Institute Of Hematology Research Articles

The relevance of genetic testing in young patients with breast fibroadenomas

Introduction. Fibroadenomas are the most common benign tumors of the mammary glands in children and adolescents. In some cases, they may be part of hereditary tumor predisposition syndromes associated with a high risk of developing malignant neoplasms throughout life, and therefore genetic testing is relevant.The purpose of the study is to discribe the spectrum of genetic mutations in cancer-associated genes according to the results of next generation sequencing (NGS) in young patients with breast fibroadenomas.Matherials and methods. Sixteen teenage girls with fibroadenomas of the breast who were followed up in Research Institute of Pediatric Oncology and Hematology from 2020 to 2023 were enrolled in this study. Genetic testing by NGS was performed.Results. Pathogenic variants in cancer-associated genes were found in 4 (25 %) patients. In two cases, fibroadenomas were a part of Cowden’s syndrome associated with PTEN inactivation; two patients carried pathogenic variants in the BRCA1 and BRCA2 genes.Conclusion. Genetic testing of young patients with breast fibroadenomas is important to optimize the management strategy in order to reduce cancer risk in high-risk groups of patients.

Clinical analysis of 14 patients aged ≤ 50 years with high-risk multiple myeloma treated with allogeneic hematopoietic stem cell transplantation

Objective: To evaluate the efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in young patients with high-risk multiple myeloma (HRMM) and analyzed the factors affecting patient prognosis. Methods: In this retrospective study, we analyzed the clinical data of 14 patients with HRMM with cytogenetic abnormalities or high-risk biological factors who underwent allo-HSCT at the Hematopoietic Stem Cell Transplantation Center of the Institute of Hematology & Blood Diseases Hospital between November 2016 and November 2022. Results: There were seven males and seven females included in the study, with a median age of 39.5 (31-50) years at the time of allo-HSCT. The median number of treatment lines before transplantation was 2 (1-6) . Before allo-HSCT, 42.9% (6/14) of the patients did not achieve complete remission, while 35.7% (5/14) of the patients achieved measurable residual disease positivity. After transplantation, all patients were evaluated for their treatment response, and the overall response rate was 100% (14/14) . All 14 patients successfully underwent allo-HSCT, with median engraftment times for neutrophils and platelets of 11 (10-14) days and 13 (9-103) days, respectively. Acute grade Ⅱ-Ⅳ graft-versus-host disease (GVHD) occurred in five patients (35.7%) , and two patients (14.3%) developed moderate-to-severe chronic GVHD. The median follow-up time after allo-HSCT was 18.93 (4.10-72.53) months, with an expected 2-year transplant-related mortality rate of 7.1% (95% CI 0%-21.1%) and an expected 2-year overall survival rate of 92.9% (95% CI 80.3%-100.0%) . Moreover, the expected 1-year and 2-year progression-free survival rates were 92.9% (95% CI 80.3%-100.0%) and 66.0% (95% CI 39.4%-100.0%) , respectively, and the 2-year cumulative incidence of relapse was 28.9% (95% CI 0%-56.7%) . Upfront allo-HSCT following complete remission after induced therapy and the presence of chronic GVHD might be favorable prognostic factors. Conclusion: allo-HSCT is an effective treatment for improving the prognosis of young patients with HRMM.

Gemcitabine-based conditioning compared to BEAM/BEAC conditioning prior to autologous stem cell transplantation for non-Hodgkin lymphoma: No difference in outcomes.

High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) remains an effective treatment for non-Hodgkin lymphoma (NHL). The limited availability of carmustine has prompted the exploration of novel alternative conditioning regimens. This study aimed to compare the efficacy and safety profile of GBM/GBC (gemcitabine, busulfan, and melphalan or cyclophosphamide) conditioning compared with the standard BEAM/BEAC regimens (carmustine, etoposide, cytarabine, and melphalan or cyclophosphamide) for ASCT in patients with NHL. A retrospective analysis was conducted on 231 NHL patients, who underwent ASCT from October 2010 to October 2021 at the Institute of Hematology & Blood Disease Hospital, including both first-line and salvage settings. This resulted in the inclusion of 112 patients in the GBM/GBC arm and 92 in the BEAM/BEAC arm. Propensity score matching was employed to validate the results. Disease subtype distribution was similar between the GBM/GBC and BEAM/BEAC groups, with diffuse large B-cell lymphoma being the most common (58.9% vs. 58.7%), followed by PTCL (17.0% vs. 18.5%) and MCL (14.3% vs. 14.1%). At 3 months post-ASCT, complete response (CR) rates were comparable (GBM/GBC 93.5% vs. BEAM/BEAC 91.1%; p = 0.607). The 4-year progression-free survival (78.4% vs. 82.3%; p = 0.455) and 4-year overall survival (88.1% vs. 87.7%; p = 0.575) were also similar. Both groups exhibited low non-relapse mortality at 4 years (GBM/GBC 1.8% vs. BEAM/BEAC 3.5%; p = 0.790) with no transplant-related mortalities reported. The GBM/GBC cohort demonstrated a higher incidence of grade 3/4 oral mucositis and hepatic toxicity, whereas the BEAM/BEAC group had more frequent cases of bacteremia or sepsis (13 cases vs. 5 in GBM/GBC). The GBM/GBC regimen is effective and well-tolerated, offering outcomes that are highly comparable to those in NHL patients conditioned with BEAM/BEAC, as demonstrated in a prognostically matched cohort.

RESULTS OF IRON SUPPLEMENTATION FOR REGULAR VOLUNTARY NON-REMUNERATED BLOOD DONORS AT NATIONAL INSTITUTE OF HEMATOLOGY AND BLOOD TRANSFUSION

Objective: To evaluate the results of iron supplementation for RRVBD at the National Institute of Hematology and Blood Transfusion (NIHBT). Subjects and methods: Including 279 RRVBD with serum ferritin below 26 ng/ml taking iron tablets containing 35 mg of elemental iron. Methods: Cross-sectional description, prospective study. Results: The average age of RRVBD taking iron tablets is 27.8 years old, the average number of blood donations is 11 times, the average time of re-testing is 169.5 days. The proportion of RRVBD taking iron tablets and testing on time is 43.4%, the proportion of RRVBD not taking iron tablets or not taking enough iron tablets is 18.3%, the proportion of RRVBD taking enough iron tablets and not coming to the test on time is 18.6%. The proportion of RRVBD dropping out of the study is 19.7%. Hematological parameters (red blood cell count, hemoglobin (Hb), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean serum iron concentration) of RRVBD taking iron tablets are within the normal range, the serum ferritin concentration of RRVBD recovered after taking iron tablets is: in the group of blood donors taking enough iron tablets and testing on time, the mean serum ferritin concentration before taking iron tablets is 15.8 ± 5.5 ng/ml and after taking iron tablets is 24.7 ± 14.9 ng/ml, the proportion of blood donors with ferritin returning to normal range after taking iron tablets is 39.7%. In group of blood donors not taking iron tablets or not taking enough iron tablets, serum ferritin before iron intake is 18.1 ± 5.3 ng/ml and after iron intake is 14.2 ± 10.9 ng/ml, the proportion of blood donors having serum ferritin returning to normal range after iron intake is 7.8%. In group of RRVBD taking enough iron tablets and not coming to the test on time, the mean serum ferritin concentration before iron intake is 16.5 ± 5.9 ng/ml and after iron intake is 28.8 ± 17.1 ng/ml, the proportion of blood donors with serum ferritin concentration returning to normal range after blood donation is 51.9%. Conclusion: The proportion of regularly repeated voluntary blood donors taking enough iron tablets and testing on time is 43.4%, the proportion of regularly repeated voluntary blood donors not taking iron tablets or not taking enough iron tablets is 18.3%, the proportion of regularly repeated voluntary blood donors taking enough iron tablets and not coming to the test on time is 18.6%, the proportion of regularly repeated voluntary blood donors not taking iron tablets and not testing is 19.7%. Hematological parameters (red blood cell count, Hb, MCV, MCH and mean serum iron concentration) of regularly repeated voluntary blood donors taking iron tablets before and after iron intake are within the normal range. The proportion of blood donors with serum ferritin concentration after iron intake returning to the normal range: blood donors taking enough iron tablets and testing on time is 39.7%, blood donors not taking iron tablets or not taking enough iron tablets is 7.8% and blood donors taking enough iron tablets and not coming to the test on time is 51.9%.

ВСТРЕЧАЕМОСТЬ АЛЛЕЛЕЙ И ГЕНОТИПОВ ПО АЛЛЕЛЬНЫМ ВАРИАНТАМ CYP2С9*2 И CYP2С9*3 СРЕДИ БОЛЬНЫХ С БОЛЕВЫМ СИНДРОМОМ, ПРИНИМАВШИХ НЕСТЕРОИДНЫЕ ПРОТИВОВОСПАЛИТЕЛЬНЫЕ СРЕДСТВА

Abstract. Introduction. The most clinically significant polymorphic markers of the CYP2C9 gene are the amino acid substitutions of CYP2C9*2. One of the human cytochrome P450 types, i.e., cytochrome CYP2C19, is essential to the metabolism of some drugs, including proton pump inhibitors. Genetic polymorphism of СУР2С19 has some pronounced interindividual differences. Significance of genetic polymorphism is detected where the occurrence of variant alleles exceeds 1% in the population. Aim of the study was to improve the principles of pharmacotherapy with nonsteroidal anti-inflammatory drugs, as related to the frequency of alleles and genotypes on the allelic variants of CYP2С9*2 and CYP2С9*3 in pain syndrome patients taking nonsteroidal anti-inflammatory drugs. Materials and Methods. The study included 69 patients with pain syndrome. Association between being the carrier of genotypes on the CYP2С9*2 and CYP2С9*3 alleles and developing gastropathies as reactions to administering anti-inflammatory drugs was investigated by conducting a prospective case-control study. Molecular genetic testing was performed based on the Laboratory of Medical Genetics of the Research Institute of Hematology and Blood Transfusion at the Ministry of Health of the Republic of Uzbekistan. Results and Discussion. No statistically significant differences were found in the frequencies of the CYP2C9 and CYP2C19 alleles between the groups of patients with and without adverse gastrointestinal reactions to administering nonsteroidal anti-inflammatory drugs or proton pump inhibitors. Conclusions. Our findings allow us to suggest that being a carrier of the allelic CYP2C9*2 and CYP2C9*3 variants should be considered as a gastropathy risk factor of using nonsteroidal anti-inflammatory drugs. It can be assumed that, to reduce the risk of adverse reactions developed in the patients of this category to nonsteroidal anti-inflammatory drugs, the latter ones need a concomitant administration with proton pump inhibitors. It is necessary to continue studying the frequencies of the alleles and genotypes on allelic CYP2С9*2 and CYP2С9*3 variant sin pain syndrome patients taking nonsteroidal anti-inflammatory drugs.

Methotrexate-induced transient encephalopathy. The experience of the Research Institute of Pediatric Oncology and Hematology named after Academician of the Russian Academy of Medical Sciences L.A. Durnov at N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia

Introduction. Methotrexate is one of the main chemotherapeutic agents of group antimetabolits, includes in the first line of therapy against osteosarcoma. The drug uses in dose 12 g/m2 according to the protocol EURAMOS-1. The range of methotrexate-induced complications includes renal toxity, hepatotoxicity, myelosuppression, skin and mucosal ulcerations, dyspeptic disorders. One of the formidable, but reversible complications, is methotrexate-induced transient encephalopathy (MIE), the clinical manifestations of which occur in more than 15 % of patients in the treatment of which high doses of methotrexate (HD MTX) are used.Materials and methods. At the Research Institute of Pediatric Oncology and Hematology named after Academician of the Russian Academy of Medical Sciences L.A. Durnov at N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia the period from 2013 to 2023 10 cases of MIE were recorded. All patients received therapy according to the protocol EURAMOS-1. The 4 out of 10 patients had a delay in the rate of elimination of HD MTX after the course of chemotherapy. No one patient had electrolyte disturbances with using HD MTX. The median occurrence of the complication’s emerging was 7 days (from 5 to 10 from the start of therapy) and most often developed after 3 courses of methotrexate 12 g/m2 , which corresponds in total 6 doses of methotrexate. Neurological symptoms: headache, visual impairment, aphasia, convulsions were transient and resolved after an average of 24 hours from the start of the treatment.Results. All 10 patients received obligatory alkalization, massive infusion therapy, neuroprotective drugs, as well as decongestant therapy as a treatment of MIE. Subsequently, therapy with methotrexate was continued for the 9 of 10 patients.Conclusions. The standard recommendations for the treatment of MIE do not currently exist. However, the development of severe neurotoxicity does not exclude the possibility of further using of HD MTX in the treatment program

Primary Ewing’s sarcoma of the kidney: description of two rare clinical cases and review of world literature

Ewing’s sarcoma (ES) of the kidney is an extremely rare malignant tumor characterized by an aggressive course, and therefore the disease has an unfavorable prognosis. Due to the rare occurrence, standards for the treatment of ES of the kidney have not been developed; an integrated approach is often used in therapy. In this article, we present a description of two clinical cases of kidney damage with ES in patients aged 10 and 16 who were treated at the Research Institute of Pediatric Oncology and Hematology named after Academician of the Russian Academy of Medical Sciences L.A. Durnov at N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia. In the first case, there was a metastatic lesion of the kidney with the localization of the primary focus in the pelvic bones, in the second, primary ES of the kidney was diagnosed. Both patients had stage IVb at the time of diagnosis (TNM classification American Joint Commission on Cancer). In both patients, after induction chemotherapy, a complete therapeutic response (complete therapeutic pathomorphosis) was obtained. In an integrated approach, in addition to standard chemotherapy, surgery and radiation therapy, in both cases, high-dose chemotherapy with autologous peripheral stem cell transplantation was used, which made it possible to create favorable conditions for long-term remission in one of the patients, even despite the initial prevalence of the process.

Corelationship of Lymphocyte Subsets and Prognosis in Juvenile Myelomonocytic Leukemia

Objective: Juvenile Myelomonocytic Leukemia (JMML) is a rare hematopoietic stem cell malignant clonal disease in children and has the characteristics of MDS/MPN. Due to the poor response of JMML to chemotherapy, hematopoietic stem cell transplantation (HSCT) is currently the only cure method for JMML. Currently, there are some reports on the distribution of lymphocyte subsets in MDS. A significant lymphocytopenia was observed in MDS patients compared with similarly aged healthy people. Another study form Polish found patients with MDS have more CD3+T cells than healthy donors. But there are few related reports in JMML. The objective of this study is to analyze relationship between the distribution of lymphocyte subsets and prognosis in JMML patients, and explore new risk stratification indicatorsfor JMML personalized therapy. Method: This study retrospectively collected JMML patients clinical data from Institute of Hematology & Blood Diseases Hospital of CAMS during Jan 2008 and Nov 2022. All completed complete blood count and peripheral blood classification, fetal hemoglobin (HbF), granulocyte colony-stimulating factor (GM-CSF) high sensitivity, bone marrow morphology, immune typing, molecular biology, cytogenetics and other tests. We analyzed the relationship between distribution of lymphocyte and prognosis in these patients. Result: 96 newly diagnosed JMML patients were admitted to this study. The median age at diagnosis was 25 (2-82) months, and male to female was 3.8:1. 66 cases underwent lymphocyte subsets by flow cytometry. Median percentage of lymphocytes is 34.3%(1.8%-90.4%, normal range: 20%-40%), median percentage of CD3+T cells is 54.85%(10.3%-91%, normal range: 57%-88%), median percentage of CD3+CD4+ T cells is 30.95%(3.54%-53%, normal range: 27%-58%), median percentage of CD3+CD8+ T cells is 18.4%(2%-49.1%, normal range: 16%-45%), median percentage of NK cells is 13.95%(2.3%-50.3%, normal range: 3%-32%), and median percentage of B cells is 23.25%(4%-69.6%, normal range: 4%-18%). These cases were followed-up to Jan 2023, with a median follow-up time of 12 months (1-104 months). The overall survival (OS) rate was 52.67%, with a median OS time of 12 months (0-103 months). There were significant differences in the percentage of CD3+T cells (30.89% ± 9.46% vs 59.05% ± 10%, P<0.01) and CD3+CD4+T cells (14.87% ± 5.82% vs 35% ± 5.41%, P<0.01) between children with single NRAS mutation and compound mutations (≥2 classical five Ras pathway mutation ). In PTPN11 mutation patients, there is a significant positive correlation between OS and the percentage of lymphocytes (P=0.018). Conclusion: Our study shows differences in percentage of CD3+ T cells and CD3+CD4+ T cells between patients with NRAS mutation and compound mutations. Patients with PTPN11 mutation and higher percentage of lymphocytes will have better prognosis.

Efficacy, Safety, and Population Pharmacokinetics of Eltrombopag in Children with Different Severities of Aplastic Anemia

OBJECTIVES: Eltrombopag (EPAG) was initially approved by the U.S. Food and Drug Administration (FDA) as first-line treatment, combined with standard immunosuppressive therapy, for patients older than two years old with severe aplastic anemia (SAA). However, the use of EPAG in children with different types of aplastic anemia (AA), especially non-severe AA (NSAA) has been limited. Therefore, we decided to investigate the efficacy, safety, and pharmacokinetics of EPAG in children with NSAA, SAA, and very severe AA (VSAA). METHODS: A prospective, open-label, observational study was conducted at the Institute of Hematology and Blood Diseases Hospital, Tianjin, China. The efficacy including complete response (CR), partial response (PR), and no response (NR), as well as safety was assessed every three months after the start of treatment. A non-linear mixed-effects population pharmacokinetic (PPK) model was used to depict the pharmacokinetic profile of EPAG. We explored the exposure-response relationship of EPAG in patients with different types of AA. This study was registered at ClinicalTrials.gov (NCT03844360). RESULTS: A total of 23 AA children with an average age of 7.9 (range of 3.0 - 14.0) years were enrolled in this study for efficacy, safety, and PPK analysis. Fifteen patients had a treatment response (5 had CR and 10 had PR). The response rate was 12.5% after 3 months, 50.0% after 6 months, and 100% after 12 months of treatment for patients with NSAA. For patients with SAA and VSAA, these response rates were 46.7%, 61.5%, and 87.5%. Hepatotoxicity occurred in one patient. Fifty-three blood samples were collected and analyzed to build the PPK model using allometric scaling with fixed exponents. Body weight significantly affected EPAG's apparent clearance and volume of distribution. The mean (range) of the area under the concentration-time curve from time zero to infinity (AUC ∞) was 316 (131 - 809) μg×h /mL. Twenty patients with genotypes were included in the genotype analysis. The apparent clearance of EPAG was significantly higher in allele-T carriers of adenosine triphosphate-binding cassette G2 (ABCG2) (rs2231142, G>T) ( p=0.02). In patients with clinical response, children with NSAA exhibited lower AUC ∞, higher apparent clearance, and higher weight-adjusted apparent clearance than those with SAA or VSAA, although the differences were not significant. CONCLUSIONS: This study enriched the efficacy and safety of EPAG in children with different types of AA. Body weight and ABCG2 genotype significantly influence EPAG clearance. The results may support further individualized treatment of EPAG in children with AA.

Effect of Ursodeoxycholic Acid for Sars-Cov-2 Prevention in Hematological Malignancies: An Observational Real-World Study

Introduction: Disease-2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).After the adjustments and optimizations of Chinese control strategies and policies for COVID-19 on December of 2022, clinical exposure increased rapidly.There are greater concerns for patients with hematological malignancies, particularly those who have undergone hematopoietic stem cell transplantation (HSCT). One promising preventive measure that has recently gained attention is ursodeoxycholic acid (UDCA). This drug is mainly used to treat biliary tract disease and other hepatobiliary disorders, particularly primary biliary cholangitis (Hirschfield GM, et al. Gut 2018); and also has been widely used at a higher dosage to prevent sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) after HSCT in the clinical setting. Recently, Brevini et al. demonstrated that UDCA downregulated ACE2 expression by reducing farnesoid X receptor signaling, resulting in reduced SARS-Cov-2 infection (Brevini T, et al. Nature 2022), indicating that pharmacological prophylaxis using UDCA against COVID-19 in vulnerable groups was feasible, but the clinical data to support this practice is limited. Therefore, we aim to present epidemiological data for Chinese patients with hematological malignancies during this epidemic wave, and investigate the protection effects offered by UDCA against COVID-19 in these patients. Methods: This investigation was a single-center, observational real-world study, and was granted by the ethics committee of the Institute of Hematology & Blood Diseases [No. QTJ2023012-EC-1]. The transplant patients were included in the “NICHE-SKIRT” project (Cao Y, et al. Am J Hematol 2023). Informed consent for the acquisition and the use of patient samples was obtained. Data for hospitalized patients at the Institute of Hematology & Blood Diseases Hospital (Tianjin, China) was reviewed between December 2022 and January 2023. COVID 19 status was assessed using hospital-reported PCR and/or antigen tests for twice a week. We analyzed follow-up records up to 14th February 2023. The primary end-point was the rate of COVID -19 infection. Results: We enrolled 393 patients with a median age of 38 years old. At the cutoff date, 297 patients (75.6%) had confirmed COVID-19 infection (72.5% in the allo-HSCT cohort). Among the 273 evaluable patients, the majority (64.8%) had asymptomatic/mild disease. The severe/critical patients accounted for only 15.8%. Seven hospitalized patients had died from COVID-19 by the last follow-up date. The median period between COVID-19 diagnosis and death was 15 days (range: 2-32 days). Lower proportion of CD3+CD4+T cells associated with more severe COVID-19 clinical spectrum (Asymptomatic/mild [n = 97] moderate [n = 46], adjusted P = 0.001; Asymptomatic/mild vs. severe/critical [n = 25], adjusted P = 0.036). Among these patients, 163 received UDCA (UDCA group) while 230 did not (non-UDCA group). The COVID-19 infection rate was lower in the UDCA group (69.9% vs. 79.6%; P= 0.039). However, patients in the UDCA group had a higher ECOG score and Charlson Comorbidity Index (Table 1), suggesting that they were more likely to have underlying health conditions. To account for this potential bias, we performed PSM, which confirmed that the UDCA group had a significantly lower rate of COVID-19 infection compared to the non-UDCA group (69.0% vs. 81.0%; P = 0.049) in the validated cohort. Univariate logistic regression analysis showed that only UDCA administration was associated with COVID-19 infection (OR: 0.598; P = 0.029). To further investigate the effect of UDCA in specific populations, we carried out an exploratory analysis. Our results suggest that males, patients with a CCI ≥ 2, a history of smoking, and those with acute lymphoblastic leukemia (ALL) may benefit the most from the protective effect of UDCA against COVID-19. Conclusion: This study aimed to investigate the prevalence and clinical outcomes of SARS-CoV-2 infections in Chinese patients with hematologic disorders during the COVID-19 epidemic that began at the end of 2022. Our findings provide support for preclinical studies suggesting that UDCA may have marginal benefit in protecting against COVID-19. However, prospective studies with a higher dose of UDCA need to be performed.

Promising Safety and Efficacy of Trovocabtagene Autoleucel (C-CAR088) Followed ASCT in Ultra High-Risk Multiple Myeloma (UHR-MM) Patients Who Failed or Had Suboptimal Response to Standard First Line Triplet Based Therapy

Background: The prognosis of MM has improved significantly nowadays. However, patients with ultra-high-risk features (UHR-MM) had dismal outcomes even treated with standard front-line therapy. This study (NCT05632380) explores the potential of new CAR-T therapy in addressing the unmet need of these patients. Trovocabtagene autoleucel (trovo-cel), an anti-BCMA CAR T-cell manufactured by Cellular Biomedicine Group, Inc., showed deep and lasting responses with a good safety profile in relapsed or refractory multiple myeloma (R/R MM). Hereby, we are reporting a phase I, open-label, single-arm study, assessing the feasibility of trovo-cel followed ASCT in UHR-MM patients who failed or had suboptimal responses to the first-line standard therapy. Methods: Eligible patients are 18-70 years old, transplant-eligible and confirmed as UHR-MM defined as follows: 1) Genetic ultra-high risk: del(17p)≥60%; or ≥2 high-risk cytogenetic abnormalities including TP53 mutation, del(17p)/P53 deletion, t(4;14), t(14;16), t(14;20), 1q21 gain/ amplification, and did not reach CR or better response after 4 cycles standard first-line therapy; 2) Primary refractory: <MR after 2 cycles or <PR after 4 cycles standard first-line therapy; 3) Early relapse: lost best response within 6 months from the standard first-line therapy; 4) primary PCL history and < CR after 4 cycles standard first-line therapy. Standard first-line therapy should be a potent standard triplet-based regimen including one PI, one IMIDs, and glucocorticoid. Quadruplet or quintuplet regimens might be used. Prior ASCT, BCMA-targeted therapy, or CAR-T treatment are excluded. Patients undergo conditioning (melphalan alone or plus fludarabine) followed by ASCT on Day 0 and trovo-cel 3.0 or 6.0×10 6 cells/kg single intravenous infusion on Day 3. Maintenance is allowed after 3 months post-transplantation per investigator's decision. Results: As of July 24, 2023, 8 UHR-MM patients completed ASCT and trovo-cel infusion. Five patients received melphalan and 3 received fludarabine combining melphalan pretreatment. Trovo-cel was administrated at 3 × 10 6 cells/kg for all 8 patients. The median age of patients was 54.5 years (range: 39-66). The median number of prior lines of therapy was 2 (range: 1-2), with VRD exposure rate of 100%. Seven patients (87.5%) had received daratumumab, with six having been treated with dara-based quadruplet or quintuplet therapy as a front setting. Two patients (25%) had genetic ultra-high risk features, four patients (50%) had primary refractory myeloma, two (25%) had early relapse myeloma, and three patients (37.5%) had primary PCL history, two (25%) had extramedullary disease. Five patients (62.5%) received bridging and 6 received maintenance therapy. The combination of ASCT and Trovo-cel was well tolerated. With a median follow-up of 184 days (range: 13-332 days), no unexpected adverse events was observed. Among evaluable 7 patients, six (85.7%) had experienced grade 1 CRS and fully recovered. Two patients (28.6%) received tocilizumab and glucocorticoid for CRS. No ICANS event was reported. As expected, hematological toxicities are the most common AEs. All 7 patients achieved hematopoietic reconstitution successfully, with a median time of 14 days for ANC (≥0.5×10 9/L) and 13 days for PLT (≥20×10 9/L) post ASCT. The ORR was 100%, with 6 CR with MRD negative (NGF, 10 -5) (85.7%), 1 VGPR (14.3%). Robust CAR T-cell expansion was observed in blood of all patients. The median time of peak of CAR-T expansion (T max) was 7 days (range 4~7), the median peak CAR-T copy number (C max) was 891,963 copies /μg gDNA and the median AUC 0~28day was 6,009,475.5 copies /μg gDNA/day. The PK profile is similar to trovo-cel single agent treatment 1] but with earlier peak of CAR-T expansion. Conclusion: The preliminary results of this clinical trial show a promising safety and efficacy profile of trovo-cel followed ASCT in UHR-MM patients. Although the follow-up time is relatively limited, we are looking forward to a consistently good safety and efficacy outcome in long-term follow-up and in more patients recruited later. Research Sponsor: Institute of Hematology & Blood Diseases Hospital Collaborator: Cellular Biomedicine Group, Inc.

Optimized Rabbit Antithymocyte Globulin Protocol Plus Sequential Cyclosporine and Levamisole Regimen for Newly Diagnosed Severe Aplastic Anemia: A Single-Arm, Single-Centre, Prospective, Phase 2 Trial

Background The inferior effect of rATG is due to the early fatal blow caused by the more potent immunosuppression. In order to retain its sustainable immunosuppression while weakening the early fatal blow. We explored a modifying schedule of administration of rATG by prolonging the course of rATG administration based on the equality of total dose, and then reported the better response and survival in severe aplastic anemia (SAA). And previously, we reported the encouraging effectiveness of cyclosporine alternately combined with levamisole (CSA and LMS regimen) in moderate AA, refractory or relapsed SAA, and SAA. We aim to establish whether the optimized rATG protocol plus sequential CSA and LMS regimen could improve SAA outcomes. Methods We conducted a single-arm, prospective, phase 2 trial at The Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College (CAMS & PUMC). Patients aged 6 years or older with confirmed, newly diagnosed SAA were eligible. Patients received optimized rATG administration (1.97 mg/kg/d for 9 days) based on the equality of total does with standard protocol (3.55 mg/kg/d for 5 days). And then CSA and LMS were alternatively administrated every other day from day 14. The initial dose of CSA was 3mg/kg/day in adults and 5mg/kg/day in children (6-18 years old). Oral LMS was alternatively administrated at a dose of 150 mg per day in adults and 2.5 mg/kg per day in children (< 40 kg) in three divided doses. The primary endpoint was overall response rate at 6 months. The trial is registered at www.clinicaltrials.gov as NCT02203396. Results: Between Aug 1, 2014 and Sep 30, 2017, 40 patients with newly diagnosed SAA were treated (median age 24 years [range 7-57 years]; 19 [47.5%] male; 18 [45%] VSAA; 1[2.5%] post-hepatitis). All of these patients were transfusion dependent. Demographic data and clinical characteristics of these patients are outlined in Table 1. The 3-month overall response rates (ORRs) was 40.0%, including 2.5% CR and 37.5% PR. The ORRs increased to 60% (15% CR and 45% PR) at 6 months and 72.5% (42.5% CR and 30% PR) at 12 months. With a median follow-up of 77 months (range 0.1-97 months), estimated 8-year OS rate and event-free survival rate were 84.9% (95% CI, 69.35-92.9%) and 66.5 (95%CI, 49.1-79.1%), respectively. No patient discontinued therapy because of treatment-related toxicity. There were two deaths-one due to infection and another due to cerebral hemorrhage. In this cohort, 4/40 patients (5.7%) evolved to clonal disorders. Of the 4 patients, 1 patients progressed to overt PNH, 2 MDS and 1 acute myeloid leukemia (AML). Cytogenetic abnormalities involved chromosome 7 occurred in one cases with AML. A total of 2 (7.1%) patients relapsed at 33 and 79 months after initial response. Both of the 2 relapsed patients acquired response again with the administration of CSA. Conclusions: Front-line sequential optimized rATG protocol with CSA and LMS regimen resulted in encouraging long-term survival. Future randomized studies should evaluate the optimized IST regimen in the treatment of patients with SAA.

Suppression of Microtubule Acetylation Mediates Theanti-Leukemic Effect of CDK9 Inhibition

Suppression of Microtubule Acetylation Mediates the Anti-Leukemic Effect of CDK9 Inhibition Xi Xie1, BaoyuanZhang1, Ping Liu1, Ruibao Ren1,2 1. Shanghai Institute of Hematology, State Key Laboratory for Medical Genomics, National Research Center for Translational Medicine at Shanghai, International Center for Aging and Cancer, Collaborative Innovation Center of Hematology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. 2. International Center for Aging and Cancer, Hainan Medical University, Haikou, Hainan Province, China. Cyclin-dependent kinase 9 (CDK9) is a crucial component of transcription and potential target for anti-cancer therapies, particularly for hematological malignancies. However, the precise mechanisms underlying the therapeutic effects of CDK9 inhibitors remain not fully understood. Here, we found that inhibiting CDK9 either pharmacologically or through gene downregulation, significantly reduced the levels of α-tubulin protein in a time- and dose-dependent manner. We further discovered that CDK9 inhibition led to increased susceptibility of α-tubulin to proteasomal degradation due to reduced acetylation at lysine 40 (K40), an important modification for microtubule stability. An acetylation-mimicking mutant of α-tubulin mitigated the anti-tumor effects of CDK9 inhibition. Mechanically, we identified that CDK9 inhibition downregulated the expression of ATAT1, the acetyltransferase responsible for α-tubulin acetylation, further compromising microtubule stability. Our study unravels a novel molecular mechanism by which CDK9 inhibition disrupts α-tubulin stability and provides valuable insights for exploring effective treatment regimens involving CDK9 inhibitors.

Treatment Patterns and Outcomes in Patients with Multiple Myeloma Who Received Ixazomib and in Patients with Triple-Class Refractory Multiple Myeloma: A Retrospective, Observational, Real-World Historical Database Analysis Study from China

Background: Multiple myeloma (MM) is a fatal, malignant disease of plasma cells characterized by an abnormal proliferation of monoclonal antibodies. China is estimated to have 22,450 newly diagnosed (ND) cases of MM and 17,360 related deaths in 2022. Emerging novel therapies have significantly improved survival in MM, and treatment guidelines have been updated to reflect these advances. Ninlaro® (ixazomib) is the first oral proteasome inhibitor (PI) approved by the US FDA in 2015 and by China's National Medical Products Administration in 2018 (conditionally) for MM patients receiving ≥1 prior therapy owing to its convincing efficacy and well-tolerated safety profile as seen in the landmark Phase III TOURMALINE-MM1 trial and the China Continuation Study. Novel drugs such as PIs, immunomodulatory drugs (IMDs), and anti-CD-38 monoclonal antibodies are the core component of MM treatment and have improved patient outcomes considerably. However, many patients remain refractory to these drugs (triple-class refractory, TCR) and have poor clinical outcomes. There is a lack of real-world evidence characterizing treatment patterns and outcomes of MM patients receiving ixazomib and TCR-MM patients, in China. The objective of this study is to bridge this data gap by providing vital information on the treatment patterns and outcomes, and healthcare resource utilization in Chinese MM patients receiving ixazomib and TCR-MM patients in real-world clinical practice. Study Design and Methods: This study is an ongoing, single-centre, non-interventional, retrospective database analysis study of MM patients identified from the Chinese National Longitudinal Cohort of Haematologic Diseases (NICHE)-MM registry, a historical and ongoing longitudinal data registry of the Institute of Haematology and Blood Diseases Hospital (IHBDH), and representing the top-tier MM care in China. The patients will be divided into two groups. Patients (aged ≥18 years) with a confirmed MM diagnosis receiving all ixazomib-based regimen as 2nd-line and above therapy (RR-MM), or as a 1st-line therapy (ND-MM) will form group one and TCR-MM patients' refractory to at least one IMiD (lenalidomide, pomalidomide or thalidomide), one PI (bortezomib, ixazomib, or carfilzomib) and one anti-CD-38 monoclonal antibody (daratumumab and isatuximab) will form group two. TCR-MM patients receiving ixazomib will be part of both groups. Patients enrolled in clinical trials will be excluded. The data for analysis will be collected from the ixazomib launch date in China (April 12, 2018) and/or the index date of the first patient enrolled in ixazomib Named Patient Program to September 2023 (tentative). Since 2000 till January 2023, the NICHE-MM registry has enrolled 3,329 MM patients of whom 156 patients have received ixazomib. This is the preliminary sample count and the final sample size will be calculated during data cleaning and analysis phases. The primary objective of this study will be to determine 1) treatment patterns and responses by lines of treatments and 2) time-to-event outcomes. The treatment patterns will include treatment name, dosage, type (induction, consolidation, or maintenance), number of cycles, duration and severe adverse event causing hospitalization. The treatment responses will include complete response (CR), stringent CR, partial response (PR), very good PR, minimal response, stable disease, and progressive disease as defined by the International Myeloma Working Group. The overall response rate of the last line of treatment for both study groups will be calculated as composite endpoint. Time-to-event outcomes will include progression-free survival, overall survival, duration of therapy, and time to next line of treatment in ND/RR-MM and TCR-MM patient groups. Secondary objectives will include assessment of patients' demographic, disease and clinical characteristics. Depending on data availability, the exploratory objective will be to determine the healthcare resource utilization and costs incurred by patients in both groups. Subgroup analysis between ND-MM vs. RR-MM or RR-MM patients receiving ixazomib in 2nd-line setting vs. TCR-MM patients receiving ixazomib in >3rd-line setting is also planned. Descriptive statistics will be used for the analyses. Our findings will also help clinicians in making strategic decision about more apt positioning of ixazomib in the treatment algorithm of MM.

Efficacy of Allogeneic Hematopoietic Stem Cell Transplantation in Young and High-Risk Multiple Myeloma Patients

Objective: With the new therapeutic agents developed over last decades, the median survival of patients with multiple myeloma has approached 10 years. However, 15-20% of patients who are classified as High-risk multiple myeloma (HRMM) patients still have a median survival of less than 3 years, which leaves room for improvements. Simultaneously, transplantation related mortality (TRM) has been decreasing since progress of supportive care during these years. Thus, this study aims to evaluate the efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in young high-risk multiple myeloma (HRMM) patients and to conduct statistical analysis of various prognostic factors in the new era. Method: This retrospective study analyzed clinical data from 14 young multiple myeloma patients with high-risk cytogenetic abnormalities or high-risk disease biological factors who underwent allo-HSCT at the Hematopoietic Stem Cell Transplantation Center of the Institute of Hematology & Blood Diseases Hospital between November 2016 and November 2022. Results: There were 7 males and 7 females involved in this study, with a median age of 39.5 (31- 50) years at the time of transplantation. The median number of treatment lines before transplantation was 2 (1-6). Before transplantation, 42.9% (6/14) of the patients did not achieve complete remission (CR), with 35.7% (5/14) of the patients performing MRD (+). After transplantation, all patients could be evaluated for treatment response, in which the overall response rate was 100% (14/14). All 14 patients successfully underwent transplantation, with median engraftment times for neutrophils and platelets of 11 (10-14) days and 13 (9-103) days, respectively. Acute graft-versus-host disease (GVHD) of grades II-IV occurred in 5 patients (35.7%), and 2 patients (14.3%) developed moderate to severe chronic GVHD. The median follow-up time after transplantation was 18.93 (4.1-72.53) months, with the 2-year TRM of 7.1% (95%CI 0-19.7%) and the expected 2-year overall survival (OS) rate of 92.9% (95% CI 80.3-100%). Meanwhile, the expected 1-year and 2-year progression-free survival rates were 85.7% (95% CI 69.2-100%) and 45.7% (95% CI 20.9-99.9%), respectively, and the presence of chronic GVHD might influence the outcome positively. Conclusion: Allogeneic hematopoietic stem cell transplantation is an effective treatment to improve the prognosis of young and high-risk multiple myeloma patients.

Clinical Characteristics, Genetic Profile and Prognosis of Adult Acute Myeloid Leukemia with NUP98 Rearrangement

Introduction: Nucleoporin 98 ( NUP98) rearrangement has been proposed in 2022 as one type of acute myeloid leukemia (AML) with defining genetic abnormalities. It occurred more often in pediatric leukemia with poor outcome. However, in adult AML with NUP98 rearrangement, patients may show different clinical characteristics, genetic profile and outcome, as we reported here. Method: We retrospectively collected and analyzed the data of adult AML patients with NUP98 rearrangement who were diagnosed at Shanghai Institute of Hematology from May 2019 to December 2022, including clinical characteristics, laboratory examination, genetic abnormalities, treatment strategies and outcome. All patients underwent next generation sequencing and RNA sequencing. Result: A total of 21 AML patients with NUP98 rearrangement were included in this study, counting for 2.3% of all AML patients (930 cases). The median age was 40 (19-64) years old. The median white blood cell and platelet count was 31.1 (1.5-313.6) and 48 (15-140) ×10 9/L, respectively. Interestingly, 11 (52.4%) patients suffered from severe or fatal hemorrhage irrelative with platelet count or coagulative function, including 4 cerebral bleeding (3 died), 1 urgent uterine bleeding, 1 gastro-intestinal bleeding, 1 retina bleeding and 4 massive bleeding of subcutaneous soft tissue or mucous membranes. The FAB types involved M2, M4 and M5. Eight patients carried normal karyotype, 6 were found with t(7;11)(p15;p15), all of whom had NUP98::HOXA9 fusion gene, 2 with +8 and 1 complex karyotype. According to ELN 2022 risk classification, 14 (66.7%) were at intermediate risk and 6 (28.6%) at adverse risk, 1 unclassified. Five fusion partners with NUP98 were detected: NUP98::NSD1 (11 cases), NUP98::HOXA9 (7 cases), NUP98::HOXA11, NUP98::HMGB3 and NUP98::TNRC18 (each with 1 case). Of which NUP98::TNRC18 was first reported by our center (see Cheng WY, et al. Proc Natl Acad Sci U S A. 2022;119(49):e2211429119). NUP98 rearrangement also co-existed with several mutations. FLT3-ITD (12 cases, of which 10 were co-existed with NUP98::NSD1) and WT1 (7 cases) were most frequently occurred. Patients with relapse/refractory disease had more additional mutations than de novo status (Figure 1). Nineteen patients were treated with standard dose of “7+3” induction therapy, and 2 with hypomethylating agents (HMA) plus venetoclax (VEN). Complete remission (CR) was achieved by 8 (38.1%) patients after first induction, 2 (9.5%) early deaths were both due to cerebral hemorrhage. Salvage induction varied from intensive chemotherapy (IC, including “7+3” and CLAG±M) to low-intensity therapy (LIT, including priming chemotherapy±HMA and HMA+VEN). FLT3 inhibitors (FLT3i) were added to 5 patients carrying FLT3-ITD, and they all achieved CR. A total of 15 (71.4%) patients achieved CR after 1-2 courses of induction (8 mainly benefited from IC, 7 mainly benefited from LIT±FLT3i), 1 survived from allogeneic hematopoietic stem cell transplantation (allo-HSCT) without reaching remission before, and 3 died from refractory disease within 6 months. Three patients relapsed after CR, 2 died without allo-HSCT, and the other one survived after CR2 and sequential allo-HSCT. A total of 14 patients underwent allo-HSCT after CR, 7 were measurable residual disease (MRD) negative and 7 were positive by flow cytometry before HSCT, none of them relapsed till the last follow-up. With a median follow-up time of 19.2 months, the median overall survival (OS) and event-free survival (EFS) were not reached, estimated 2-year OS and EFS rate were 66.7% and 57.1%, respectively. For patients achieving CR or not, the median OS were not reached vs 3.2 months (95% CI 0-8.361, P<0.001, Figure 2). Ten patients were diagnosed with NUP98::NSD1 co-occurring with FLT3-ITD (once considered as unfavorable prognosis), ending up with a CR rate of 70%, and a 2-year OS and EFS rate of 80% and 60%, respectively, making no significant difference compared to others ( P=0.236 and 0.725, respectively). Conclusion: Adult AML with NUP98 rearrangement may combine with a set of partner fusion genes and mutations, with NUP98::NSD1 and FLT3-ITD as the most common combination. Both IC an LIT can induce CR, and FLT3i will benefit those with FLT3 mutations, also prevention of fatal bleeding should be paid attention to. After achieving CR with whatever method and whatever MRD status, allo-HSCT is the key to long-term survival.

Efficacy and Safety of Human Umbilical Cord-Derived Mesenchymal Stem Cells in the Treatment of Immune Thrombocytopenia: A Prospective, Single Centre, Single Arm, Phase I Trial

Background Patients with refractory immune thrombocytopenia (ITP) often suffer severe bleeding events and have poor responses to various treatments. Umbilical cord-derived mesenchymal stem cells (UC-MSCs) have been used to treat multiple autoimmune diseases due to their low immunogenicity and strong immunomodulatory potential. To explore the safety and efficacy of UC-MSCs in treating refractory ITP, we conducted this phase Ⅰ clinical trial. Methods Patients diagnosed with refractory ITP were screened for the study. The major inclusion criteria included age 18 to 60 years, ITP duration lasting for more than six months, platelet count < 30 × 10 9/L and concomitant bleeding manifestations at enrolment. The study consisted of two parts: a dose-escalation phase for exploring the safety and efficacy of three different dosage groups according to the traditional 3+3 protocol and a dose-expansion phase for further verifying the optimal UC-MSC dosage. UC-MSCs were administered at doses of 0.5×10 6 cells/kg, 1.0×10 6 cells/kg, and 2.0×10 6 cells/kg per week four times in the dose-escalation phase and 2.0×10 6 cells/kg per week four times in the dose-expansion phase. The adverse events, platelet counts, and bleeding symptoms were evaluated and recorded during the administration and follow-up period. The study protocol was approved by the Ethics Committees of the Institute of Hematology and Blood Diseases Hospital, and informed consent was obtained from each participant according to the Declaration of Helsinki (ClinicalTrials.gov ID: NCT04014166). Results Between November 2019 and August 2022, 18 refractory ITP patients hospitalized in our centre were successfully screened and enrolled in the study. Twelve patients were enrolled in the dose-escalation phase (three additional patients were added in the 2.0×10 6 cells/kg group due to the dose-limiting toxicity), and six patients were included in the dose-expansion phase. Thirteen patients (13/18, 72.2%) had one or more TEAEs. SAEs occurred in four patients (4/18, 22.2%), including gastrointestinal haemorrhage (2/4), profuse menstruation (1/4), and acute myocardial infarction (1/4). There were 0.0% (0/3), 66.7% (2/3), and 50.0% (6/12) patients in the 0.5×10 6, 1.0×10 6 and 2.0×10 6 cells/kg cohorts who achieved a response after treatment, respectively. The overall response rate was 44.4% (8/18) in all patients who received UC-MSCs. Conclusion UC-MSC infusion achieved a 44.4% overall response rate in patients with refractory ITP and mild adverse events.

MRD Positivity Was the Poor Prognostic Factor for Adverse-Risk AML Patients with Allogeneic Hematopoietic Stem Cell Transplantation: A Multicenter Trohpy Study

Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is recommended for acute myeloid leukemia (AML) patients with adverse-risk. However, when patients within this group would proceed to allo-HSCT is controversial. We aimed to identify the optimal timepoint for allo-HSCT for adverse-risk AML patients. Methods: This is a multicenter, retrospective designed study, based on the transplant database of Wuhan Tongji Hospital, Shanghai Ruijin Hospital, and Peking University Institute of Hematology (PUIH) (TROPHY group). Consecutive AML patients receiving allo-HSCT from January 2017 to June 2022 were screened, and the eligibility criteria were as followed: (1) aged ≥ 16 years; (2) adverse-risk AML based on ELN 2022 criteria; (3) achieving CR1 before allo-HSCT. The last follow-up was June 30, 2023. MRD status was monitored after the first consolidation chemotherapy (MRDc 1), after the second consolidation chemotherapy (MRDc 2), before allo-HSCT (MRD bft), and at 1, 2, 3, 4.5, 6, 9, and 12 months after allo-HSCT and at 6-month intervals thereafter. 0.1% was used as a threshold to distinguish MRD-positivity detected by multiparameter flow cytometry (MFC). The study was approved by the institutional review board of each participated hospital and was conducted in accordance with the Declaration of Helsinki. Results: A total of 391 adverse-risk AML patients were enrolled. 114 patients showed MRDc1 positivity. The 2-year probability of relapse, leukemia-free survival (LFS), and overall survival (OS) after allo-HSCT was 26.9% (95% CI: 18.1%-35.7%) vs. 9.4% (95% CI: 5.2%-13.6%) (P < 0.001), 60.7% (95% CI: 51.7%-71.1%) vs. 81.5% (95% CI: 76.3%-87.1%) (P < 0.001), and 74.4% (95% CI: 66.3%-83.3%) vs. 88.6% (95% CI: 84.4%-93.0%) (P < 0.001), respectively, for patients with MRDc 1 positivity and MRDc 1 negativity. Among patients with MRDc 1 positivity (n = 69), 24 (34.8%) turned MRD negativity after second consolidation therapy (MRDc 2 negativity). The similar trends were observed in patients with MRDc 2 positivity. The 2-year probability of relapse, LFS, and OS after allo-HSCT was 26.4% (95% CI: 18.1%-34.7%) vs. 9.4% (95% CI: 5.4%-13.3%) (P < 0.001), 61.2% (95% CI: 52.8%-71.0%) vs. 81.6% (95% CI: 76.6%-87.0%) (P < 0.001), and 75.6% (95% CI: 68.3%-83.8%) vs. 87.6% (95% CI: 83.3%-92.0%) (P < 0.001), respectively, for patients with MRD bft positivity and MRD bft negativity. Maintenance therapy provided better protection from relapse than preemptive therapy. In multivariate analysis, MRDc 1 positivity was associated with poorer LFS, MRDc 2 positivity was associated with a higher risk of relapse, and MRD bft positivity was associated with worse EFS after allo-HSCT. Conclusion: For the adverse-risk AML patients according to ELN2022 criteria, MRD is still the most important prognostic index for survival. Patients who achieved MRD negativity after the first consolidation chemotherapy could get similar clinical outcomes compared with those who achieved MRD negativity after the additional rounds of consolidation.

The Clinical Complexity of Langherans Cell Histiocytosis in Adult Patients: Experience of the Institute of Hematology of Bologna

Langerhans cell histiocytosis (LCH) in adult patients is a rare disease with protean manifestations, including single system unifocal (SSU) or multifocal (SSM) presentation or multisystemic (MS) involvement. Clinical care of adult patients is based on case series and reports. Regimens applied in pediatric patients show unacceptable toxicity in the adult setting. Our single-center experience with LCH is presented. Data on 30 patients diagnosed between 1997 and 2022 have been reviewed. Patients with isolated pulmonary histiocytosis were excluded. Responses to any treatment were classified according to the acknowledged criteria. Progression-free survival (PFS) after frontline treatment was calculated on all treated patients. Overall survival (OS) was determined on the whole cohort irrespective of any treatment received. Eighteen male and 12 female patients received a diagnosis of LCH at a median age of 46 years (range 20-75). Sixteen patients had single system (SS) disease, with SSU involvement in 12 cases and SSM involvement in 4 cases. The skeleton was the mostly involved system (Figure), while SSU extra-skeletal disease was detected in 25% of cases. Fourteen patients had MS disease: axial skeleton, lungs, hypophysis, skull, skin and appendicular skeleton were the predominantly involved sites, in this order. Ten patients with SS disease received chemotherapy because of symptoms (mostly bone pain) or due to multifocal dissemination. Two patients underwent radiotherapy (RT), 2 had their disease completely excised and 1 received systemic steroids. One patient was observed. A complete response (CR) was obtained in 60% of treated cases, while a partial response (PR) in 27%. Four patients relapsed after frontline therapy and were rescued with RT or autologous transplant. Among patients with MS disease, chemotherapy (MACOP/VNCOP-B, cladribine, vinblastine) was applied in 6 cases; 2 patients received RT and 1 systemic steroids. One patient underwent surgery and 4 were observed because of asymptomatic disease. A CR was obtained in 70% of treated patients and a PR in 10%. Five patients relapsed, with symptomatic disease requiring treatment (chemotherapy and RT) in 3 cases. Median PFS among all treated patients was 177 months. OS was 91% at 20 years. Appropriate treatment based on disease extension, site involvement and clinical manifestations yields high remission rates and long term PFS and OS. The optimal approach to relapsed patients remains undefined.

RUNX1 Mutation Does Not Significantly Impact the Outcome of Newly Diagnosedadult AML: A Retrospective Study of Chinese AML Patients

Background RUNX1 is one of the recurrent mutated genes in newly diagnosed acute myeloid leukemia (AML) with a frequency of 6%~15%. Although historically recognized as a provisional distinct entity, the AML subtype with RUNX1 mutations (AML- RUNX1mut) was eliminated from the 2022 WHO classification system. With the update of AML diagnosis and treatment protocol, different outcomes of AML- RUNX1muthave been reported. However, an in-depth study about the prognostic value of RUNX1 mutations, epecifically the classification change related to AML- RUNX1mut in a large well-annotated cohort is lacking. Methods The clinical data of 1065 AML (excluding acute promyelocytic leukemia and RUNX1 germline mutations) patients according to WHO 2016 and treated from January 2017 to December 2021 at Jiangsu Institute of Hematology were retrospectively collected and analyzed after informed consent. All AML diagnosis samples were analyzed by targeted Next Generation Sequencing (NGS) panel covering 172 frequently mutated genes in hematological malignancies. Demographic and clinical data, disease characteristics at diagnosis, first-line treatment and clinical outcome data were available for all patients. The survival time of allogeneic hematopoietic stem cell transplantation patients was censored at the time of stem cell transfusion. Cytogenetic and molecular characteristics were used to classify patients into ELN2017 and ELN2022 risk groups (excluding the effect of RUNX1 mutation). Results RUNX1 mutations were detected in 112 (10.5%) patients, namely, 66 (58.9%) male and 46 (41.1%) female. A total of 132 RUNX1 alterations were detected with a medianvariant allelic frequency of 40% (3%~93%). RUNX1 mutations were associated with older age (48.5 vs. 46.0 years old, P=0.087) and antecedent myeloid disorders (6.3% vs. 1.0%, P<0.001). One or more comutations were detected in 106 (94.7%) AML- RUNX1mut patients. The most frequent co-gene abnormalities were FLT3-ITD and DNMT3A mutations which represented the 23.2% and 18.7%. Mutations of CEBPA bZIP, NPM1 and translocations of t(8;21), t(16;16)/inv(16) were uncommon in AML- RUNX1mut with a frequency of 6.3%, 1.8%, 2.7%, 0%, respectively (Table 1). Compared with AML with wild-type RUNX1 (AML- RUNX1wt), AML- RUNX1mut patients had a lower complete remission rate (19.6% vs. 29.7%, P=0.034), lower overall response rate (ORR) (73.5% vs. 84.3%, P=0.006) and higher no response rate (26.5% vs. 15.5%, P=0.021) in the first induction chemotherapy. When comparing groups based on the ELN2017 risk stratification criteria, no significant difference in ORR was observed between RUNX1mut and RUNX1wt patients in the favorable (91.2% vs. 94.0%, P=0.572), intermediate (75.0% vs. 78.4%, P=0.570) and adverse (63.3% vs. 71.4%, P=0.370 ) subgroups (Table 2). The median duration of follow-up of the entire cohort was 8.7 months ( RUNX1wt: 8.4 months; RUNX1mut: 10.0 months). Comparing the two groups, patients with RUNX1 mutations had a lower 5-year overall survival (OS) rate (35.4% vs. 42.3%; HR=1.563; 95% CI: 1.091~2.237, P=0.026), but no significant difference was observed in the 5-year event-free survival (EFS) rate (40.8% vs. 35.4%; HR=1.084; 95% CI: 0.750~1.570, P=0.098) (Table 2). However, when patients were stratified according to the ELN2017 guidelines (excluding the effect of RUNX1 mutation), outcomes did not differ between patients withor without RUNX1 mutation in the favorable (OS: P=0.629, EFS: P=0.137), intermediate (OS: P=0.629, EFS: P=0.114) and adverse (OS: P=0.544; EFS: P=0.714) subgroups. Similar results were obtained according to the ELN2022 guidelines. In multivariate analysis, RUNX1 was not an independent prognostic factor for OS (HR=1.353, 95% CI: 0.922~1.985, P=0.122) and EFS (HR=1.422, 95% CI: 0.975~2.075, P=0.068), while significantly worse OS and EFS were observed in patients with mutated FLT3-ITD, TP53, and DNMT3A ( P-values were all less than 0.05). Conclusion RUNX1 mutations were rarely isolated genetic abnormities that conferred inferior outcomes. However, on the basis of ELN prognosis risk stratification, RUNX1mutation had no impact on the clinical outcomes of AML patients in stratified subgroups. RUNX1 was not an independent prognostic factor for survival. Overall, our findings agree with the updated WHO classification system for AML that AML- RUNX1mut should not be recognized as a distinct AML entity.