bluuebunny/crossref_metadata_2025 huggingface dataset:
Elevated Dosing of Recombinant Human Thrombopoietin Accelerates Platelet Engraftment in Allogeneic Hematopoietic Stem Cell Transplantation: A Prospective, Dosage-Optimization, Controlled Clinical Study
Authors: Feng Dan , Liu Qingzhen , MA Qiaoling , Jiang Erlie
Published: December 2024

Objective: The optimal dosage of recombinant human thrombopoietin (rhTPO) for enhancing platelet engraftment following allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains undefined. We have crafted a prospective, dose-exploration, controlled clinical study to evaluate the effectiveness and safety of escalating doses rhTPO in facilitating platelet engraftment post-transplantation.

Methods: The study encompassed 57 individuals undergoing allo-HSCT. Commencing day +1 post-transplantation, patients were administered rhTPO therapy. The experimental group, comprising 27 patients, received a continous daily dosage of 22500 U of rhTPO until platelet engraftment was achieved. While the control group, consisting of 30 participants, was given a continuous daily dosage of 15000 U of rhTPO，also until platelet engraftment occurred.

Results: Patients in the experimental group, who received 22,500 U/day rhTPO, achieved a significantly earlier median time to platelet engraftment compared to the control group (12 vs. 13 days, P=0.042, z=4.142) and reached platelet counts of ≥30×109/L more rapidly (13 vs. 16 days, z=3.936, P=0.047). There was a noticeable trend in the experimental group towards earlier attainment of higher platelet thresholds of 50×109/L, 75×109/L, and 100×109/L (15 vs. 20 days, 18 vs. 22 days, 22.5 vs. 28 days). No instances of delayed platelet engraftment were noted in either group. By day 21, the cumulative platelet engraftment rate stood at 96.3% for the experimental group and 83.3% for the control group. By day 60, both groups had achieved a full 100% engraftment rate. Additionally, the experimental group experienced an earlier median time to neutrophil engraftment (11 vs. 12.5 days, z=4.534, P=0.033). During the follow-up period, both groups showed a 100% one-year overall survival rate. The one-year relapse-free survival rates were 96.3% for the experimental group and 93.3% for the control group, indicating no significant disparity. Notably, the cumulative incidence of moderate to severe acute graft-versus-host disease (aGVHD) was significantly lower in the experimental group (14.8% vs. 40.0%, P=0.043). Safety assessments, encompassing evaluations of adverse events such as thrombosis and bleeding, confirmed that the higher dosage of rhTPO was both safe and reliable.

Conclusion: Escalating the dosage of rhTPO injections demonstrates a safe and efficacious approach to enhancing platelet engraftment in patients following allo-HSCT. This strategy not only accelerates the recovery of platelet levels but also contributes to the overall therapeutic regimen without compromising patient safety.
Fatty Acid Synthase (FASN) Maintains Leukemogenesis By Suppressing Progranulin-Engaged Lysosomal and Inflammatory Signaling
Authors: Su Meng , Lv Zhiyi , LU Yating , Xie Xinshu , Ouyang Jie , Zhong Pengcheng , Sheng Yue , Huang Yong , Mei Yang
Published: December 2024

Cancer cells rely on lipogenesis in addition to the exogenous lipid up-taking, in which the lipogenic enzyme fatty acid synthase has aberrant over-expression in various cancers, including myeloid leukemia. However, the precise role of FASN in the leukemogenesis remains elucidative. Here, by genetic manipulation of FASN in vitro and in vivo, we demonstrated that FASN was essential for leukemogenesis. Ablation of FASN either by RNA interference or CRISPR-Cas9 knockout impeded the leukemic cell growth, survival, clonogenicity in vitro and leukemic burden in vivo. The absence of FASN minimally affected normal hematopoiesis but significantly attenuated or delayed leukemic progression in the oncogenic MLL-AF9 leukemia mouse model, leading to prolonged animal survival. By screening a library of platensimycin derivatives, we identified compound MS-C19 as a potent FASN inhibitor, which is superior to Orlistat or TVB-3166. Pharmaceutical targeting FASN by MS-C19 suppressed leukemic cell growth, clonogenicity and cell survival and induced myeloid differentiation in both leukemia cell lines and clinical AML blasts. Mechanistically, both MS-C19 insult and FASN deficiency triggered the activation of lysosomal and inflammatory gene expression. Depletion of Progranulin, a lysosomal and neuroinflammatory gene, in the presence of FASN depletion, significantly reverted the inhibition of leukemic cell growth, survival, and clonogenicity caused by FASN knockdown. Thus, mammalian FASN could be a therapeutic target for myeloid leukemia, and inhibition of FASN by the lead compound MS-C19 provides a promising approach for leukemia intervention.
Metabolic Rewiring of AML-Experienced Hematopoietic Stem and Progenitor Cells
Authors: Chen Ding-Wen , Wafula Eric K. , Schrey Julie M. , Fan Jian-Meng , Adams Sarah , Jung Seul K , Taylor Deanne M , Kurre Peter
Published: December 2024

Relapse is the leading cause of mortality in acute myeloid leukemia (AML). Inflammation is linked to disease prognosis in AML, but its role in remission and relapse are not well understood. Inflammation is also a known regulator of hematopoietic stem and progenitor cells (HSPCs), and recent studies identified an unexpected role in their long term innate immune reprogramming.

We recently reported in a murine model of AML that residual healthy HSPCs contribute to the inflammatory bone marrow (BM) microenvironment. In additional interim pilot studies, we adoptively transferred “AML-experienced” HSPCs (HSPCAML) to naïve recipients, followed 16 weeks later by a lipopolysaccharide (LPS) challenge. Bulk RNA-Seq from these HSPCAML revealed significant transcriptional changes compared to a control cohort. To further test whether HSPCAML develop a long-term innate immune memory of sterile inflammation in the AML BM niche, we turned to a clinically relevant inducible model of KMT2A AML (MLL-AF9). We generated chimera by co-transplanting BM from inducible (i)MLL-AF9 transgenic mice (CD45.1; rtTA+/+ hMLL-AF9-IRES-NGFR+/+) and WT mice (CD45.1/2) into WT recipients (CD45.2). This provides a dynamic fully tractable model where leukemia exposure of healthy HSPC and remission can be dynamically controlled in vivo via doxycycline (DOX).

Recent studies in experimental infection have defined altered immunometabolism as a key component of inflammatory HSPC immune reprogramming. We induced AML for 5 weeks (on DOX), followed by 4 weeks off DOX, and harvested FACS-purified HSPCAML (CD45.1/2+ NGFR- Lin- cKit+ Sca1+) to perform a real-time metabolic function assay (Seahorse). Results showed elevated basal extracellular acidification rate (ECAR) indicative of heightened basal glycolysis in HSPCAML. Consistent with this observation, RNA-Seq analysis of HSPCAML from identically prepared cohorts revealed 3974 differentially expressed genes (DEGs), with gene set enrichment for glycolysis pathways. Models of trained immunity (TI) indicate that memory generation is epigenetically imprinted, and ATAC-Seq analysis of HSPCAML revealed a significant increase in differentially accessible regions in HSPCAML. Through GSEA analysis of differentially accessible promoters and enhancer regions, we observed enrichment for inflammation and metabolic related pathways in HSPCAML. Lastly, by subjecting chimeric animals off DOX to LPS challenge, we found enrichment of tumor necrosis factor (TNF) associated gene sets in HSPCAML via RNA Seq analysis, demonstrating a heighten inflammatory response consistent with trained cells.

Altogether, our data suggest that sterile inflammation in the AML BM niche trains healthy HSPC through a process of immune reprogramming, consistent with a model whereby leukemia may durably alter hematopoietic function.
Pola-R-CHP Regimen Exhibited a High Response Rate and Good Treatment Tolerability for Newly Diagnosed Double-Expressor Lymphoma
Authors: Zhao Xia , Liu Zhihe
Published: December 2024

Background:

Double-expressor lymphoma (DEL) is characterized by the overexpression of C-MYC and BCL2 proteins without underlying chromosomal rearrangements. Although it is not classified as a distinct entity in the current World Health Organization classification, DEL accounts for 20% to 30% of diffuse large B-cell lymphoma (DLBCL) patients. Currently, the prognosis for DEL patients remains poor despite receiving R-CHOP or R-EPOCH regimens as first-line chemotherapy.

Aims:

This study aimed to assess the clinical efficacy and treatment tolerance of the Pola-R-CHP regimen in DEL patients.

Methods:

In this study, newly diagnosed DEL patients were recruited from our hospital in China between June 2023 and April 2024. The cut-off values for C-MYC and BCL2 protein expression were defined as greater than 40% and 50%, respectively. Clinical information, overall response rates, and adverse events of all patients were collected. The Pola-R-CHP regimen consisted of polatuzumab vedotin (1.8 mg per kilogram of body weight), plus intravenous rituximab (375 mg per square meter), cyclophosphamide (750 mg per square meter), liposomal doxorubicin (30 mg per square meter) on day 1 of each cycle, and oral prednisone (100 mg once daily) on days 1 through 5 of the first six cycles.

Results:

Twenty-three newly diagnosed DEL patients were enrolled, with a median age of 68 years (range 37-79 years). The male-to-female ratio was 11:12. According to the Ann Arbor stage, 78.3% of patients were in stages III/IV, and 52.2% had an International Prognostic Index (IPI) score ≥3. Additionally, 69.6% had at least two extranodal lesions, commonly involving the spleen, gastrointestinal tract, kidneys, adrenal glands, uterus, and ovaries. White blood cell count, hemoglobin, and platelet levels were generally normal. Elevated levels of lactic dehydrogenase and β2 microglobulin were observed in 60.9% and 65.2% of patients, respectively. Based on Hans's algorithm, 82.6% of patients were classified as non-GCB. The median Ki-67 value was 80% (range 60%-95%), and three patients were CD5 positive. P53 protein expression greater than 50% was observed in 69.6% of patients. All patients completed at least three cycles of the Pola-R-CHP regimen. The overall response rate (ORR) was 91.3%, with a complete response rate (CRR) of 47.8% at the end of the third cycle. By the end of treatment, the ORR was 83.3%, and the CRR was 72.2%. The common adverse events of this Pola-R-CHP regimen were hematologic toxicities, and 43.5% of patients exhibited grade 3/4 granulocytopenia after three cycles.

Conclusion:

The Pola-R-CHP regimen demonstrated high response rates and good tolerability in patients with DEL, establishing it as an effective therapeutic option.
IM2 Regimen Is Effective and Safe for Relapsed or Refractory T-Cell Lymphoblastic Lymphoma/Leukemia
Authors: Tang Shixuan , Niu Jiahua , Xia Xinxin , Huang Chongmei , Qiu Huiying , Zhang Ying , Xu Xiaowei , Shen Chang , Wei Yu , Yang Jun , Zhou Kun , Tong Yin , Cai Yu , Dong Baoxia , Wan Liping , Song Xianmin
Published: December 2024

Patients with refractory or relapsed (R/R) T-cell lymphoblastic lymphoma/leukemia (T-LBL/ALL) typically exhibit poor responses to salvage chemotherapy, leading to a dismal prognosis. IM2 as a novel salvage regimen for R/R T-LBL/ALL, which is composed of Ifosfamide, liposome Mitoxantrone or Idarubicin, and Methotrexate, was retrospectively assessed for its efficacy and safety. Total 23 patients were enrolled into the study, which included 13 diagnosed as LBL and 10 as ALL. Among the cohort, 78% were male, 48% presented with mediastinum giant mass. Following 1 to 6 cycles of IM2, 7 patients (30.4%) achieved complete remission (CR), 7 (30.4%) achieved partial remission (PR), resulting in a best overall response rate (ORR) of 60.8%. Treatment-related adverse events (AEs) were observed in 91% of patients, with no treatment-related deaths. With a median follow-up time of 7 months (range, 2-50 months), the median OS and PFS of all the patients were 9 months and 5 months, respectively. The estimated 2-year OS and PFS were 39.2% and 37.2%. The median survival for patients achieving CR after IM2 was 24 months (range 6-50 months), with 1-year overall survival (OS) and progression-free survival (PFS) rates of 87.5% and 77.8%, respectively. Multi-variate Cox analysis revealed that allogeneic peripheral blood stem cell transplantation (allo-PBSCT) after IM2 therapy was an independent favorable prognostic factor for OS and PFS. The study suggested that IM2 regimen might be an effective and safe choice for R/R T-LBL/ALL.
Pola-R-CHP Regimen for Frontline Therapy in Diffuse Large B Cell Lymphoma with High-Risk Factors
Authors: Zhao Xia , Liu Zhihe
Published: December 2024

Background:

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of malignant tumors. Currently, the first-line R-CHOP chemotherapy regimen can cure approximately 60% of DLBCL patients, but about 40% still experience refractory or relapses. Further studies have found that patients with refractory or relapses often present with high-risk factors at initial diagnosis, such as high international prognostic index (IPI), extranodal involvement, double-expressor lymphoma (DEL), and double-hit lymphoma.

Aims:

This study aimed to evaluate the clinical efficacy and treatment tolerance of the Pola-R-CHP regimen for DLBCL patients with high-risk factors.

Methods:

We enrolled newly diagnosed DLBCL patients with high-risk factors who were treated with Pola-R-CHP as the first-line regimen at our hospital in China between April 2023 and May 2024. In this study, high-risk factors included an IPI >2, DEL, P53 protein overexpression (>50%), and extranodal involvement >2 at diagnosis. We collected clinical information, overall response rates, and adverse events for all patients. The Pola-R-CHP regimen included polatuzumab vedotin (1.8 mg/kg), rituximab (375 mg/m²), cyclophosphamide (750 mg/m²), liposomal doxorubicin (30 mg/m²) on day 1 of each cycle, and prednisone (100 mg orally, once daily) on days 1 through 5 of each of the first six cycles.

Results:

Forty-seven newly diagnosed DLBCL patients with high-risk factors were eventually enrolled, with a median age of 68 years (range 33-79). The male-to-female ratio was 1.1:1.0. Based on the Ann Arbor staging system, 78.7% of patients were classified as stage III/IV, and 61.7% had an IPI >2. Additionally, 48.9% of patients had at least three extranodal lesions, with the spleen, gastrointestinal tract, kidneys, adrenal glands, and bone marrow, being the most commonly involved organs. Furthermore, 66.0% of patients had B symptoms. White blood cell count, hemoglobin, and platelet count were nearly normal across all patients, while high levels of lactic dehydrogenase and β2 microglobulin were found in 63.8% and 61.7% of patients, respectively. According to the Hans algorithm, 76.6% of patients were in the non-GCB group, and the median Ki-67 value was 80% (range 60%-95%). Five patients were CD5 positive, and 48.9% were diagnosed with DEL. Among the cohort, 53.2% of patients exhibited expression greater than 50%. All patients completed at least three cycles of the Pola-R-CHP regimen. The overall response rate (ORR) was 93.6%, with a complete response rate (CRR) of 48.9% at the end of the third cycle. By the end of treatment, the ORR was 89.7%, and the CRR was 76.9%. The most common adverse events were hematologic toxicities, with 36.1% of patients experiencing grade 3/4 granulocytopenia after three cycles.

Conclusion: The Pola-R-CHP regimen showed high response rates and good tolerability in DLBCL patients with high-risk factors, proving it to be an effective therapeutic option.
T(11;14) with Multiple Myeloma: Standard Risk Survival but Slow and Poor Response
Authors: Liu Yuntong , Qiu Lu-Gui , An Gang
Published: December 2024

Introduction:

Presence of t(11;14) on plasma cells is considered a standard-risk prognostic factor per IMWG risk-stratification. However, recent studies suggest inferior PFS and OS observed among t(11;14) patients relative to the standard-risk myeloma patients.

Methods:

This study aimed to evaluate the impact of t(11;14) in newly diagnosed multiple myeloma (NDMM) patients on treatment response rate, response kinetics, and survival based on mutually exclusive risk groups. We describe 790 patients with newly diagnosed myeloma treated with available baseline FISH data (within 90 days post-diagnosis) from January 2010 until June 2021, including 99 patients with t(11;14) alone, 58 with t(11;14) plus other high-risk cytogenetic abnormalities [t(11;14)+HR] including chromosome 1 abnormalities [C1A1, including gain/amp1q and/or del(1p)] and/or del(17p), 224 standard-risk (SR) patients without t(11;14) and 409 in the high-risk cytogenetic abnormality (HRCA) group including t(4;14), t(14;16), t(14;20), C1A1 and/or del(17p) but without t(11;14).

Results:

Our study have showed NDMM patients in the t(11;14)alone group had similar PFS (49.3 vs. 50.7 months; P= 0.392) and OS (112.4 vs. NR months; P= 0.982) as those in the SR patients, but had a significantly worse response than the SR group (t(11;14)alone vs. SR: ≥VGPR 72.9% vs. 85.2%, P= 0.011; ≥CR 50.0% vs. 66.8%, P= 0.005; MRD- 60.0% vs. 76.0%, P=0.009). Paradoxically, depth of response does not seem to be significantly associated with better survival in the t(11;14)alone group (PFS: < VGPR vs. CR, P=0.235, MRD- vs. MRD+, P= 0.159; OS: <VGPR vs. CR, P=0.256, MRD- vs. MRD+: P= 0.082). Response kinetics analyses showed that the t(11;14)alone group had a significantly slower time to response than the other subgroups (t(11;14)alone vs. SR vs. HRCA: median time to VGPR=4.93 vs. 3.01 vs. 2.63 months; P< 0.05; median time to MRD negativity= 9.19 vs. 4.25 vs. 4.27 months; P<0.001).

Conclusion:

The slow rate of response may explain the paradoxical relationship between poorer depth of response and standard risk survival outcomes, suggesting the need for individualised therapeutic strategies for this group of patients. On the other hand, t(11;14) coexistence does not provide a survival benefit for high-risk genetic patients. Patients with t(11;14) plus other high risk cytogenetic abnormalities requires early and more aggressive treatment options, such as BCL-2 inhibitors.
Caplacizumab in the Treatment of Thrombotic Thrombocytopenic Purpura: A Systematic Review and Meta-Analysis of Observational Studies
Authors: Khan Salman , Karmani Vikash Kumar , Ali Aizaz , Khan Malik W.Z. , Ahmad Muhammad , Niazi Muhammad , Qandil Hamzah , Yetiskul Ekrem , Khamis Zaid , Araji Ghada , Sarkis Tyler , Mohan Preet , Afif Sarah
Published: December 2024

Introduction: Thrombotic Thrombocytopenic Purpura (TTP) is an uncommon thrombotic disorder characterized by the formation of platelet-rich microthrombi due to a reduction in ADAMTS13 levels. Caplacizumab has surfaced as a viable therapeutic alternative. Consequently, we conducted a thorough review and meta-analysis to evaluate caplacizumab in the management of TTP.

Method: We conducted a systematic review and meta-analysis in accordance with PRISMA guidelines, searching PubMed, Google Scholar, and Cochrane CENTRAL databases from inception to December 2023. The evaluated outcomes included Time to normalization of platelet count, Days of Plasma Exchange, Length of Hospitalization, Relapses, Exacerbations, and Refractory Disease. Additionally, we included patients who had undergone at least one therapeutic plasma exchange. The Review Manager software was utilized to perform the meta-analysis, wherein risk ratios (RR) were calculated, 95% confidence intervals were ascertained, and statistical significance was established as a p-value <0.05. The presence of variation between studies was evaluated using X2 tests and I2 statistics.

Results: We screened 4064 articles and included 7 observational studies (925 patients). Our meta-analysis indicated that TTP patients treated with caplacizumab achieved a statistically insignificant reduction in the duration needed to achieve normal platelet counts (RR= 0.70; 95% CI= 0.44 - 1.14), number of days of plasma exchange (RR= 0.69; 95% CI= 0.36 - 1.32), length of hospitalization (RR= 0.84, 95% CI = 0.53 - 1.34), refractory disease (RR= 0.48, 95% CI= 0.19 - 1.17), and exacerbations (RR= 0.33, 95% CI= 0.09 - 1.14). However, there was an insignificant rise in the relapse rate (RR= 1.03; 95% CI= 0.38 - 2.80) as compared to the control group.

Conclusion: In summary, our study demonstrates that adding caplacizumab to standard TTP therapy significantly reduces the time to achieve normal platelet counts, shortens the duration of plasma exchange, minimizes hospitalization, and lowers the rates of refractory disease and exacerbations. These findings highlight the effectiveness of caplacizumab in improving key clinical outcomes for TTP patients.

Keywords: Caplacizumab; Meta-analysis; Platelet count; Relapse; Thrombotic Thrombocytopenic Purpura
Tislelizumab in Combination with Chidamide, Prednisone, Etoposide, and Lenalidomide Followed By Autologous Stem Cell Transplant in Patients with Relapsed or Refractory Hodgkin Lymphoma
Authors: Wang Yawen , Xue Hongwei
Published: December 2024

Background

Approximately 10% to 30% of Hodgkin lymphoma (HL) patients suffer primary refractory or disease relapse (R/R). Our objective is to assess the efficacy and safety of tislelizumab in combination with chidamide, prednisone, etoposide, and lenalidomide (T-CPEL) as an introductory treatment following autologous hematopoietic stem cell transplantation (ASCT) or tislelizumab combined with bendamustine (TB) as consolidation in R/R HL.

Methods

Patients with R/R classic HL (cHL) who received T-CPEL regimen were included in our retrospective cohort study.

Results

Between January 2020 and December 2022, a total of 11 patients with R/R cHL were enrolled in our project. The average number of previous systemic therapies was 2 (range 1-6). All patients received at least four cycles of the T-CPEL regimen as an introductory treatment. There was an overall response rate (ORR) of 90.9%, with a complete remission (CR) rate of 36.4%. Five eligible patients underwent ASCT after receiving TB, while six ineligible patients only received TB consolidation therapy. The median follow-up was 21.6 months, and the expected three-year progression free survival (PFS) and overall survival (OS) rate were estimated to be 81.8% and 100.0%, respectively. During the introduction regimen of T-CPEL, 14 adverse events were recorded, most of which were grade one or grade two. No treatment-related deaths or discontinuation occurred.

Conclusion

The salvage therapy consisting of tislelizumab plus CPEL demonstrated both effectiveness and tolerability in treating R/R cHL cases. Furthermore, following ASCT or TB therapy, there was an increased likelihood for achieving a cure.
Efficacy and Safety of Prophylactic Use of Peg-Rhg-CSF before CAR-T Cell Infusion in MM Patients
Authors: Xu Jintao , Guo Dan , Hong Lemin , Lu Jinfeng , Li Bingzong , Hongming Huang
Published: December 2024

Background:Infection caused by leukopenia is an important complication of CAR-T cell therapy, and there is no unified consensus on the use of CSF during CAR-T therapy. It is not clear whether the prophylactic use of PEG-rhG-CSF can alleviate leukopenia and reduce the chance of infection, or whether it may increase the risk of CRS and ICANS.

Aims:We explore the efficacy and safety of prophylactic use of PEG-rhG-CSF before CAR-T cell reinfusion in MM patients, in order to provide some data support for the application of PEG-rhG-CSF in CAR-T cell therapy.

Methods:We studied 30 patients with MM who received anti-BCMA CAR-T cell or anti-BCMA and CD19 CAR-T cell therapy (ChiCTR2000033567). Patients received FC pretreatment from days -4 to -1 and were infused with 1-2*106/Kg CAR-T cells. Among them, 11 patients received PEG-rhG-CSF 3-6 mg on day 0, and 19 patients did not receive PEG-rhG-CSF. The response status, incidence of CRS and ICANS, incidence and duration of neutropenia and agranulocytosis, and antibiotic use of the two groups were analyzed.

Results:There was no significant difference in the remission rate above VGPR within 3 months after reinfusion between the PEG group and the non-PEG group (72.73% vs. 78.95%, p=1.000). The incidence of CRS in the two groups was 1 case in stage I, 1 case in stage II, 1 case in stage III, and 1 case in stage IV in the PEG group, and 2 cases in stage II and 1 case in stage IV in the non-PEG group. ICANS occurred in 1 case in each group. There was also no significant difference in the incidence of neutropenia (90.91% vs.100%, p=0.367). The incidence of agranulocytosis in PEG group was significantly reduced (27.27% vs. 73.68%, p=0.023), and the duration of agranulocytosis was significantly shorter than that in the control group (mean 1.36 vs. 5.89, p=0.013). There was no significant difference in the antibiotic usage rate (63.64% vs. 73.68%, p=0.687), which included preventive drugs such as SMZ-CO and acyclovir.

Conclusion:This study showed that the prophylactic use of PEG rhG CSF in MM patients before CAR-T cell therapy could shorten the degree and duration of neutropenia without aggravating the occurrence of CRS, and reduce the risk of severe infection. This provides certain data support for guiding the application of PEG-rhG-CSF in CAR-T cell therapy for MM patients.
Transcriptomic Analysis Shows a Common Multi-Organ Inflammatory/Complement Signature in Hemolysis-Induced Damage
Authors: Peliconi Julie , Lavergne Julien , Brochier Camille , Guinot Florent , David Tovo , Roumenina Lubka T , Grunenwald Anne
Published: December 2024

Introduction: Intravascular hemolysis is a major contributor to tissue injury in transfusion reactions, hemoglobinopathies such as sickle cell disease (SCD) and hemolytic anemias. The release of hemoglobin and heme, usually confined to red blood cells, leads to oxidative stress, endothelial activation, and a prothrombotic and pro-inflammatory phenotype. Nevertheless, the underlying mechanism is not fully understood.

Methods: To understand the organ injury in hemolytic conditions, we used RNAseq to explore the transcriptomic changes of lung, spleen, liver and kidney in a mouse model of hemolytic crisis triggered by phenylhydrazine injection. We analyzed immune cell influx by MCP counter and the impacted biological pathways by Gene Set Enrichment Analysis (GSEA). As complement was one of the common enriched pathways in all tested organs of the hemolytic mice accompanied by C5a elevation in plasma, we expressed and validated a recombinant version of the mouse C5 inhibiting antibody BB5.1 and tested it in the mouse model. The transcriptional response to complement inhibition was assessed by Quantigene (80-gene plex).

Results: Phenylhydrazine-induced hemolysis caused dysregulation of the renal (165 DEG, differentially expressed genes), pulmonary (521), hepatic (704) and splenic (1696) transcriptomes. GSEA analysis revealed an enrichment of gene sets linked to xenobiotic metabolism, reflecting heme degradation, cell death, cell cycle arrest, metabolic reprogramming and inflammatory pathways related to TNFa, IL6 and IL2, as well as the complement system. Indeed, C5a plasma levels in phenylhydrazine-treated mice were increased. Inhibition of C5 with BB5.1 (1g/mouse) reduced C5a release and attenuated the inflammatory response to hemolysis, particularly in the lung.

Conclusion: Here we provide the first transcriptomic signature atlas of mouse organs with intravascular hemolysis, underpinning a key role of inflammation, oxidative stress and metabolic reprogramming and complement activation. These findings support further exploration of complement-targeted therapies to ameliorate hemolysis and preserve organ function in SCD patients.
Safety and Efficacy in Pediatric Patients with Relapsed/Refractory Classic Hodgkin Lymphoma Enrolled on an Intergroup Randomized Phase II Study of the Combinations of Ipilimumab, Nivolumab and Brentuximab Vedotin (E4412)
Authors: Forlenza Christopher J. , Jegede Opeyemi , Ansell Stephen M. , Steidl Christian , Natkunam Yasodha , Scott David W. , Mehta-Shah Neha , Amengual Jennifer E. , Cole Peter D. , Kahl Brad S. , Diefenbach Catherine S.
Published: December 2024

Background: The Phase 1/2 ECOG-ACRIN sponsored intergroup trial E4412 (NCT01896999) investigated brentuximab vedotin (BV) combined with the checkpoint inhibitors nivolumab (N) and ipilimumab (I) in patients with relapsed or refractory classic Hodgkin lymphoma (R/R HL). Here we present the safety and efficacy results for the cohort of pediatric patients aged 12-17 years. Methods: Patients were randomly assigned to treatment with the doublet of BV/N or triplet of BV/N/I, with the following dosing: BV 1.8mg/kg every 21 days for up to 16 cycles; Nivolumab 3mg/mg every 21 days for up to 34 cycles; Ipilimumab 1mg/kg every 9 weeks for up to 9 doses. Response evaluation by PET/CT was performed after 4 cycles. Transplant-eligible patients with CR could discontinue protocol therapy to receive a consolidative autologous stem cell transplant (ASCT). Results: Sixteen pediatric patients with a median age of 16 (range 12-17) were randomized. 75% of patients had received only 1 prior line of treatment with none having previously received BV and only 1 patient with prior ASCT. All patients were treated (8 in each arm) and included in the pediatric safety analysis cohort receiving at least one cycle of therapy. There were four reported grade (gr) 3 or greater toxicities: lymphopenia (gr 3) and neutropenia (gr 3) on the BV/N arm; and neutropenia (gr 4) and rash (gr 3) on the BV/N/I arm. Rash of any grade was more common in patients treated with BV/N/I (n=6) compared to BV/N (n=1). Peripheral sensory neuropathy was reported in 2 patients (BV/N, gr 2, n=2) There were no grade 5 toxicities. Fourteen patients (7 in each arm) were evaluable for response. The CR rate on both the BV/N and BV/N/I arms was 100%. The median survival follow up was 23.7 months (15.7 - 31.7). The 24-month PFS was 57% for BV/N and 100% for BV/N/I. Six patients (2 BV/N; 4 BV/N/I) discontinued protocol therapy to receive a consolidative ASCT. The 24-month PFS for patients consolidated with an ASCT was 100%, with all events occurring in patients randomized to BV/N, but not receiving an ASCT. Conclusion: Pediatric patients receiving both BV/N and BV/N/I had 100% CR rate with limited toxicity. Although this is a small cohort, there have been no progression events observed in patients treated with BV/N/I, including 3 patients treated without a consolidative ASCT.
Immune Reconstitution Following Allogeneic HSCT in Hematological Diseases
Authors: Naseeb Summaira , Ahmed Parvez , Nasir Shahzad , Zahur Umar , Mahmood Syed Karman , Chaudhry Brig Qamar Un N , Ur Rahman Khalil , Peter Hina , Fatima Mehroz
Published: December 2024

Objective: To evaluate immune reconstitution following allogeneic hematopoietic stem cell transplantation

Study Design: Retrospective cohort study

Place and Duration of the Study: Department of Bone Marrow Transplant, Quaid-e-Azam International Hospital Islamabad, Pakistan; from January 2023 to January 2024.

Methodology: We evaluated 50 adult and pediatric patients undergoing allogeneic HSCT for malignant and nonmalignant diseases from year 2022 to 2023. Absolute lymphocyte count, lymphocyte subsets and immunoglobulin levels were performed at 6 and 12 months post-transplant. Patients who did not have complete medical records or faced graft failure/rejection before 6 months post-transplant were excluded from the study.

Results:

In our study absolute lymphocyte count recovery was observed in 94% of patients on D+180 that increased to 100% on D+365. The average number of cells being 2599.84/μL (SD=1281.742) and 2926.96 μL (SD=1065.378) on D+180 and D+365 respectively. By day 180 post-transplant, 84% of patients had achieved CD3+CD8+ recovery, while CD16+CD56+ and CD19+ cell recovery was seen in 74% and 56% cases respectively. Day +180 CD3+CD4+ recovery was seen in only 8% patients that increased to 21% by day +365. Normal lymphocyte recovery values at day 365 post-transplant were: CD3+CD8+ in 84% patients, CD16+CD56+ and CD19+ cells in 78% patients. Early CD3+CD4+ recovery was seen in patients with age <18 years, non-malignant diseases and with no or minimal GVHD but the values were not statistically significant. Age adjusted normal immunoglobulin levels for IgG, IgM and IgA by day +180 were achieved in 92%, 90% and 84% patients while after 1 year 98%, 90% and 96% patients had normal levels of IgG, IgM and IgA respectively. Patients receiving CD34+ dose >5 x 106/kg had significantly early neutrophil engraftment (p=0.025); mean 11.40 days (SD 1.67) versus 13.76 days (SD 1.43) for CD34 dose ≤ 5 x 106/kg.

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Conclusion: Majority of the patients achieved normal immunoglobulin levels and lymphocyte subsets by day 180 post HSCT while CD3+CD8+ T cell recovery was seen in 8% and 21% patient by day 180 and 365 post-transplant, respectively.

Key Words: Hematopoietic stem cell transplant, lymphocyte subsets, immune reconstitution
Safety and Efficacy of Allogeneic NKG2D NKR-NK for Acute Myeloid Leukemia
Authors: Zhou Li , Shen Haihao , Fang Fang , Zhang Ming , Hu Zuhong , Wu Congmiao , Tao Qianshan , Li Yingwei , Wu Fan , Pan Ying , Wang Zhitao , Xiao Weihua , Zhai Zhimin
Published: December 2024

Objective: CAR-T cells have shown significant clinical efficacy in treating acute lymphoblastic leukemia, but their effectiveness in treating patients with acute myeloid leukemia (AML) is limited, necessitating the exploration of alternative treatments. Theoretically, compared to CAR-T cells, CAR-NK cells possess more favorable toxicity profiles, particularly in mitigating adverse effects such as cytokine release syndrome and graft-versus-host disease. However, issues regarding the in vivo proliferation and long-term survival of CAR-NK cells remain unresolved, typically requiring large-dose infusions. Our study tested the safety of infusing high-dose NKG2D NKR-NK cells into AML patients.

Methods: NK cells from healthy donors were transduced into NKG2D NKR-NK cells and expanded in vitro. The cytotoxicity of NKG2D NKR-NK cells against peripheral blood progenitor cells from AML patients was validated in vitro. The safety and antitumor efficacy were further confirmed in severely immunodeficient NCG mice and in xenograft AML mouse models. Additionally, NKG2D NKR-NK cells were intravenously infused into clinical trial participants to observe their in vivo antitumor activity and safety, using a dose-escalation approach to determine the maximum safe dose.

Results: NKG2D NKR-NK cells exhibited high cytotoxicity against AML-targeted cells in vitro (90% killing rate for K562 cells, 60% for HL-60 cells, and 8% for KG-1 cells). In the xenograft AML mouse model, NKG2D NKR-NK cells significantly reduced tumor burden, demonstrating strong antitumor effects. Intravenous infusion of NKG2D NKR-NK cells into AML patients did not result in any observable severe adverse effects, confirming the safety of NKG2D NKR-NK cells in the treatment of four patients at the current maximum single dose of 3.1×109 cells.

Conclusion: Our data indicate that NKG2D NKR-NK cells are effective and safe in vitro and in mouse models, and are safe in four AML patients.
Allo-Reactable Lymphocytes Collected Early Phase in Cord Boold Transplant Can be Used As Cell Source for Donor Lymphocyte Infusion
Authors: Zong Sa , Bu Chaoke , Liu Nan , Chen Cunming , He Yuelin , Li Chunfu
Published: December 2024

Background: Approximately 5%-37% of patients develop persistent thrombocytopenia following hematopoietic stem cell transplantation (HSCT). One of therapy is donor lymphocyte infusions (DLI). But in cord blood (CB) transplant (CBT), DLI is difficult because of donor lymphocytes unavailable. We hypothesized peripheral lymphocytes collected early phase (PLCEP) in CBT still retain allo-reaction and may be used as cell source for DLI. Here, we reported the first case with PLCEP-DLI.

Objective: To prove the effect of PLCEP-DLI.

Methods: Lymphocytes were collected in early phase in CBT as DLI cell source, and the DLI was given when the patient has thrombocytopenia.

Case report: A 2 year old boy, with body weigh of14.8kg, was diagnosed with thalassemia major at the age of 8 months, and then, began to receive regular infusion. He received dual HSCT from haploidentical donor combined with matched CB in August 2021, with conditioning regimen comprised of BU+CY+TT+Flu+ATG. CB stably engrafted finally.

At day 685 after HSCT, the patient was re-admitted due to “subcutaneous hemorrhagic spot for 2 weeks”. The routine blood test showed that neutrophils were 5.69*10e9/L, hemoglobin 112g/L, and platelets 2*10e9/L. Cells in peripheral blood (PB) sourced from cord blood in 100%. Anti-platelet and anti-HLA antibodies were positive (4+), with 0.4% red cell fragments and rare platelets on PB smear. Scanning of viruses, such as CMV, EBV, ADV, and B19 was negative. Direct and indirect Coomb's tests were negative.

Immune thrombocytopenia was diagnosed and drugs (IVIg, steroid, Rituximab Eltrombopag, and intravenous TPO) were given. In spite of short respondence and negative anti-platelet and anti-HLA antibodies, platelets were still low (1-8*10e9/L) along with hyperplasia marrow and 110 megakaryocytes on bone marrow smear. On day 700 after transplant, the patient received PLCEP-DLI with CD3+ cells of 4.94*10e6/kg following lymphocyte-depleted therapy of Flu (30mg/ m2 *3d) and CY (200mg/ m2 *1d) and immunosuppressant discontinuation.

On day 6 after DLI, skin rash appeared and disappeared after Ruxolitinib. The platelets recovered to 20, 50 and 123*10e9/L on day 9, 20, and 27, respectively. Up to June 30, 2024 (1048 days after HCT), the platelet was normal.

Summary: The case showed PLCEP-DLI was effect. which could effectively correct the immune thrombocytopenia in post-CBT. Allo-reactable lymphocytes collected early phase in CBT can be used as cell source for post-CBT DLI, however, the result of the case need to be proved in more cases in the future.
Progression of Disease within 24 Months (POD24) Based Prognostic Signature: A New Method for Personalized Risk Assessment in Patients with Mantle Cell Lymphoma
Authors: He Yizi , Wang Caiqin , Li Yajun , Zeng Ruolan , Xia Chen , Li Yixue , Xiao Ling , Zhou Hui
Published: December 2024

Background

Mantle cell lymphoma (MCL) is an uncommon lymphoproliferative disorder with extremely heterogeneous in both biological and clinical aspects. Its diverse clinical presentations necessitate a personalized prognostic model to stratify patients into subgroups with distinct survival outcomes.

Methods

Recognizing the limitations of existing models in capturing disease complexity, we utilized clinical and molecular data from nine Chinese medical centers to validate the progression of disease within 24 months (POD24) and to develop a novel prognostic risk model to predict the survival outcome of MCL patients.

Results

POD24 was observed in 37.7% of evaluable patients (369/979), with a significantly shorter median overall survival of 21 months compared to 122 months for those without POD24 (P < 0.0001).Patients with POD24 were more likely to present with B symptoms (P = 0.003), elevated lactate dehydrogenase (LDH) levels (P < 0.0001), splenomegaly (P < 0.0001), Ki-67 expression (P < 0.0001), and a poorer performance status (P = 0.005). Additionally, they were more likely to have undergone autologous stem cell transplantation (ASCT) (P = 0.037). The POD24-based risk model （POD24 ,age, LDH level, MIPI score, splenomegaly, Ki67 expression and ASCT）demonstrated the highest sensitivity for predicting survival, with an impressive area under the curve (AUC) for the risk score of 0.869.

Conclusion

Our study confirms the robust predictive power of POD24 and introduces a novel risk model that integrates POD24 with clinical factors. Our new prognostic model might be helpful to effectively classify MCL patients with high-risk groups in terms of survival rate, which may help select high-risk MCL patients for more intensive treatment at time of relapse. This novel developed model greatly improved the prognostic predictive accuracy, which could be used to individualize the survival outcomes of patients and has the potential translation into clinical practice in the future.
Immunoglobulin Light Chain Renal Amyloidosis Patients with t(11;14) Have Much More Possibility to be Present As Nephrotic Syndrome
Authors: Liu Menghan , Geng Chuanying , Gao Wen , Chen Wenming , Yang Guangzhong
Published: December 2024

Immunoglobulin Light Chain Renal Amyloidosis patients with t(11;14) have much more possibility to be present as nephrotic syndrome

Introduction：Systemic immunoglobulin light chain (AL) amyloidosis is a clonal plasma cell disorder characterized by organ dysfunction secondary to deposition of misfolded light chains. Approximately 70% of patients with AL amyloidosis have renal involvement presented with heavy proteinuria or nephrotic syndrome and can progressed to end-stage renal disease. We sought to explore the clinical characteristics and outcomes between patients presenting with or without nephrotic syndrome.

Methods:

A total of 37 patients of newly diagnosed AL amyloidosis with renal involvement between 2015/9/26 and 2023/11/30 were included in this single-center, retrospective observational study. The diagnosis of AL amyloidosis was confirmed by tissue biopsy. Exclusion criteria included known as prior AL amyloidosis related treatment, multiple myeloma, baseline end-stage renal disease, dialysis or renal transplant. Demographic and clinical characteristics, FISH results, along with outcomes including best hematologic response, renal response and overall survival (OS) were assessed. The definition of both hematological response and renal response was based on the International Myeloma Working Group (IMWG) criteria

Results：

37 participants were included for statistical analyses, including 24（64.9%）patients with nephrotic syndrome (AN group) and 13 patients（35.1%）without nephrotic syndrome (AM group). The two groups share a similar incidence rate of cytogenetic abnormalities, while the prevalence of t(11;14）was significantly higher in AN group than AM group (62.5% vs. 46.2%, p=0.027). Although the small number of patients with renal stage III (n=2) were enrolled, which were all classified in AN group.

Regardless of treatment regimen, there was no difference between the two groups in terms of hematologic remission. Compared with the AN group, a significantly higher proportion of deep renal remission （≥VGPR）were observed in AM group (53.8% vs. 20.8%, p＜0.001). Meanwhile, we classified the patients into four subgroups according to the different treatments, including bortezomib-based, melphalan-based, dara-based and others regimen groups. No statistical significance was found comparing different treatment groups due to the small sample size.

The median follow-up of the patients was 52.3 months. There was a tendency for the AM group to have longer OS compared with the AN group, but no statistical significance was achieved（75% vs. 61.5%，p =0.312），which needed to be confirmed in an cohort with expanded sample sizes.

Conclusions:

Nephrotic syndrome was more likely to be presented in AL amyloidosis patients with t(11;14), leading to a relatively poor organ response to chemotherapy.
Risk Stratification for Diffuse Large B-Cell Lymphoma Integrating Interim 18f-FDG PET-CT Analysis and the National Comprehensive Cancer Network IPI: A Multicentre Retrospective Study
Authors: Wang Jiesong , Wang Xianhuo , Zhang Huilai
Published: December 2024

The treatment of diffuse large B-cell lymphoma (DLBCL) requires an accurate interim assessment of therapeutic effect. The prognostic evaluation of interim 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography-computed tomography (PET-CT) remains controversial. Our objective was to assess the prognostic significance of the interim National Comprehensive Cancer Network International Prognostic Index (iNCCN-IPI) and PET-CT-related parameters in predicting patient outcomes and to achieve accurate risk stratification. In this study, we retrospectively analysed the clinicopathological and PET-CT data of 498 patients diagnosed with DLBCL across three medical centres in China. The change in total lesion glycolysis (ΔTLG), the iNCCN-IPI, interim abdominal residual disease (iARD) status, and the change in the maximum standardized uptake value (∆SUVmax) were identified as independent prognostic factors via univariate and multivariate Cox regression analyses. The prognostic significance of these variables was corroborated via machine learning classifiers. Based on the results of multivariate analysis, we developed a prognostic model, iPET-NCCN-IPI, which stratifies DLBCL patients into two distinct prognostic risk groups. The predictive performance of the model was validated by calculating the area under the receiver operating characteristic curve (AUC) and the C-index via the bootstrap resampling method. Additionally, compared with the Deauville score, iPET-NCCN-IPI demonstrated superior prognostic capability, distinguishing potentially poor prognostic outcomes among patients with a Deauville score of 3. In conclusion, we demonstrated that the NCCN-IPI and PET-CT-related parameters at interim evaluation are independent prognostic factors for DLBCL patients. Compared with the Deauville score, the newly developed prognostic tool iPET-NCCN-IPI has superior prognostic predictive ability and can be used to identify patients with potentially poor prognoses among those with a Deauville score of 3.
Divergent Prognostic Factors in High-Risk Vs. Standard-Risk Elderly Patients after Allo-HCT for AML/MDS
Authors: Guo Wenwen , Cao Yigeng , Jiang Erlie
Published: December 2024

Allogeneic hematopoietic cell transplantation (allo-HCT) is increasingly relevant for elderly patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) due to expanding eligibility. How to improve the prognosis of this patient group remains challenges. This retrospective analysis enrolled 254 patients aged 50-65 who underwent allo-HCT after myeloablative conditioning (MAC) regimens in the past decade. Patients were stratified into high- and standard-risk groups based on their pretransplant disease status and measurable residual disease (MRD) level. In the standard-risk group (n=79), older age (≥55 years) and higher hematopoietic cell transplantation-specific comorbidity index (HCI-CI) scores (≥2) were associated with worse leukemia-free survival (LFS) (hazard ratio [HR], 1.76, p = 0.030; HR, 2.34; p = 0.006) and overall survival (OS) (HR, 1.78, p = 0.032; HR, 2.53, p = 0.003). However, age and HCT-CI scores were not associated with prognosis in high-risk patients. In the high-risk group (n=175), normal/underweight body mass index (BMI < 24 kg/m2) was associated with worse LFS (HR, 2.30; p = 0.007) and OS (HR, 2.94; p = 0.001). Therefore, older age and higher HCT-CI scores were associated with clinical outcomes in standard-risk elderly patients. Meanwhile, the pretransplantation BMI and transplantation type significantly influenced the outcomes of high-risk patients.