Secondary solid malignancies in long-term survivors after total body irradiation.

BACKGROUND: Total body irradiation (TBI)-based allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for selected patients with acute myeloid leukemia (AML). Yet, secondary malignancies contribute to long-term morbidity and mortality with TBI potentially influencing these risks. METHODS: This retrospective study analyzed the cumulative incidences of secondary solid malignancies and precancerous lesions of 89 consecutive AML patients after TBI-based conditioning before 1st allo-HSCT between 2000 and 2016. TBI was performed with an average dose rate of 4 cGy/min and a twice-daily fractionation. Cause-specific hazard models analyzed risk factors for secondary malignancies/precancerous lesions and the competing risks of dying before developing secondary malignancies/precancerous lesions. RESULTS: The median patient age at TBI was 42.5 years (interquartile range, 32.5-51.2), while the median follow-up was 15.2 years (interquartile range, 13.0-18.2). Most patients received a myeloablative conditioning (MAC) containing 8 Gy (n = 47) and 12 Gy TBI (n = 11). Reduced-intensity regimens (RIC, 4 Gy TBI) were applied in 31 patients. Of note, patients receiving RIC were older than patients receiving MAC. The most common cancer types were non-squamous cell carcinomas (n = 14) after exclusion of a patient diagnosed with sarcoma within less than a year after TBI. The cumulative incidences of secondary malignancies and precancerous lesions were 8% (95%CI, 4-16), 14% (95%CI, 7-23), and 17% (95%CI, 9-27) at 10, 15 and 20 years, while the cumulative incidences of premature deaths were 59% (95%CI, 48-69), 59% (95%CI, 48-69), and 64% (95%CI, 49-76). In multivariate analyses, higher patient age at TBI was associated with lower rates of secondary malignancies/precancerous lesions, while higher patient age translated into a trend towards premature deaths (before patients could develop malignancies). Higher TBI doses, mainly applied in younger patients, translated into lower rates of secondary malignancies/precancerous lesions while lacking associations with mortality. Chronic GVHD requiring systemic immunosuppression was associated with premature deaths. CONCLUSIONS: Although this study indicates an inverse relationship between TBI doses applied and treatment-related malignancies, confounding by competing risks is present. The age dependency may be explained by the fact that older patients had a lower life expectancy independent of malignancies, illustrating the pitfalls of competing risks. TRIAL REGISTRATION: The study was retrospectively registered.

Advances in pathogenesis research and challenges in treatment development for acute myeloid leukemia.

Acute myeloid leukemia (AML) develops when hematopoietic stem cells acquire chromosomal and genetic abnormalities, transforming into leukemia stem cells (LSCs) and further gaining driver mutations. Advances in genomic analysis have identified numerous new gene mutations involved in AML development. Recent research has shown that individuals with germline mutations in genes like DDX41 and CEBPA develop AML upon acquiring additional somatic mutations, and the latest WHO classification separates AML with such mutations into distinct disease groups. LSCs are regulated by different metabolic processes than normal stem cells, contributing to drug resistance and relapse. LSCs rely on oxidative phosphorylation (OXPHOS) metabolism for energy production, and venetoclax inhibits this process, affecting LSCs. Resistant LSCs show enhanced glycolysis, which suggests that targeting both OXPHOS and glycolysis is crucial. While targeted therapies like FLT3, BCL-2, and IDH inhibitors have shown efficacy, resistance remains an issue, highlighting the need for new treatment strategies. CAR-T cell therapy is an emerging immunotherapy that shows particular promise for targeting CD123 and CLL-1, with acceptable toxicity. Future developments in CAR-T cell therapy and other immunotherapies are anticipated to improve AML treatment outcomes.

Mutational cooperativity of RUNX1::RUNX1T1 isoform 9a and oncogenic NRAS in zebrafish myeloid leukaemia.

RUNX1::RUNX1T1 (R::RT1) acute myeloid leukaemia (AML) remains a clinical challenge, and further research is required to model and understand leukaemogenesis. Previous zebrafish R::RT1 models were hampered by embryonic lethality and low penetrance of the malignant phenotype. Here, we overcome this by developing an adult zebrafish model in which the human R::RT1 isoform 9a is co-expressed with the frequently co-occurring oncogenic NRASG12D mutation in haematopoietic stem and progenitor cells (HSPCs), using the Runx1+23 enhancer. Approximately 50% of F0 9a+NRASG12D transgenic zebrafish developed signs of haematological disease between 5 and 14 months, with 27% exhibiting AML-like pathology: myeloid precursor expansion, erythrocyte reduction, kidney marrow hypercellularity and the presence of blasts. Moreover, only 9a+NRASG12D transplant recipients developed leukaemia with high rates of mortality within 40 days, inferring the presence of leukaemia stem cells. These leukaemic features were rare or not observed in animals expressing either the NRAS or 9a oncogenes alone, suggesting 9a and NRAS cooperation drives leukaemogenesis. This novel adult AML zebrafish model provides a powerful new tool for investigating the basis of R::RT1 - NRAS cooperativity with the potential to uncover new therapeutic targets.

Nudt15-mediated inflammatory signaling contributes to divergent outcomes in leukemogenesis and hematopoiesis.

NUDT15 encodes nucleotide triphosphate diphosphatase that is responsible for metabolizing purine analog drugs, and its genetic mutation results in severe side effects from thiopurine therapy. However, the functions of Nudt15 in leukemic stem cells (LSCs) and hematopoietic stem cells (HSCs) remain unknown. Here we reveal the Nudt15-regulating self-renewal of both mouse LSCs and HSCs. Our data show that Nudt15 negatively regulates murine leukemogenesis and its deficiency prolongs the survival of murine AML recipients by impairing LSC self-renewal, while Nudt15 ablation markedly enhances mouse HSC regenerative potential and self-renewal. Mechanistically, Nudt15 modulates inflammatory signaling in mouse LSCs and HSCs, leading to divergent self-renewal outcomes. Nudt15 depletion inhibits mouse LSC self-renewal by downregulating Ifi30, resulting in elevating intracellular ROS level. Gata2, a key regulator, is required for Nudt15-mediating inflammatory signaling in mouse HSCs. Collectively, our results present new crucial roles of Nudt15 in maintaining the functions of mouse LSC and HSC through inflammatory signaling and have a new insight into clinical implications.

Modeling and therapeutic targeting of t(8;21) AML with/without TP53 deficiency.

Acute myeloid leukemia (AML) with t(8;21)(q22;q22.1);RUNX1-ETO is one of the most common subtypes of AML. Although t(8;21) AML has been classified as favorable-risk, only about half of patients are cured with current therapies. Several genetic abnormalities, including TP53 mutations and deletions, negatively impact survival in t(8;21) AML. In this study, we established Cas9+ mouse models of t(8;21) AML with intact or deficient Tpr53 (a mouse homolog of TP53) using a retrovirus-mediated gene transfer and transplantation system. Trp53 deficiency accelerates the in vivo development of AML driven by RUNX1-ETO9a, a short isoform of RUNX1-ETO with strong leukemogenic potential. Trp53 deficiency also confers resistance to genetic depletion of RUNX1 and a TP53-activating drug in t(8;21) AML. However, Trp53-deficient t(8;21) AML cells were still sensitive to several drugs such as dexamethasone. Cas9+ RUNX1-ETO9a cells with/without Trp53 deficiency can produce AML in vivo, can be cultured in vitro for several weeks, and allow efficient gene depletion using the CRISPR/Cas9 system, providing useful tools to advance our understanding of t(8;21) AML.

[Safety and efficacy of 7-day administration of azacitidine and venetoclax combination therapy (7+7 therapy)].

Acute myelogenous leukemia (AML) has a poor prognosis in patients who are ineligible for intensive chemotherapy. The combination of azacitidine and venetoclax has been shown to have high overall efficiency and remission rates, even in patients ineligible for aggressive chemotherapy. However, myelosuppression is often prolonged after treatment, and infection can also occur. Severe myelosuppression is often addressed by dose titration, but specific dose titration methods have not been clarified. We used the standard induction therapy with azacitidine plus venetoclax, and if blasts decreased to 20% or less, switched to 7+7 therapy to shorten venetoclax to 7 days starting from the next cycle. In the 19 patients we treated (median age 80 years), response rate above MLFS was 100%, CR 57.9%, CRc (CR+CRi) 78.8%, median OS 693 days, median PFS 458 days, and median OS was not reached in previously untreated patients. This indicates that 7+7 is a highly effective and well-tolerated treatment.

Acute Myeloid Leukemia Secondary to Treatment with Oxaliplatin Combined with Capecitabine for Colorectal Cancer.

BACKGROUND: Treatment-related acute myeloid leukemia (t-AML) is often secondary to some cytotoxic drugs or occurs after radiotherapy and immunosuppression therapy. As commonly used drugs in colorectal cancer chemotherapy, oxaliplatin and capecitabine have obvious cytotoxicity, which may also be an important factor causing t-AML. METHODS: In this study, we report the development of treatment-related acute myeloid leukemia in a pT4NIMO colorectal cancer patient after an approximate 16-month latency period following treatment with 6 cycles of oxali-platin (190 mg on Day 1) plus capecitabine (1.5 g orally twice daily on Days 1 - 14) in combination with recombinant human granulocyte-colony stimulating factor treatment. The patient developed severe anemia with thrombocytopenia after treatment. After a peripheral blood smear and bone marrow biopsy, the diagnosis of AML-M2a was confirmed. RESULTS: The patient was diagnosed with t-AML approximately 16 months after treatment. Our case illustrates the possibility of some cytotoxic drugs inducing t-AML after colorectal cancer treatment. CONCLUSIONS: We suggest that clinicians conduct long-term epidemiological follow-up and epidemiological investigations on patients treated with oxaliplatin and capecitabine. In addition, clinicians should carefully check the complete blood cell count on routine follow-ups and observe the morphological changes of white blood cells in peripheral blood smears, even for asymptomatic patients who have undergone chemotherapy. In this way, we can observe the possibility of its development into secondary leukemia.

[Venetoclax Combined with CACAG Regimen in the Treatment of Patients with Refractory/Relapse Acute Myeloid Leukemia: A Prospective Clinical Study].

OBJECTIVE: To investigate the efficacy and safety of Venetoclax combined with CACAG regimen in treatment of patients with refractory/relapse acute myeloid leukemia(R/R AML). METHODS: The study was a singlecenter prospective clinical trial. The enrolled patients met the criteria for R/R AML. Treatment included Azacidine(75 mg/m2，d 1-7), Ara-C (75-100 mg/m2, q12h, d 1-5), Aclacinomycin(20 mg d1,d3,d5), Chidamide(30 mg d1,d4), Venetoclax(100 mg d1, 200 mg d2, 400 mg d3-d14, in combination with Triazole Drug, reduced to 100 mg/d), and granulocyte colony-stimulating factor (300 µg /d until neutrophil recovery). The primary endpoint of observation was overall response rate after 1 course of treatment. RESULTS: A total of 19 patients were enrolled from January 2022 to April 2023. After 1 course of treatmen, the overall response rate was 81.3%(13/16), the CR rate was 68.8%(11/16), and the PR was 12.5%(2/16). Among the 11 patients who got CR/CRi, 8 cases achieved CRm (minimal residual disease negative CR) and 3 cases did not. As of March 27, 2023, the median follow-up time was 111(19-406) days. The six-month overall survival and progression-free survival rates were both 55.7%, the 1-year overall survival and progression-free survival rates were 46.4% and 47.7%, respectively. In addition, compared with the non-CRm group, CRm patients had a better PFS (377 days vs 111 days, P =0.046). Treatment-related adverse events were mainly 3-4 degrees of bone marrow suppression, complicated by various degrees of infection(n=12), hypokalemia(n=12) and hypocalcemia (n=10) and elevated liver enzymes (n=8), of which 3/4 degrees accounted for 47.4%(9/19). CONCLUSION: The Venetoclax combined with CACAG regimen is an effective salvage therapy for patients with R/R AML, with high remission rate and safety profile.

How adoptive transfer of components of the donor immune system boosts GvL and prevents GvHD in HLA-haploidentical hematopoietic transplantation for acute leukemia.

Why a new Perspective in allogeneic hematopoietic transplantation? A summary. Nowadays, for high-risk acute leukemia patients without an HLA-matched donor (sibling or volunteer), hematopoietic transplants that use HLA-haploidentical grafts combined with enhanced post transplant immune suppression (i.e., high-dose cyclophosphamide) are widely used. They are associated with low TRM rates. However, they are also associated with significant chronic GvHD while they only partially abrogate leukemia relapse rates. One may speculate that post-transplant immune suppression, required for GvHD prophylaxis, weakens the anti-leukemic potential of the graft. Historically, haploidentical transplants became feasible for the first time through transplantation of T cell-depleted peripheral blood hematopoietic progenitor cells. Lack of post-transplant immune suppression allowed the emergence of donor-versus-recipient NK-cell alloreactions that eradicated AML. In an attempt to improve these results we recently combined an age-adapted, irradiation-based conditioning regimen with transplant of T-cell-depleted grafts and infusion of regulatory and conventional T cells, without any post transplant immune suppression. With the obvious limitations of a single center experience, this protocol resulted in extremely low relapse and chronic GvHD rates and, consequently, in a remarkable 75% chronic GvHD/relapse-free survival in over 50 AML patients up to the age of 65 many of whom at high risk of relapse.

Pre- and Postnatal Exposures to Tobacco Smoking and Survival of Childhood Acute Lymphoblastic and Myeloid Leukemias in California, United States.

BACKGROUND: Tobacco smoke adversely affects the prognosis of adult cancers including myeloid leukemia, but less is known in children. METHODS: We evaluated whether pre- and postnatal exposures to tobacco smoke decrease 5-year survival of 1,235 childhood acute lymphoblastic leukemia (ALL) and 188 childhood acute myeloid leukemia (AML) cases derived from a population-based case-control study in California. Cases were diagnosed between 1995 and 2015 (median follow-up time of 13.2 years overall). We obtained data on tobacco smoking (before conception, during pregnancy, after birth), parental education and income, clinical features, and vital status through 2020. Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for mortality associated with smoking, adjusting for sociodemographic characteristics and risk group (ALL only). RESULTS: About 23% of mothers and 39% of fathers reported smoking and 130 children with ALL and 52 with AML died within 5 years. For AML, increased risks of death were observed among children whose fathers smoked before conception compared with nonsmoking fathers [HR = 1.41; 95% confidence interval (CI), 0.95-3.44 and 3.47; 95% CI, 1.37-8.81, respectively for <20 vs. ≥20 cigarettes per day; Ptrend = 0.01]. HR for child's passive smoking was 1.74, 95% CI, 0.81-3.73. Paternal preconception smoking may also reduce 5-year survival among ALL with favorable prognostic molecular subtypes (high hyperdiploidy and absence of IKZF1 gene deletion), although the associations did not reach statistical significance (Pheterogeneity = 0.07). CONCLUSIONS: Paternal preconception smoking decreased 5-year survival of childhood AML. IMPACT: Knowledge of exposure to tobacco smoking should be integrated in the treatment plan of childhood leukemias.

A multicenter phase Ib trial of the histone deacetylase inhibitor entinostat in combination with pembrolizumab in patients with myelodysplastic syndromes/neoplasms or acute myeloid leukemia refractory to hypomethylating agents.

Patients with myelodysplastic syndromes/neoplasms (MDS) or acute myeloid leukemia (AML) with hypomethylating agent failure have a poor prognosis. Myeloid-derived suppressor cells (MDSCs) can contribute to MDS progression and mediate resistance to anti-PD1 therapy. As histone deacetylase inhibitors (HDACi) decrease MDSCs in preclinical models, we conducted an investigator-initiated, NCI-Cancer Therapy Evaluation Program-sponsored, multicenter, dose escalation, and expansion phase Ib trial (NCT02936752) of the HDACi entinostat and the anti-PD1 antibody pembrolizumab. Twenty-eight patients (25 MDS and 3 AML) were enrolled. During dose escalation (n=13 patients), there was one dose-limiting toxicity (DLT) on dose level (DL) 1 (G5 pneumonia/bronchoalveolar hemorrhage) and two DLTs at DL 2 (G3 pharyngeal mucositis and G3 anorexia). Per the 3 + 3 dose escalation design, DL 1 (entinostat 8 mg PO days 1 and 15 + pembrolizumab 200 mg IV day 1 every 21 days) was expanded and another 15 patients were enrolled. Hematologic adverse events (AEs) were common. The most common non-hematologic ≥G3 AEs were infection (32%), hypoxia/respiratory failure (11%), and dyspnea (11%). There were no protocol-defined responses among the 28 patients enrolled. Two patients achieved a marrow complete remission (mCR). Using a systems immunology approach with mass cytometry and machine learning analysis, mCR patients had increased classical monocytes and macrophages but there was no significant change of MDSCs. In conclusion, combining entinostat with pembrolizumab in patients with advanced MDS and AML was associated with limited clinical efficacy and substantial toxicity. Absence of an effect on MDSCs could be a potential explanation for the limited efficacy of this combination. ClinicalTrial.gov Identifier: NCT02936752.

Nonchromosomal birth defects and risk of childhood acute leukemia: An assessment in 15 000 leukemia cases and 46 000 controls from the Childhood Cancer and Leukemia International Consortium.

Although recent studies have demonstrated associations between nonchromosomal birth defects and several pediatric cancers, less is known about their role on childhood leukemia susceptibility. Using data from the Childhood Cancer and Leukemia International Consortium, we evaluated associations between nonchromosomal birth defects and childhood leukemia. Pooling consortium data from 18 questionnaire-based and three registry-based case-control studies across 13 countries, we used multivariable logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between a spectrum of birth defects and leukemia. Our analyses included acute lymphoblastic leukemia (ALL, n = 13 115) and acute myeloid leukemia (AML, n = 2120) cases, along with 46 172 controls. We used the false discovery rate to account for multiple comparisons. In the questionnaire-based studies, the prevalence of birth defects was 5% among cases vs 4% in controls, whereas, in the registry-based studies, the prevalence was 11% among cases vs 7% in controls. In pooled adjusted analyses, there were several notable associations, including (1) digestive system defects and ALL (OR = 2.70, 95% CI: 1.46-4.98); (2) congenital anomalies of the heart and circulatory system and AML (OR = 2.86, 95% CI: 1.81-4.52) and (3) nervous system defects and AML (OR = 4.23, 95% CI: 1.50-11.89). Effect sizes were generally larger in registry-based studies. Overall, our results could point to novel genetic and environmental factors associated with birth defects that could also increase leukemia susceptibility. Additionally, differences between questionnaire- and registry-based studies point to the importance of complementary sources of birth defect phenotype data when exploring these associations.

SOHO State of the Art Updates and Next Questions: Oral Therapy in Acute Myeloid Leukemia.

With the recent development of several new effective agents, treatment of patients with acute myeloid leukemia (AML) is evolving. Molecularly targeted agents developed against leukemogenic pathways are demonstrating significant promise both as monotherapy and in combination with standard regimens. Although oral chemotherapeutic agents have long been used in the treatment of various malignancies, their use in patients with AML has been hitherto limited. The availability of most newly approved targeted agents in oral formulation has provided us with the potential for developing all oral regimens in AML. This is particularly important for the older, less fit patients allowing reduced requirements for hospital visits in order to administer therapy, especially when in remission and for continuation of therapy. A potential barrier to the success of such regimens is adherence to therapy with prior studies demonstrating increased success of therapy with high adherence. Strategies to develop completely oral regimens are likely to further revolutionize AML therapy especially in the elderly.

Favorable response of a patient with primary B/myeloid mixed phenotype acute Leukemia to CD19-CAR-T: Case report and literature review.

RATIONALE: Mixed phenotype acute leukemia (MPAL) is a rare and heterogeneous type of leukemia known for its poor prognosis. The optimal treatment strategy for this condition currently lacks consensus, leaving uncertainty in its management. Nonetheless, a potential therapeutic option for patients with refractory MPAL who express target antigens is donor-derived chimeric antigen receptor T (CAR-T) cell therapy. PATIENT CONCERNS: We recently reported a 61-year-old woman with MPAL and elucidated its diagnosis and treatment. DIAGNOSIS: The diagnosis of MPAL was established based on the classification of World Health Organization in 2016. INTERVENTIONS: Despite undergoing 3 different acute lymphoblastic leukemia (ALL) regimens and 1 acute myelogenous leukemia (AML) regimen, the patient did not achieve remission. Subsequently, the patient received human CD19-targeted CAR-T cell therapy. OUTCOMES: The patient achieved a successful and complete remission after CAR-T cell therapy. Tragically, 8 months after CAR-T infusion, the patient experienced a relapse characterized by CD19-negative disease and ultimately passed away. LESSONS: This case underscores the potential efficacy and safety of human-derived CD19 CAR-T cell therapy in treating refractory MPAL. While this particular patient outcome was unfortunate, it suggests that CAR-T cell therapy may still hold promise as a viable treatment option for MPAL patients unresponsive to other therapies. Further research in this field is warranted to determine the most effective treatment strategies for managing this challenging disease.

Microbiota, Diet and Acute Leukaemia: Tips and Tricks on Their Possible Connections.

Acute leukaemia is probably one of the most recurrent cancers in children and younger adults, with an incidence of acute lymphoblastic leukaemia in 80% of cases and an incidence of acute myeloid leukaemia in 15% of cases. Yet, while incidence is common in children and adolescents, acute leukaemia is a rare disease whose aetiology still requires further analysis. Many studies have investigated the aetiology of acute leukaemia, reporting that the formation of gut microbiota may be modified by the start and development of many diseases. Considering that in patients affected by acute lymphoblastic leukaemia, there is an inherent disequilibrium in the gut microbiota before treatment compared with healthy patients, increasing evidence shows how dysbiosis of the gut microbiota provokes an inflammatory immune response, contributing to the development of cancer. Our analysis suggeststhe key role of gut microbiota in the modulation of the efficacy of leukaemia treatment as well as in the progress of many cancers, such as acute leukaemia. Therefore, in this paper, we present an examination of information found in literature regarding the role of dietary factors and gut microbiota alterations in the development of leukaemia and suggest possible future preventive and therapeutic strategies.

Aspacytarabine for the treatment of patients with AML unfit for intensive chemotherapy: a phase 2 study.

High-dose cytarabine is associated with gastrointestinal and cerebellar toxicity, precluding its use for older or unfit patients with acute myeloid leukemia (AML). Aspacytarabine, an inactive prodrug of cytarabine, was evaluated as monotherapy in a phase 2b study of patients unfit for intensive chemotherapy (NCT03435848). Sixty-five patients with AML were treated with aspacytarabine 4.5 g/m2 per day (equimolar to 3 g/m2 per day cytarabine) for 6 doses per treatment. The median age was 75 years; 60.6% of patients had de novo AML, 28.8% had AML secondary to myelodysplastic syndrome, and 10.6% had therapy-related AML. Overall, 36.9% achieved complete remission (CR) with full count recovery. CR rates in patients with secondary AML, patients with prior treatment with hypomethylating agents, and patients with TP53 mutation were 26.7%, 25%, and 36%, respectively. Median overall survival was 9 months (range, 6-15.9) and was not reached among responders. Hematologic recovery was observed in all responding patients by day 26 without prolonged cytopenias. Adverse events typically precluding the use of high-dose cytarabine in older or unfit patients were not observed. These data suggest that aspacytarabine may be an effective regimen with a reduction in the attendant toxicities associated with high-dose cytarabine, an important consideration when treating AML and other hematologic disorders that use high-dose cytarabine. This trial was registered at www.clinicaltrials.gov as #NCT03435848.

Phase 1 study of selinexor in combination with salvage chemotherapy in Adults with relapsed or refractory Acute myeloid leukemia.

Selinexor, an oral inhibitor of the nuclear transport protein Exportin-1, shows promising single-agent activity in clinical trials of relapsed/refractory (R/R) acute myeloid leukemia (AML) and preclinical synergy with topoisomerase (topo) IIα inhibitors. We conducted a phase 1, dose-escalation study of selinexor with mitoxantrone, etoposide, and cytarabine (MEC) in 23 patients aged < 60 years with R/R AML. Due to dose-limiting hyponatremia in 2 patients on dose level 2 (selinexor 40 mg/m2), the maximum tolerated dose was 30 mg/m2. The most common grade ≥ 3 treatment-related non-hematologic toxicities were febrile neutropenia, catheter-related infections, diarrhea, hyponatremia, and sepsis. The overall response rate was 43% with 6 patients (26%) achieving complete remission (CR), 2 (9%) with CR with incomplete count recovery, and 2 (9%) with a morphologic leukemia-free state. Seven of 10 responders proceeded to allogeneic stem cell transplantation. The combination of selinexor with MEC is a feasibile treatment option for patients with R/R AML.

Impact of preexisting autoimmune disease on myelodysplastic syndromes outcomes: a population analysis.

Preexisting autoimmune disease affects between 10% and 30% of patients with myelodysplastic syndromes (MDS). Studies comparing outcomes in patients with MDS with and without autoimmune disease show discordant results. Using the Surveillance, Epidemiology, and End Results Medicare database, we conducted a population analysis to define the impact of autoimmunity on MDS outcomes. Cases were ascertained between 2007 and 2017 and claim algorithms used to identify autoimmune disease, demographic characteristics, comorbidity scores, MDS histology, transfusion burden, treatment with hypomethylating agents, and hematopoietic stem cell transplantation. Cox regression models estimated the impact on survival, and competing-risk regression models defined the effect on leukemic transformation. We analyzed 15 277 patients with MDS, including 2442 (16%) with preexisting autoimmune disease. The epidemiologic profile was distinctive in cases with preexisting autoimmunity, who were younger, were predominantly female, and had higher transfusion burden without difference in MDS histologic distribution. Autoimmune disease was associated with 11% decreased risk of death (hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.85-0.94; P < .001). The effect on risk of leukemic transformation differed based on MDS histology. In low-risk MDS histologies, autoimmunity was associated with a 1.9-fold increased risk of leukemia (HR, 1.87; 95% CI, 1.17-2.99; P = .008), whereas no significant effect was seen in other groups. These results suggest that autoimmune disease affects survival in MDS and is associated with decreased mortality. The survival effect was evident in low-risk histologies despite higher risk of progression to leukemia. This could represent inflammation-driven hematopoiesis, simultaneously favoring less aggressive phenotypes and clonal expansion, which warrants further investigation.