bluuebunny/crossref_metadata_2025 huggingface dataset:
R-Squared (R2) – How much variation is explained?
Authors: Gao Jian
Published: December 2023

Linear regression is a simple yet powerful tool that has been extensively used in all fields where the relationships among variables are of interest. When linear regression is applied, the coefficient of determination or R-squared ( R2) is commonly reported as a metric gauging the model’s goodness of fit. Despite its wide usage, however, R2 has been commonly misinterpreted as the proportion or percent of variation in the dependent variable that is explained by the independent variables (PVE -- percent of variation explained). This study demonstrated R2 substantially overstates the true PVE. When the assumptions of linear regression are met, R2 overstates PVE by up to 100%. For instance, when R2 is 0.99, 0.80, 0.50, or 0.10, the true PVE is 0.9, 0.55, 0.29, or 0.05, respectively. The misinterpretation of R2, which greatly exaggerates the effect of the interventions or causes on the outcomes, could exert undue influence on clinical decisions in medicine and policy decisions in other fields such as environmental protection and climate change research. Therefore, when linear regression is applied, reporting the true PVE is warranted.
Machine Learning Models for Hematogone Enumeration and Differentiation between Hematogones and Leukemic-Blasts in B-Acute Lymphoblastic Leukemias
Authors: Liu Xiaolong Sean
Published: December 2023

Background:

Hematogone (htg) counts are usually low in bone marrows but often increase in reactive or neoplastic conditions. When increased, htgs resemble leukemic-blasts in B-lymphoblastic leukemias (B-ALL) phenotypically. The differentiation between htgs and leukemic-blasts is critical as hematogone counts in marrows with reactive conditions may increase around or beyond B-ALL leukemic-blast diagnostic level and, conversely, leukemic-blast counts may be low in some B-ALL marrow samples. Additionally, current hematogone enumeration by the gating approach is operator dependent.

Objective:

To enumerate htgs and differentiate htgs from leukemic-blasts using machine-learning (ML) models.

Research Methods:

Cases with reported htgs (CReH), B-ALL, and controls (548, 124, and 771 marrow samples, respectively) were selected using key word search from historical flow cytometry (FC) results. Datasets for analysis were from FC-panel: FS_SS_CD5_CD10_CD20_ CD19_CD45.

Three preliminary models, the htg enumeration model (HEM), immature cell enumeration models for B-lineage (IEM_B), and htg similarity model (HSM), were used (data not published). HSM classified a given htg-population or leukemic-blast-population into three categories: Htg-p (htg-population), Borderline, and non-Htg-p.

Results:

HEM distinguished CReHs with median 530 from the controls with median 5 (figure 1). Only six (<1%) of the controls had >500 htgs.

IEM_B was used for separating hgt-populations in CReHs or leukemic-blast-populations in B-ALL cases from other cell populations. HSM classified 100 (95.2%) out of 105 hgt-populations from CReHs (≥1000 htgs) as Htg-p, and, due to fluorescence intensity downward shift, 4 as non-Hgt-p and 1 as Borderline. Conversely, HSM classified 113(92%) out of 123 leukemic-blast-populations from B-ALL as non-Hgt-p, 6 (5%) as Hgt-p and 4 (3%) as Borderline. Multiple scatter plots (figure 1a) illustrate two-dimensional distributions of a leukemic cluster classified as non-Hgt-p in a B-ALL case compared with those of a standard hematogone cluster.

Conclusion:

In an experimental setting, HEM is an efficient/high-throughput alternative for hgt-enumeration with high-consistency and is operator-independent. In the majority of B_ALL cases, HSM was able to differentiate leukemic-blast-populations from htg-populations. Future models will use additional markers, including leukemia-specific ones, to increase models' specificity.
Efficacy and Safety of Single Versus Tandem Autologous Stem Cell Transplantation in Multiple Myeloma: A Single-Center Retrospective Analysis in China
Authors: Qiu Zongjian , Li Xiaofan , Zhan Rong , Li Nainong
Published: December 2023

Background: Currently, there is a lack of comparative data on the efficacy and safety of single or tandem ASCT in China. This study aimed to review the efficacy and safety of single or tandem ASCT in MM patients without selection criteria for specific studies.

Methods: Utilizing matched case-control study, we retrospectively analyzed the clinical data of 80 newly diagnosed MM (NDMM) patients who underwent ASCT in our department between November 2014 and June 2021, with 40 patients in each group receiving either single or tandem ASCT.

Results: In single ASCT group, the percentage of ≥CR before or post ASCT was 50% and 70%, respectively. In tandem ASCT group, the percentage of ≥CR pre ASCT was 47.5%, while the percentage of ≥CR after 1 st and 2 nd ASCT was 65% and 85%, respectively. From 1 st transplantation, the median progression-free survival (PFS) was 33.2 and 71.1 months for the single and tandem arm, respectively (P=0.0099), and the median overall survival (OS) for the single and tandem arm was 38.3 and 75.8 months, respectively (P=0.0519). In the single and tandem group, 7-year PFS was 29.9% and 57.0%, while 7-year OS was 26.3% and 43.5%, respectively. The median PFS was 23.2 and 61.2 months for the single and tandem arm in patients with high risk (P=0.038), while the median OS was 32.4 months and 65.8 months, respectively (P=0.045). No transplant-related mortality occurred in both cohorts. The median times to neutrophil and platelet engraftment for single group were 11 days and 13 days, respectively. In the tandem group, the median times to neutrophil engraftment post 1 st and 2 nd transplantations were 11 days and 12 days, respectively, while the mean engraftment times for platelets were 12 days and 17 days. Mucositis, engraftment syndrome, and infection were common but manageable complications.

Conclusion: Upfront tandem ASCT could deepen the depth of response and prolong PFS in MM patients and could be performed feasibly and safely in patients with myeloma, especially when novel agents are not available in China.
Identification of HLA Class I Alleles in Patients with Paroxysmal Nocturnal Hemoglobinuria with Different Clone Sizes
Authors: Zhang Zhuxin , Hu Qinglin , Zhuang Junling , Han Bing
Published: December 2023

Introduction Paroxysmal nocturnal hemoglobinuria (PNH) is a hematological disease characterized by complement-mediated hemolysis, thrombosis, and bone marrow failure. Human leukocyte antigen (HLA) evolutionary divergence and mutations were widely analyzed in aplastic anemia (AA). However, there were few studies in PNH thus far.

Methods Patients with newly diagnosed PNH at Peking Union Medical College Hospital (PUMCH) were recruited from April 2019 to April 2021 according to International PNH Interest Group standards. They were analyzed the genotypes of classical HLA class I loci (A, B, C) using whole-exome sequencing (WES). Patients were further stratified into four groups according to the clone size (Group A: <10%; Group B: 10% ≤ to ≤50%; Group C: 50% < to ≤80%; Group D: >80%) to identify the association between HLA class I alleles and PNH clone size.

Result Samples from 40 patients were enrolled, including 20 classic PNH and 20 bone marrow failure (BMF)/PNH. There were 29 males and 11 females. The median age was 32 years (range, 16-70). The median PNH clone size measured by flaer-granulocyte ratio was 72% (range 1-99%). Among the 59 identified alleles in PNH, HLA-B genotypes, which were reported to be associated with severe AA, accounted for the highest percentage (46%). A*02:01, the most common one and found in all the four groups, was reported as one of the risk alleles overrepresents in AA. The alleles found in group A were significantly different from those in group B, C, and D ( P = 0.004, 0.006, and < 0.001, respectively). But there was no significant difference between B, C, and D groups ( P > 0.05). 47% of the alleles identified in group A were reported in AA, whereas only 26%, 23%, and 26% of the detected alleles in Group B, C, and D were reported in AA, respectively. The other alleles in B, C, D groups were mainly for the susceptibility of autoimmune diseases or drug-related adverse reactions. Among them, HLA-B*46:01, the most common and found in B, C and D groups, may indicate weak antigen presentation and immune ability. B*44, B*57:01, C*07:01 were unique in Group B, B*38:02 were identified in Group C and HLA-B*27 expressed most in Group D, which were mainly on cell survival, drug hypersensitivity, and complement activation.

Conclusion

Significantly different alleles were observed between PNH with smaller clone sizes (< 10%) and PNH with larger clone sizes (≥10%). Patients with smaller clone sizes had similar HLA class Ⅰ alleles to AA; whereas those with larger clone sizes had numerous unique alleles which may contribute to the pathogenesis of PNH.

Keywords: paroxysmal nocturnal hemoglobinuria, human leukocyte antigens, clone size, class I allele, pathogenesis
Characteristics of Coronavirus Disease in Allogeneic Hematopoietic Stem Cell Transplantation during the Omicron Wave: A Single-Center Study
Authors: Zhu Panpan , Yang Luxin , Liu Lizhen , Lai Xiaoyu , Shi Jimin , Zhao Yanmin , Yu Jian , Fu Huarui , Ye Yishan , Wu Yibo , Huang He , Luo Yi
Published: December 2023

This study outlined the clinical characteristics, outcomes, and risk factors for coronavirus disease 2019 (COVID-19) of 492 patients with allogeneic hematopoietic stem cell transplantation (allo-HSCT) during the Omicron wave. The median follow-up of the whole cohort was 62 days. The commonest underlying disease were myeloid malignancies (58.5%) and acute lymphocytic leukemia (30.5%). Of the 492 patients, 415, 67, and 10 had mild, moderate, and severe COVID-19, respectively. The incidence of moderate-to-severe COVID-19 was 15.7% (77/492). The 60-day overall survival and complete resolution rates were 98.1% and 80.6%, respectively. Risk factors for moderate-to-severe COVID-19 were corticosteroid use within 3 months before diagnosis (Odds ratio [OR], 2.115; 95% confidence interval [CI], 1.262-3.546; P=0.004), interval between allo-HSCT and coronavirus disease diagnosis <6 months (OR, 2.234; 95% CI, 1.259-3.969; P=0.006), and anti-thymocyte globulin use for graft-versus-host disease prophylaxis (OR, 3.450; 95% CI, 1.040-11.444; P=0.043). In conclusion, during the Omicron wave, patients with allo-HSCT had a low coronavirus disease-related mortality, and there was a high rate of moderate-to-severe disease and prolonged disease. Prevention in the early post-transplantation period is critical for allo-HSCT recipients receiving corticosteroids.
Efficacy Evaluation of a Tetracyclic Triterpene Compound Targeting Multiple Apoptosis Proteins for the Development of a Multiple Myeloma Treatment
Authors: Kim Hye Ran , Lee Young Eun , Lim Ha Jin , Choi Yong Jun , Park Joo Heon , Shin Jong Hee , Park Chang Soo , Shin Myung Geun
Published: December 2023

Introduction:Multiple myeloma (MM) is an incurable hematologic cancer that originates in plasma cells and occurs primarily in older patients over 60. This study screened for hit compounds for MM treatments targeting mitochondria and apoptosis proteins. Further, non-clinical testing, including molecular docking analysis, was performed.

Methods: Based on our previous studies, candidate compounds targeting mitochondria were screened (www.medchemexpress.com). The killing effect of the compounds on MM cell lines (RPMI8226, IM9, and U266) was examined using a sulforhodamine B assay. Apoptosis mechanisms were investigated in vitro. Complex immunocompromised mice were established by injecting RPMI8226-RFP-FLuc cells through the tail vein. Efficacy of the KBB-N2 activity was assessed following intraperitoneal (15 or 30 mg/kg/day) and tail vein (7 mg/kg/day) infusions for three days a week at daily intervals. Toxicity, pharmacokinetics, and molecular docking analyses were performed according to the established protocols.

Results: The hit compound, KBB-N2, a tetracyclic triterpene, was identified as an MM-targeted compound with cytotoxic effects. The primary mechanism of action of KBB-N2 in MM cells was inhibiting the activity of the mitochondrial electron transport (ETC) complex, resulting in the generation of excess intracellular reactive oxygen species (ROS), which led to tumor cell death by ROS-mediated apoptosis. In addition, exposure to KBB-N2 inhibited the activity of catalase, a powerful antioxidant enzyme in MM cells. Severe suppression of normal hematopoietic stem cell function was observed with lenalidomide administration at a concentration of 25 μM. However, this toxicity was not observed when KBB-N2 was administered at doses up to 60 μM. KBB-N2 activity involves PARP cleavage and caspase activation in the apoptotic pathway. Furthermore, KBB-N2 inhibited cell growth and exerted cytotoxicity. KBB-N2 induced apoptosis by activating the P53 apoptosis pathway in MM cells. In vivo, all untreated tumor-bearing mice showed rapid tumor growth and severe plasmacytomas, which led to death within seven weeks. Mice treated with KBB-N2 had significantly inhibited tumor growth and longer survival times. The molecular docking assay revealed the optimal docking conformation binding energy of KBB-N2 with docking scores (kcal/M) of -7.3 and -9.8 for ETC complexes I and III, respectively.

Conclusions: The triterpene compound, KBB-N2, was identified as a hit compound and may act as a targeted agent for MM treatment. The antimyeloma activity of KBB-N2 involves interference with the ETC complex and leads to MM cell death.
CD19/CD22 CAR T-Cell Therapy Following Autologous Transplantation Is an Optimizing Strategy in Relapsed/Refractory Central Nervous System Lymphoma
Authors: Yu Qiuxia , Gang Daizi , Wang Jue , Huang Liang , Li Chunrui , Zhang Yicheng , Zhou Xiaoxi , Cao Yang
Published: December 2023

Background and Objectives: Relapsed/refractory (R/R) primary and secondary central nervous system lymphomas (PCNSL, SCNSL) are associated with short survival and represent an unmet need, requiring novel effective strategies.

Methods: We retrospectively compared the safety and efficacy of CD19/22 CAR T-cell therapy combined with HDT-ASCT (ASCT+CAR-T group), CD19/22 CAR T-cell cocktail therapy (CAR-T group) and targeted drugs combined with chemotherapy (Targeted drugs group) in treating R/R CNSL patients.

Results: The median age of the Targeted drugs group is older than that of the other two groups, 73.3%, 100% and 41.2% patients were secondary CNS lymphoma in ASCT+CAR-T group, CAR-T group and Targeted drugs group, respectively. The incidence of Grade 3/4 hematological toxicities in ASCT+CAR-T and CAR-T group was more than Targeted drugs group. Patients in two CAR-T therapy group exhibited comparable incidence and severity of CRS and ICANS. The ORR was 83.3% in ASCT+CAR-T group, 64.3% in CAR-T group and 58.8% in Targeted drugs group respectively (Figure 1). As of December 31, 2022, the median follow-up time after therapy was 15.53 months (range, 0.53-50.53 months). The median duration of OS and PFS was not reached in the ASCT+CAR-T group. The median PFS and OS in the CAR-T group were 3.07 months and 9.67 months, respectively. In the Targeted drugs group, the median PFS and OS were 6.63 months and 12.30 months, respectively. The 1-year PFS and OS rate of the patients in the ASCT+CAR-T group (66.67% and 76.52%) was significantly higher than that of the patients in the CAR-T group (18.75% and 50%) ( P=0.0006 and P=0.0253) and targeted drugs group (17.65% and 52.94%) ( P=0.0004 and P=0.0358) (Figure 1). In both univariable and multivariate analysis, PD before treatment was indicated worser PFS (HR: 3.134, 95% CI, 1.144 to 8.587, P=0.026), rather than OS, both in ASCT+CAR-T and CAR-T group and compared with CAR-T group, patients received ASCT+CAR-T treatment had better PFS (HR: 0.279, 95% CI, 0.120 to 0.651, P=0.003), rather than OS. PFS and OS of patients with PD before treatment, patients with ECOG ≥2, with high risk factors, and with＞3 prior lines of therapy in the ASCT+CAR-T group were superior to CAR-T group (Supplementary Figure 1). In the ASCT+CAR-T group, PFS, rather than OS, of patients without systemic disease in the ASCT+CAR-T group was superior to those with systemic disease ( P=0.0335).

Discussion: Our results support the development of CAR T -cells in R/R CNSL. With the durability of remission and low toxicity, ASCT combined with CART therapy appears to be a more effective and safe treatment option for primary and secondary relapsed/refractory CNS lymphoma.
Update of Swatch Study: Selinxor Combined with Lenalidomide and Rituximab (R2) in Adults with Diffuse Large B Cell Lymphoma (DLBCL) and Indolent Non-Hodgkin's Lymphoma (iNHL)
Authors: Wang Li , Li Zhiming , Zhang Lina , Zhang Liling , Mei Jay , Zhao Wei Li
Published: December 2023

Background：

Patients (pts) with relapsed/refractory (R/R) DLBCL and iNHL who are ineligible for, or relapse after, high-dose chemotherapy (HDC)/autologous stem cell transplantation (ASCT) have a poor prognosis and limited treatment options. Selinexor, a selective inhibitor of nuclear export has received accelerated approval by the U.S. Food and Drug Administration, for the treatment of adult patients with R/R DLBCL. Phase I/II study (NCT05265975), selinexor in combination with lenalidomide and rituximab (R2) for R/R DLBCL and iNHL, is ongoing. Phase I results were previously reported at ICML 2023 (Weili Zhao et al., ICML 2023, #658) and the recommended phase 2 dosing (RP2D) was determined.

Aims:

Here we update the preliminary results of SWATCH study.

Methods：

Additional 6 subjects will be recruited at this dose level 60mg to further confirm the safety and tolerability of RP2D. Eligible pts were treated with 6 cycles of rituximab (375mg/m2 on day 1), lenalidomide (25mg on d1-10) and selinexor (dose level: 60mg, on days 1, 8,15 of each 28-day cycle), followed by selinexor and lenalidomide maintenance until disease progression. Dose limiting toxicities (DLT) was defined as the occurrence of severe toxicities during the first cycle: grade 3 febrile neutropenia> 5 days, grade 4 neutropenia or thrombocytopenia >7 days, grade 3/4 thrombocytopenia with hemorrhage, or any grade 3 non-hematologic toxicity >7 days.

Results:

From May 2022 to April 2023, 16 pts were enrolled and no DLT occurred. At baseline in these 16 pts, refractory to last line was 93.75% and primary refractory was 68.75%. Among 12 efficacy evaluable pts, 3 pts achieved complete response (CR), 5 pts achieved partial response (PR) and another 4 pts achieved progressive disease (PD). Most AEs were grade 1 or 2 and were reversible with supportive care or dose modification. At data cutoff (June 1, 2023), 7 pts were still receiving treatment and no pts came off study due to intolerability or AEs. Median PFS and median DOR were 11.2 months and not reached.

Conclusion：

Selinexor in combination with lenalidomide and rituximab showed encouraging preliminary efficacy and generally tolerable toxicity with an ORR of 66.7%, CR of 25% and median PFS 11.2 months in all evaluable dose level pts, and with an ORR of 80% and CR of 20% in evaluable selinexor 60mg dose (RP2D). This study is currently enrolling patients in the dose expansion group.
A Predictive Model Combining Clinical Characteristics and Nutritional Risk Factors for Overall Survival after Umbilical Cord Blood Transplantation
Authors: Tu Meijuan , Huang Aijie , Ning Lijuan , Tang Baolin , Zhang Chunli , Sun Guangyu , Wan Xiang , Song Kaidi , Yao Wen , Qiang Ping , Wu Yue , Zhu Xiaoyu
Published: December 2023

Background: Umbilical cord blood transplantation (UCBT) is a curable therapy for hematological disease; however, the impact of nutritional status on UCBT outcomes remains controversial. To evaluate the joint effect of clinical characteristics and nutritional status on the prognosis of patients who underwent UCBT, we screened various factors to establish a predictive model of overall survival (OS) after UCBT.

Methods: We performed an integrated clinical characteristic and nutritional risk factor analysis and established a predictive model that could be used to identify UCBT recipients with poor OS.

Results : Four factors, including disease status, conditioning regimen, calf skinfold thickness and albumin level, were identified and used to develop a risk score for OS, which showed a positive predictive value of 84.0%. A high-risk score (≥2.225) was associated with inferior 3-year OS post-UCBT [67.5% (95% CI, 51.1%-79.4%), P=0.001]. Then, we built a nomogram based on the four factors that showed good discrimination with a C-index of 0.833 (95% CI, 0.743-0.922). Internal validation was performed by using the bootstrap method (corrected C-index:0.804). Multivariate analysis suggested that a high calf skinfold thickness (≥20.5mm) and a low albumin level (<33.6g/L) conferred poor disease-free survival (DFS).

Conclusion: The predictive model combining clinical and nutritional factors could be used to predict OS in UCBT recipients, which may promote preemptive treatment.
Human Single Domain Antibody-Based CAR-T Cells Targeting BAFF-R Demonstrate Promising Preclinical Activity in B Cell Malignancies
Authors: Zhang Cuiling , Luo Qian , Wu Sungui , Xu Le , Wei Qiaoe , Zhang Yanying , Guan Chaoyang , Dong Xiaoqing , Tan Taochao , Chen Bing
Published: December 2023

Background: B-cell activating factor-receptor (BAFF-R) is a potential B-cell specific target, highly expressed in B cell malignancies and regulates B cell proliferation and survival. Single-chain antibody-based CAR-T cells targeting BAFF-R (PMB101) has demonstrated antitumor effects against human B cell malignancies and can overcome CD19 antigen loss (Qin et al. Sci Transl Med. 2019;11(511)). However, CARs built on antigen-specific single chain antibody variable fragment (scFv) may have some immunological risks. Recently, single variable domain of heavy chain antibodies are becoming an alternative to scFv to construct CARs. To improve the function of BAFF-R CAR-T cells, we designed CARs with only a fully human heavy-chain variable domain.

Methods: A fully human antibody phage display library (IMARS, IASO Biotherapeutics) was used to select anti-BAFF-R clones using optimal protein/cell alternate panning. The enzyme-linked immunosorbent assay (ELISA) and flow cytometry were applied to evaluate the specificity of clones. The screened clones were grafted into a second-generation CAR with CD8α hinge, 4-1BB costimulatory and CD3ζ intracellular signaling domains to generate CAR-T cells. PMB101 and CAR-T cells constructed with VAY736 were used as positive controls. Non-transduced T cells from the same donor were used as a negative control.

Results: Four candidate clones including clone 1, 5, 77 and 80 were finally screened by in vitro functional evaluation, among which clone 5, 77 and 80 were variable domain heavy chain antibodies. The expression levels of the degranulation marker CD107a on CAR-T cells constructed with the four candidate clones were significantly upregulated after coculture with BAFF-R positive tumor cells, while BAFF-R negative tumor cells could not effectively activate CAR-T cells (data not shown). The four clones exhibited similar cytotoxicity in CAR-T cells compared with the PMB101 and VAY736 CAR-T cells using the luciferase-based cytotoxicity assay (data not shown). Xenografts were established in NPG mice following intravenous injection of 1 x 10 6 jeko-1 cells expressing the firefly luciferase gene on day - 5, and a single dose of 4 x 10 6 CAR T cells were infused IV on day 0. Compared to the other groups, no progressive tumor growth was discovered in mice treated with clone 5 CAR-T cells until day 49. Clone 5 CAR-T cells showed excellent in vivo antitumor activity to PMB101 and conferred long-term survival (data not shown).

Conclusion: We developed a novel BAFF-R CAR-T cell product structured on single-domain antibody. This product demonstrated promising preclinical activity, and it may provide an alternative choice for patients with B cell malignancies.
Safety Profile in Patients with Chronic Lymphocytic Leukemia Undergoing Treatment with 1st and 2nd Generation Bruton Tyrosine Kinase Inhibitors: Multicentric Real-World Experience
Authors: Lopez Garcia Alberto , Garcia Alfonso , Macia Ester , Morillo Daniel , Miranda Carolina , Bermejo Laura , Yuste Maria , Llamas Sillero Maria Pilar , Cordoba Raul
Published: December 2023

INTRODUCTION

Chronic lymphocytic leukemia (CLL) is the most frequent leukemia, being more frequent in older adults.

Bruton's tyrosinkinase inhibitors (BTKi) have revolutionized the treatment, displacing immunochemotherapy treatment in all patient profiles.

The selectivity profile in the action of these drugs means that the toxicity of first and second generation BTKi is different, resulting in higher rates of atrial fibrillation and arterial hypertension, mainly in patients treated in the second line or later, while maintaining their efficacy.

Real-life studies are needed to be able to demonstrate the effects in first-line treatment in a more heterogeneous patient profile, without the strict exclusion and inclusion criteria used in clinical trials.

METHODS

An observational, retrospective, multicenter, retrospective study was performed. Patients with in treatment with Ibrutinib or Acalabrutinib in first line or later were included. Demographic data, comorbidity, cytogenetic and mutational disease data, adverse effect profile, comprehensive geriatric assessment (if applicable) and treatment response evaluation data are collected.

RESULTS

A total of 91 patients were included with a median age of 73.22 years SD 11.06. Fifty-three (58.2%) were male. Fifty-three (58.2%) were treated in frontline, 31.9% (29) in second line and 9.9% (9) in subsequent lines.

Acalabrutinib was used in 25 (27.5%) patients and Ibrutinib in 66 (72.5%). Patient characteristics are shown in Table 1.

Differences were revealed between these two BTKis in terms of line of treatment, with the majority being treated first (P=0.006) and Rai stage, with Rai II predominating (P=0.014). No differences were found between the two BTKis according to the rest of the characteristics.

In terms of toxicity, 14 (15.4%) of patients treated with Ibrutinib developed arterial hypertension, compared to no patients in the Acalabrutinib arm (p=0.009).

With respect to the development of cardiac toxicity, 19 (20.9%) patients suffered some cardiotoxic event, 3 (3.3%) in patients on acalabrutinb and 16 (17.6%) on ibrutinib, with no significant differences found between the two drugs (p=0.2). No significant differences were found with respect to other toxicities (hematologic, digestive, bleeding and infections). Table 2

No differences were found in terms of progression-free survival or overall survival.

CONCLUSIONS

The iBTKs have changed the treatment of CLL, although the second-generation iBTKs have a safer cardiovascular profile and are just as effective in our cohort, even in the frontline.
Abbv-101, a Highly Potent and Selective Clinical Stage Bruton Tyrosine Kinase Degrader for the Treatment of B-Cell Malignancies
Authors: Pan Chin , Gururaja Tarikere L , Li Haiyan , Nguyen Henry , Zhai Yongjiao , Xie Xiaoping , Ding Rong-Xian , Mathew Rebecca , Hoh Hana Y , Jia Zhaozhong J , Liu Bo , Shu Cassandra , Assaily Wissam , Lam Lloyd T , Riehm Jacob J , Stevenson Claudina , Will Christine , Innocenti Federico , Rivkin Alexey
Published: December 2023

Bruton tyrosine kinase (BTK), a clinically validated target for various B-cell malignancies, plays a critical role in regulating cell growth, adhesion and homing to key lymphoid tissues that provide a microenvironment favorable to cancer cells. Despite the success of approved covalent BTK inhibitors in diseases such as CLL, most patients do not achieve complete response with monotherapy and eventually relapse, often via the emergence of the BTK-C481S mutation. Additionally, covalent BTK inhibitors have not shown sufficient differentiation from standard-of-care (SoC) in B-cell malignancies such as diffuse large B cell lymphoma (DLBCL) to warrant approval to date. To address these unmet needs, a next-generation orally bioavailable BTK degrader ABBV-101 has been developed. Unlike BTK inhibitors that solely bind to and impede the catalytic domain of BTK, ABBV-101 eliminates the protein in a highly selective fashion. This degradation mechanism targets both the catalytic and scaffolding functions of BTK, and thus may enable deeper and more durable responses in patients with B-cell malignancies.

In preclinical studies, the BTK degrader ABBV-101 has shown potent in vitro and in vivo efficacy in BCR pathway-dependent leukemia/lymphoma models, including covalent BTK inhibitor resistant BTK-C481S systemic mouse CLL and human DLBCL models. ABBV-101 degrades BTK-WT and BTK-C481S with similar sub-nanomolar potency in the human DLBCL cell line TMD8 which translates to potent cellular growth inhibition. In addition to the BTK-C481S mutation, ABBV-101 demonstrates similar potent activity against novel BTK mutations associated with resistance to reversible BTK inhibitors in the clinic, an emerging unmet need. ABBV-101 induces complete tumor regression in the BTK-C481S TMD8 DLBCL xenograft model. A spontaneous mouse CLL model carrying BTK-C481S mutation was developed through crossing BTK-C481S knock-in mice with the Emu-TCL1 transgenic mice in the C57BL/6 background. ABBV-101 completely inhibits BTK-C481S Emu-TCL1 CLL burden increase in the blood compartment and reduces CLL burden in the spleen and lymph nodes, whereas covalent BTK inhibitors show no activity. Further, ABBV-101 induces complete tumor regressions in multiple non-GCB DLBCL PDX models, demonstrating deeper and more durable response than covalent and reversible inhibitors. Combination with a BCL-2 inhibitor enhances the efficacy of ABBV-101 in CLL and DLBCL models. Kinome and global proteomics profiling showed ABBV-101 to be highly selective, a designed feature that may enable favorable tolerability in patients. ABBV-101 is currently in phase 1 clinical trial for a variety of B-cell malignancies. ClinicalTrials.gov identifier: NCT05753501
Secondary Acute Myeloid Leukemia from a Previous Chronic Myeloproliferative Neoplasm: A Study of Grelam-Chile Concerning Chilean Patients on Behalf of AML Pethema Registry
Authors: Espinoza Marcela , Romero Monica Alejandra , Jerez Joaquín , Bass Francisca , Lizama Veronica , Benavente Rafael , Sanchez Matias Eugenio , Aranguiz Natalia , Lopez Miguel Nicolas , Guerra Maria Carolina , Hidalgo Sebastián , Pérez Verónica , Linares Belkys Mercedes , Holloway Melo Robert , Carcamo Lucas , Rojas Christine , López-Vidal Hernán , Sanchez Juan Manuel , Samaniego Francisco , Montesinos Pau , Martinez-Cuadron David
Published: December 2023

Introduction: Secondary Acute Myeloid Leukemia (sAML) from Chronic Myeloproliferative Neoplasm (chMPN) is associated with an unfavorable prognosis and is characterized by a unique set of cytogenetic and molecular features distinct from de novo AML. The only cure for these patients is allogeneic Stem Cell Transplantation (SCT), which usually is not possible given the advanced age and comorbidities from this patient population. Methods: We present a retrospective analysis of sAML Chilean patients due to chMPN from the multicentric epidemiological registry of AML of the PETHEMA Spanish Group. Results: There are 802 AML Chilean patients incorporated in the online PETHEMA platform. 158 are sAMLand 26 are secondary to chMPN. Compared with the sAML group, patients with previous chMPN were mainly male (56% vs. 76%, respectively), had a larger white blood cell count (32,720 mm3 vs. 61,130 mm3), and had splenomegaly (P <0.05). There was no difference in age (median 62,35 years old), peripheral blood blasts (media 28,8%), fibrinogen (287 mg/dl), or other laboratory tests (p>0.05). Regardless of the type of chMPN: Chronic Myeloid Leukemia: 8 patients: Chronic myelomonocytic leukemia: 5, Primary Myelofibrosis: 5, Chronic Myeloproliferative Syndrome not specified subtype: 6, Polycythemia Vera/essential Thrombocytosis 2. 50% received previously chemotherapy, mainly Tyrosine Kinase Inhibitors (7) and hydroxycarbamide (7). Regardless sAML % had an abnormal karyotype. Treatment used, it was Anthracycline/Daunorubicin (38%), azacytidine with or without Venetoclax (19%), and palliative care (23%). In the first induction, the rate of Complete response (CR), or complete response with incomplete hematological response (iCR), was reached in only 3 patients, and these had negative MRD. From the patients with partial responses, 9 patients received a second line of treatment, mainly azacytidine. After that, three more patients reached CR. Only one patient received allogeneic SCT. The average stay in the hospital was 41,4 days, and Overall survival (OS) was 12,2 months (OS in all sAML was 14,2 months, N.S. p>0.05). The mortality rate was 84%, and the main cause was progressive disease in 60% of those cases. Conclusion: We present our local experience with this type of sAML. The outcome remains poor; it seems that allogeneic SCT is the only cure, but most patients cannot reach it. More research is needed to improve the high rates of mortality for this patient population.
Underrepresentation of Older Adults in Clinical Trials of Chimeric Antigen Receptor (CAR) T-Cell Therapy for Hematologic Malignancies: An FDA Analysis
Authors: Seam Pamela , Mahat Upendra , Bouchkouj Najat , Sharma Poornima , Peredo-Pinto Helka , Elmacken Mona , Kaushal Megha , Jia Yuxia , Wang Shu , Xu Zhiheng , Kasamon Yvette , Kanaparu Bindu , Richardson Nicholas , Gormley Nicole
Published: December 2023

Background: As the population ages, the prevalence of hematologic malignancies in older adults will continue to increase. Older adults, especially older than 75 years, are routinely underrepresented in clinical trials evaluating hematologic malignancies, largely due to access and logistics, comorbidities, toxicity concerns, and eligibility restrictions. Given the recent approvals of multiple CAR T-cell therapies for patients with hematologic malignancies, we evaluated the rates of enrollment of older adults (age ≥ 65 years) in registrational trials of CAR T-cell therapies submitted to the U.S. Food and Drug Administration (FDA).

Methods: We conducted a pooled analysis of the registrational trials submitted to the FDA between 2017 and 2021 that supported approvals of autologous CAR T-cell therapies in patients with hematologic malignancies. Datasets submitted with the biologic license applications were pooled and analyzed descriptively for demographics, disease characteristics, and efficacy outcomes. Patients between the ages of 65 and 74 and age 75 and above were analyzed separately.

Results: Thirteen registrational trials evaluating six CAR T-cell products in 1,319 patients with hematologic malignancies were submitted to FDA. The median age at enrollment was 60 years (range: 3 to 86). In total, 7% (88) of patients were 75 years and older, 28% (366) were between the ages of 65 and 74 years, and 66% (865) were under the age of 65 years. The hematologic malignancies included large B-cell lymphoma (59%), multiple myeloma (15%), follicular lymphoma (13%), B-cell acute lymphoblastic leukemia (9%), and mantle cell lymphoma (5%). Response rates by age group and histology are shown in Table 1 and Table 2.

Conclusions: Older adults, particularly those aged 75 years or older, were underrepresented in the trials supporting FDA approval of CAR T-cell therapies considering the predominant hematologic malignancies included in this pooled analysis and the median age of diagnosis of these diseases in the U.S. population. Although clinically meaningful efficacy was achieved across age groups and diseases, more data are needed to determine the impact of age on efficacy outcomes in specific malignancies. In this analysis, data were limited among patients 75 years and older in all histologies except large B cell lymphoma. Work to evaluate the impact of age on safety and tolerability outcomes is ongoing. To improve accrual, greater efforts to understand and reduce barriers to clinical trial enrollment for older adults are needed, especially given the expanding use of CAR T-cell therapies and their toxicity profiles.
BCMA-Directed CAR-T Cell Therapy Is Associated with a Higher Risk of Infections: A Systematic Review and Meta-Analysis
Authors: Bindal Poorva , Banegas Marcela , Paredes Rodrigo , Jose Hernandez Maria , Aggarwal Pushan , Arnason Jon E. , Alonso Carolyn
Published: December 2023

Background:

Chimeric antigen receptor (CAR) T-cell therapy is a rapidly evolving immunotherapy for hematological malignancies. With increasing access to this modality, there is an urgent need for a comprehensive understanding of infectious complications to optimize prophylaxis and improve clinical outcomes. We conducted a systematic review and meta-analysis to assess the incidence and characteristics of infectious complications in adult patients receiving CAR T-cell therapy.

Methods:

The study was registered on PROSPERO and we searched 5 electronic databases from inception to 2022. Each author independently screened titles, reviewed full texts to identify eligible studies and extracted data from included studies using Covidence, a data extraction tool for conduction of standard systematic reviews. A random effects model was used, and proportions were used as a measure of outcome. We assessed heterogeneity using I^2 statistic. Risk of bias assessments were conducted using the RoB 2.0 for RCTs and ROBINS I tool for non-RCTs.

Results:

Our search identified 12,441 studies of which 363 underwent full-text review (Figure 1). 33 studies were eligible for inclusion in the analysis and enrolled a total of 2866 patients. The pooled incidence of an infectious event in adult patients after CAR T-cell therapy was 38% (95%CI 0.31, 0.46; p<0.01; I2 = 98%]. No significant difference was noted in the incidence among studies with a longer follow up duration compared to studies with follow up of £ 30 days [40% (95% CI 0.30-0.50) vs 32% (95% CI 0.24-0.40), p=0.20 respectively]. BCMA-directed CAR T-cell therapies used for management of multiple myeloma had a significantly higher incidence of infectious complications compared to CD19 targeted agents, 64% (95% CI 0.53-0.74, I2 = 65%) versus 39% (95% CI 0.30-0.49; I2 = 98%; p <0.01) respectively, Figure 2. Clostridium difficile and Escherichia coli were the most common pathogens causing bacterial infections, while cytomegalovirus was the most commonly identified viral pathogen affecting these patients.

Conclusion:

In this study, BCMA-directed CAR T-cell therapies were associated with a significantly higher risk of infectious complications. The results of this study can guide the development of strategies to prevent and manage infectious complications in this patient population.
Role of Nutrition Support in Improving Outcomes in Allogeneic Stem Cell Transplant Patients
Authors: Al Bawaliz Anas , Sidhu Jasdeep Singh , Cecil Abigail , Gunaratnam Bakeerathan , Emmons Robert V.B. , Chao Ju-Hsien , Yasin Hassaan , Hegazi Mohamed
Published: December 2023

Introduction: Allogeneic hematopoietic stem cell transplant (Allo-SCT) can be associated with several complications related to the cytotoxic conditioning regimen, infections associated with immune suppression, and GVHD. Malnutrition amongst Allo-SCT patients has been reported to be an independent negative prognostic factor. It may be evident on presentation or develop as a sequela of decreased appetite, mucositis, and digestive GVHD. Whether supportive nutrition (enteral feeding or total parenteral nutrition (TPN)) contributes to favorable transplant outcomes is yet to be determined.

Methods: We conducted a retrospective single-center study that evaluated patients who underwent Allo-SCT from Jan 2018 through Sept 2021. A chart review was conducted, and relevant data was collected. Primary outcomes were the impact of nutrition support (enteral feeding, TPN or both) among malnourished patients during the first 100 days post-transplant (T+100) on mortality and the composite outcome of acute GVHD incidence, infection rate, and days to engraftment. A higher composite score indicated worse outcomes. GVHD grading was based on the CIBMTR grading system (I-IV). The data was analyzed using Chi-Square and two-sample t-test.

Results: A total of 70 Allo-SCT patients were identified. Of them, 42 (60%) were diagnosed with malnutrition, of which 23 (55%) received nutrition support. The mortality rate in patients who required nutrition support was significantly higher compared to those who did not receive nutrition support (83% (19/23) vs 11% (2/19)) with an odds ratio of 40 for this association (CI 6.5-248.9, p-value < 0.0001). The composite outcome was statistically higher amongst patients requiring nutrition support (mean 2.0, median score 1.8, SD 0.6) compared to those who did not need nutritional support (mean 1.6, median score 1.5, SD 0.4). These differences were found to be statistically significant using the Satterthwaite method (p-value 0.0218).

Conclusion: Based on this data, we found that a reactive approach of nutrition support in the setting of malnutrition had no benefit on mortality and our pre-defined composite outcome during the first 100 days of allogeneic stem cell transplantation. This is fuel for conducting a prospective study using a preemptive enteral feeding approach to prevent the development of malnutrition and related complications.
High-Resolution Proximity-Guided Cytogenomics Improves Patient Stratification and Uncovers New Variants in Acute Myeloid Leukemia
Authors: Eacker Stephen , Malig Maika , Langford Kyle , Muratov Alexander , Wood Mary , Sala-Torra Olga , Sullivan Shawn T , Liachko Ivan , Yeung Cecilia C.S. , Radich Jerald P.
Published: December 2023

Cytogenetic methods are a cornerstone of the modern diagnostic workflow for acute myeloid leukemia and related disorders. The goal of these methods is to identify structural genomic aberrations that drive the cancer or otherwise act as an indicator of patient risk. Despite their success, any one cytogenetic test is limited either in resolution, ability to provide unbiased survey of the genome, or ability to detect balanced aberrations. To address these limitations, we have applied proximity ligation sequencing (PLS) to characterize structural variants (SV) in AML genomes. PLS captures ultra-long-range sequence information without high-molecular-weight DNA and requires a modest (5-7x) sequence coverage of the genome. Applying this method to AML diagnostic specimens, we find that PLS identifies cytogenetically defined translocations (reciprocal and non-reciprocal) and inversions with specificity and sensitivity >0.95. The high resolution of PLS (<10kb) detected non-canonical variants missed by standard methods as well as structural variants below limits of detection by karyotyping, identifying variants in over half the patients previously determined to have a normal karyotype (Table 1). This included previously described variants of clinical significance as well as a recurrent inversion not previously described in AML. These observations highlight the effectiveness of PLS to provide high-resolution insights into known clinically relevant variants and discover variants missed by traditional methodologies.
Responses to Combination Chemotherapy with MAPK Pathway Inhibition in Relapsed and Refractory LCH
Authors: Karri Vivekanudeep , El-Mallawany Nader Kim , Lin Howard , Abhyankar Harshal A , Agrusa Jennifer Elise , Velazquez Jessica , Eckstein Olive S. , Gulati Nitya , Allen Carl E , McClain Kenneth L.
Published: December 2023

MAPK pathway inhibition (MAPKi) is associated with high response rates in patients with Langerhans cell histiocytosis (LCH), but monotherapy may not be curative and efficacy in LCH-associated neurodegeneration (LCH-ND) is not known. Based on upregulation of Bcl-xL by MAPK activation, we hypothesize that MAPKi may render LCH cells more sensitive to chemotherapy-induced cytotoxicity.

We assessed the safety and efficacy of combination therapy in 10 patients with refractory systemic disease and LCH-ND. Records of patients treated with combination therapy at Texas Children's Hospital from October 2018 to July 2023 were reviewed for clinical responses as well as peripheral blood/tissue BRAFV600E mutation status, ataxia rating scores, and toxicity.

The median age at the start of combination therapy was 6.82 years (range, 0.48-20.45 years) with a median of 4 treatments prior to this therapy regimen (range, 1-14). Almost all Clofarabine was administered outpatient (typical starting dose 25 mg/m2/day x 5 days). MAPK inhibitors included BRAFV600E inhibitors (50%) and MEK inhibitors (50%). Overall response was 8/10 (80%), with 5/5 (100%) objective response rate (ORR) for systemic disease. Further, 5/6 (83%) demonstrated reduced or extinguished peripheral BRAFV600E+ fraction by the end of combination therapy. Ataxia rating scores were improved in 2/3 (67%) individuals with clinical neurodegeneration. Common toxicities during treatment included fever, skin rash, arthralgia, and cytopenia.

Combining therapy was well-tolerated and associated with clinical and molecular improvement in most patients with highly refractory systemic LCH and LCH-ND. Further prospective multi-center trials are required to optimize this approach, determine potential for combination therapy to achieve cure, and compare risks and benefits to chemotherapy or MAPK inhibitor monotherapy.
Impact of Diabetes Mellitus in Hospital Outcomes Among Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplantation: A NIS 2016 to 2020 Database Study
Authors: Neupane Niraj , Srivastava Arnav , Mahmoud Amir , Budhathoki Pravash , Shah Anish , Agrawal Shubham , Joshi Utsav , Kharel Himal , Sanjeevi Aditya , Dhakal Binod
Published: December 2023

Impact of Diabetes Mellitus in Hospital Outcomes among Patients with Multiple Myeloma undergoing stem cell transplantation: A NIS 2016 to 2020 database Study.

Background.

Diabetes Mellitus (DM) is one of the comorbidities included in the Hematopoietic Cell Transplant-Specific Comorbidity Index (HCT-CI), which predicts the risk of non-relapse mortality (NRM) and overall mortality (OM) after transplantation. Therefore, they refrained from getting an Autologous stem cell transplant (ASCT) due to the concern of higher toxicity. However, limited data exist to assess this association. In this analysis, we intend to find the impact of DM on hospital outcomes in MM undergoing ASCT.

Methods:

A retrospective analysis of the NIS database was conducted using International Classification of Diseases (ICD-10) codes to identify hospitalization with ASCT for multiple myeloma and obesity with BMI > 30 kg/m2. STATA version MP14.2 was used for analysis. We used Fischer's exact test to compare proportions, the student's t-test to compare continuous variables, and multivariate regression analysis to calculate the adjusted odds ratio after controlling age, gender, primary payer, and CCI. Transplant complication includes (transplant rejection, transplant failure, and transplant infection).

Results:

Among 31,390 hospitalizations, 5475 (17.44%) were Diabetic. The mean age to get ASCT was 63 vs. 61, P < 0.001) with DM and without DM. Both groups had male predominance, with Caucasians being the most common race. The mean Charlson comorbidity index (CCI) in DM was 3 vs. 2.32 without DM. After Multivariate analysis, we found ICU admission (AOR: 0.28, 95% CI: 0.14-0.54, P <0.001), length of hospital stay (16.53 vs. 16.79, P <0.001) and acute kidney injury (AOR: 0.70, 95% CI: 0.56-0.87, P = 0.02) was significantly decreased with DM. However, there was no significant difference in the rate of blood transfusion (AOR: 0.87, 95% CI: 0.68-1.11, P = 0.87), transplant complication (AOR: 0.66, 95% CI: 0.42-1.01, P = 0.06), hospital mortality (AOR: 0.45, 95% CI: 0.19-1.03, P = 0.06). The only increase in the patient with DM was Mean hospital charges ($206,796.4 vs. $200,878.3, P = 0.013).

Conclusion:

This analysis shows that while some complications were decreased, blood transfusion rate and hospital mortality were not significantly affected. The study highlights the potential implications of DM in this patient population and warrants further investigation to individualize and optimize transplant outcomes.