bluuebunny/crossref_metadata_2025 huggingface dataset:
Heavy Menstrual Bleeding (HMB) Is a Common Symptom in Patients with Bleeding Disorder of Unknown Cause (BDUC)
Authors: Monard Amaury , Tegels Sanne , Merry Inge , Derikx Floor , Henskens Yvonne , Beckers Erik AM , Moenen Floor CJI
Published: December 2024

Background: Patients with an increased bleeding tendency without any abnormalities in laboratory hemostasis tests are classified as having a bleeding disorder of unknown cause (BDUC). The large majority of BDUC patients is female and the most common bleeding symptoms are mucocutaneous, including heavy menstrual bleeding (HMB). Data on HMB and its impact on different aspects of daily life, such as social and work-related activities, in BDUC patients is limited. The aim of this study was to investigate the prevalence of HMB and the HMB-related quality of life in women with BDUC in comparison with patients with known bleeding disorders (BD) and no bleeding disorder (NBD).

Methods: Clinical and laboratory data from a total of 195 female patients from the prospective predictors of bleeding Predictors of Bleeding Evaluation in Adult Hematologic Patients with Bleeding Tendencies cohort (ProBe-AHP study) were used to analyze the prevalence of HMB in patients with an increased bleeding tendency. HMB was defined as a score of ≥1 on the HMB symptoms scoring scale of the International Society of Thrombosis and Hemostasis bleeding assessment tool (ISTH-BAT). Additionally, the Menorrhagia Multi-Attribute Scale (MMAS) was completed. The MMAS entails questions on six domains, including psychological wellbeing and physical health, and provides a score ranging from 0 to 100. Lower scores indicate a poorer HMB-related quality of life. Results from an MMAS population study from Peking was used as a reference group (general population).

Results: From the 195 included patients, 68 were diagnosed with a BD, 81 were diagnosed with BDUC and 46 were classified as NBD. The prevalence of HMB was 69% in BD, 83% in BDUC and 41% in NBD, which was a statistically significant difference between the three groups (p<0.001). A total of 53 MMAS questionnaires were completed and returned (BD n=21, BDUC n=21 and NBD n=9). MMAS score was lowest in the BD group (median [IQR]: 44 [ 39-95]), followed by the BDUC group (median [IQR]: 69 [43-86]) and the NBD group (median [IQR]: 69 [ 33-74]). Compared to data from the general population (mean ± SD: 95 ± 10), MMAS score was significantly lower in BDUC patients and BD patients.

Conclusion: HMB is a highly prevalent symptom in women with BD and with BDUC. Menstruation related quality of life was impaired in BDUC patients and even more in BD patients compared to the general population.
High-Dose Cytarabine with Idarubicin Versus High-Dose Cytarabine within First Consolidation for Acute Myeloid Leukemia in First Complete Remission: An Open-Label, Multicenter, Randomized, Phase 3 Trial
Authors: Feng Zinan , Zhang Yu , Liu Hui , Yu Sijian , Liu Qifa , Xuan Li
Published: December 2024

Backgrounds ：

Whether adding anthracycline to intermediate- or high-dose cytarabine as consolidation is beneficial remains unclear in acute myeloid leukemia (AML). We investigated the efficacy and safety of high-dose cytarabine with idarubicin as consolidation for AML in first complete remission (CR1).

Methods:

We performed the open-label, randomized phase 3 trial at 16 hospitals in China. Eligible AML patients in CR1 were randomly assigned (1:1) to receive either high-dose cytarabine with idarubicin (IA3+3) (idarubicin 10mg/m2, d1-3 and cytarabine 2g/m2, q12h, d1-3) or high-dose cytarabine (HDAC) (cytarabine 3g/m2, q12h, d1-3) regimens as first consolidation. The primary endpoint was the rate of measurable residual disease negativity (MRD-) after first consolidation. Secondary endpoints included cumulative incidence of relapse (CIR), overall survival (OS), disease-free survival (DFS), treatment-related mortality (TRM) and adverse events (AEs).

Results

Between November 2018 and December 2021, a total of 407 eligible patients were enrolled and randomly assigned to IA3+3(n=204) or HDAC(n=203) groups. The MRD- rates for IA3+3 and HDAC groups were 65.2% (95%CI: 58.6%-71.8%) and 53.2% (46.3%-60.1%) (RR=1.23, 95%CI:1.04-1.44, P =0.01). Median follow-up time was 37.3 months, the 3-year CIR, DFS, OS and TRM were 22.6% (95%CI :16.8%-29.0%) and 34.0% (27.1%-41.1%) (P=0.01), 68.4% (95%CI :61.5%-75.3%) and 52.9% (45.4%-60.5%) (P=0.003), 75.5% (95% CI :69.0%-82.1%) and 69.6% (62.4%-76.7%) (P=0.18), 8.8% (95%CI :5.2%-13.6%) and 13.0% (8.5%-18.5%) (P=0.23) in two groups, respectively. Ultimately, the patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) were 87 and 114 cases, respectively (P=0.006). Within 28 days after first consolidation, the most common grade 3 or higher AEs were thrombocytopenia (196[96%]vs 196[97%]), neutropenia (195[96%] vs 185[91%]), anemia (165[81%] vs 152[75%]), febrile neutropenia (146[72%] vs 128[63%]) and infections (104[51%] vs 83[41%]). One patient died from infection in IA3+3 group.

Conclusions

IA3+3 resulted in deeper remissions, reduced relapse and was well-tolerated compared to HDAC. This deeper remission improved DFS and translated into treatment advantage, with fewer patients undergoing allo-HSCT. This regimen may be an appropriate consolidation option for AML in CR1.
Driving Cell Therapy in Treatment of MRD-Positive Acute Pediatric Lymphoblastic Leukemia after Allogeneic-HSCT: Blinatumomab + DLI
Authors: Rossitti Emanuela , Pagano Gennaro , Cacace Fabiana , Caprioli Valeria , D'Amico Maria Rosaria , De Simone Giuseppina , Sabbatino Maria Simona , Wierda William G. , Tambaro Francesco Paolo Paolo
Published: December 2024

Background

Persistence of Measurable Residual Disease (MRD > 10-4) in Acute Lymphoblastic Leukemia (ALL) is high risk for relapse after allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) with a very dismal prognosis. The role of Donor Lymphocytes Infusion (DLI) in the treatment of MRD-positive ALL is still debated, while favorable results have been observed in the treatment of MRD-positive relapse with the CD3-CD19 bi-specific T cell engager blinatumomab.

Methods

Three pediatric patients with high risk B-ALL were treated according to AEIOP ALL 2009 and AIEOP ALL 2017 protocols and referred for allo-HSCT. Two patients were male. Median age was 16 years (3-17). Patient 1 was primary refractory to 2 lines of chemotherapy and blinatumomab and achieved MRD-positive complete remission (CR) after 2 courses of inotuzumab. Patient 2, affected by secondary ALL, achieved CR1 after 1 course of chemotherapy and subsequently received 2 courses of blinatumomab, due to treatment chemotherapy-associated toxicity, achieving MRD-negative CR1. Patient 3 developed CNS relapse during maintenance, then received salvage therapy according to the INTREALL HR 2010 and 1 course of blinatumomab, achieving MRD-positive CR1.

Results

All patients underwent allo-HSCT and were MRD-positive at 8, 31 and 23 weeks post allo-HSCT, respectively. All patients discontinued immunosuppressive therapy and received 4, 1 and 3 courses of DLI + blinatumomab, respectively. Blinatumomab was started one week after each dose of DLI. Only patient 1 experienced grade 2 liver GvHD. None of the patients experienced serious adverse events needing blinatumomab discontinuation. All 3 patients reached an MRD-negative complete remission (CR). Median follow-up post HSCT was 30 months (11-30). Patient 2 and 3 are still in CR with persistent negative MRD, while patient 1 died for disease relapse (isolated CNS relapse).

Conclusions

The role of cellular therapy with DLI is still debated. Blinatumomab directs T cells to bind CD19 present on malignant B cells and engages CD3 on T cells causing activation and inducing cytotoxicity against the ALL cells. The use of blinatumomab allowed recruitment of fit donor-derived T lymphocytes (not exposed to immune suppressive agents) against ALL B cells. This hypothesis is supported by the fact that patient 1, who received blinatumomab pre-HSCT and had disease progression (probably due to the lack of T cells showed by flow cytometry), achieved MRD-negative response after receiving DLI+blinatumomab post-transplant. All patients reached MRD-negative status and 2 subsequently developed CNS relapse; none received CNS prophylaxis post-HSCT. We hypothesize that blinatumomab + DLI is able to clear the hematological disease, but it is not effective in preventing CNS relapse.
Delayed Physical Growth and Related Factors in Pediatric Patients with Transfusion-Dependent Thalassemia
Authors: Zhao Jingyu , Yu Xiao , Xu Jing , Gao Zhen , Liu Yanjie , Wang Anni , Dong Jin , Yuan Weiping , Shi Jun , Kuang Zhexiang
Published: December 2024

Objectives To investigate the physical growth status of pediatric patients with transfusion-dependent thalassemia (TDT) and assess the clinical and economic factors associated with delayed physical growth.

Methods We extracted sociodemographic and clinical data on 338 pediatric patients with TDT, including physical growth indicators (height and weight), family economic status and disease related treatment, from thalassemia disease database at a grade-A tertiary hematological specialty hospital in China between October 2023 and May 2024. Length/height-for-age and body mass index-for-age (BMI-for-age) were assessed using the ‘Growth Standard for Children under 7 Years of Age’ and the ‘Standard for Height Level Classification among Children and Adolescents Aged 7-18 Years’ issued by the National Health Commission, as well as the ‘Dietary Guidelines for Chinese Residents’. Logistic regression was performed to explore the impact of sociodemographic and clinical factors on length/height-for-age and BMI-for-age, respectively.

Results Among the 338 pediatric patients with TDT, 192 were male and 146 were female, with a median age of 12 (0.8-18.0) years and a median time since diagnosis of 10.3 (0.5-17.9) years. Of these patients, 21 (6.2%) had ⍺ thalassemia, 288 (85.2%) had β thalassemia, and 29 (8.6%) had mixed ⍺ and β thalassemia. Overall, 88 (26.00%) children were stunted as their length/height failing below -2 standard deviations (SDs) from the national growth standard median. There were 95 (28.1%) children with length/height between -2 SDs and -1SD, and 155(45.9%) children with length/height≥-1SD. Meanwhile, 77 (22.8%) patients were underweight, 241 (71.3%) were at a healthy weight, and 20 (5.9%) were classified as overweight/obese based on their BMI-for-age. The majority of TDT children had a family monthly income falling within the ranges of 3000-5000 yuan and 5000-10000 yuan, accounting for 135 (39.9%) and 118 (34.9%) cases, respectively. Pre-transfusion hemoglobin (HGB) levels were categorized as ≤70 g/L, 70-90 g/L, and >90 g/L in 19 (5.6%), 123 (36.4%), and 196 (58.0%) cases, respectively. Thirty (8.9%) pediatric patients exhibited serum ferritin (SF) levels of ≥5000ug/L, 321 (95.0%) received chelation therapy, and 16 (4.7%) underwent splenectomy. Multivariate regression analysis revealed that pre-transfusion HGB≤70g/L, SF≥5000ug/L, and a monthly family income below 10000 yuan were all significantly associated with an increased risk of stunting (all P<0.05). Moreover, a longer time since diagnosis was a hazardous factor for being underweight (P=0.013).

Conclusions Pediatric patients with TDT who had pre-transfusion HGB≤70g/L, SF≥5000ug/L, lower monthly family income or longer time since diagnosis were at a higher risk for delayed physical growth.
Patterns of Vaccine Titers after Childhood Leukemia Treatment
Authors: Kasavaraju Megana , Gowda Madhu
Published: December 2024

Background

The CDC recommends that all children follow the primary immunization series vaccination schedule to prevent vaccine-preventable diseases. The primary immunization begins at birth and completes at 18 months, with boosters given from 4-6 years old. Acute lymphoblastic leukemia (ALL) is a common childhood cancer which typically affects children from 2-4 years old. The treatment for acute lymphoblastic leukemia (ALL) targets lymphocytes, which are cells that play a role in memory retention for vaccine immunity. The purpose of this experiment is to determine whether there is loss of vaccine immunity in children treated for ALL and whether there is a difference between the high-risk ALL protocols and standard-risk ALL protocols. Understanding loss of immunity in children treated for ALL can help to establish reimmunization guidelines in order to protect survivors from vaccine-preventable diseases.

Methods

This retrospective study consisted of chart reviews of 45 pediatric patients who are ALL survivors at Children's Hospital of Richmond. Titers drawn from these patients were compared to the general population using a one-proportion z-test. The ALL group was then divided into high-risk protocol and standard-risk protocol groups. Titers and lymphocyte enumeration panels were then compared between the two groups using a two-proportion z-test.

Results

The results of this study showed that there was a significantly higher percentage of negative hepatitis B, varicella, MMR, and Dtap titers for the ALL group than in the general pediatric population (p<.01). However, there was no significant difference between children treated with high-risk protocols and standard-risk protocols (p = .42). The standard-risk group had 44% negative titers while the high-risk group had 53%. Additionally, the standard-risk group had 78% abnormal lymphocyte enumeration panel while the high-risk group had 86%.

Conclusion

This study showed that children treated with chemotherapy for ALL lose immunity against vaccine preventable diseases and require reimmunization to protect them from future infection. Additionally, there is no significant statistical difference in immunity between the children treated with high-risk protocols vs standard-risk protocols. However, the percentage of negative titers and abnormal lymphocyte enumeration panels in the high-risk group was greater than the standard-risk group, so there may be some clinical significance. Therefore, routine revaccinations should be implemented after chemotherapy and children treated with high-risk protocols may require more follow-ups and precautions. Limitations of this study include small sample size and possible revaccinations at outside hospital systems. Future studies will look at the rate of lymphocyte recovery in standard vs high-risk protocol groups to further assess impacts of chemotherapy protocols on immunity.
Potent in Vitro and In Vivo Efficacy of Hdz-C123A, a GSPT1 Degrader-Antibody Conjugate Targeting CD123 in Acute Myeloid Leukemia
Authors: Dong Xiaowu , Guo Yu , Zhang Jingyu , Shen Zheyuan , Wu Shuang , Geng Shuangshuang , Ma Xinna , Hu Miao , Zhou Xinglu
Published: December 2024

Introduction:

Antibody-drug conjugates (ADCs), as an emerging class of targeted therapies, have garnered significant attention in cancer treatment due to their clinical potential in recent years. Currently, most ADC payloads are cytotoxic agents, prompting the need for novel payloads. Given the catalytic mechanism of action and expanded targeting capabilities, degraders are considered potential candidates for the next-generation payloads. We identified a potent and conjugable GSPT1 degrader CDG0501 through our Rosetta For Molecule Glue (RFMG) model and CRBN-based degrader library. Considering CD123 is a cell surface protein overexpressed in several hematologic malignancies, including AML and myelodysplastic syndrome (MDS), with restricted expression in normal hematopoietic stem cells, CDG0501 was conjugated to a humanized IgG1 targeting CD123 via a tumor-enriched protease-cleavable linker, resulting in HDZ-C123A, a stable and homogeneous conjugate with a drug-to-antibody ratio of 8. After a series of evaluations, HDZ-C123A has been validated as a promising pre-clinical candidate for further clinical development.

Results: CDG0501 showed sub-nanomolar to nanomolar activity against multiple acute myeloid leukemia (AML) and non-Hodgkin lymphoma (NHL) cell lines. In CD123-expressing cell lines, HDZ-C123A exhibited picomolar proliferative inhibition activity, which was 20-1000 times more potent than several GSPT1 degraders, including CC-90009, and showed robust activity in Mylotarg-resistant cell lines. Ex vivo experiments revealed a stronger potency of HDZ-C123A in AML patient-derived blasts compared to CC-90009 and venetoclax. HDZ-C123A demonstrated minimal toxicity to peripheral blood mononuclear cells derived from healthy subjects, highlighting the potential of conjugation strategies to improve degraders' narrow therapeutic index. HDZ-C123A showed significant anti-tumor efficacy and safety in several hematologic xenograft models and patient-derived models following single-dose administration. Particularly in the MV4-11 xenograft model, complete response was observed at doses as low as 1 mg/kg, Pharmacodynamic studies demonstrated that tumor growth inhibition correlated with the abundance of GSPT1 and related biomarkers.

Conclusions:

In summary, CDG0501, as a potent GSPT1 degrader, demonstrates potential as a next-generation payload in preclinical studies. HDZ-C123A, constructed based on CDG0501, shows promising potential as a first-in-class CD123-targeting degrader-antibody conjugate for AML treatment.
Final Results of a Phase 2, Single Arm Trial Evaluating Letermovir for Cytomegalovirus Prophylaxis in Patients with Hematological Malignancies Treated with Alemtuzumab
Authors: Reneau John C. , Huang Ying , Hanel Walter , Chung Catherine , Brammer Jonathan E. , William Basem
Published: December 2024

Cytomegalovirus (CMV) reactivation is a common complication in immunocompromised patients, including those treated with alemtuzumab. Letermovir is a potent antiviral approved CMV prophylaxis following allogeneic bone marrow transplantation. This trial aimed to investigate the efficacy of letermovir in preventing CMV reactivation in patients treated with alemtuzumab.

This was a single arm trial that included patients with hematologic malignancies treated with alemtuzumab who were seropositive for prior CMV exposure (IgG positive). Patients began letermovir 480 mg daily within 14 days of starting alemtuzumab and continued through 3 months after the last dose of alemtuzumab. The primary objective was to estimate the rate of CMV reactivation while on letermovir. CMV PCR was performed at least every 2 weeks during the study period.

The trial enrolled six patients. The median age was 74 (56-80) and 50% were male. Four patients (66.7%) had T-cell prolymphocytic leukemia, one patient (16.7%) had Sezary syndrome, and one patient (16.7%) had erythrodermic mycosis fungoides.

None of the patients enrolled experienced CMV reactivation during the study period. The most common adverse events of grade 3 or higher at least possibly attributable to letermovir included thrombocytopenia (50%), leukopenia (33.3%), anemia, diarrhea, prolonged APTT, elevated alkaline phosphatase, lymphopenia, neutropenia, and sinus bradycardia (16.7% each).

The trial was closed prior to completing accrual due to low enrollment, limiting the ability to draw definitive conclusions. Overall, the trial showed that letermovir may be effective in preventing CMV reactivation in patients treated with alemtuzumab. Further research in a larger trial is needed to validate these findings.
Ability of Platelet CREB3L1 mRNA Expression Analysis to Detect Ph-Negative MPNs: Independent Confirmation in Archival Patient Samples
Authors: Stolyar Marina , Olkhovskiy Igor , Gorbenko Aleksey
Published: December 2024

Background. Previously [1] mRNA of CREB3L1 gene expression level could reliably distinguish Ph-MPN from reactive hypercytosis it was found using RNA-seq analysis and subsequent quantitative RT-PCR in platelet-rich plasma. This reasonably suggests the prospect of creating a single simple test that would avoid the costly diver mutation analysis and bone marrow biopsy in the first step of Ph-MPN diagnosis.

Aims. Evaluate the diagnostic potential of the CREB3L1 mRNA expression in archival cDNA transcriptome samples of platelets from patients examined in our laboratory for suspected MPNs.

Methods. We used frozen at -20°C cDNA samples obtained from platelet RNA of patients examined between March 11 and June 30, 2015. A total of 49 samples from patients with confirmed Ph-MPNs (PV-26, ET-18 and MF-5) were included. Of these, 43 patients had the V617F JAK2 mutation (Me VAF = 33.5%), one patient had a mutation in exon 12 of JAK2 and one patient had a double mutation V617F JAK2 + CALR del. In three patients, driver mutations could not be detected (tri-negative MPN). The comparison group included samples from 47 patients also referred to the laboratory with suspected MPN, but who did not receive confirmation of this diagnosis. Measurement of the CREB3L1 mRNA expression level was performed according to the PCR-RT method described in the article [1] with minimal modifications. The calculation was performed using the ∆Сt method. Statistical analysis was performed using the R program.

Results. In all patients with MPNs, CREB3L1 mRNA expression in platelets was 62.5; 41.4-88.1 (Me;Q25-Q75). No dependence on routine hematological parameters, VAF V617F JAK2 values or clinical variant of MPNs was found in this sample. CREB3L1 mRNA platelets expression in patients with unconfirmed MPN was determined at a minimal level only in 21 patients and was significantly lower - 10.0; 5.8-12.1 (P<0.0001). The remaining patients in this group did not have CREB3L1 mRNA expression.

Summary and Conclusions. The ability of CREB3L1 mRNA expression analysis to identify different variants of Ph-MPNs in a retrospective study was independently confirmed using archival platelet cDNA samples from patients in the Siberian region.

Literature:

1. Morishita S, Yasuda H, Yamawaki S, Kawaji H, Itoh M, Edahiro Y, Imai M, Kogo Y, Tsuneda S, Ohsaka A, Hayashizaki Y, Ito M, Araki M, Komatsu N. CREB3L1 overexpression as a potential diagnostic marker of Philadelphia chromosome-negative myeloproliferative neoplasms. Cancer Sci. 2021;112(2):884-892. doi: 10.1111/cas.14763.
Safety and Efficacy of Dara-Based Regimen Followed with ASCT in Transplant-Eligible, Newly-Diagnosed Systemic Light Chain Amyloidosis
Authors: Le Can , Li Juan
Published: December 2024

Objectives:Daratumumab in combination with cyclophosphamide, bortezomib (Dara-VCd), and dexamethasone is the currently standard frontline therapy for newly-diagnosed AL amyloidosis. However, up to one-fourth of patients do not achieve a deep response (≥VGPR) with D-VCd induction. ASCT can upgrade hematologic responses in patients with suboptimal response to Dara-VCd. This study will assess the efficacy and safety of Dara-based induction therapy followed with ASCT consolidation in AL amyloidosis.

Methods:This was a retrospective analysis comparing VD induction followed by ASCT (VD+ASCT) with Dara-based induction followed by ASCT (Dara-based +ASCT) in the treatment of patients with newly diagnosed AL amyloidosis. The median induction cycles were 4.

Results:A total of 22 patients with AL amyloidosis were included in the analysis between 03/2011 and 12/2023 in our center. Among these patients,16 patients were in VD+ASCT group and 6 patients were in Dara-based +ASCT group. The median age at diagnosis was 52.5(46.3-57) in VD+ASCT group and 59(54.5-62.3) in Dara-based +ASCT group. At diagnosis,73.3% (11/15) had Mayo 2004 stage I in VD+ASCT group, with 66.7% (4/6) having Mayo 04 stage I in Dara-based +ASCT group. There were 100% kidney involvement in both groups. At the end of induction therapy, the rate of hematologic CR was 37.5% (6/16) in VD+ASCT,66.7% in Dara-based +ASCT (P=0.348). Five of the sixteen patients (31.3%) with renal involvement achieved a renal response in VD+ASCT group, with 3 of the six patients (50%) in Dara-based +ASCT group(P=0.624) after induction therapy. The best hematologic response after ASCT was CR in 9(56.3%) patients treated with VD+ASCT, in 5(83.3%) patients with Dara-based +ASCT. Six of the sixteen patients (37.5%) achieved a renal response in VD+ASCT group, with 5 of the six patients (83.3%) in Dara-based +ASCT group after induction therapy. TRM in two groups were 0.

Conclusions:Dara-based regimen followed with ASCT is safe and can upgrade hematologic responses in carefully selected patients with newly-diagnosed AL amyloidosis.
Utilizing BTK Inhibitors for Maintenance and Long-Term Control Following CAR-T Cell Therapy in B-Cell Non-Hodgkin Lymphoma
Authors: Liu Rui , Yang Fan , Ma Lixia , Guo Yuelu , Fu Zhonghua , Deng Biping , Zheng Qinlong , Ke Xiaoyan , Hu Kai
Published: December 2024

Background:

Following chimeric antigen receptor (CAR)-T cell therapy, achieving long-term durability in approximately 30% to 40% of relapsed/refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL) cases remains a significant challenge. There is ongoing consideration that BTK inhibitors may serve as a potential option for maintenance therapy in these patients.

Methods:

A retrospective analysis was conducted on patients who were evaluated as remission (complete remission or partial remission) 3 months after CD19-CAR-T treatment, and were treated with BTKi maintenance therapy to observe the progression-free survival and overall survival of the patients.

Results:

From December 2019 to March 2024, a total of 37 patients were included in the study, with diagnoses comprising CNS lymphoma (14/37), CLL/Richter (5/37), MCL (2/37), DLBCL (14/37), and tFL (3/37). Of these patients, 43% (16/37) were male, with a median age of 52 years (range 21-74). Among them, 23 patients received zanubrutinib, while 14 received either Orelabrutinib or ibrutinib. NGS testing was conducted in 24 patients, revealing MYD88 and/or CD79B mutations in 8/24 cases. Median maintenance duration was 510 days (range 90-1370). Median follow-up time was 30.61 months, with only 2 patients experiencing relapse and 3 deaths recorded. Median progression-free survival (PFS) and overall survival (OS) were not reached. Comparing patients with and without MYD88/CD79B mutations, the 3-year PFS rates were 85.7% vs. 70% (p=0.375). Patients eligible for BTK inhibitors (CNS involvement, chronic lymphocytic leukemia, mantle cell lymphoma) compared to others(DLBCL and tFL) had 3-year PFS rates of 78.3% and 90% (p=0.230), respectively.

Conclusion:

BTK inhibitors could serve as maintenance therapy for patients achieving remission with B-NHL CAR-T within three months, with potentially greater benefits observed in those with the MCD genetic subtype.
Efficacy and Safety of Mosunetuzumab in Relapsed/Refractory Non-Hodgkin Lymphoma: A Systematic Review
Authors: Elemian Shatha , Habbas Ahmad , Jumean Samer , Al Omour Bader , Hamad Munther , Tan Jia Yi , Chan Kok Hoe , Guron Gunwant , Shaaban Hamid
Published: December 2024

Background:

Bispecific antibodies (BsAbs) represent a promising new class of immunotherapy for lymphoma treatment. mosunetuzumab, a CD20xCD3 T-cell engaging bispecific monoclonal antibody, directs T cells to eliminate malignant B cells. It was the first to receive approval for relapsed or refractory follicular lymphoma. This study evaluates the safety and efficacy of intravenous mosunetuzumab in various treatment regimens for relapsed/refractory non-Hodgkin lymphoma.

Methods:

A systematic literature search was conducted on PubMed using keywords “Mosunetuzumab” AND “lymphoma” from inception to January 1, 2024. Four non-randomized clinical trials (nRCTs, N=303) were identified and included in accordance with PRISMA guidelines.

Results:

In 4 clinical trials 303 patients were concluded, of which 186 patients were diagnosed with diffuse large B-cell lymphoma (DLBCL), and 117 patients were diagnosed with follicular lymphoma (FL), 98 patients with DLBL received mosunetuzumab plus polatuzumab vedotin, 80 patients with DLBCL received mosunetuzumab monotherapy, 90 patients with FL were treated with mosunetuzumab monotherapy, and 27 patients with FL received mosunetuzumab in combination with lenalidomide. 186 patients had diffuse large B-cell lymphoma (DLBCL), and 117 patients had follicular lymphoma. overall response rate (ORR), complete response (CR), and partial response (PR) were reported in 42%, 24%, 18% patients with DLBCL who received intravenous mosunetuzumab monotherapy respectively. ORR, CR, and PR were reported in 59%, 46% and 13% patients with DLCBL receiving mosunetuzumab plus polatuzumab vedotin. ORR, CR, and PR were reported in 72% 54% and 18% patients, respectively, treated with intravenous mosunetuzumab monotherapy in follicular lymphoma. ORR, CR, and PR were reported in 92%, 77% and 15% patients, respectively, treated with combination with lenalidomide in follicular lymphoma. Cytokine release syndrome (CRS) was the most common side effect occurred at any grade, neutropenia was the most common reported grade ≥3 followed by CRS, grade 3 or more of immune cell-associated neurotoxicity syndrome was limited.

Conclusions:

Mosunetuzumab in combination with lenalidomide demonstrated higher efficacy and good tolerability in patients with relapsed/refractory non-Hodgkin lymphoma, especially in achieving high response rates inFL. Intravenous mosunetuzumab monotherapy was active in both DLBCL and FL with low rates of toxicity and favorable safety profile. Long-term follow-up is necessary to assess durability of responses and overall safety and survival outcomes with these different treatment approaches.
Autologous hematopoietic stem cell transplantation may overcome the adverse impact of IKZF1 on the prognosis of B-ALL in CR1 with no detectable minimal residual disease
Authors: Wang Jiali , Ma Xiaoxiao , Zhang Rongli , Jiang Erlie
Published: December 2024

Purpose: Ikaros family zinc finger 1 (IKZF1) mutation may serve as a poor prognostic factor in B-cell acute lymphoblastic leukemia (B-ALL). This study explored the impact of autologous hematopoietic stem cell transplantation (auto-HSCT) on the outcome of B-ALL patients with IKZF1 alterations.

Methods: we detected the IKZF1 mutation at diagnosis in the bone marrow of adult patients with B-ALL, and analyzed the clinical data of these patients retrospectively.

Results: A total of 44 B-ALL patients in CR1 were enrolled in the study, including 12 recipients of auto-HSCT and 32 of allo-HSCT. Auto-HSCT demonstrated comparable 2-year overall survival (OS) (60% vs. 83.3%, p = 0.88) and leukemia-free survival rates (60% vs. 81.1%, p = 0.96) compared to allo-HSCT for patients with negative MRD. Additionally, there was no significant difference in the 2-year cumulative incidence of relapse (CIR) between auto-HSCT and allo-HSCT groups (38.9% vs. 19.5%, p=0.65), and non-relapse mortality (NRM) rates were lower in the auto-HSCT group at 0% compared to 13.2% in the allo-HSCT group (p=0.22). The treatment efficacy was evaluated from a model stratified on the risk classification and minimal residue disease (MRD) status after 1 or 2-3 chemotherapy cycles. The results revealed that after 1 cycle of chemotherapy, auto-HSCT showed promising 2-year OS(100% vs. 85.7% , p=0.35)and LFS rates(100% vs. 85% , p=0.35) , with no significant difference compared to allo-HSCT. Additionally, it displayed lower CIR and NRM(0% vs. 14.3%,p=0.35), indicating potential advantages. For MRD-negative patients after 2-3 cycles of chemotherapy, allo-HSCT may be more beneficial, as shown by the favorable 2-year OS(50% vs. 100%, p=0.018) and LFS rates(50% vs. 100%, p=0.0082), despite similar CIR(33.3% vs. 14.3%,p=0.11).

Conclusion: Auto-HSCT may be an attractive treatment for B-ALL patients of IKZF1 mutation with negative MRD after three chemotherapy cycles,especially after 1 cycle of chemotherapy. These findings provide valuable insights into the treatment efficacy of auto-HSCT and allo-HSCT in different MRD-negative patient subgroups, offering important implications for therapeutic strategies in this specific patient population.

Keywords: acute lymphoblastic leukemia, IKZF1, Allo-HSCT, Auto-HSCT,MRD
pkm2 Binds to the Regulatory Regions of Gata-1 and stat5 in β-Thalassemic Mouse Erythroblasts
Authors: Federti Enrica , Pietrobono Silvia , Riccardi Veronica , Ceolan Jacopo , Pozzetto Huot Richard , Mazzi Filippo , Kavaz Tolunay , Andolfo Immacolata , Russo Roberta , Melisi Davide , Iolascon Achille , De Franceschi Lucia
Published: December 2024

β-thalassemia is a worldwide distributed hereditary red cell disorder characterized by chronic anemia due to the combination of reduced red cell survival and ineffective erythropoiesis. Clinical management of β-thalassemic (β-thal) patients is primarily based on red blood cell transfusion and iron-chelation therapy. We previously showed increased expression of pyruvate kinase M2 (PKM2) in both mouse and human β-thal erythroblasts when compared to healthy ones, as a possible adaptative mechanism against chronic oxidation. Studies in other disease models have shown that PKM2 might acquire nuclear localization as phospho-PKM2 (p-PKM2, Ser 37), associating with different transcriptional factors such as GATA. Here, we analyzed sorted erythroid precursors (CD44+TER119+FscHigh cells) from bone marrow of wild-type (n=8) and Hbbth3/+ (β-thal, n=6) mice. In β-thal erythroid precursors, we found increased p-PKM2 when compared to wild-type erythroblasts. To better understand p-PKM2 distribution, we used immunomicroscopy with specific anti-PKR and anti-p-PKM2 antibodies. In both wild-type and β-thal erythroid precursors, PKR was similarly localized in the cytoplasm of erythroblasts. Conversely, we found increased amount of p-PKM2 as large clusters in the nucleus of β-thal erythroid precursors when compared to wild-type cells. To understand whether PKM2 binds to regulatory regions of erythropoiesis relevant genes, we performed Chromatin Immunoprecipitation (ChIP) assay using specific anti-PKM2 antibody in sorted erythroid cells from both mouse strains. In β-thal erythroblasts, PKM2 binds to site in the promoter regions of Gata1 and Stat5. We noted that in β-thal erythroid precursors, the binding of PKM2 on Gata1 promoter results in the upregulation of Gata1 expression, the association of PKM2 with that of Stat5 leads to Stat5 downregulation when compared to wild-type mice. In addition, PKM2- binding sites on Stat5 promoter appear to colocalize with NF-kB consensus motifs, suggesting a possible functional synergy between these two transcription factors. This is extremely interesting since STAT5 is involved in cell responsiveness to erythropoietin and GATA1 contributes to cell differentiation during erythropoiesis. Furthermore, the crosstalk between STAT5 and NF-kB suggests the possible involvement of pro-oxidant and pro-inflammatory pathways in β-thal ineffective erythropoiesis. In conclusion, in β-thal mouse erythroblasts we show for the first time nuclear compartmentalization of PKM2 when compared to healthy cells. Our data demonstrate that PKM2 binds to regulatory regions of Gata1 and Stat5. This later appears to synergize with NF-kB in β-thal mouse erythroblast, suggesting a novel crosstalk between STAT5 and NF-kB in ineffective β-thal erythropoiesis.
Homoharringtonine Combining with Azacitidine and Venetoclax (HAV) As First-Line Induction Therapy for Newly Diagnosed Adult Acute Myeloid Leukemia Patients
Authors: Lu Wenyi , Chen Xiangli , Zang Yuzhu , Zhu Zunmin , Zhang Wenhui , Bai Yanliang , Chen Yuqing , Jiang Li , Xing Yanyan , Liu Yuanbo , Shi Jie , Gao Zhenxing
Published: December 2024

The targeted therapy regimen of venetoclax combined with demethylating agents has demonstrated a complete remission (CR) rate of approximately 70% in elderly or unfit patients with newly diagnosed acute myeloid leukemia (AML). However, its efficacy in newly diagnosed fit AML patients has been unsatisfactory, leading to a lack of recommendation for this cohort. Recent reports suggest that combining venetoclax with homoharringtonine enhances its anti-leukemic effects, with promising results observed in refractory/relapsed AML cases. This study aims to evaluate the safety and efficacy of the homoharringtonine, azacitidine, and venetoclax (HAV) regimen in treating newly diagnosed adult AML.

This retrospective study analyzed newly diagnosed AML patients who received induction therapy with the HAV regimen at Henan Provincial People's Hospital from January 2021 to December 2023. The HAV regimen comprised homoharringtonine (2 mg/d, days 1-7), azacitidine (75 mg/m²/d, days 1-7), and venetoclax (100 mg on day 1, 200 mg on day 2, 400 mg on days 3-14). The primary endpoint was the composite complete remission rate (cCR) after one cycle of induction therapy (CR+CRi). Secondary endpoints included event-free survival (EFS), overall survival (OS), and adverse effects.

A total of 24 newly diagnosed adult AML patients were included, with a median age of 62 years (range: 28-82 years). According to the 2022 ELN risk stratification, 3 patients were classified as favorable, 11 as intermediate, and 10 as adverse-risk. After one cycle of induction with the HAV regimen, the cCR rate was 95.8%, and the MRD-negative CR rate was 62.5%. Safety analysis revealed that grade ≥3 adverse reactions included neutropenia in 23 patients (95.8%), thrombocytopenia in 22 patients (91.7%), anemia in 11 patients (45.8%), febrile neutropenia in 23 patients (95.8%), and pneumonia in 7 patients (29.2%). No treatment-related deaths occurred. The median follow-up time was 221 days, with a 1-year OS rate of 90% (95% CI: 76.9%-100%) and a 1-year EFS rate of 72.4% (95% CI: 51.6%-93.2%).

In conclusion, the HAV regimen is an effective and safe induction therapy for newly diagnosed AML patients, achieving a high complete remission rate. This regimen offers a promising treatment strategy for adult patients with newly diagnosed AML.
A Multiomic, Single-Cell Measurable Residual Disease (scMRD) Assay for Simultaneous Assessment of DNA Mutations and Surface Immunophenotypes in Acute Myeloid Leukemia
Authors: Thompson Kathryn , Geller Benjamin , Nousheen Lubna , Krishnan Indira , Wang Shu , Mendoza Daniel , Druley Todd E. , Sciambi Adam
Published: December 2024

The small population of cancerous cells that remain following treatment, known as measurable residual disease (MRD), is the major cause of relapse in acute myeloid leukemia (AML). Usually, these refractory cells have gained additional resistance mutations or changed their surface immunophenotypes in ways that preclude detection and phasing by current gold standard flow cytometry or bulk next-generation sequencing assays. For this reason, a multiomic single-cell MRD (scMRD) assay could offer a more comprehensive indicator of relapse and the potential for faster response. Here, we present a new scMRD assay with a 0.01% limit of detection that provides single-cell clonal architecture and immunophenotyping to not only identify residual leukemia cells, but also identify putative DNA or protein targets for novel biomarker insights. The assay enables rare-cell detection on a standard Mission Bio Tapestri® run by adding (i) an upfront enrichment for blast cells, (ii) a DNA and protein panel specifically designed for characterization of clonal architecture in AML MRD hotspots and biomarkers, (iii) an automated analysis pipeline to evaluate single-cell multiomics output, and (iv) multiplexing for simultaneous analysis of up to three patient samples in a single run via germline variant identification. By utilizing Mission Bio's technology for sequencing single cells, this pipeline can identify and correlate co-occurring de novo variants, thereby reducing false positive rates over bulk assays that do not correlate variants. Furthermore, it can create phylogenetic trees of the detected MRD cells and present their surface protein signature and arm-level copy number. To demonstrate assay features and reproducibility, surrogate MRD samples were constructed using positive control cell lines (expressing CD34 and CD117 markers) or diseased cells spiked into healthy bone marrow cells before processing them with the scMRD assay. We detected the 0.01% cell line spike-ins in 20 of 20 samples tested, with an average blast enrichment of 30.8x. We further applied the scMRD assay to bone marrow aspirate samples from AML patients and achieved 0.01% diseased cell spike-in detection. The scMRD assay resolved the genotype clonal architecture, identifying multiple leukemic clones with co-occurring mutations and readily distinguishing pre-leukemic from leukemic clones. The integration of genotype and immunophenotype further enhanced MRD detection by identifying genotype-specific protein expression patterns. By combining high reproducibility with multiomics, this assay offers a potential scalable solution for comprehensive MRD detection that could possibly guide patient stratification and therapeutic decision-making in the future.
RNA-Lnp-Mediated CAR-T Cell Manufacturing: A Paradigm Shift in Precision Immunotherapy
Authors: Sun Xiulian , Zhao Sheng , Wang Wei
Published: December 2024

The landscape of cancer treatment is being revolutionized by the advent of chimeric antigen receptor T (CAR-T) cell therapies, which harness the power of the immune system to target and eliminate cancer cells. Despite their remarkable therapeutic potential, the production of CAR-T cells remains a complex and personalized process, fraught with challenges such as genetic modification risks, manufacturing inefficiencies, and the need for scalable solutions. This study introduces a novel RNA-lipid nanoparticle (RNA-LNP) technology for the efficient and safe delivery of therapeutic RNAs, including messenger RNA (mRNA), circular RNA (circRNA), and self-amplifying RNA (saRNA), into T cells, thereby enhancing the manufacturing process of CAR-T cells.

Our methodology involves the generation of RNA-LNPs through a precisely controlled process, ensuring uniform particle size and RNA encapsulation efficiency. The RNA-LNPs are then complexed with the therapeutic RNAs and administered to T cells. The RNA-LNP technology offers several advantages over traditional CAR-T cell manufacturing methods, including the avoidance of genomic integration, reduced immunogenicity, and the flexibility to modulate the expression levels of therapeutic proteins. The RNA-LNP system is designed to encapsulate and protect the fragile RNA molecules, facilitating their delivery into T cells with high efficiency. The encapsulated mRNA enables rapid and transient expression of the CAR protein, circumventing the need for permanent genetic alteration. This approach significantly reduces the risk of off-target effects and potential genotoxicity associated with viral vector-based gene therapies. Furthermore, the inclusion of circRNA in the RNA-LNP formulation provides a stable and enduring source of CAR transcripts with reduced immunogenicity, potentially extending the therapeutic window and safety of the treatment. To augment the functionality of the engineered CAR-T cells, saRNA is employed to further expand the existence period of CAR transcripts and therapeutic window by its self-amplifying capability. In this study, we compared the CAR expression and functional CAR-T cells among different types of RNA.

The RNA-LNP-mediated delivery of therapeutic RNAs represents a paradigm shift in the field of CAR-T cell therapy. It simplifies the manufacturing process, enhances the safety profile of the treatment, and provides a versatile platform for the development of next-generation cell-based immunotherapies. Our findings pave the way for a more accessible, efficient, and personalized approach to cancer treatment, offering renewed hope to patients and clinicians alike.
Triple-Drug Regimen for Naïve MDS and AML Patients: Efficacy and Safety of Chidamide, Azacitidine, and Venetoclax in a Prospective Multicenter Study
Authors: Zhang Min , Zhao Miaomiao , Ge Renying , Cao Xie-Na , Xue Mei , He Jing , Zhong Zhaodong , Fu Xin
Published: December 2024

Purpose:Treatment options for myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) patients remain limited, underscoring the need for novel, more effective therapeutic strategies. This prospective, open-label study evaluated the efficacy and safety of a triple combination regimen comprising chidamide, azacitidine, and venetoclax (VAC regimen) in treatment-naïve patients with these hematologic malignancies.

Patients and Methods: Sixteen newly diagnosed patients (6 MDS, 10 AML) with an average age of 57.9 years were treated with the VAC regimen consisting of chidamide, azacitidine, and venetoclax. The primary endpoint was overall response rate (ORR). Secondary endpoints included complete remission (CR) rate, event-free survival (EFS), overall survival (OS), and safety/tolerability.

Results: The ORR was 93.8%, with a remarkable CR rate of 87.5% (CR in 12 patients, CRi in 2 patient). Rapid hematologic recovery was observed, with a median time to tri-lineage recovery of 15 days. The 6-month EFS and OS rates were 80.8% and 81.8%, respectively, demonstrating promising survival outcomes. Three MDS patients underwent allogeneic stem cell transplantation following remission.All participants experienced AEs, predominantly non-hematological in nature. The frequent non-hematological AEs included infections (notably pneumonia), nausea, fatigue, vomiting, hypokalemia, hypoalbuminemia, and febrile neutropenia, with most of these being mild or moderate (grade 1/2).Given the adverse event (AE) data, the VAC regimen demonstrated an acceptable safety profile.

Conclusions: The VAC regimen demonstrated exceptional efficacy and an encouraging safety signal in treatment-naïve MDS and AML patients. These promising results highlight the potential of this novel triple combination as a frontline therapeutic option warranting further investigation in larger randomized trials.