Bispecific antibody treatment of multiple myeloma: latest updates from the 2022 ASH annual meeting.

Background: Effective novel therapies for multiple myeloma (MM) patients who are unresponsive to conventional treatments (triple-class refractory) are an urgent need. Bispecific antibodies (BsAbs) offer a promising new approach to stimulate T cells and induce tumor cell death by targeting molecules on the surface of malignant plasma cells and CD3 on the surface of T cells. Objectives: Addressing the issue of improving the prognosis of triple-class refractory MM patients has become a significant clinical challenge. Design: This is a brief report. Methods: This article summarizes the latest updates of BsAbs treatment of MM from the 2022 ASH annual meeting. Results: BsAbs that target B-cell maturation antigen and G protein-coupled receptor family C group 5 memberD have demonstrated remarkable clinical activity and favorable safety profiles. Many potential targets for myeloma cells are currently undergoing phase I/II clinical trials, and these off-the-shelf bispecific molecules are likely to become a critical part of the MM treatment landscape. Conclusion: This article provides an overview of the latest advances in BsAbs immunotherapy for refractory and relapsed MM and highlights significant findings from the 2022 ASH annual meeting.

Dyslipidemia in diffuse large B-cell lymphoma based on the genetic subtypes: a single-center study of 259 Chinese patients.

Background: Diffuse large B-cell lymphoma (DLBCL) is a kind of highly heterogeneous non-Hodgkin lymphoma, both in clinical and genetic terms. DLBCL is admittedly categorized into six subtypes by genetics, which contain MCD, BN2, EZB, N1, ST2, and A53. Dyslipidemia is relevant to a multitude of solid tumors and has recently been reported to be associated with hematologic malignancies. We aim to present a retrospective study investigating dyslipidemia in DLBCL based on the molecular subtypes. Results: This study concluded that 259 patients with newly diagnosed DLBCL and their biopsy specimens were available for molecular typing. Results show that the incidence of dyslipidemia (87.0%, p <0.001) is higher in the EZB subtype than in others, especially hypertriglyceridemia (78.3%, p = 0.001) in the EZB subtype. Based on the pathological gene-sequencing, patients with BCL2 gene fusion mutation are significantly correlative with hyperlipidemia (76.5%, p = 0.006) and hypertriglyceridemia (88.2%, p = 0.002). Nevertheless, the occurrence of dyslipidemia has no remarkable influence on prognosis. Conclusion: In summary, dyslipidemia correlates with genetic heterogeneity in DLBCL without having a significant influence on survival. This research first connects lipids and genetic subtypes in DLBCL.

The efficacy and cardiac toxicity of different-dose pegylated liposomal doxorubicin in elderly patients with diffuse large B lymphoma.

OBJECTIVES: In order to explore the impact of pegylated liposomal doxorubicin (PLD) dose intensity on survival outcomes of newly diagnosed elderly patients with diffuse large B-cell lymphoma (DLBCL), we performed a retrospective study to compare the efficacy and adverse effects of RCEOP (70 mg/m2 ), RCdOP (20-30 mg/m2 ) and RCDOP (30-45 mg/m2 ). The optimal PLD dose of patients with different clinical characteristics of subgroups was explored to provide a clue for the selection of clinical PLD dose. METHODS: A total of 335 DLBCL patients (60-85 years old) who were newly diagnosed and completed at least four cycles of RCE(D)OP were selected. The patients were mainly divided into RCEOP (126 cases) (epirubicin 70 mg/m2 ), RCdOP (151 cases) (PLD 20-30 mg/m2 ) and RCdOP (58 cases) (PLD 30-45 mg/m2 ). The effects of different doses of PLD on clinical efficacy, cardiotoxicity and prognosis of patients were retrospectively analyzed. Subgroup analysis was performed to compare the clinical characteristics of different subgroups. RESULTS: Our study showed that PLD and epirubicin had similar efficacy (overall survival (OS) p = 0.776; progression-free survival (PFS) p = 0.959). RCDOP (30-45 mg/m2 PLD) group had a higher complete remission (CR) rate of 75.9% compared with RCdOP (20-30 mg/m2 PLD) group (P D vs. d = 0.018). In the overall population, there was no significant difference in survival between RCDOP and RCdOP groups (OS P D vs. d = 0.661; PFS P D vs. d = 0.212). In patients with underlying cardiovascular diseases, the PFS of the RCDOP group was significantly better than the RCdOP group (p = 0.043). Meanwhile, patients in the RCDOP group tended to have a better prognosis than those in the RCEOP group (OS: RCDOP vs. RCEOP p = 0.054, PFS: RCDOP vs. RCEOP p = 0.053). There was no significant difference in the incidence of cardiotoxicity and other adverse events among the three groups. For the low-risk (age-adjusted-International Prognostic Index = 0/1) old patients without cardiovascular disease, RCdOP was considered a better strategy in OS (p = 0.020). CONCLUSION: In the general population, the CR rate in the RCDOP group was significantly higher than that in the RCdOP group (p = 0.018). For elderly DLBCL patients with cardiovascular disease, the effect benefit brought by the PLD dose was more obvious, and the PFS of the RCDOP group was significantly better than that of the RCdOP group (p = 0.043). Full dose of PLD is an efficient alternative in the treatment of patients with preexisting cardiovascular diseases.

A real-world study of infectious complications of venetoclax combined with decitabine or azacitidine in adult acute myeloid leukemia.

PURPOSE: The purpose of this study was to identify the incidence, sites and main pathogens, and risk factors for infectious complications occurring in patients with adult acute myeloid leukemia (AML) during the first course of venetoclax combined with decitabine or azacitidine. METHODS: A retrospective cohort analysis was performed of 81 patients with AML older than 14 years who received the first cycle of venetoclax combined with a hypomethylating agent (HMA) between March 2018 and March 2021 at our institution. Infectious complications, if any, were documented. RESULTS: Among a total of 81 cases of AML, 59 (72.8%) patients occurred infections, including fever without an identifiable source (28.8%), clinically documented infections (40.7%), and microbiologically documented infections (30.5%). The most commonly isolated organism in culture was Candida albicans, followed by Klebsiella pneumonia, and Pseudomonas aeruginosa. The 4-week and 8-week mortality rates were 3.7% and 7.4%, respectively. In multivariate analysis, a high proportion of blasts in bone marrow, decreased hemoglobin level, and fever with or without a documented infection at baseline were significant independent risk factors for infectious complications. CONCLUSION: Compared with conventional chemotherapy, the incidence of infectious complications of venetoclax combined with decitabine or azacitidine significantly decreased. Pretreatment high leukemia burden and fever were independent risk factors for infections.

The favorable prognostic value of the loss of sex chromosomes in patients with t(8;21) acute myeloid leukemia: an exploratory study.

BACKGROUND: Acute myeloid leukemia (AML) with t(8;21) is generally associated with a favorable clinical course. Loss of sex chromosome (LOS) are frequently observed in t (8;21) AML, but the prognostic value of LOS remains uncertain. METHODS: A total of 73 patients with AML with t(8;21) were studied and divided into t(8;21) with LOS group (n = 36) and t(8;21) alone group (n = 37). The patients with t(8;21) AML with ACAs other than LOS were excluded. The clinical characteristics of these two groups were compared, and the prognostic value of LOS was evaluated based on disease-free survival (DFS) and overall survival (OS). RESULTS: The clinical characteristics (except for gender) were found to have no significant difference between these two groups, and the male patients tended to account for a larger proportion in the former group (P = .001). The OS of the t(8;21) AML with LOS group was significantly longer than that of the t(8;21) AML alone group (P = .005). While not obvious, the patients with LOS seemed to have longer DFS (P = .061). The multivariable analysis also showed LOS to be an independent favorable prognostic factor of t(8;21) AML (P = .022). CONCLUSIONS: Our results suggested that LOS could be associated with a favorable prognosis in t(8;21) AML patients without other ACAs, and for this subtype of AML, longer DFS and a satisfactory and stable survival can be achieved with high-dose cytarabine (HDAC) consolidation treatment.

Synchronous diagnosis and treatment of acute myeloid leukemia and chronic lymphocytic leukemia: Two case reports.

BACKGROUND: The concurrence of acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) is rare. Previous reports of such cases have focused mainly on clinical diagnosis and characteristics, so the mechanism remains unclear, and therapy options have been poorly explored. CASE SUMMARY: Here, we report two cases of synchronous AML and CLL. Flow cytometry revealed two distinct abnormal cell populations (myeloblasts and lymphoid cells) according to scatter characteristics. CD5-positive B cell lymphoma with myeloid leukemia invasion was observed on lymph node biopsy. Chemotherapy regimens indicated for both AML and CLL were used in our patients, and our patients achieved complete response after chemotherapy. Next-generation sequencing of 88 genes was performed. CONCLUSION: We conclude that early mutation and dysregulation at the hematopoietic stem cell stage and the accumulation of multiple rearrangements may cause the concurrence of CLL and AML. The treatment of infection and combination therapy aimed at the CLL component are significant in the management of patients with concurrent CLL and AML.

Fatal hemorrhagic pneumonia in patients with hematologic diseases and Stenotrophomonas maltophilia bacteremia: a retrospective study.

BACKGROUND: Fatal hemorrhagic pneumonia is one of the most severe manifestations of Stenotrophomonas maltophilia (SM) infections. Here, we aimed to investigate the clinical characteristics of SM bacteremia and to identify the risk factors of hemorrhagic pneumonia caused by SM in patients with hematologic diseases. METHODS: The clinical records of 55 patients diagnosed with hematologic diseases and SM bacteremia were retrospectively reviewed. We compared patients' clinical characteristics and outcomes between the hemorrhagic pneumonia group and non-hemorrhagic pneumonia group. RESULTS: Twenty-seven (49.1%) patients developed hemorrhagic pneumonia. The overall mortality rate of SM bacteremia was 67.3%. Hemorrhagic pneumonia (adjusted HR 2.316, 95% CI 1.140-4.705; P = 0.020) was an independent risk factor of 30-day mortality in hematological patients with SM bacteremia. Compared with the non-hemorrhagic pneumonia group, patients in the hemorrhagic pneumonia group were older and showed clinical manifestations as higher proportions of isolated SM in sputum culture, neutropenia and elevated procalcitonin (PCT). Multivariate analysis showed that neutropenia, high levels of PCT, prior tigecycline therapy within 1 month were independent risk factors associated with hemorrhagic pneumonia. CONCLUSIONS: Neutropenia, high level of PCT and prior tigecycline therapy within 1 month were significant independent predictors of hemorrhagic pneumonia in hematologic patients with SM bacteremia. Due to no effective antibiotics to prevent hemorrhagic pneumonia, prophylaxis of SM infection and its progression to hemorrhagic pneumonia is particularly important.

Hypertriglyceridemia in Newly Diagnosed Acute Promyelocytic Leukemia.

The primary aim of the present retrospective study was to investigate lipid profiles and kinetics in acute promyelocytic leukemia (APL) patients. We analyzed 402 newly diagnosed APL patients and 201 non-APL patients with acute myeloid leukemia (as control). Incidence of hypertriglyceridemia in APL patients and non-APL patients was 55.82% and 28.4% (p = 0.0003). The initial levels of triglycerides, total cholesterol, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol were higher in APL patients than in control (all p < 0.0001). In APL patients, triglyceride levels were significantly increased during induction treatment with all-trans retinoic acid and arsenic. Multivariable analysis showed that age, being overweight (body mass index ≥25) and APL were independent risk factors for hypertriglyceridemia in all patients before treatment. High triglyceride levels were not significantly associated with disease-free survival or overall survival in the APL patients. In summary, in the current study triglyceride levels were significantly elevated in APL patients before treatment, and they increased during induction treatment, but there were no significant corresponding effects on survival.

The diagnostic and prognostic value of MRI in central nervous system involvement of acute myeloid leukemia: a retrospective cohort of 84 patients.

ABSTRACT Objective: To assess the diagnostic and prognostic value of magnetic resonance imaging (MRI) in Acute Myeloid Leukemia (AML) complicated with central nervous system leukemia (CNSL). Methods: A total of 84 patients with AML and confirmed of CNSL from January 2010 to September 2019 were selected and underwent MRI scan. We retrospectively analyzed their MRI findings, summarized the imaging features of AML central infiltration, and assessed the guiding significance of MRI on diagnosis and prognosis of this disease. Results: A total of 52 patients (61.90%, 52/84) had abnormal MRI findings, of which 31 cases clearly indicated intracranial infiltration of leukemia. Among the 31 patients, the most common site of infiltration is parenchyma (19/31). Most MRI of these patients showed multiple lesions with low T1 signal and high T2 signal, which were more obvious on enhanced scan. Sensitivity of MRI in diagnosing AML central infiltration was 36.90%. Despite of its low sensitivity, it still had superior diagnostic value on some patients with false-negative CSF. The median disease-free survival (DFS) and overall survival (OS) time of patients with MRI clearly indicated central invasion were 4 and 9 months, respectively. But there was no significant difference in survival analysis compared with MRI negative patients (including abnormal but non-invasive). Conclusion: MRI manifestation of central infiltration in AML patients has certain characteristic findings, which is helpful to improve the diagnostic efficiency. Prognosis of MRI positive patients is relatively worse than that of MRI negative patients however there is no siginificant difference.

Risk factors of early death in adult patients with secondary hemophagocytic lymphohistiocytosis: a single-institution study of 171 Chinese patients.

Background: Adult secondary hemophagocytic lymphohistiocytosis (HLH) is a potentially life-threatening syndrome characterized by excessive activation of mononuclear-phagocytic system resulting in hyperinflammatory response. To date, the factors influencing early death of HLH are still not fully elucidated. Patients and Methods: We did a retrospective study of 171 adult patients with newly diagnosed HLH at our institution from January 2012 to April 2018. All patients' clinical features, laboratory findings, treatments and prognosis were reviewed. Results: The median age was 49 years (range, 18-88 years), and 110 (64.3%) were male. The major underlying trigger of HLH was malignancy (88/171, 51.5%), especially non-Hodgkin lymphoma. In a multivariate analysis, age ≥54 years (P = 0.002), platelet ≤39.5 × 109/L (P = 0.028), activated partial thromboplastin time (APTT) ≥54 sec (P = 0.048), triglyceride ≥3.23 mmol/L (P < 0.001), lactate dehydrogenase (LDH) ≥1300 U/L (P = 0.012) and malignancy (P = 0.001) were significantly associated with early death in HLH. Then, patients were classified into four groups according to the number of risk factors at the time of diagnosis: low risk (zero, one or two risk factors), low intermediate risk (three risk factors), high intermediate risk (four risk factors) and high risk (at least five risk factors), with the 30-day overall survival (OS) of 92.4%, 58.8%, 30.0% and 4.8%, respectively (P < 0.001). Conclusions: Patients with old age, thrombocytopenia, prolonged APTT, hypertriglyceridemia, elevated LDH and malignancy had inferior survival. It is important to identify those patients at risk of early death, which may guide treatment and reduce mortality.

Factors Affecting Early Death and Survival of Patients With Acute Promyelocytic Leukemia Treated With ATRA-Based Therapy Regimens.

PURPOSE: To perform a retrospective analysis of the prognostic relevance of clinicopathologic parameters in a well-documented cohort of patients treated with all-trans-retinoic acid (ATRA)-based induction regimens in order to discover which indicators can predict a high risk of early death (ED) and patient survival. PATIENTS AND METHODS: We analyzed data of 288 newly diagnosed adult acute promyelocytic leukemia patients in Hangzhou, China. The median follow-up time was 32 months (range, 6-78 months). RESULTS: The 3-year disease-free and overall survival rates were 90.83% and 91.69%, respectively. In the multivariable analysis, older age (≥ 60 years) was the only independent risk factor for ED (hazard ratio [HR] = 15.057; P = .004). High white blood cell count was not a risk factor for ED (P = .055), but it was for relapse (HR = 2.7; P = .009). FLT3 mutation (HR = 3.9; 95% confidence interval, 1.4 to 10; P = .007) and older age (≥ 60 years) (HR = 5.3; 95% confidence interval, 2.4 to 11; P < .001) were prognostic factors for poorer disease-free and overall survival. Interestingly, CD15 negativity (HR = 0.23; P = .049) was a prognostic factor for relapse. The ED rate was 5.9% (17/288 patients). CONCLUSION: The perceived impact of the identification of these high-risk factors should be described in order to decide whether any modifications to treatment strategy should be entertained.

Adult onset haemophagocytic lymphohistiocytosis prognosis is affected by underlying disease: analysis of a single-institution series of 174 patients.

BACKGROUND: Haemophagocytic lymphohistiocytosis (HLH) is a rare clinical syndrome characterised by activation of the mononuclear phagocytic system, and often leads to progressive multiple organ failure. The diagnosis of HLH is made late by most physicians. METHODS: To confirm the diagnosis of acquired HLH made in a single-institution series of adult patients with HLH-04 criteria, we applied the HScore and evaluated prognostic factors associated with clinical outcome. RESULTS: A total of 174 patients with a median age of 51 years (range 17-90) were included. Male/female ratio was 111/63. In 92/174 (52.9%) patients, there were potential haematological diseases (4 acute leukaemia, 1 thrombotic thrombocytopenic purpura, 3 Hodgkin's lymphoma [HL], 17 B-cell non-Hodgkin's lymphoma [NHL], 67 T-cell NHL including 22 natural killer / T-cell NHL [NK/t-cell NHL). Six (3.4%) patients had autoimmune disease and 76 (43.7%) undiagnosed underlying disease. There were 44 (25.3%) patients with Epstein-Barr virus infection, 11 (6.3%) with cytomegalovirus, 1 (0.5%) syphilis, 9 (5.2%) hepatitis B virus and 3 (1.7%) human immunodeficiency virus. More than 95% of patients had hyperferritinaemia, high lactate dehydrogenase, fever and low albumin, whereas 89.1% of patients had bone marrow phagocytosis. By the HScore, 4/174 patients had a >50% and 16/174 patients had a >90% probability of not having HLH. All 174 patients fulfilled more than five of the HLH-04 diagnostic criteria, but 16 of them had a low probability of HLH by the HScore. In a multivariate analysis, lymphopenia and hypofibrinogenaemia were independent prognostic factors for death. CONCLUSION: In our study, viral infection was not an independent prognostic factor. NK/T-cell -NHL was associated with worse prognosis compared with B-cell NHL and T-cell NHL (p = 0.036) and similar to other aetiologies.

Effectivity of a modified Sanz risk model for early death prediction in patients with newly diagnosed acute promyelocytic leukemia.

Early death is the main obstacle for the cure of patients with acute promyelocytic leukemia (APL). We have analyzed risk factors of early death from 526 consecutive newly diagnosed APL patients between 2004 and 2016. The overall incidence of early death was 7.2% (38/526). The peak hazard of early death occurred in the first 0-3 days. Multivariate logistic analysis demonstrated white blood cell (WBC) counts [odds ratio (OR) = 1.039; 95% confidence interval (CI): 1.024-1.055; P < 0.001], age (OR = 1.061; 95% CI: 1.025-1.099; P = 0.001) and platelet counts (OR = 0.971; 95% CI: 0.944-0.999; P = 0.038) were independent risk factors for early death. Furthermore, receiver-operator characteristic (ROC) curve analyses revealed a simple WBC/platelet ratio was significantly more accurate in predicting early death [areas under the ROC curve (AUC) = 0.842, 95% CI: 0.807-0.872) than WBC counts (AUC = 0.793; 95% CI: 0.756-0.827) or Sanz score (AUC = 0.746; 95% CI: 0.706-0.783). We stratified APL patients into four risk subgroups: low risk (WBC ≤ 10 × 109/L, platelet >40 × 109/L), intermediate risk (WBC/platelet <0.2 and age ≤ 60, not in low risk), high risk (WBC/platelet ≥0.2 or age > 60, not in low and ultra-high risk) and ultra-high risk (WBC > 50 × 109/L), the early death rates were 0, 0.6, 12.8, and 41.2%, respectively. In conclusion, we proposed a modified Sanz risk model as a useful predictor of early death risk in patients with APL.

Risk factors and clinical characteristics of non-promyelocytic acute myeloid leukemia of intracerebral hemorrhage: A single center study in China.

BACKGROUND: Although high mortality in patients with acute leukemia (AL) is associated with intracranial hemorrhage (ICH), the clinical features and pathogenesis of AL patients with cerebral hemorrhage are not well known. METHODS: We diagnosed 90 patients with ICH from a total of 1467 patients with non-promyelocytic AL who had been hospitalized in the First Affiliated Hospital of Medical School of Zhejiang University from January 2010 to October 2015. Moreover, the risk factors of ICH death were evaluated. RESULT: Median age at ICH was 51years old, in which men accounted for 52.2%. They also accounted for 85.6% of acute myeloid leukemia. The relative incidence of ICH was the highest in M2 and M5 (60.1%). ICH presented with higher peripheral blood white blood cell count (WBC) (P<0.001), lower peripheral platelet counts (P<0.001), lower albumin (P<0.001), lower fibrous protein (P<0.001) and prolongation of prothrombin time (P<0.001) compared to those observed in the patients of NICH group; multivariate analysis, independent risk factors for death in patients with ICH include: WBC≥30.00×109/l and prothrombin time≥12.91 s. CONCLUSIONS: Leukocytosis and coagulation dysfunctions might be the main pathogenesis of acute leukemia complicated with cerebral hemorrhage.

HAG (Homoharringtonine, Cytarabine, G-CSF) Regimen for the Treatment of Acute Myeloid Leukemia and Myelodysplastic Syndrome: A Meta-Analysis with 2,314 Participants.

BACKGROUND: In China, the combination of homoharringtonine, cytarabine, and G-CSF (HAG) has been extensively applied for treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). METHODS: We performed a meta-analysis of 2,314 patients (AML, n = 1754; MDS, n = 560) to determine the overall safety and efficacy of this regimen. RESULTS: The complete response (CR) rate of AML patients (53%) was significantly higher than that of MDS/transformed-AML patients (45%; P = 0.007). The CR rate of patients with newly diagnosed AML (62%) was significantly higher than in patients with relapsed/refractory AML (50%; P = 0.001). There were no significant difference in CR rates between elderly AML patients (54%) and all AML patients (P = 0.721). When compared with non-HAG regimens for AML/MDS induction therapy, the CR rate of patients treated with HAG was significantly higher than in treated with intensive chemotherapy (P = 0.000). No significant differences in CR rates were observed between patients treated with HAG and those treated with CAG (cytarabine, aclarubicin, G-CSF) regimens (P = 0.073). HAG regimen was well tolerated, with early death (ED) in 2%, grade IV myelosurrpression in 52% and infection in 50%. Reports of ED and rates of myelosuppression were reduced as compared with intensive chemotherapy (P = 0.000 and P = 0.000, respectively). CONCLUSION: The HAG regimen is an effective and safe regimen for the treatment of AML and MDS, and appears to be more effective and better tolerated than intensive chemotherapy. Future randomized controlled trials and further meta-analyses are strongly needed to confirm its efficacy and safety, especially in comparison with intensive chemotherapy.

Evaluating frequency of PML-RARA mutations and conferring resistance to arsenic trioxide-based therapy in relapsed acute promyelocytic leukemia patients.

The aim of the study is to better understand the mechanism of relapse and acquired clinical resistance to arsenic trioxide (ATO) and/or all-trans retinoic acid (ATRA). Thirty relapsed acute promyelocytic leukemia (APL) patients were followed. Fifteen patients experienced two or more relapses; nine patients had clinical resistance to ATO-based therapy. The frequency and clinical significance of promyelocytic leukemia (PML)-retinoic acid receptor alpha (RARA) mutational status using Sanger sequencing were evaluated. Overall, eight different types of mutations in the RARA region (V218D, R272Q, T278A, T291I, N299D, R294W, A300G, and L220_F228delinsP) were identified in 11 patients. Eight missense mutations (L211P, C213R, S214L, A216V, L217F, D219H, S221G, and D241G) were found in the PML portion of PML-RARA in 14 patients, with A216V as the predominant mutation. Eight patients were found to harbor both PML and RARA mutations over the course of the disease. The PML-region mutations were associated with response to ATO-based therapy (P < 0.0001), number of relapses (P = 0.001), and early relapse (P = 0.013). Notably, one case sampled at nine different time points showed alternating clonal dominance over the course of treatment. This study demonstrated frequent mutations of PML-RARA and supported a clonal selection model in relation to APL relapse and ATO resistance.