Therapy-related myeloid neoplasms after treatment for ovarian cancer: A retrospective single-center case series.

OBJECTIVE: Therapy-related myeloid neoplasms (t-MNs) are often fatal and arise as late complications of previous anticancer drug treatment. No single-center case series has examined t-MNs in epithelial ovarian cancer (EOC). METHODS: All patients with EOC treated at Chiba University Hospital between 2000 and 2021 were included. We retrospectively analyzed the characteristics, clinical course, and outcomes of patients who developed t-MNs. RESULTS: Among 895 cases with EOC, 814 cases were treated with anticancer drugs. The median follow-up period was 45 months (interquartile range, 27-81) months. Ten patients (1.2%) developed t-MNs (FIGO IIIA in one case, IIIC in three, IVA in one, and IVB in five). Nine patients were diagnosed with myelodysplastic syndrome and one with acute leukemia. One patient with myelodysplastic syndrome developed acute leukemia. The median time from the first chemotherapy administration to t-MN onset was 42 months (range, 21-94 months), with t-MN diagnoses resulting from pancytopenia in four cases, thrombocytopenia in three, and blast or abnormal cell morphology in four. The median number of previous treatment regimens was four (range, 1-7). Paclitaxel + carboplatin therapy was administered to all patients, gemcitabine and irinotecan combination therapy to nine, bevacizumab to eight, and olaparib to four. Six patients received chemotherapy for t-MN. All patients died (eight cancer-related deaths and two t-MN-related deaths). None of the patients was able to restart cancer treatment. The median survival time from t-MN onset was 4 months. CONCLUSIONS: Patients with EOC who developed t-MN were unable to restart cancer treatment and had a significantly worse prognosis.

Venetoclax plus hypomethylating agents in DDX41-mutated acute myeloid leukaemia and myelodysplastic syndrome: Mayo Clinic series on 12 patients.

Venetoclax (VEN) is an FDA-approved selective inhibitor of B-cell leukaemia/lymphoma-2 (BCL-2), used for treating elderly or unfit acute myeloid leukaemia (AML) patients unable to undergo intensive chemotherapy. Combining VEN with hypomethylating agents (HMAs) has shown impressive response rates in high-risk myelodysplastic syndromes (MDS) and relapsed/refractory AML. However, the efficacy of VEN and HMAs in treating DDX41-mutated (mDDX41) MDS/AML patients remains uncertain. Despite the favourable prognostic nature of mDDX41 MDS/AML patients, there is a lack of clinical experience regarding their response to different treatment regimens, leading to an unknown optimal therapeutic approach.

Azacitidine (Vidaza®) in Pediatric Patients with Relapsed Advanced MDS and JMML: Results of a Phase I/II Study by the ITCC Consortium and the EWOG-MDS Group (Study ITCC-015).

BACKGROUND: Advanced myelodysplastic syndrome (MDS) and juvenile myelomonocytic leukemia (JMML) are rare hematological malignancies in children. A second allograft is recommended if a relapse occurs after hematopoietic stem cell transplantation, but the outcome is poor. OBJECTIVE: We conducted a phase I/II multicenter study to evaluate the safety, pharmacokinetics, and activity of azacitidine in children with relapsed MDS/JMML prior to the second hematopoietic stem cell transplantation. METHODS: Patients enrolled from June 2013 to March 2019 received azacitidine intravenously/subcutaneously once daily on days 1-7 of a 28-day cycle. The MDS and JMML cohorts followed a two-stage design separately, with a safety run-in for JMML. Response and safety data were used to evaluate efficacy and establish the recommended dose. Pharmacokinetics was also analyzed. The study closed prematurely because of low recruitment. RESULTS: Six patients with MDS and four patients with JMML received a median of three and five cycles, respectively. Azacitidine 75 mg/m2 was well tolerated and plasma concentration-time profiles were similar to observed in adults. The most prevalent grade 3-4 adverse event was myelotoxicity. No responses were seen in patients with MDS, but 83% achieved stable disease; four patients underwent an allotransplant. Overall response rate in the JMML cohort was 75% (two complete responses; one partial response) and all responders underwent hematopoietic stem cell transplantation. One-year overall survival was 67% (95% confidence interval 38-100) in MDS and 50% (95% confidence interval 19-100) in JMML. CONCLUSIONS: Azacitidine 75 mg/m2 prior to a second hematopoietic stem cell transplantation is safe in children with relapsed MDS/JMML. Although the long-term advantage remains to be assessed, this study suggests that azacitidine is an efficacious option for relapsed JMML. CLINICAL TRIAL REGISTRATION: EudraCT 2010-022235-10.

Therapy-related myeloid neoplasm in early breast cancer patients treated with adjuvant chemotherapy.

BACKGROUND: Long-term complications are becoming more important as the survival rate of breast cancer improves. Treatment-related myeloid neoplasm is an important long-term complication in breast cancer survivors as it has a poor prognosis. OBJECTIVE: We evaluated the incidence and risk factors for the development of treatment-related acute myeloid leukaemia (AML)/myelodysplastic syndrome (MDS) in patients treated with early breast cancer. METHODS: We accessed the national Korean database to identify 153,565 patients diagnosed with breast cancer between January 2007 and October 2016 who underwent surgery for breast cancer. We estimated the cumulative incidence of AML/MDS and analysed the risk factors for developing AML/MDS. RESULTS: Of 153,575 patients, 79,321 received anthracycline-based adjuvant therapy, 14,317 received adjuvant therapy without anthracyclines and 46,657 did not receive adjuvant chemotherapy. Overall, 120 developed AML (105 in the anthracycline group, 9 in the non-anthracycline group and 6 in the control group), and 128 developed MDS (96, 9 and 23 in each group). The 10-year cumulative incidence of AML/MDS was the highest in the anthracycline group (0.221% and 0.199%), followed by the non-anthracycline group (0.122% and 0.163%) and the control group (0.024% and 0.089%). The risk of developing AML/MDS was significantly higher in patients treated with anthracyclines (hazard ratio [HR] 9.531; p < 0.0001 for AML and HR 2.559; p < 0.0001 for MDS) compared to patients in the control group. CONCLUSION: This study found that anthracycline-based adjuvant therapy significantly increased the risk of AML/MDS in Korean breast cancer patients, with the risk persisting for at least 10 years. While the cumulative incidence was low, the long-term risks of AML/MDS should be taken into account considering the poor outcomes associated with these neoplasms.

[Environmental and occupational risk factors for myelodysplastic syndrome]. / Facteurs de risques environnementaux et professionnels de syndrome myélodysplasique.

Chemotherapy and radiotherapy for a previous cancer can lead to subsequent myelodysplastic syndrome (MDS). However, these therapy-related cases are hypothesized to explain only 5 % of diagnosed MDS cases. Environmental or occupational exposure to chemicals or radiations has also been reported to be associated with higher risk of MDS. The present review analyses those studies evaluating the association of MDS with environmental or occupational risk factors. There is sufficient evidence that environmental or occupational exposure to ionizing radiation or benzene can cause MDS. Tobacco smoking is also a sufficiently documented riskfactor for MDS. A positive association has been reported between exposure to pesticides and MDS. However, there is only limited evidence that this association could be causal.

Population Pharmacokinetics of Oral Azacitidine, and Exposure-Response Analysis in Acute Myeloid Leukemia.

Oral azacitidine (oral-AZA) maintenance is approved for adults with acute myeloid leukemia (AML) in remission post-intensive chemotherapy, not proceeding to hematopoietic stem cell transplantation. This study aimed to develop a population pharmacokinetic (PopPK) model to characterize oral-AZA concentration-time profiles in patients with AML, myelodysplastic syndrome, or chronic myelomonocytic leukemia. PopPK-estimated exposure parameters were used to evaluate exposure-response relationships in the phase III QUAZAR AML-001 study. The PopPK dataset comprised 286 patients with 1,933 evaluable oral-AZA concentration records. The final PopPK model was a one-compartment model with first-order absorption incorporating an absorption lag time and first-order elimination. Regression analyses identified two oral-AZA exposure parameters (area under the plasma concentration-time curve at steady state (AUCss ); maximum plasma concentration (Cmax )) as statistically significant predictors for relapse-free survival (hazard ratio (HR) = 0.521, P < 0.001; HR = 0.630, P = 0.013; respectively), and AUCss as a significant predictor for overall survival (HR = 0.673, P = 0.042). The probability of grade ≥ 3 neutropenia was significantly increased with increases in AUCss (odds ratio (OR) = 5.71, 95% confidence interval (CI) = 2.73-12.62, P < 0.001), cumulative AUC through cycles 1 to 6 (OR = 2.71, 95% CI = 1.76-4.44, P < 0.001), and Cmax at steady-state (OR = 2.38, 95% CI = 1.23-4.76, P = 0.012). A decreasing trend was identified between AUCss and relapse-related schedule extensions, vs. an increasing trend between AUCss and event-related dose reductions. As the majority (56.8%) of patients required no dose modifications, and the proportions requiring schedule extension (19.4%) or dose reduction (22.9%) were almost equal, oral-AZA 300 mg once daily for 14 days is the optimal dosing schedule balancing survival benefit and safety risk.

Efficacy and safety of luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): interim analysis of a phase 3, open-label, randomised controlled trial.

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) are the standard-of-care treatment for anaemia in most patients with lower-risk myelodysplastic syndromes but responses are limited and transient. Luspatercept promotes late-stage erythroid maturation and has shown durable clinical efficacy in patients with lower-risk myelodysplastic syndromes. In this study, we report the results of a prespecified interim analysis of luspatercept versus epoetin alfa for the treatment of anaemia due to lower-risk myelodysplastic syndromes in the phase 3 COMMANDS trial. METHODS: The phase 3, open-label, randomised controlled COMMANDS trial is being conducted at 142 sites in 26 countries. Eligible patients were aged 18 years or older, had a diagnosis of myelodysplastic syndromes of very low risk, low risk, or intermediate risk (per the Revised International Prognostic Scoring System), were ESA-naive, and required red blood cell transfusions (2-6 packed red blood cell units per 8 weeks for ≥8 weeks immediately before randomisation). Integrated response technology was used to randomly assign patients (1:1, block size 4) to luspatercept or epoetin alfa, stratified by baseline red blood cell transfusion burden (<4 units per 8 weeks vs ≥4 units per 8 weeks), endogenous serum erythropoietin concentration (≤200 U/L vs >200 to <500 U/L), and ring sideroblast status (positive vs negative). Luspatercept was administered subcutaneously once every 3 weeks starting at 1·0 mg/kg body weight with possible titration up to 1·75 mg/kg. Epoetin alfa was administered subcutaneously once a week starting at 450 IU/kg body weight with possible titration up to 1050 IU/kg (maximum permitted total dose of 80 000 IU). The primary endpoint was red blood cell transfusion independence for at least 12 weeks with a concurrent mean haemoglobin increase of at least 1·5 g/dL (weeks 1-24), assessed in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study treatment. The COMMANDS trial was registered with ClinicalTrials.gov, NCT03682536 (active, not recruiting). FINDINGS: Between Jan 2, 2019 and Aug 31, 2022, 356 patients were randomly assigned to receive luspatercept (178 patients) or epoetin alfa (178 patients), comprising 198 (56%) men and 158 (44%) women (median age 74 years [IQR 69-80]). The interim efficacy analysis was done for 301 patients (147 in the luspatercept group and 154 in the epoetin alfa group) who completed 24 weeks of treatment or discontinued earlier. 86 (59%) of 147 patients in the luspatercept group and 48 (31%) of 154 patients in the epoetin alfa group reached the primary endpoint (common risk difference on response rate 26·6; 95% CI 15·8-37·4; p<0·0001). Median treatment exposure was longer for patients receiving luspatercept (42 weeks [IQR 20-73]) versus epoetin alfa (27 weeks [19-55]). The most frequently reported grade 3 or 4 treatment-emergent adverse events with luspatercept (≥3% patients) were hypertension, anaemia, dyspnoea, neutropenia, thrombocytopenia, pneumonia, COVID-19, myelodysplastic syndromes, and syncope; and with epoetin alfa were anaemia, pneumonia, neutropenia, hypertension, iron overload, COVID-19 pneumonia, and myelodysplastic syndromes. The most common suspected treatment-related adverse events in the luspatercept group (≥3% patients, with the most common event occurring in 5% patients) were fatigue, asthenia, nausea, dyspnoea, hypertension, and headache; and none (≥3% patients) in the epoetin alfa group. One death after diagnosis of acute myeloid leukaemia was considered to be related to luspatercept treatment (44 days on treatment). INTERPRETATION: In this interim analysis, luspatercept improved the rate at which red blood cell transfusion independence and increased haemoglobin were achieved compared with epoetin alfa in ESA-naive patients with lower-risk myelodysplastic syndromes. Long-term follow-up and additional data will be needed to confirm these results and further refine findings in other subgroups of patients with lower-risk myelodysplastic syndromes, including non-mutated SF3B1 or ring sideroblast-negative subgroups. FUNDING: Celgene and Acceleron Pharma.

Efficacy and Safety of Valproic Acid in Myelodysplastic Syndrome and Acute Myeloid Leukemia; a Narrative Review.

Loads of new therapeutic regimes have been turned up to manage Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), particularly in elderly patients who are unfit for intensive chemotherapy. Despite accumulating research, the best MDS and AML management approach is indeterminate. Myelodysplastic syndrome implies a group of various hematopoietic stem cell disorders that may progress to acute myeloid leukemia. These disorders are more frequent in older adults. To the high rate of morbidity and abundant toxicities related to the therapeutic approaches, also, the treatment would be challenging. The clinical effectiveness of valproic acid, a histone deacetylase inhibitor, in MDS and AML patients is unknown, even though it has demonstrated positive activities to promote differentiation and apoptosis in cancer cells. We investigated the clinical research on the effects of valproic acid in conjunction with various drugs, including low-dose cytarabine, all-trans retinoic acid, DNA-hypomethylating agents, hydrazine, and theophylline. We conclude that VPA is a safe and effective treatment option for MDS and AML patients, particularly when used in conjunction with all-trans retinoic acid, DNA-hypomethylating drugs, and hydralazine. However, more randomized clinical studies are required to identify an ideal regimen.

Association between meat, fish, and fatty acid intake and incidence of acute myeloid leukemia and myelodysplastic syndrome: the Japan Public Health Center-based Prospective Study.

BACKGROUND: The association between meat, fish, or fatty acid intake and acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) has been investigated in a few studies, and the results were inconsistent. In addition, most studies are mainly based on the United States and European countries, in which the dietary patterns differ from that in Asia. Therefore, the risk of AML/MDS from meat, fish, or fatty acid intake in Asia requires further exploration. The aim of this study was to investigate the association between AML/MDS incidence and meat, fish, or fatty acid intake using the Japan Public Health Center-based prospective study. METHODS: The present study included 93,366 participants who were eligible for analysis and followed up from the 5-year survey date until December 2012. We estimated the impact of their intake on AML/MDS incidence using a Cox proportional hazards model. RESULTS: The study participants were followed up for 1,345,002 person-years. During the follow-up period, we identified 67 AML and 49 MDS cases. An increased intake of processed red meat was significantly associated with the incidence of AML/MDS, with a hazard ratio of 1.63 (95% confidence interval, 1.03-2.57) for the highest versus lowest tertile and a Ptrend of 0.04. Meanwhile, the intake of other foods and fatty acids was not associated with AML/MDS. CONCLUSION: In this Japanese population, processed red meat was associated with an increased incidence of AML/MDS.

Clinicopathologic Features of Therapy-Related Myeloid Neoplasms in Patients with Myeloma in the Era of Novel Therapies.

The development of therapy-related myeloid neoplasms (t-MN) is a rare complication that can occur in myeloma patients treated primarily with novel therapies. To better understand t-MNs in this context, we reviewed 66 such patients and compared them with a control group of patients who developed t-MN after cytotoxic therapies for other malignancies. The study group included 50 men and 16 women, with a median age of 68 years (range, 48-86 years). Therapies included proteasome inhibitors, immunomodulatory agents, and high-dose melphalan-based autologous stem cell transplantation (HDM-ASCT) in 64 (97%), 65 (98.5%), and 64 (97%) patients, respectively; 29 (43.9%) patients were exposed to other cytotoxic drugs besides HDM. The latency interval from therapy to t-MN was 4.9 years (range, 0.6-21.9 years). Patients who received HDM-ASCT in addition to other cytotoxic therapies had a longer latency period to t-MN compared with patients who only received HDM-ASCT (6.1 vs 4.7 years, P = .009). Notably, 11 patients developed t-MN within 2 years. Therapy-related myelodysplastic syndrome was the most common type of neoplasm (n = 60), followed by therapy-related acute myeloid leukemia (n = 4) and myelodysplastic syndrome/myeloproliferative neoplasm (n = 2). The most common cytogenetic aberrations included complex karyotypes (48.5%), del7q/-7 (43.9%), and/or del5q/-5 (40.9%). The most frequent molecular alteration was TP53 mutation, in 43 (67.2%) patients and the sole mutation in 20 patients. Other mutations included DNMT3A, 26.6%; TET2, 14.1%; RUNX1, 10.9%; ASXL1, 7.8%; and U2AF1, 7.8%. Other mutations in less than 5% of cases included SRSF2, EZH2, STAG2, NRAS, SETBP, SF3B1, SF3A1, and ASXL2. After a median follow-up of 15.3 months, 18 patients were alive and 48 died. The median overall survival after the diagnosis of t-MN in the study group was 18.4 months. Although the overall features are comparable to the control group, the short interval to t-MN (<2 years) underscores the unique vulnerable status of myeloma patients.

All-trans retinoic acid enhances the cytotoxic effect of decitabine on myelodysplastic syndromes and acute myeloid leukaemia by activating the RARα-Nrf2 complex.

BACKGROUND: Decitabine (DAC) is used as the first-line therapy in patients with higher-risk myelodysplastic syndromes (HR-MDS) and elderly acute myeloid leukaemia (AML) patients unsuitable for intensive chemotherapy. However, the clinical outcomes of patients treated with DAC as a monotherapy are far from satisfactory. Adding all-trans retinoic acid (ATRA) to DAC reportedly benefitted MDS and elderly AML patients. However, the underlying mechanisms remain unclear and need further explorations from laboratory experiments. METHODS: We used MDS and AML cell lines and primary cells to evaluate the combined effects of DAC and ATRA as well as the underlying mechanisms. We used the MOLM-13-luciferase murine xenograft model to verify the enhanced cytotoxic effect of the drug combination. RESULTS: The combination treatment reduced the viability of MDS/AML cells in vitro, delayed leukaemia progress, and extended survival in murine xenograft models compared to non- and mono-drug treated models. DAC application as a single agent induced Nrf2 activation and downstream antioxidative response, and restrained reactive oxygen species (ROS) generation, thus leading to DAC resistance. The addition of ATRA blocked Nrf2 activation by activating the RARα-Nrf2 complex, leading to ROS accumulation and ROS-dependent cytotoxicity. CONCLUSIONS: These results demonstrate that combining DAC and ATRA has potential for the clinical treatment of HR-MDS/AML and merits further exploration.

Dose-finding trial of azacitidine as post-transplant maintenance for high-risk MDS: a KSGCT prospective study.

This 3+3 dose-escalation phase I multicenter study investigated the optimal dose of azacitidine (AZA) for post-hematopoietic stem cell transplantation (HSCT) maintenance, which remains unknown in Japan. Recipients of a first HSCT for high-risk myelodysplastic syndromes (MDS, n = 12) or acute myeloid leukemia (AML) with antecedent MDS (n = 3) received post-HSCT AZA maintenance in 2015-2019. The optimal AZA dose was defined as the dose at which 50-70% of patients can complete four cycles without dose-limiting toxicity (DLT). The initial dose level 1 was set as 30 mg/m2 for 5 days per 28-day cycle, and dose levels 0, 2, and 3 were set as 20, 40, and 50 mg/m2. DLT was defined as any grade 3 non-hematological or grade 4 hematological toxicity. The 15 evaluable patients were 55 (37-64) years old. The median observation of the post-HSCT survivors was 935 (493-1915) days. The median number of days post-HSCT to the start of AZA was 101 (59-176). In the first, second, and third cohorts, five of nine patients completed four cycles at dose level 1. In the final cohort, five of six additional patients completed at the same dose. In total, 10 (67%) patients tolerated AZA 30 mg/m2, which was determined as optimal. DLT occurred in five cases: grade 3 hepatotoxicity, pneumonia, enterocolitis, and grade 4 thrombocytopenia and neutropenia. The 2-year overall survival and disease-free survival rates post-HSCT were 77.0% and 73.3%. Post-HSCT AZA maintenance was well-tolerated and merits further evaluation for patients with MDS or AML with antecedent MDS. Trial registration: UMIN000018791.

Epidemiologic outlook of therapy-related myeloid neoplasms and selection of high-risk patients: A Korean nationwide study.

BACKGROUND: Although a considerable proportion of patients with cancer receive chemotherapy (CT) or radiotherapy (RT), only a very few patients eventually develop therapy-related myeloid neoplasms (t-MNs). METHODS: To identify subsets of cancer patients who have substantially elevated risk of developing t-MNs. Incidences and risks of t-MNs after contemporary CT or RT in patients newly diagnosed major cancers during 2009-2013 were analyzed. By merging two Korean nationwide health care big data sets, patients were selected and observed on follow-up to until t-MN development or December 2019. RESULTS: Among 250,155 patients, 555 (0.22%) were diagnosed with t-MNs with a standard incidence ratio (SIR) of 3.40 (95% CI, 3.13-3.70). Patients had bone/joint cancers (SIR, 94.25; 95% CI, 50.71-137.80) and a remarkably high SIR for t-MN development. Patients receiving both CT and RT had the highest SIR (4.64; 95% CI, 4.08-5.20), followed by those receiving CT only (SIR, 3.30; 95% CI, 2.89-3.70). Contrarily, RT alone did not increase t-MN risk (SIR, 1.16; 95% CI, 0.76-1.56). More exposure to leukemogenic agents resulted in the higher t-MNs development. CONCLUSIONS: The increased risk of developing acute myeloid leukemia or myelodysplastic syndrome after CT and/or RT was confirmed and subsets with substantially elevated risk for developing t-MNs were found. Such patients would be suitable for a prospective cohort for investigating t-MN pathogenesis by time series analyses.

Volasertib as a monotherapy or in combination with azacitidine in patients with myelodysplastic syndrome, chronic myelomonocytic leukemia, or acute myeloid leukemia: summary of three phase I studies.

BACKGROUND: This report summarizes three phase I studies evaluating volasertib, a polo-like kinase inhibitor, plus azacitidine in adults with myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia, or acute myeloid leukemia. METHODS: Patients received intravenous volasertib in 28-day cycles (dose-escalation schedules). In Part 1 of 1230.33 (Study 1; NCT01957644), patients received 250-350 mg volasertib on day (D)1 and D15; in Part 2, patients received different schedules [A, D1: 170 mg/m2; B, D7: 170 mg/m2; C, D1 and D7: 110 mg/m2]. In 1230.35 (Study 2; NCT02201329), patients received 200-300 mg volasertib on D1 and D15. In 1230.43 (Study 3; NCT02721875), patients received 110 mg/m2 volasertib on D1 and D8. All patients in Studies 1 and 2, and approximately half of the patients in Study 3, were scheduled to receive subcutaneous azacitidine 75 mg/m2 on D1-7. RESULTS: Overall, 22 patients were treated (17 with MDS; 12 previously untreated). Across Studies 1 and 2 (n = 21), the most common drug-related adverse events were hematological (thrombocytopenia [n = 11]; neutropenia [n = 8]). All dose-limiting toxicities were grade 4 thrombocytopenia. The only treated patient in Study 3 experienced 18 adverse events following volasertib monotherapy. Studies 1 and 2 showed preliminary activity (objective response rates: 25 and 40%). CONCLUSIONS: The safety of volasertib with azacitidine in patients with MDS was consistent with other volasertib studies. All studies were terminated prematurely following the discontinuation of volasertib for non-clinical reasons by Boehringer Ingelheim; however, safety information on volasertib plus azacitidine are of interest for future studies in other diseases.

Therapy-related myeloid neoplasms following treatment for multiple myeloma-a single center analysis.

Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) can be late complications following mutagenic treatment. Limited data is available on the outcome of patients developing therapy-related MDS and AML after treatment for multiple myeloma (MM). We identified 250 patients with therapy-associated MDS or AML in the Duesseldorf MDS registry. Of those, 50 patients were previously diagnosed with multiple myeloma (mm-MDS/AML). We compared them to patients with de novo MDS (n = 4862) and to patients with MDS following other underlying diseases (tMDS) (n = 200). mm-MDS patients and tMDS patients showed similar karyotypes and degrees of cytopenia. However, mm-MDS patients had significantly higher blast counts and more often belonged to the high-risk group according to the International Prognostic Scoring System (IPSS) (both p < 0.05). Although the rate of progression to AML was similar in mm-MDS and tMDS, both transformed significantly more often than de novo MDS (p < 0.05). Median overall survival of patients with mm-MDS (13 months; range: 1-99) and tMDS (13 months; range 0-160) was also similar yet significantly shorter than patients with de novo MDS (32 months; range 0-345 months; p < 0.05). Furthermore, survival of mm-MDS patients was not affected by myeloma activity. Despite significantly more high-risk disease and higher blast cell counts, myeloma-associated MDS-patients show features akin to other tMDS. Survival is similar to other tMDS and irrespective of myeloma remission status or transformation to AML. Thus, patient outcome is not determined by competing clones but rather by MDS governing the stem cell niche.

Recurrent arthritis as an unexpected side effect associated with azacitidine in a patient with myelodysplastic syndrome.

INTRODUCTION: Hypomethylating agents have confirmed efficacy for myelodysplastic syndrome and acute myeloid leukemia and are widely used. Although arthralgia is common side effect associated with hypomethylating agents, arthritis has not been reported previously. CASE REPORT: We present the first recorded patient with arthritis after azacitidine treatment. The patient we presented here had severe cytopenias requiring transfusion with erythrocyte and platelet suspensions, and a complete hematological response was obtained for myelodysplastic syndrome after three cycles of azacitidine (AZA) treatment. However, interestingly, after each AZA treatment cycle, the patient had recurrent attacks of arthritis. MANAGEMENT AND OUTCOMES: The episodes of arthritis were possibly acute flares of pre-existing crystal-induced arthritis, as exhibited with azacitidine treatments and were managed effectively with nonsteroidal anti-inflammatory drugs. DISCUSSION: Because it is a rare condition, clinicians should not overlook AZA as a possible cause of arthritis exacerbations when arthritis of unknown etiology develops in patients treated with AZA.

Next generation sequencing in therapy-related myeloid neoplasms compared to de novo myeloid neoplasms.

INTRODUCTION: Therapy-related myeloid neoplasms (t-MN) are frequently categorized according to previous therapy or pattern of cytogenetic abnormalities. Our objective was to evaluate and compare the mutational profile of de novo and t-MN by next generation sequencing. METHODS: Sixty-four samples from patients with t-MN, previously treated for a solid tumor (mainly breast), or de novo AML, MDS, MDS/MPN were selected for our study. The library was prepared using diagnostic samples and the TruSight Myeloid sequencing panel targeting 54 genes. Samples were sequenced on a MiSeq. The classification system of the Belgian ComPerMed Expert Panel was used for the biological variant classification. RESULTS: Taking only pathogenic, probably pathogenic variants and variants of unknown significance into account 141 variants in 33 genes were found in 52 of 64 samples (81%; mean number of variants per patient = 2; range = [1-11]; 67 variants in 25 genes in t-MN and 74 variants in 25 genes in de novo MN). Overall, the most frequently detected variants included TET2 (n = 22), TP53 (n = 12), DNMT3A (n = 10) and FLT3, NPM1, RUNX1 (n = 8 each). CONCLUSION: Our study revealed a high variety of variants both in t-MN and de novo MN patients. There was a higher incidence of FLT3 and TP53 variants in t-MN compared to de novo MN.

Therapy-related myeloid neoplasms resembling juvenile myelomonocytic leukemia: a case series and review of the literature.

Therapy-related myeloid neoplasms (t-MN) are a distinct subgroup of myeloid malignancies with a poor prognosis that include cases of therapy-related myelodysplastic syndrome (t-MDS), therapy-related myeloproliferative neoplasms (t-MPN) and therapy-related acute myeloid leukemia (t-AML). Here, we report a series of patients with clinical features consistent with juvenile myelomonocytic leukemia (JMML), an overlap syndrome of MDS and myeloproliferative neoplasms that developed after treatment for another malignancy.

Analysis of Secondary Leukemia and Myelodysplastic Syndrome After Chemotherapy for Solid Organ Tumors Using the Food and Drug Administration Adverse Event Reporting System (FAERS).

PURPOSE: As the prognosis of cancer patients deteriorates, secondary carcinogenesis after chemotherapy, especially secondary hematological malignancies, becomes a serious problem. However, information on the frequency and time of onset of secondary hematological malignancies and the risk of hematological malignancy with different drugs is scarce. This study aimed to evaluate the incidence of leukemia and myelodysplastic syndrome in patients with solid tumors, including breast, colon, gastric, pancreatic, small cell lung, non-small cell lung, esophageal, ovarian, cervical, and endometrial cancers. METHODS: Using the United States Food and Drug Administration Adverse Event Reporting System, we analyzed the reporting rates, reporting odds ratios, and the reporting onset times of secondary leukemia and myelodysplastic syndrome for each drug used. RESULTS: The leukemia reporting rates were higher in breast, small cell lung, ovarian, and endometrial cancers than in other cancers, and the myelodysplastic syndrome reporting rates were higher in ovarian and endometrial cancers than in other cancers. For each cancer type, the reporting odds ratios of cytocidal anticancer agents, such as taxanes, anthracyclines, alkylating agents, platinum, and topoisomerase inhibitors, were higher than those of other drugs. Alternatively, the reporting odds ratios of molecular targeted drugs and immune checkpoint inhibitors were not higher than those of other drugs. Approximately half of the cases of leukemia and myelodysplastic syndrome were reported within 1 to 4 years after chemotherapy. CONCLUSIONS: Our study clarified the risks of leukemia and myelodysplastic syndrome for several anticancer drugs in patients with solid tumors. Our data may aid in the assessment of the risks of secondary leukemia and myelodysplastic syndrome when medical oncologists, clinical pharmacists, and patients select chemotherapy regimens.