image:Summary/Conclusion: Within AML, SF3B1 mutations are enriched in AML patients with GATA2::MECOM and AML-MRC. This association with poor risk subtypes dominates the prognosis of SF3B1mut AML. The high VAF of SF3B1 mutations and the persistence of SF3B1 mutations in AML patients in complete remission suggest the early acquisition of SF3B1 mutations in a pre-leukemic clone in a number of patients. While an antecedent MDS or MDS/MPN has been documented in some cases of SF3B1mut AML, it might be unidentifiable in others. Alternatively, SF3B1mut clonal hematopoiesis of indeterminate potential (CHIP) may represent a relevant pre-phase of SF3B1mut AML.

Clinical Efficacy of Haplo-HSCT of ATG Combined with PTCy for Children with Myelodysplastic Syndrome

To investigate the efficacy and safety of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) in combination of ATG and post-transplant cyclophosphamide (PTCy) -induced immune tolerance after transplantation in treatment of childhood myelodysplastic syndromes(MDS）. From July 2016 to November 2020, a total of 8 children with MDS receiving the haploidentical allo-HSCT combined with ATG and PTCy-induced immune tolerance after transplantation in our hospital were enrolled, whose clinical data were retrospected and analyzed. Median age at diagnosis of the 8 children (1 male and 7 females) was 6.4 (range, 10 months to 15 years) years old. The median medical history of MDS was 2.7 years (range, 3 months to 8 years). Among the 8 patients, 7 cases were diagnosed with refractory cytopenia of childhood and one with refractory anemia with excess of blasts. The HSC donors were father, mother or brother of patients and HLA matching in 6-9/12 loci were identical. All the donors were healthy and didn't carry the same pathogenic genes as the recipients. The median age of donors was 36.4 (range, 25 to 49) years old. The median mononuclear cell (MNC) number of the graft was 19.8, ranging in (13.2-47.3)×108/kg, and the median CD34+ cell number was 11.8×106/kg, ranging in (5.0-18.3)×106/kg. Graft-versus-host disease prophylactic regimen was started on day 3 and 4 after transplantation, in which cyclophosphamide (50 mg/kg·d) was administered by intravenous infusion. From day 5 after transplantation, low-dose tacrolimus was administered by intravenous infusion and mycophenolate mofetil was administered orally. The median time of neutrophil and platelet engraftment was 12.6 (rang, 11 to 15) days and 13.3 (rang, 11 to 18) days, respectively. All the patients achieved full donor chimerism on neutrophil engraftment after transplantation. The median follow-up time was 1 032 (rang, 747 to 1 536) days. Both overall survival rate and disease-free survival rate were 100%. Haplo-HSCT combined with ATG and PTCy-induced immune tolerance after transplantation is a safe and effective treatment for children with MDS.

Abstract OT2-24-02: ZEST: Randomized phase III study evaluating efficacy and safety of niraparib in patients with HER2-negative BRCA-mutated or triple-negative breast cancer with detectable circulating tumor DNA after definitive therapy

Abstract OT2-24-02: ZEST: Randomized phase III study evaluating efficacy and safety of niraparib in patients with HER2-negative BRCA-mutated or triple-negative breast cancer with detectable circulating tumor DNA after definitive therapy

278. Immunocompromised Patients with Prolonged Viral Shedding of SARS-COV-2

BackgroundMost individuals diagnosed with mild to moderate COVID-19 are no longer infectious after day 10 of symptom onset and those with severe or critical illness from COVID are typically not infection after day 20 day of symptom onset. Recovered persons can continue to test positive for SARS-CoV-2 by PCR via detection of non-viable RNA in nasopharyngeal specimens for up to three months (or longer) after illness onset. It is also know known that severely immunocompromised patients may produce replication-competent virus greater than 20 days from symptom onset and may require, per CDC recommendations, “additional testing and consultation with infectious diseases specialists and infection control experts”. We aim to discuss four case studies of severely immunocompromised patients who exhibited signs of persistent COVID-19 infection of COVID and how we managed transmission-based precautions in our hospital through sequencing and evaluation of cycle thresholds (CT) values and subgenomic RNA detection. MethodsResidual nasopharyngeal (NP) samples were collected on patients exhibiting persistent COVID like symptoms. These samples underwent N gene and N gene subgenomic RNA (sgRNA) real-time reverse transcription polymerase chain reaction (rRT-PCR) testing. ResultsAnalysis of longitudinal SARS-CoV-2 sequence data demonstrated within-patient virus evolution, including mutations in the receptor binding domain and deletions in the N-terminal domain of the spike protein, which have been implicated in antibody escape. See Figures 1 and 2. Figure 1. Timelines of Identified Patients 1 and 2 Patient 1: 46-year-old woman with recently diagnosed stage IV diffuse large B-cell lymphoma for which she was treated with 2 cycles of R-CHOP. Patient 2: 38-year-old woman with history of myelodysplastic syndrome, peripheral blood stem cell transplant with chronic graft versus host disease of the GI tract, skin, and eyes as well as CMV enteritis, and she was maintained on rituximab, mycophenolate mofetil, prednisone, and monthly IVIG without recent changes to her immunosuppression.Figure 2. Timeline of Identified Patients 3 and 4 Patient 3: 44 year-old man with prior history of thymoma s/p thymectomy Patient 4: 46 year-old man who was initially diagnosed with marginal zone lymphoma approximately 2.5 years ago. He was initially treated with bendamustine and rituximab and achieved remission. He was then continued on maintenance rituximab without significant complications for a planned two years.ConclusionDifferentiating between prolonged viral shedding of non-infectious RNA and persistent replicating viable virus can be difficult to determine without full evaluation of a patient’s clinical picture and timeline. Consultation between laboratory, infectious diseases, and infection prevention experts to provide appropriate level of guidance for precautions and treatment may be warranted. Testing by PCR and analysis of CT values may provide key findings of viral replication in immunocompromised hosts, indicating the need for evaluation of additional treatment and maintaining isolation status in healthcare settings.Disclosures All Authors: No reported disclosures

Clinicopathological analysis of myeloid sarcoma with megakaryocytic differentiation

Myeloid sarcoma (MS) is defined as a tumour mass consisting of myeloid blasts that occurs at an anatomical site other than bone marrow. MS with megakaryocytic differentiation (MSmgk) is extremely rare and its clinicopathological features have not been well described. We reviewed 11 cases in 11 patients of extramedullary mass-forming malignant tumours composed of immature non-lymphoid haematopoietic cells expressing CD41 with or without concurrent bone marrow lesions. The patients consisted of seven men and four women (1.75:1 male-to-female ratio). The mean and median ages at diagnosis were 50 and 62 years, respectively, ranging from 2 to 78 years. Extramedullary mass lesions were solitary in three cases (27%) and multiple in eight cases (73%). Tumour locations were lymph nodes (6 cases), subcutaneous tissue (3 cases), intramuscular (1 case), and bone (1 case). Seven of the 11 patients (64%) had a history of myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN). Three patients (27%) developed MS during remissions of acute myelogenous leukaemia, and one patient had a recurrence of MS at other sites. Follow-up data were available for four cases. Tumour cells were positive for CD41, CD33, CD34, MPO, and CD68 in 11 (100%), three (27%), seven (64%), four (36%), and seven (64%) cases, respectively. Cytogenetic analysis was successfully performed in two cases. Complex but inconsistent abnormalities were evident. When compared with cases of MS without megakaryocytic differentiation, the survival of MSmgk was significantly shorter (p=0.0033). Compared to MS without megakaryocytic differentiation, MSmgk is more likely to follow MDS/MPN, to involve multiple sites, and to be associated with poorer outcomes. More detailed studies, including genomic or gene expression analyses, could confirm the characteristics of MSmgk.

Transcriptomic Signitures of Azacitidine (AZA) and Decitabine (DAC) Resistance in MDS and CMML

INTRODUCTION: Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) are heterogeneous myeloid neoplastic disorders characterized by ineffective hematopoiesis leading to cytopenias and increased risk of transformation to acute myeloid leukemia (AML) . The hypomethylating agents (HMA) azacitidine (AZA) and decitabine (DAC) improve the natural history of MDS and CMML patients (Fenaux et al 2009). However, over half of the cases experience primary failure defined by a lack of response to HMA treatment which is associated with poor prognosis and a median survival of 4-6 months (Garcia-Manero et al. 2016, Jabbour et al. 2010). The highly heterogeneous pathophysiology of myeloid neoplasms and poorly understood mechanisms underlying therapeutic action of HMAs pose substantial challenges in understanding the biology of HMA failure in MDS and CMML.METHODS: We established a cohort of baseline bone marrow (BM) cells that were collected from 17 CMML and 34 MDS patients with excessive blasts (MDS-EB) prior to their HMA based therapies (Figure 1). RNA-Seq based transcriptomic analysis was performed in CD34+ BM hematopoietic stem and progenitor cells (HSPCs) of patients, known to be the cellular origin of these diseases, to identify biological signatures of primary HMA resistance.RESULTS: Similar to the recent reports regarding the lack of common gene expression signatures in HMA resistant AML cell lines (Leung et al. 2019) , RNA-Seq in patient cohort detected fewer than 0.5% of the total number of differentially expressed genes in non-responders in common for both AZA and DAC. Of note, all the AZA and a large portion of DAC associated genes with down-regulations in non-responders encode immunoglobulins, which is consistent with several recent findings indicating impaired differentiation B cells in association with unfavorable outcomes in MDS and CMML (Ribeiro et al. 2006 and Kahn et al. 2015). We performed flow cytometry analysis in BM cells available for 13 patients prior to start of HMA treatments (5 non-responders and 8 responders), and detected that HMA non-responders had a strong tendency (P=0.07) of decreased baseline frequencies of B cells in their BM than HMA responders.GSEA analysis based on leading edge genes identified over 200 and 300 biological signaling pathways to be associated with AZA and DAC failure respectively, with 78 pathways commonly correlated with treatment failure of both drugs (28 up-regulated and 60 down-regulated, Table 1). Clustering of these commonly altered pathways based on biological functions revealed that most of them are known to have a role in MDS and CMML pathogenesis and/ or drug resistance. For instance, neurotransmitter, olfactory pathways, and associated G-protein coupled receptor signals was recently reported to play a role in regulating the maintenance and differentiation of BM HSPCs (Shao et al. 2021 and Shim et al. 2013), whereas cell junction signaling that involves integrins and increased MAP2K-MAPK signaling were also reported to be associated with AZA resistance in MDS and CMML (Unnikrishnan et al. 2017).Among commonly down-regulated biological pathways in non-responders of AZA and DAC, there were clusters of immunoglobulin-associated signals, protein translation regulatory pathways that involve ribosomal proteins, cell cycle signaling, respiratory chain, and Golgi transport signals. Decreased expression of ribosomal proteins and related impairment of ribosomal functions were known mechanism in MDS and CMML development (Ebert et al. 2008 and Schneider et al. 2016). Furthermore, decreased respiratory chain and Golgi transport signals were also identified by transcriptomic investigation in the DAC resistant TF1-RES cell lines.In addition to the commonly altered signals for both AZA and DAC resistance, innate immune signaling pathways including interferon and toll-like receptor signals were significantly up-regulated in DAC non-responders but down-regulated in AZA non-responders.CONCLUSIONS: In this study, the transcriptomic data between responders and non-responders to AZA and DAC were investigated separately, thereby drug-specific as well as the common biomarkers associated with treatment failures of both drugs could be identified. The relatively low proportion of genes and pathways shared by AZA and DAC non-responders suggest the difference underlying biological mechanisms of AZA and DAC failure. [Display omitted] DisclosuresSasaki: Novartis: Consultancy, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees. Wei: Daiichi Sanko: Research Funding.

POST-BRONCHOSCOPY UVULAR HEMATOMA

TOPIC: Procedures TYPE: Fellow Case Reports INTRODUCTION: Bronchoscopy can cause post-procedural throat discomfort due to oropharyngeal irritation. We report an unusual complication of bronchoscopy that resulted in a similar presentation. CASE PRESENTATION: A 31-year-old man with a history of myelodysplastic syndrome (MDS) complained of severe throat discomfort, difficulty swallowing, and hoarseness of voice a few minutes after undergoing bronchoscopy for bilateral lung infiltrates. He was thrombocytopenic at 31,000 prior to the procedure; normal coagulation profile; never been on anticoagulation or antiplatelet agents. Bronchoscopy was introduced through the Laryngeal mask airway (LMA), and the procedure lasted less than 15 minutes. Post-procedural suctioning was done.The patient noted hoarseness of voice and difficulty swallowing post-procedure. Physical examination revealed a swollen elongated uvula with a distally located hematoma. The patient received Solumedrol and admitted for observation, subsequently managed conservatively with Tylenol. DISCUSSION: Flexible bronchoscopy is a safe procedure with a low incidence of complications. Our patient had an unusual cause of throat discomfort post-bronchoscopy and he was found to have uvular hematoma secondary to uvular damage with laryngeal mask airway and post-procedural suctioning. CONCLUSIONS: Though uvular hematoma has been described in patients taking antiplatelet agents and with endotracheal intubation, it has not been previously reported in patients with moderate thrombocytopenia and LMA. Careful Suctioning should be done to avoid trauma in patients with thrombocytopenia. REFERENCE #1: Steven M. Weiss.et al. Complications of Fiberoptic Bronchoscopy in Thrombocytopenic Patients. Chest. Volume 104, Issue 4, October 1993, Pages 1025-1028. DISCLOSURES: No relevant relationships by Rajesh Kunadharaju, source=Web Response No relevant relationships by Hiwot Mengiste, source=Web Response No relevant relationships by Musa Saeed, source=Web Response

S638 Gastrointestinal Bleed in Patients With History of Myelodysplastic Syndrome: Inpatient Mortality Increased in Patients With Malnutrition

S638 Gastrointestinal Bleed in Patients With History of Myelodysplastic Syndrome: Inpatient Mortality Increased in Patients With Malnutrition

Allo-HSCT for acute myeloid leukemia with myelodysplastic-related changes: a clinical analysis

目的评价异基因造血干细胞移植（allo-HSCT）治疗急性髓系白血病伴骨髓增生异常相关改变（AML-MRC）的疗效及预后因素，分析AML-MRC患者基因突变谱系并探讨影响移植预后的分子生物学特征。方法对2006年至2020年于中国医学科学院血液病医院接受allo-HSCT的75例AML-MRC患者进行回顾性分析。将75例患者分为：H组［既往有骨髓增生异常综合征（MDS）或MDS/骨髓增殖性肿瘤（MPN）病史］、C组（新诊断的AML-MRC伴MDS相关细胞遗传学异常）和M组（新诊断的AML-MRC伴多系发育异常），分析三组患者临床特征差异以及对移植预后的影响。对43例患者行骨髓靶向二代测序（137个基因）。结果①75例AML-MRC患者，男41例，女34例，中位年龄41（18～56）岁，中位随访时间为35（95％ CI 30～49）个月，中位总生存（OS）时间为78个月（95％CI 23个月～未达到）。移植后3年OS率为57.1％（95％CI 45.6％～71.4％），无事件生存（EFS）率为52.0％（95％CI 40.8％～66.1％），累积复发率（CIR）为26.8％（95％CI 16.6％～30.0％），移植相关死亡率（TRM）为22.7％（95％ CI 13.2％～33.8％）。多因素分析显示，移植前处于非第1次完全缓解（CR1）状态是移植后OS和EFS的独立危险因素。影响OS的独立危险因素还包括−5/5q−染色体核型异常、移植后未发生慢性移植物抗宿主病（慢性GVHD）。②75例患者中H组59例（78.7％），其中20例转化为白血病（转白）前曾接受去甲基化药物治疗；C组9例（12.0％），M组7例（9.3％）。M、H、C组移植后3年OS率分别为71.4％（95％CI 44.7％～100.0％）、55.0％（95％CI 41.8％～72.5％）、55.6％（95％ CI 31.0％～99.7％）（P＝0.700），EFS率分别为71.4％（95％CI 44.7％～100.0％）、46.5％（95％CI 34.0％～63.8％）、55.6％（95％CI 31.0％～99.7％）（P＝0.600）；原发性AML-MRC与继发性AML-MRC相比，移植后3年OS、EFS率差异无统计学意义［61.9％（95％CI 41.9％～91.4％）对55.0％（95％ CI 41.8％～72.5％），P＝0.600；61.9％（95％CI 41.9％～91.4％）对46.5％（95％CI 34.0％～63.8％），P＝0.400］。转白前接受去甲基化治疗（20例）与未接受去甲基化治疗（39例）患者比较，转白时间差异无统计学意义［195（16～937）d对162（9～3167）d，P＝0.804］，且两组患者OS和EFS差异无统计学意义（P＝0.400，P＝0.700）。③对43例（57.3％）患者骨髓样本行二代基因测序，共发现73个突变类型，检出率最高的是U2AF1（11例，25.6％），其他检出率>10％的突变包括RUNX1（10例，23.3％）、NRAS（10例，23.3％）、ASXL1（6例，14.0％）、PTPN11（5例，11.6％）、TET2（5例，11.6％）。单因素分析显示U2AF1［P＝0.875，HR＝1.110（95％ CI 0.295～4.195）］、RUNX1［P＝0.685，HR＝0.728（95％ CI 0.157～3.375）］、NRAS［P＝0.919，HR＝0.923（95％CI 0.196～4.334）］突变对移植后OS没有影响。结论−5/5q−染色体异常、未发生慢性GVHD、移植前非CR1状态是影响AML-MRC患者移植后OS的独立危险因素；MHC亚组分类不是影响移植预后的因素；去甲基化药物治疗可能无助于延缓MDS患者转白以及延长移植后OS期。

A Retrospective Real-World Study of Incident Comorbidities and Complications Among Acute Myeloid Leukemia Patients and Non-Cancer Comparison Patients in the US

Introduction Clinical trials suggest that the burden of Acute Myeloid Leukemia (AML) to patients is substantial, with commonly observed comorbidities associated with disease and treatment including infections, hematologic, hemorrhagic, cardio/cerebrovascular, hepatic, and renal events. There are no large population-based real-world studies that assessed comorbidities and complications in AML patients overall and in particular, among the most challenging AML patients to treat: relapsed and/or refractory (R/R) patients.Objective To estimate frequency, incidence rates, and time to event for selected incident comorbidities and complications among AML patients and a subgroup with evidence of R/R disease, compared to non-cancer patients, leveraging a large adjudicated claims database.Methods A retrospective cohort analysis was conducted using the QuintilesIMS Real-World Data Adjudicated Claims - US (formerly known as PharMetrics Plus) database covering the years 2005-2015. Adult patients (>18 years) with at least one inpatient or outpatient claim indicating a diagnosis of AML (ICD-9-CM code: 205.0x) between January 1, 2006 and October 31, 2015 were identified, with index date defined as the date of the first observed AML diagnosis. A comparison patient of the same age, gender, geographic region, insurance type, and patient enrollment year without evidence of any cancer during baseline was matched 1:1 to each AML patient and assigned the same index date as the respective AML match. All patients were followed from 12 months prior to index (baseline) through 12/31/2015, disenrollment from the health plan, or death, whichever came first (with requirements of a minimum 2 months follow-up). Patients were considered to have evidence of refractory AML if they had >2 cycles of chemotherapy (new cycle defined as 14-60 days since previous chemotherapy; same cycle if <14 days from previous chemotherapy). Patients were considered to have evidence of relapsed AML if they had at least one diagnosis code indicating relapse (ICD-9 205.02), or received chemotherapy after a >60-day period with no evidence of chemotherapy, or diagnosis/procedure codes indicating repeated stem cell/bone marrow transplant. Study measures included frequency, incidence, and time to event for infections, hematologic, cardio/cerebrovascular, hepatic, hemorrhagic, renal events, and other events of interest during follow-up. Separate Multivariate Cox Proportional Hazards models were used to evaluate associations between AML and three specific outcomes (cardiovascular, type 2 diabetes [T2D], stroke) in the full study sample, controlling for baseline demographic (age, sex, region) and clinical characteristics (NCI comorbidity score, history of myelodysplastic syndrome).Results A total of 6,252 AML patients were identified and matched 1:1 to non-cancer patients (mean age: 54 years, 54% male in both groups). AML patients had higher NCI comorbidity index scores during baseline than non-cancer patients (0.9 vs. 0.3, p<0.001). These patients had higher incidence rates of selected comorbidities and complications during follow-up and shorter times to events than non-cancer patients (Table 1). The most common comorbidities and complications were neutropenia/febrile neutropenia (36.8%, 249.1 per 1,000 person-years [PYs]), pneumonia (21.6%, 130.3 per 1,000 PYs), and other hemorrhages (20.0%, 125.5 per 1,000 PYs). Results from Cox models suggest that AML patients had significantly higher risks of cardiovascular events (HR=3.9, 95% CI 3.4-4.6), T2D (HR=4.7, 95% CI 4.0-5.5), and stroke (HR= 2.6, 95% CI 2.2-3.1), all p<0.01. A subset of 2,804 study patients had evidence of R/R AML, including 1,225 (19.6%) with refractory (mean ± SD time to refractory disease 3.7 ± 2.6 months) and 1,579 (26.3%) with relapse (mean ± SD time to relapse 4.2 ± 7.4 months). Results were similar in terms of patterns of incident comorbidities and complications for the R/R subgroup.Conclusions This retrospective analysis found that AML patients had higher baseline comorbidities and higher rates of selected incident comorbidities and complications after diagnosis compared to non-cancer patients. The results were similar in R/R patients. This study provides real-world evidence of overall pre-disposition and risks among AML patients that might have clinical significance in terms of treatment, patient management, and risk communication. [Display omitted] DisclosuresNear:QuintilesIMS: Employment; Daiichi Sankyo Inc.: Research Funding. Iqbal:Daiichi Sankyo Inc.: Employment. Huang:QuintilesIMS: Employment; Daiichi Sankyo Inc.: Research Funding. Dhopeshwarkar:Daiichi Sankyo Inc.: Employment. Lang:QuintilesIMS: Employment; Daiichi Sankyo Inc.: Research Funding. Wallis:Daiichi Sankyo Inc.: Employment.

Acute Myeloid Leukemia and Myelodysplasia Related Changes: Trends in Survival between 2000 and 2013

Background:Acute Myeloid Leukemia with myelodysplasia-related changes (AML-MRC), formerly known as the Acute myeloid leukemia with multilineage dysplasia is a distinct hematological disorder characterized by the presence of more than 20% blasts in peripheral blood or bone marrow and dysplasia in 50% or more of the cells in two or more myeloid cell lineages in the absence of recurrent cytogenetic abnormalities seen in AML and with no prior history of cytotoxic treatment for an unrelated disease (2). The presence of myelodysplasia was considered an independent prognostic factor in the past until it was disputed in a study by Wandt et al in 2008 (4). This heterogeneous disorder is associated with poor prognosis only when associated with Myelodysplastic syndrome (MDS) related cytogenetic abnormalities and are preceded by MDS, which is the majority(3). Induction chemotherapy is the treatment of choice in young healthy patients and hypomethylating agents (HMA) such as azacitadine and decitabine have been used in elderly patients who are unfit to receive induction chemotherapy if they are treatment naive(1). No significant advancements have been made in the treatment of this category of AML in the elderly patients with previous history of MDS treated with HMA. Our objective is to evaluate the survival trends of this entity over the last decade.Methods:We utilized National Cancer Institute Surveillance, Epidemiology, and End Results (SEER-18) database to identify adult patients with Acute Myeloid Leukemia (AML) with myelodysplastic related features. Several cohorts were categorized by race, gender and age were categorized. We grouped patients into three different time periods as: 2000-2004, 2005-2009 and 2010-2013. 1-year and median overall survival (OS) were computed using Kaplan Meier Curve and log rank test. Cox proportional hazard model was used for multivariate analysis.Results:The database comprised of 1733 patients from 2000-2013. Majority of the patients were male Caucasians, aged 60- 79 years. Median overall survival among the different year of diagnosis cohort was found to be comparable by KM curve (6 months, 6 months and 7 months for 2000-2004, 2005-2009 and 2010-2013 respectively) with p value of 0.112 by log rank test. On multivariate analysis using cox PH model, after adjusting for age, sex, race, income and area of residence, survival among patients in 2010 to 2013 was found to be significantly better compared to 2000 to 2004 (HR of 0.84, 95% confidence interval of 0.73 to 0.97, P 0.015). The one year OS rate was 35.7 % ±2, 30.3 % ±1.8, 31.7 % ±2.3 for 2010-2013, 2005-2009 and 2000-2004 cohorts respectively.Conclusion:Survival for patients with AML-MRC has improved over the decade, most likely attributable to improved supportive care since there hasn't been any major breakthrough in treatment of these patients.References1) Dombret, H., Seymour, J. F., Butrym, A., Wierzbowska, A., Selleslag, D., Jang, J. H., Kumar, R., Cavenagh, J., Schuh, A. C., Candoni, A., Récher, C., Sandhu, I., Bernal del Castillo, T., Al-Ali, H. K., Martinelli, G., Falantes, J., Noppeney, R., Stone, R. M., Minden, M. D., McIntyre, H., Songer, S., Lucy, L. M., Beach, C. L., & Döhner, H. (2015). International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood, 126(3), 291-299. Accessed August 02, 2017.2) Brunning RD, Matutes E, Harris NL, et al. Acute myeloid leukemia with multilineage dysplasia. In: Jaffe E, Harris NL, Stein H, et al, eds. World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. 3rd ed. Lyon, France: IARC; 2001:88-89.3) Huck A, Pozdnyakova O, Brunner A, Higgins JM, Fathi AT, Hasserjian RP. Prior cytopenia predicts worse clinical outcome in acute myeloid leukemia. Leuk Res. 2015 Oct. 39 (10):1034-40.4) Wandt H, Schakel U, Kroschinsky F, et al. MLD according to the WHO classification in AML has no correlation with age and no independent prognostic relevance as analyzed in 1766 patients. Blood. 2008;111:1855- 1861. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Germline SAMD9 and SAMD9L Alterations in Adult Myelodysplastic Syndromes

While familial leukemia and bone marrow failure syndromes present typically in children, it is possible that less damaging variants, such as heterozygous alterations of recessive genes, may be identified in older patients with seemingly spontaneously acquired disease. This may be particularly true for recessive variants with lower penetrance. Gain-of-function germline (GL) mutations in SAMD9 have been described in the context of MIRAGE syndrome, characterized by Myelodysplasia Infection, Restriction of growth, Adrenal hypoplasia,Genital phenotypes and Enteropathy. Recently, pediatric myelodysplastic syndromes (MDS) families affected by a somatically acquired -7/del(7q) were found to have GL mutations in SAMD9 and SAMD9L on 7q21.2. Here, we focused on sporadic adult myeloid neoplasm patients to assess how frequently mutations in SAMD9 and SAMD9L occur with or without -7/del(7q).We first sequenced a cohort of patients for the presence of variants in SAMD9/SAMD9L . Paired disease and normal GL DNAs were obtained from 312 MDS patients for whole exome sequencing (WES; n=220) and targeted deep sequencing (n=92). GL DNA was obtained from either buccal mucosa or paired CD3+ T cells. We used Broad Institute's Exome Aggregation Consortium (ExAC) data as ethnically matched healthy control (n=45,950).We defined “rare variants” as those present in <1% of ethnically matched healthy controls. Among 312 patients with myeloid neoplasms, we identified a total of 30 rare GL variants of SAMD9/SAMD9L in 29 patients (9.3%). Validation was performed by Sanger sequencing or PCR amplicon sequencing. None of these alterations were present in any of the previously described familial cases. All patients had a heterozygous configuration except for one. We used an algorithm that predicts the pathogenic significance of SAMD9/SAMD9L alterations by evaluating conserved amino acid residues and alterations of protein features. We identified 18 (10 in SAMD9 and 8 in SAMD9L) which were most likely to be functionally deleterious; 7/19 in SAMD9 and 9/11 in SAMD9L were not previously described, emphasizing their rarity. For example, I268T and D550V of SAMD9 which are present only in MDS patients, and E220G, G235S, W333C and Y705C SAMD9L alterations, were predicted to be highly deleterious based on structure/function analyses according to prediction algorithms. While those with known population frequencies were not over-represented individually, their combined frequency was higher in MDS vs . ethnically matched healthy controls, with an odds ratio = 1.54 (95% CI: 1.04-2.27, P=.03), and frequencies of 29/312 (9.3% in MDS) vs . 2,896/45,950 (6.3% in healthy controls). Two patients had a family history of MDS and unexplained anemia.We then focused on patients with -7/del(7q). In total, 82 out of 312 patients (26%) had -7/del(7q); 5 of these 82 patients (6.1%) had SAMD9 alterations. Variant allele frequencies (VAFs) were significantly lower in unpurified bone marrow fractions than in GL controls in 3 out of 5 patients. For example, the GL of one patient had the S86F alteration in SAMD9 in a heterozygous configuration, whereas the tumor of the patient with somatically acquired -7 showed lower VAFs. This observation suggests that the SAMD9/SAMD9L variant allele was selectively deleted at the onset of MDS, resulting in retention of only the wild-type allele during clonal selection (Figure 1). SAMD9/SAMD9L can maintain cell growth by attenuating proliferation. SAMD9/SAMD9L GL mutations identified in familial MDS cases strongly repressed cell proliferation by working as gain-of-function mutations. Somatic acquisition of -7/del(7q) can rescue the growth-repressing effects from GL gain-of-function alterations. However, cells which lost the GL gain-of-function alterations by -7/del(7q) to gain a survival advantage progressed to MDS due to haploinsufficiency of chr7 genes. This interpretation is further supported by the observation of a lower frequency of variants in those with vs . without -7/del(7q) (5/82 (6.1%) in -7/del(7q) carriers vs. 24/230 (10.4%) in diploid cells). Our results support a model wherein SAMD9/SAMD9L variants are selectively lost in MDS with -7/del(7q).In conclusion, while deletion of several important genes on chr7q are likely to be pathogenic in sporadic adult MDS, we show here that GL alterations in SAMD9/SAMD9L may also drive selection of -7/del(7q) clones in a small fraction of adult MDS. [Display omitted] DisclosuresMakishima:Yasuda Medical Foundation: Research Funding. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees.