Complete remissions in subpopulations by assigned treatment group

Representativeness of Study Participants

Measurable residual disease (MRD) response analysis

Hematologic and non-hematologic toxicity related to induction chemotherapy

Pregnancy complicated by aplastic anaemia (AA) is rare but high risk, with historically poor maternal-fetal outcomes. Contemporary multidisciplinary management may improve prognosis, underscoring the need to clarify current outcomes and risk factors. We conducted a single-centre retrospective cohort study of 54 women with AA who had a total of 65 pregnancies, including those diagnosed with AA during pregnancy (n = 8) and those with a pre-existing AA diagnosis (n = 57). Most patients with new-onset AA presented with severe cytopenia at diagnosis. Although none responded to therapy during pregnancy, all six who continued their pregnancies had live births; two opted out due to severe cytopenia. In the pre-existing AA group, 88% of pregnancies resulted in live births, with a 47% rate of severe maternal or fetal complications. Pre-delivery haemoglobin and platelet counts were significantly lower in the complication group (73 g/L and 20 × 109/L vs. 85 g/L and 29 × 109/L, p < 0.05). Active disease (relapse or lack of remission) before delivery was strongly associated with adverse outcomes (78% vs. 37%, p = 0.002). No maternal deaths or neonatal haematological abnormalities were observed. Pregnancy with AA can achieve favourable outcomes with multidisciplinary management. Pre-delivery disease activity and haematological parameters (haemoglobin and platelet counts) are significant predictors of complications.

ABSTRACT Objectives Studies on the efficacy and safety of haploidentical hematopoietic stem cell transplantation (haplo‐SCT) with anti‐thymocyte globulin (ATG) in patients aged ≥ 60 years remain limited. Methods We performed a study presenting data from 54 patients aged ≥ 60 years with hematologic malignancies who underwent haplo‐SCT with ATG. Results The median follow‐up was 15 months. The median overall survival (OS) at 1‐, 2‐, and 3‐year was 68.4%, 51.2%, and 47.6%, respectively. The cumulative incidence of non‐relapse mortality (NRM) at 1 and 3 years post haplo‐SCT was 22.9% and 34.8%, respectively. The cumulative incidence of 1‐ and 3‐years relapse rate was 11.3% and 25.6%. The 100‐day cumulative incidence of Grade II–IV acute graft‐versus‐host disease (aGvHD) was 23.1%, while the 3‐year cumulative incidence of extensive chronic graft‐versus‐host disease (cGvHD) was 10.4%. The absence of complete remission at the time of haplo‐SCT was identified as a risk factor for OS, relapse, and NRM. Conclusions Our study suggests that haplo‐SCT with ATG is a safe and effective treatment option for patients aged ≥ 60 years. Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission.

Epstein-Barr virus (EBV) reactivation is a common complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT), particularly in patients receiving high-dose anti-thymocyte globulin (ATG)-containing conditioning regimens. If left untreated, EBV reactivation may progress to post-transplant lymphoproliferative disorder (PTLD), a life-threatening condition. While preemptive therapy with the standard dose of rituximab (RTX), 375 mg/m², is recommended for EBV-related complications, such a high dose may be unnecessary in post-transplant settings where the total lymphocyte mass is significantly reduced compared to lymphoma conditions. This retrospective study assessed the efficacy and safety of fixed low-dose RTX (100-200 mg per dose) as an exploratory dose de-escalation preemptive therapy for low-load EBV DNA-emia (<10,000 copies/mL) occurring within four months post-transplantation. Among 83 high-risk patients, RTX achieved a high EBV clearance rate of 93.9% (95% CI: 88.6%-99.2%), with comparable effectiveness observed between the 100 mg and 200 mg dosage groups. Viral clearance was rapid, with most patients becoming EBV-DNA negative after 1 to 2 doses. RTX was well tolerated, with no treatment discontinuations due to adverse events. Despite preemptive RTX, four patients (5%) developed PTLD, which aligns with previously reported rates in similar populations. At a median follow-up of 41.6 months, the 3-year overall survival (OS) rate was 67.7%, with no significant differences in OS, relapse, or nonrelapse mortality between the two dosage cohorts. These findings suggest that a fixed low-dose RTX regimen, as an exploratory dose de-escalation strategy, is safe, effective, and well-tolerated for the preemptive management of low-load EBV DNA-emia in allo-HSCT recipients. While these results are hypothesis-generating, they indicate rapid viral clearance and favorable long-term outcomes, warranting further validation in comparative studies.

Intensive, multiagent chemotherapy remains the cornerstone of conventional therapy for B-cell acute lymphoblastic leukemia (B-ALL), but is poorly tolerated by older adults or those with major comorbidities. Dose reductions or omissions in chemotherapy alone are significantly associated with a higher risk of relapse. Novel immunotherapies, especially inotuzumab ozogamicin (InO) and blinatumomab (BiTE), delivered alongside or sequentially after low-intensity chemotherapy achieve high complete remission (CR) rates of 90-97% and deep molecular responses, with 1-year overall survival (OS) of 84-100% in older or high-risk patients (pts) and manageable toxicity (NCT01371630; NCT03739814). However, antigen escape-mediated resistance and optimal regimen sequencing/dosing still compromise long-term benefit. We hypothesize that sequential delivery of BiTE followed by InO may preempt resistance by eliminating antigen-loss variants through complementary mechanisms, while low-intensity chemotherapy primes the microenvironment for enhanced immunotherapy. This single-arm trial (NCT06985485) at the First Affiliated Hospital of Soochow University in China will evaluate the safety and efficacy of low-intensity chemotherapy combined with full-course sequential immunotherapy in B-ALL. The study will enroll 26 newly diagnosed B-ALL pts aged ≥60 years or 15-60 years, who are either unfit for intensive chemotherapy or fit but have declined it (fit-declined). Unfit pts must have Eastern Cooperative Oncology Group performance status ≥2 or at least one of: 1) congestive heart failure requiring therapy or left ventricular ejection fraction of ≤50%, 2) diffusing capacity of carbon monoxide of ≤65% or forced expiratory volume in the first second of ≤65%, 3) creatinine >2×the upper limit of normal [ULN] or creatinine clearance <45 mL/min), 4) total bilirubin >1.5×ULN or aspartate aminotransferase/alanine aminotransferase/alkaline phosphatase >3×ULN), 5) active uncontrolled infection, 6), cognitive impairment, 7) other chemotherapy-contraindicated comorbidities. Induction therapy consists of low-intensity chemotherapy combined with BiTE with or without TKIs. Regimen included dexamethasone 8 mg/m²/day intravenously injection (IV), days 1-14, vindesine 4 mg, IV, day 7, followed by blinatumomab dosed by body weight: pts ≥45 kg receive fixed dosing (9 µg/day days 1-7, 28 µg/day days 8-28), pts <45 kg receive BSA-adjusted dosing (5 µg/m²/day days 1-7, 15 µg/m²/day days 8-28). Philadelphia chromosome-positive ALL pts receive second-generation TKIs, with subsequent switch to third-generation TKIs upon resistance.If morphologic remission is not achieved after initial therapy, a salvage cycle with InO (0.8 mg/m², day 1, IV) will be administered. Those with persistent treatment failure will discontinue protocol therapy and transition to alternative therapies (e.g. hematopoietic stem cell transplantation, or clinical trials). Post-remission consolidation chemotherapy includes high-dose methotrexate followed by sequential immunotherapy: BiTE (per weight-stratified dosing), then after a 2-week break, InO (0.8 mg/m² on day 1), followed by another 2-week break. This sequence is repeated for 4 cycles. Each cycle includes two lumbar punctures for central nervous system prophylaxis, administered before BiTE and before InO, respectively. Pts then enter long-term follow-up, and those who relapse are withdrawn from the study. The primary endpoint is OS, analyzed using the Kaplan-Meier method to estimate median survival time and corresponding 95% confidence intervals (CI). Secondary endpoints include: CR rate and objective response rate, assessed by the Clopper-Pearson method for 95% CIs; event-free survival and relapse-free survival, estimated via Kaplan-Meier; non-relapse mortality and cumulative incidence of relapse, calculated using competing risks analysis; and safety endpoints. This study aims to establish a full-course immunotherapy approach potentially reducing chemotherapy in this population while addressing challenges like antigen escape via sequential CD19/CD22 targeting.

Infections are frequent complications in patients with hematological disorders, and pathogen diagnosis remains challenging. Metagenomic next-generation sequencing (mNGS) is an unbiased high-throughput technology that has been widely applied in the diagnosis of infectious diseases. However, to date, there are no established international guidelines or expert consensuses regarding the use of mNGS to diagnose infections in patients with hematologic disorders. The Anti-Infection Study Group of the Chinese Society of Hematology invited experts in the fields of hematology, microbiology, and mNGS technology to draft an expert consensus focused on clinical indications, sample collection, quality control, and interpretation of results. This consensus will likely contribute to clarifying the medical indications for mNGS testing, optimizing the interpretation of reports, and becoming an inspiration for global practice.

With the advances in allogeneic hematopoietic cell transplantation(allo-HCT)and supportive care,the number of allo-HCT for elderly patients has been increasing in recent years.

PURPOSE:To assess the efficacy and safety of an induction regimen composed of idarubicin, cytarabine, and cladribine (IAC) in patients with de novo acute myeloid leukemia (AML). PATIENTS AND METHODS:Adult patients with newly diagnosed AML were randomized to the IAC group (cladribine 5 mg/m2/day for 5 days, idarubicin 8 mg/m2/day for 3 days, and cytarabine 100 mg/m2/day for 7 days) and the IA group (idarubicin 12 mg/m2/day for 3 days and cytarabine 100 mg/m2/day for 7 days) at a 1:2 ratio. The primary endpoint was complete remission (CR) after induction. Secondary endpoints included 2-year overall survival (OS), disease-free survival, and cumulative incidence of relapse. RESULTS:A total of 618 adult patients with newly diagnosed AML were enrolled. The overall CR rate was 80.5% in the IAC group compared with 72.4% in the IA group (P = 0.029). The 2-year OS was 81.3% in the IAC group compared with 70.0% in the IA group (P = 0.011). Patients on the IAC regimen achieved a higher CR rate compared to those on the IA regimen, particularly in those with adverse risk (69.8% vs. 49.1%, P = 0.008), 2-year OS (80.1% vs. IA 58.1%, P = 0.014), and disease-free survival (78.8% vs. 51.3%, P = 0.009). In the subgroup of patients older than 45 years of age, the IAC regimen exerted better CR (77.1% vs. 62.6%, P = 0.033) and 2-year OS (74.7% vs. IA 55.0%, P = 0.019). There were no differences in chemotherapy-related toxicities between the groups. CONCLUSIONS:Cladribine added to the IA regimen was safe and effective in de novo AML. Patients with adverse risk or those between 45 and 60 years of age might benefit significantly on both response and survival with the IAC regimen.

Introduction: Venetoclax in combination with Azacitidine (VA) is the first-line induction regimen recommended by NCCN guidelines for AML patients who are ineligible or decline intensive chemotherapy. However, studies have identified multiple mechanisms developing resistance to the regimen. Among them, mature monocytic differentiation appears to be an important developmental event driving relapse/refractory responses to VA (Pei S et al. Cancer Discov, 2020; Bisaillon R et al. Leukemia, 2020), suggesting the need to further define the mature monocytic AML disease and design more effective treatment strategies. We propose to define Immunophenotypically mature Monocytic AML patients (Im-Mono AMLs) by a flow criteria where blasts and promonocytes express at least two monocytic markers including CD11b, CD14, CD36 and CD64 and are negative for at least one primitive marker: CD34 or CD117. In addition, given that the monocytic developmental hierarchy is sensitive to histone deacetylase inhibitors (HDACi) (Zeng AGX et al.Nat Med,2022), we add Chidamide (C), a selective HDACi, in combination with VA to form a newly designed VAC regimen. In this study, we compare the efficacy and safety of VAC versus VA as induction therapy for the newly diagnosed (ND) Im-Mono AMLs who are unfit or decline intensive chemotherapy. Methods: Patients with ND Im-Mono disease, identified by the flow cytometry criteria described above, were enrolled in this study. Participants were drawn from a clinical trial (NCT05566054), and due to the limited number of cases, additional cases were included from a retrospective cohort. The patients were divided into two groups: VA group, receiving Azacitidine (75mg/m2 on days 1-7) and Venetoclax (escalated doses of 100mg, 200mg, and 400mg by day 28), and VAC group, receiving Chidamide (10mg/day on days 1-7) combined with VA. Patients who did not respond to the 1st cycle of treatment were allowed to receive alternative induction regimen. For post-remission therapy, patients could continue with the original regimen, switch to other regimens, or undergo hematopoietic stem cell transplantation. The primary endpoint was ORR (CR+CRi+MLFS) after the 1st cycle. Secondary endpoints included MRD-negative CR rate (defined as < 1 × 10−3 by flow cytometry), overall survival (OS), and adverse events. Results: Between January 2021 and June 2024, a total of 48 patients were enrolled. 20 patients received VAC regimen, and 28 patients received VA regimen. There were no significant differences in baseline characteristics between the two groups of patients (P > 0.1). At the end of the 1st cycle of treatment, the ORR in VAC group was 75%, which was significantly higher than the 46.4% in VA group (P = 0.048). The MRD-negative CR rate was 86.7% in VAC group and 84.6% in VA group (P = 1.000). At a median follow-up of 7.57 months (range, 0.9-24.7), the median OS was not reached in both groups. Besides, the incidence of grade 3 or higher febrile neutropenia (57.6% vs. 52.6%), infection (21.2% vs. 23.7%), and sepsis (9.1% vs. 13.2%) were not significantly different between VAC and VA group (P > 0.1). Patients in VAC group required similar platelets (4.5U vs. 5U, P = 0.859) and red blood cell infusions (5.5U vs. 5U, P = 0.979) during induction as compared with those in VA group. Mechanistically, the laboratory experiments showed that Venetoclax and Chidamide exhibit strong synergistic anti-leukemic effects in Venetoclax resistant monocytic cell line THP-1 harboring NRAS, KMT2A-rearrangment and TP53 mutations, all of which are known to be worse prognosis factors for VA. Moreover, Venetoclax and Chidamide could target primitive and monocytic leukemia subpopulations in primary AML samples, respectively, effectively treating the developmental heterogeneity of AML disease. Conclusion: Despite VA regimen being an active and promising strategy for AML, the inherent heterogeneity of AML contributes to primary or secondary resistance to VA, presenting major clinical challenges. It is crucial to better define the developmental heterogeneity and devise new treatment strategies. In this report, we newly defined Im-Mono AMLs who show poor responses to VA. In contrast, VAC regimen achieved a considerably higher remission rate without increased adverse effects in these patients. This provides proof-of-principle for combining HDAC and BCL2 inhibitors to address disease heterogeneity and improve AML treatment outcomes.

Acute leukemia of ambiguous lineage (ALAL) is a rare type of acute leukemia and is extremely difficult to treat. Here, we present six patients with CD19-positive ALAL who were successfully treated with blinatumomab-based combination treatment in the front-line setting. Five were diagnosed with B-cell/myeloid mixed phenotype acute leukemia (MPAL) and one with B-cell/T cell MPAL. All six patients achieved complete remission after one cycle of blinatumomab combination treatment. Furthermore, 3 (50%) patients achieved MRD-negative (<0.01%) by flow cytometry and 2 (50%) of four patients with evaluable molecular MRD achieved molecular remission. At some point during the treatment, 5 (83.3%) patients achieved MRD negativity and all four patients with evaluable molecular MRD had molecular remission. The overall survival was 100%, and the event-free survival was 83.3% after a median follow-up time of 15 months. This study provides preliminary evidence that blinatumomab-based combination therapy is an effective and safe treatment for patients with CD19-positive ALAL in the front-line setting.

The clinical outcomes and incidence of Philadelphia chromosome-negative B cell acute lymphoblastic leukaemia (ph-neg B-ALL) vary significantly across different age groups, influencing the prognosis. Despite recent advancements in diagnostic and therapeutic techniques, the detailed prognosis for ph-negative B-ALL across age demographics remains to be elucidated. In this study, clinical data were obtained from 80 patients with ph-neg B-ALL who were diagnosed at our centre. Ribonucleic acid sequencing was performed using their initial bone marrow aspirate samples. By employing weighted gene co-expression network analysis (WGCNA) on 408 anoikis-related genes (ARGs), four different modules were identified and subsequently analysed through bioinformatics. The WGCNA revealed distinct co-expression modules among ARGs. Specifically, the ARGs in the turquoise module might assess the risk associated with newly diagnosed ph-neg B-ALL. Additionally, the study revealed significant heterogeneity in the immune microenvironment and genome variance, highlighting the notable heterogeneity within the disease. 408 ARGs were screened out and four different co-expression modules were constructed by WGCNA algorithms from the RNA-sequencing data of 80 ph-neg B-ALL patients; The ARGs in the turquoise module were the most, and it can be used to divide the de novo ph-neg B-ALL patients to different risk groups(high-risk and low-risk); The ph-neg B-ALL patients can be divided into PS-1 and PS-2, there is heterogeneity of genomes between PS-1 and PS-2; Immune infiltration difference exists in between PS-1 and PS-2. In conclusion, our study holds significant value in exploring the molecular pathways and mechanisms associated with anoikis implicated in ph-neg B-ALL, and in facilitating the development of treatments and prognostic tools for this disease

Letermovir (LTV) prophylaxis is effective in reducing the incidence of clinically significant cytomegalovirus (CMV) infection (cs CMVi) after allogeneic haematopoietic stem cell transplantation (allo-HSCT). Since our centre began administering LTV prophylaxis in June 2022, we have observed a certain increase in the incidence of Epstein–Barr virus (EBV) reactivation after haploidentical HSCT. We retrospectively analysed 230 consecutive patients who underwent haploidentical HSCT with rabbit anti-thymocyte globulin (ATG) from October 2022 to June 2023. The LTV group included 133 patients who received LTV prophylaxis, and the control group included 97 patients who did not receive LTV prophylaxis. At 1 year after HSCT, EBV reactivation was observed in 36 patients (27

Background: The combination of a hypomethylating agent (HMA) and venetoclax (Ven) has become the standard of care for patients with newly diagnosed acute myeloid leukemia (AML) who are not candidates for intensive chemotherapy. Due to the regimen's simplicity, effectiveness, and lower toxicity, research is being conducted to explore its broader application. However, data on its efficacy in patients with CBFβ::MYH11(+) AML are scarce, as these patients have typically been excluded from most Ven-related studies. To address this gap, we have conducted an investigation into the efficacy of HMA+Ven in patients with CBFβ::MYH11(+) AML. Methods: We retrospectively analyzed 42 patients with CBFβ::MYH11(+) AML who received induction treatment with HMA+Ven at the First Affiliated Hospital of Soochow University between 2019 and 2024. Patients were divided into two cohorts: (1) those with newly diagnosed AML and (2) those with relapsed AML. The primary objective of this study was to evaluate the overall response rate, which included complete remission (CR), CR with incomplete blood count recovery (CRi), and morphologic leukemia-free state. Measurable residual disease (MRD) was monitored using real-time quantitative reverse transcriptase-polymerase chain reaction. The absolute copy numbers of the fusion gene transcripts were normalized to those of the ABL gene (expressed as copies per 10^4 copies of ABL). Complete molecular remission (CMR) was defined as a fusion transcript level of less than 0.01%. The choice of postinduction therapy was at the discretion of the treating physician. The probability of overall survival (OS) was estimated using the Kaplan-Meier method. Results: Thirty-eight patients with newly diagnosed CBFβ::MYH11(+) AML were treated. The median age was 48 years (range, 15-79 years), and 23 were males. Thirty-three (86.8%) patients had tyrosine kinase gene mutations (including KIT, N/KRAS, and FLT3). After a single course of induction therapy, 34 patients (89.5%) achieved CR and 4 patients (10.5%) achieved CRi for a composite CR/CRi rate of 100%. The median transcript level of CBFβ::MYH11 at the end of cycle 1 was 54 copies (range, 0-2065). The post-induction therapy was varied according to the treating physician's discretion, and 14 patients received a second course of HMA plus Ven. The median transcript level after cycle 2 was 32 copies (range, 0-171). CMR was achieved in 3 patients within 2 cycles of HMA+Ven (one after the first cycle and two after the second cycle). The median duration of follow-up in the frontline cohort is 13 months (range, 2-52 months), and the 2-year probability of OS was 94.6% (95% CI, 87.6-100%). One patient died of infection in the consolidation with high-dose cytarabine, one patient died of disease recurrence and twelve patients proceeded to allogeneic hematopoietic stem cell transplantation (allo-HSCT) due to persistent MRD or relapse. Ten patients with relapsed CBFβ::MYH11(+) AML were treated, including 6 patients from the aforementioned cohort. The median age was 51 years (range, 19-79 years), and 8 were males. Eight (80%) patients had tyrosine kinase gene mutations. Four out of the six patients with prior treatment using HMA plus Ven, and one out of the four patients without prior HMA plus Ven treatment, achieved CR/CRi after one cycle of re-induction therapy. Among the responders, 3 patients proceeded to myeloablative allogeneic HSCT directly, while two patients who did not undergo allo-HSCT remained in CR2 for 2 and 3 months at last follow-up, respectively. As expected, the treatment was well-tolerated, and all side effects were temporary and reversible. No death was observed in the entire cohort during the induction period. Conclusion: Combination therapy with HMA+Ven yielded impressive responses as frontline therapy in patients with CBFβ::MYH11(+) AML. However, the efficacy of this combination in the salvage setting showed reduced response rates.