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Background Therapeutic options remain limited for elderly acute myeloid leukemia (AML) considering the poor tolerance to intensive chemotherapy. Venetoclax in combination with modified intensive chemotherapy has been shown achieved significantly improved efficacy in elderly AML patients. Methods We conducted a retrospective study to evaluate the efficacy and safety of venetoclax plus daunorubicin and cytarabine induction chemotherapy (daunorubicin 60mg/m2 days 1–2, intravenously, cytarabine 100mg/m2 days 1–5, intravenously, and venetoclax 100mg day 3, 200mg day 4, 400mg days 5–10, orally, modified DAV regimen) in untreated fit de novo elderly AML. Results Twelve elderly patients who received a modified DAV regimen at our institution were enrolled from March 2021 to June 2022. Eleven of twelve (91.6%) patients achieved complete remission (CR), including 10 patients who achieved CR after one induction cycle and one patient who achieved CR after receiving a second repeated induction cycle. One patient with no response withdrew after one cycle of induction. All patients achieved measurable residual disease negativity detected by muti-parameter flow cytometry in responders. The median follow-up was 108 days. The median event-free survival (EFS) and overall survival (OS) were 398 days and not achieved separately, with an estimated 1-year EFS and OS rate of 75.0% and 100%, respectively. The most severe adverse events during induction therapy included 12 neutropenia (100%), 12 thrombocytopenia (100%), 12 anemia (100%), 5 febrile neutropenia (41.7%) and 4 pneumonia (33.3%). Myelosuppression recovered rapidly, without treatment-related deaths. Conclusions Our study showed the encouraging efficacy and good tolerability of the modified DAV regimen in untreated fit elderly AML patients.

Familial erythrocytosis (congenital erythrocytosis, FE), is a rare congenital disorder defined by elevated hemoglobin and hematocrit, with different genetic background. Clinically, FE is difficult to distinguish from polycythemia vera（PV）. A 53-years-old male was diagnosed with polycythemia vera without discovery of the JAK2 mutation when he was 31-years-old. The patient's family history revealed his father， a 86-years-old male， also suffered polycythemia for more than 20 years. The pedigree of the Chinese family with erythrocytosis is shown in Figure 1a. The index patient was a 53-years-old male (patient Ⅱ-1, Fig.1), who was hospitalized in our department in 2019 with a 22-year history of elevated red cell mass (RCM). When he was 31-years-old, he initially diagnosed with polycythemia vera without discovery of the JAK2 mutation. Over the last two decades he had irregular phlebotomy almost every two years and seldom prescribed any cytoreductive treatment. At our department he accepted 2 venesections because of Hct level of 64%. Upon medical history taking he reported that his father had suffered by polycythemia with more than 20 years, and were undergoing occasional phlebotomies.The father of the index patient was a 86-years-old male (patient Ⅰ-1, Fig.1), who was diagnosed with polycythemia for more than 20 years and suffered from diabetes. Similar to his son, he did not use any cytoreductive agent, and he had been phlebotomized occasionally. He was chronically treated with low-dose of aspirin . In our department he was treated with erythrocyte separation because of Hct level of 58.9%. He did not report any thrombembolic event. For the last one year of follow-up, the patient continued taking aspirin and her Hct level fluctuated between 54% and 57% while rejected to receive erythrocyte separation again.The elder sister (subject Ⅱ-2 Fig.1) of the index patient did not have any clinical and laboratory signs of elevated RCM as of January 2019, she was a 57-years-old female, who suffered from hypertension and diabetes.The daughter (subject Ⅲ-1 Fig.1) and the nephew (subject Ⅲ-2 Fig.1) of the index patient also did not have any clinical and laboratory signs of elevated RCM as of January 2019. They were subjected to whole exome sequencing (WES), the results revealed four mutations in all three of them, among, a frameshift mutation in the 15-hydroxyprostaglandin dehydrogenase（HPGD） gene is contained in both father and son, which at position c.310_311 ,translating into c.310_311delCT nucleotide mutation and p.L104Afs*3 amino acid mutation. In order to verify the mutation, we adopt the method of Sanger sequencing, then confirmed the presence of the same HPGD frameshift mutation in the index patient and his father. However, The mutation was absent in the elder sister of the index patient, when she was examined by WES and Sanger sequence. The ARHGAP26 mutation is contained in all three of them, but is a type of somatic mutation. The two mutations of VHL and FANCD2 are inexistent in the index patient, but are contained in his father and his elder sister. In conclusion, here we reported the first extensive genetic and clinical study of a family with two members carrying the HPGD gene frameshift mutation. Although functional studies were not made to confirm the pathogenic role of this mutation, the type and location of the mutation suggest that it can be the cause of the erythrocytosis observed in two patients. This study demonstrated the utility of the WES/NGS as the tool for identification of mutations in congenital erythrocytosis as well as helps to discovery these rare erythrocytosis-associated genes. The role and pathogenesis in haematopathy of HPGD mutation has been seriously underestimated, which is deserved to be explored in depth. Acknowledgment:The research was supported by the Public Technology Application Research Program of Zhejiang, China (LGF21H080003), the Key Project of Jinhua Science and Technology Plan, China (2020XG-29 and 2020-3-011), the Academician Workstation of the Fourth Affiliated Hospital of the Zhejiang University School of Medicine (2019-2024), the Key Medical Discipline of Yiwu, China (Hematology, 2018-2020) and the Key Medical Discipline of Jinhua, China (Hematology, 2019-2021). Correspondence to: Dr Jian Huang, Department of Hematology, The Fourth Affiliated Hospital of Zhejiang University School of Medicine. N1 Shangcheng Road. Yiwu, Zhejiang, Peoples R China. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Acute myeloid leukemia(AML) originates from the abnormal clonal proliferation of myeloblast which often combined with clinical symptoms. Cytogenetic and molecular abnormalities are frequent in AML patience. To date, the driver genes for leukemia remain largely undiscovered. Monoclonal immunoglobulinemia is a group of diseases caused by excessive proliferation of plasma cells or immunoglobulin-producing lymphoid plasma cells and B lymphocytes. It can develop into malignant plasma cell disease. Herein, we report a AML patient was concomitant with monoclonal immunoglobulinemia, the patient was also accompanied by BCOR mutation and TLS-ERG fusion gene. A 55-year-old married female was admitted into our hospital due to repeated edema for 3 weeks. On admission, peripheral blood counts: PLT142×10^9/L, HB77g/L↓, WBC35.2×10^9/L.Bone marrow examination showed the mononuclear cell system proliferated actively, and the primitive infantile monocytes accounted for 86%. Cell morphology suggested M5b(Figure1A ). Fusion gene screening in bone marrow revealed that TLS-ERG expression. Immunophenotype of bone marrow cell:Abnormal myeloid primitive cells accounted for 96.39% of the nuclear cells,expressCD33, CD13, CD123, CD34, CD9, MPO(Figure 1D). Karyotype analysis of bone marrow cells showed in Figure 1B. Thus, AML was diagnosed. Next-generation DNA sequencing technology showed that BCOR (51.7%),PLCG1(49.9%),DIS3(48.4%),BRAF(51.6%), JAK2(45.1%) ,JAK3(49.0%) were mutated. Meanwhile, we found that Peripheral blood immunofixation electrophoresis showed that Gamma region is seen with a monoclonal light chain lambda component((Figure 1C.).Then, the patient underwent one cycle of IA(Idabisine hydrochloride 10mg d1-4, cytarabine 0.075g q12h d1-7). Twenty-five after chemotherapy onset, bone marrow examination showed that primitive and immature monocytes accounted for 3%. Chromosome become normal. Minimal residual disease(MRD):0.01%. The disease reached complete remission(CR). Peripheral blood immunofixation electrophoresis turned negative. Fusion gene detection showed that TLS-ERG turned negative. BCOR mutation was not detected by Next-generation DNA sequencing. Mutations of PLCG1,DIS3,BRAF,JAK2,JAK3 still exist. Monoclonal immunoglobulinemia and AML are both clonal diseases, but originated from different clones. This case has both malignant clones of granulocyte stem cell and malignant clones of B line, so it is worthy of discussion. By comparing CR before and after we found that while the patient's M protein turned negative, the TLS-ERG fusion gene and BCOR gene mutation also disappeared. The TLS-ERG fusion gene is formed by the rearrangement of TLS and ERG genes on chromosomes 16 and 21. The current study holds that the expression of this fusion gene indicates rapid disease progression and poor prognosis. BCOR mutations can be found in AML and often coincide with DNMT3 gene mutations, suggesting it may affect the occurrence of leukemia through epigenetics. BCOR is a newly discovered corepressor of BCL-6, which can play a supporting role when BCOR combines with DNA; when BCOR is overexpressed, it can enhance the inhibition of BCL-6. BCL-6 is highly expressed in tumor cells,it encodes transcriptional repressors which are required for the formation of germinal center and may affect apoptosis. We thinked that the monoclonal immunoglobulinemia of this patient may caused by the BCOR abnormal expression which increased the inhibitory effect of BCL-6 and affect the apoptosis of B cells, and B cells continue to secrete immunoglobulin. BCOR mutations are associated with poor prognosis. The patient with TLS-ERG fusion gene which is a poor prognosis gene.However, the BCOR gene mutation site is a non-hot spot mutation which has few clinical studies. Whether the BCOR gene mutation results in the combination of the two diseases requires further study. Acknowledgment:The research was supported by fundings of the public technology research projects of Yiwu,China (2016-S-05), the key medical discipline of Yiwu,China(Hematology,2018-2020),and the academician workstation of the Fourth Affiliated Hospital of Zhejiang University School of Medicine. Correspondence to: Dr Jian Huang, Department of Hematology, The Fourth Affiliated Hospital of Zhejiang University School of Medicine. N1 Shangcheng Road. Yiwu, Zhejiang, Peoples R China. Email: househuang@zju.edu.cn Figure 1 Disclosures No relevant conflicts of interest to declare.