bluuebunny/crossref_metadata_2025_split huggingface dataset:
Improving clinical outcomes in multiple myeloma: Weight maintenance strategies to reduce complications during autologous hematopoietic transplantation.
Authors: Shah Anvay , Bradshaw Danielle , Shah Vishrut , Dalgetty Mark , Athota Sruthi , Boghani Faizan , Stokes Michael , Branham Zachery , Mian Mohammad , Keruakous Amany R. , Chauhan Ayushi , Cortes Jorge E. , Bryan Locke Johnson , Jillella Anand P. , Kota Vamsi 
Published: June 2024

e19533 Background: Multiple myeloma (MM) is the second most prevalent hematological disease. The introduction of melphalan as high-dose therapy followed by autologous hematopoietic cell transplantation (HDT/ASCT) for younger patients has dramatically changed treatment outcomes. Monitoring daily weights has been well documented in Acute promyelocytic leukemia (APL) induction, though little has been documented in myeloma patients receiving ASCT. Monitoring daily weights can be a useful tool in maintaining patients' euvolemic status and can help to facilitate appropriate resuscitation of patients who are otherwise prone to sepsis and fluid overload. At our center over the last few years, we have standardized an approach to monitoring and maintaining the weights of MM patients at or near their pre-admission level with fluids and diuresis, as needed. We report outcomes of weight monitoring on morbidity and mortality during ASCT for MM. Methods: We conducted a retrospective chart review of MM patients receiving ASCT at our center between January 2019 and December 2022. Patients whose weights were monitored and maintained within 3 kilograms of admission weight were identified. We looked at the length of stay (LOS) and ICU transfers during this time. We reviewed the records of 205 patients induced at our center. Results: The mean age was 62 years at the time of transplant (34-78). 119 of the 205 patients identified as men (58%). Out of 205 patients, 152 patients did not have their weights maintained. Of these 152 patients, 7 were transferred to ICU. 53 patients had weights maintained, of which 1 patient was transferred to ICU (OR 0.089 (95% CI 0.018-0.6725) (p = 0.019)). The mean LOS for all patients was 12.97 days. Mean LOS was 12.41(n = 53) and 13.18(n = 152) days for patients whose weights were and were not followed, respectively (mean difference of 0.77 days) (95 % CI of -0.15 to 1.68) (p = 0.0992). 3 of the 205 patients died during admission. In these patients, weights were not maintained before ICU transfer. (OR = 0.4072 (0.0207-8.0136) (p = 0.55)). Conclusions: Fluid overload and sepsis are significant concerns in the treatment of MM. Our findings suggest that maintaining euvolemia can effectively manage patients on the floor and limit and in some cases prevent ICU transfers. Although there are limitations to our study due to its retrospective, single-center nature, the cost-effectiveness and noninvasive means of maintaining euvolemic status support its potential application to standard treatment protocols. Further prospective studies are warranted to validate these findings. [Table: see text]
Survival outcomes in patients with primary plasma cell leukemia treated with novel therapies at University of California San Diego Health: A single institution experience.
Authors: Ghamsari Farid , Trando Aaron , Jeong Ah-Reum , Saunders Ila M. 
Published: June 2024

e19538 Background: Plasma Cell Leukemia (PCL) is a rare, but aggressive and devastating disease for which there is a paucity of data regarding the efficacy and safety of modern therapies to guide management. Data prior to the use of modern therapies showed abysmal overall survival (OS) of approximately 4-12 months. There is generally agreement that novel therapies have improved outcomes, but data supporting this is sparse due to the rarity of the disease. As such, there is currently no standard of care agreed upon by experts, and the specific approach for treatment currently varies by provider. Methods: In this single-center retrospective study, we review the outcomes of patients diagnosed with primary plasma cell leukemia (pPCL) from 2008 to 2023 who received at least one of the novel therapies of immunomodulatory drugs (IMiD), protease inhibitors (PI), and/or anti-CD38 antibodies at University of California San Diego Health. Baseline characteristics and efficacy outcomes were collected. Results: A total of 11 patients were identified who met the inclusion criteria. The median age at time of diagnosis was 50. The median circulating plasma cells at diagnosis was 34%. All but 2 patients had > 20% circulating plasma cells. The remaining two had circulating plasma cells of 10% and 14% meeting the newly re-worked definition of plasma cell leukemia. One patient had a single extramedullary plasmacytoma at the time of diagnosis. High risk cytogenetics, defined as having t(4;14), t(14;16), t(14;20), Del17p, Gain1q, were characterized for all patients. 4 had one high risk mutation, 3 had two mutations. Only one patient’s first line did not include any of the novel therapies. 81% of patients’ first line of therapy included a form of cytotoxic chemotherapy (of which 55% of those were cisplatin, doxorubicin, cyclophosphamide, etoposide (PACE)). The most common first line of therapy was bortezomib (V), dexamethasone (D), PACE, +/- thalidomide (T) or lenalidomide (R), and +/- stem cell transplant (SCT). The other 19% of first line therapies contained exclusively novel therapies; namely VTD and daratumamab-RVD. Seven patients underwent SCT. One patient who underwent allogeneic transplant as part of their first line therapy has not yet relapsed 5 years post-transplant. Median OS was 28.8 months (95% CI 17.3 –not reached (NR)). First progression free survival (PFS) was 5.7 months (95% CI 2.3 – NR). For patients with available data, overall response rate (ORR) to 1st line of therapy was 60%. Conclusions: Our results demonstrate that the outcomes of patients with PCL have greatly improved with the use of novel therapies. The small sample size and heterogeneity of the treatments prohibited correlative statistical analysis. Prospective studies are needed to determine the best treatment option for this high-risk population which is excluded from most myeloma trials.
A phase 1 single-arm, open-label study of emavusertib (CA-4948) in combination with azacitidine and venetoclax in patients (pts) with acute myeloid leukemia (AML) in complete response (CR) with measurable residual disease (MRD).
Authors: de la Fuente Burguera Adolfo , Cerchione Claudio , Scholl Sebastian , Middeke Jan Moritz , Nitika Nitika , Lane Maureen E , Zhao Wanying , Angelides Steven , Roemeling Reinhard von , Platzbecker Uwe 
Published: June 2024

TPS6587 Background: Emavusertib is a novel potent oral inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4) with additional inhibitory activity against FMS-like tyrosine kinase 3 (FLT3) and CDC-like kinases (CLK1/2/4). Inhibition of these 3 onco-proteins by emavusertib may address the unmet need for novel therapies in AML. Clinical studies with emavusertib monotherapy have demonstrated a significant reduction in AML blasts with clinical and molecular responses in pts with relapsed or refractory AML (Metzeler 2022). Azacitidine + venetoclax (aza+ven) is an approved therapy for newly diagnosed pts with AML, unfit for intensive chemotherapy. Pre-clinical studies have demonstrated that emavusertib in combination with aza+ven has synergistic and antileukemic effects. In the VIALE-A study, composite CR (CRc) (CR, CRh, or CRi) in the absence of MRD of <1 residual blast/1000 leukocytes (MRD negative [MRD−]) resulted in longer duration of response (DOR), event-free survival, and overall survival (OS) compared with AML pts who achieved CRc but were MRD+ (Pratz, 2022). Therefore, adding emavusertib to aza+ven in CR or CRh, MRD+ pts may convert MRD status without significant toxicity and become a potential new regimen in front-line therapy. Methods: This is a single-arm, open-label Phase 1 study of emavusertib in combination with first line aza+ven in AML pts ≥60 years of age who achieved CR or CRh with MRD+ status based on local testing. The primary objective is to determine a safe and tolerable dosing schedule for the triple combination. Secondary objectives include determining the MRD conversion rate, pharmacokinetics, DOR, and OS. The study will enroll approximately 24 pts at 5 to 10 sites globally. Pts will have received aza+ven as first line therapy and achieved CR or CRh after 1-6 cycles of aza+ven. If MRD status remains positive, emavusertib will be added to the existing aza+ven regimen. Key exclusion criteria include residual toxicities and significant comorbidities. In the first cohort, the starting emavusertib dose is 200 mg BID for 7 days per cycle of 28 days. The duration of emavusertib treatment will extend to 14 and 21 days, in subsequent cohorts. The pts will continue triple treatment (emavusertib+aza+ven) until consent withdrawal, disease progression, intolerable toxicity, or not achieving MRD- after 6 cycles of treatment. Enrollment to cohort 1 began in December 2023. (EU CT Number 2023-505828-58). Clinical trial information: 2023-505828-58.
Phase 1b trial of IRAK 1/4 inhibition for low-risk myelodysplastic syndrome refractory/resistant to prior therapies.
Authors: Garcia-Manero Guillermo , Silverman Lewis R. , Sekeres Mikkael A. , Yan Lucy 
Published: June 2024

TPS6591 Background: Chronic stimulation of both the interleukin-1 receptor (IL-1R) and toll-like receptors (TLRs) in myeloid progenitors is thought to promote a proinflammatory environment in the bone marrow that causes persistent cytopenia in patients with low-risk myelodysplastic syndrome (LR-MDS). The serine/threonine kinases IRAK1 and IRAK4 are critical for the signaling downstream of IL-1R and most TLRs promote production of proinflammatory cytokines and NLRP3 inflammasome-driven pyroptosis, leading to bone marrow inflammation and cell death. IRAK1/4 is a potential target for inhibition for the treatment of LR-MDS by decreasing inflammation and cell death within the bone marrow, allowing for restoration of hematopoiesis. R289 is a prodrug for R835, a potent and selective inhibitor of IRAK1 and IRAK4 kinases. The safety and pharmacokinetic properties of R289/R835 were evaluated in a phase 1 study in healthy volunteers (Study C-906289-001). R289 was well tolerated with no serious or severe adverse events (AEs) reported. Most AEs were mild and transient; the most common AEs (mild/moderate) were headache and GI disturbance. Overall, the study supported the further evaluation of R289. An open-label, phase 1b study to determine the tolerability and preliminary efficacy of R289 for patients with LR-MDS refractory to prior therapies is currently enrolling patients. Methods: The R289 phase 1b open label, single arm, multi-center study (NCT05308264) includes a dose escalation phase (up to 24 patients) and a dose expansion phase (up to 10 patients). Inclusion criteria for both phases: patients ≥18 years with a definitive diagnosis of LR-MDS. Exclusion criteria include prior MDS treatment(s) within 4 weeks of study treatment. Dose Escalation Phase: A 3+3 dose escalation design will be used to determine the maximum tolerated dose (MTD). An initial R289 dose of 250 mg qd, will be given orally, with or without food, progressing to 1 g qd with dose limiting toxicity (DLT) assessed at each dose level. The DLT evaluation period will be 28 days. After completion, patients without DLTs may remain at their respective dose levels if clinical benefit continues without toxicity. Dose Expansion Phase: R289 will be administered to up to 10 additional patients with LR-MDS at a dose not exceeding the MTD in the dose escalation phase. The primary endpoint is safety and tolerability of R289. Secondary endpoints include preliminary efficacy and pharmacokinetics of R289. Statistical analyses will be primarily descriptive. The trial is currently ongoing at 9 US sites. Clinical trial information: NCT05308264 .
Phase 2 study evaluating selinexor monotherapy in patients with JAKi-naïve myelofibrosis and moderate thrombocytopenia.
Authors: Scandura Joseph , Gerds Aaron Thomas , Ritchie Ellen K. , Wang Xulong , Kye Steve , Rampal Raajit 
Published: June 2024

TPS6593 Background: While multiple JAKi therapies are approved in myelofibrosis, thrombocytopenia, which commonly occurs in myelofibrosis and is associated with poor outcomes, is an on-target side effect; use of suboptimal ruxolitinib doses used to manage adverse effects leads to reduced efficacy. In a Phase 1 study (NCT04562389) of selinexor, an investigational XPO1 inhibitor, plus the JAKi ruxolitinib in JAKi-naïve myelofibrosis the most common AEs in the 60 mg cohort were nausea (79%), anemia (64%), thrombocytopenia (64%), and fatigue (57%). Nausea events were predominantly Grade 1 and transient in nature. Among patients who received at least one prophylactic antiemetic (64% of 60 mg cohort), nausea (Grade 1 only) was experienced by 67% of patients compared with 100% of those who did not receive prophylactic antiemetics (Grades 1-3). In the selinexor 60 mg cohort, 79% of the intent-to-treat population achieved SVR35 and 58% achieved TSS50 at Week 24. Response rates were consistent across subgroups, including sex and regardless of ruxolitinib dose. In a Phase 2 study, selinexor monotherapy in patients with myelofibrosis refractory or intolerant to JAKi therapy (NCT03627403; ESSENTIAL) was generally tolerable and preliminary signs of efficacy were observed with single-agent selinexor. These results provide rationale to explore selinexor monotherapy in myelofibrosis subpopulations with high unmet need such as those with thrombocytopenia. Methods: XPORT-MF-044 (NCT05980806) is a two arm, sequential, multicenter, open-label, Phase 2 study evaluating the efficacy of selinexor (40 mg or 60 mg QW; N=29 per arm) in patients with JAKi-naïve MF and moderate thrombocytopenia (platelet count: 50-100x109/L) with optional expansion arms (n=30 per arm). Optional ruxolitinib or pacritinib, or momelotinib treatment (based on platelet count) may be added for patients whose SVR from baseline is <10% at week 12 or <35% at week 24. Inclusion criteria include ≥18 years of age, spleen volume ≥450 cm3 by MRI or CT scan, DIPSS intermediate-1 with symptoms, intermediate-2, or high-risk, ECOG ≤2, platelet counts of 50-100x109 /L, and not eligible for stem cell transplantation. Select exclusion criteria include >10% blast in peripheral blood or bone marrow and previous treatment with JAKi for myelofibrosis. Primary endpoint is SVR35 at week 24. Key secondary endpoints are safety, TSS50 at week 24, anemia response at week 24, overall survival, and overall response rate. Clinical trial information: NCT05980806 .
BELLWAVE-011: Phase 3 randomized trial of nemtabrutinib versus ibrutinib or acalabrutinib in untreated chronic lymphocytic leukemia/small lymphocytic lymphoma.
Authors: Tadmor Tamar , Eyre Toby A. , Benjamini Ohad , Chaudhry Arvind , Shen Juan , Leng Siyang , Farooqui Mohammed Z.H. , Lavie David 
Published: June 2024

TPS7088 Background: Bruton tyrosine kinase (BTK) inhibitors have significantly improved survival in patients (pts) with chronic lymphocytic leukemia (CLL). Nemtabrutinib is a reversible noncovalent inhibitor of wild-type and C481-mutated BTK that has shown promising antitumor activity in pts with CLL (Woyach JA et al. Cancer Discovery 2023). In this ongoing trial, we evaluate the efficacy and safety of nemtabrutinib versus investigator’s choice of ibrutinib or acalabrutinib in pts with untreated CLL/small lymphocytic lymphoma (SLL) requiring therapy (NCT06136559). Methods: This randomized, open-label, parallel group, active-controlled phase 3 trial will enroll approximately 1200 pts aged ≥18 years. Eligible pts will have confirmed CLL/SLL with active disease based on the IWCLL criteria, which include one of the following: 1) progressive marrow failure or lymphocytosis, 2) massive, progressive, or symptomatic splenomegaly or lymphadenopathy, 3) autoimmune complications, 4) extranodal involvement, or 5) disease-related symptoms. The study will enroll patients who are treatment naïve, with an ECOG performance status 0-2, adequate organ function, and provide blood, bone marrow, and/or a lymph node sample. Pts are excluded if they have Richter Transformation, central nervous system (CNS) involvement by CLL/SLL, an active second malignancy, or a severe bleeding disorder. Pts will be randomized 1:1 to receive oral nemtabrutinib 65 mg QD, or investigator’s choice of oral ibrutinib 420 mg QD or acalabrutinib 100 mg BID. Randomization will be stratified by TP53aberration, clinical stage, investigator’s choice of comparator, and region. Treatment will continue on both arms until unacceptable toxicity, disease progression, or withdrawal. Disease response assessments by physical examination, constitutional symptoms, imaging, and evaluation of blood and bone marrow will be performed Q12W up to week 97, and Q24W thereafter. Primary efficacy endpoints are objective response (OR) and progression free survival (PFS) by BICR per iwCLL 2018 criteria. Secondary endpoints are overall survival (OS), duration of response (DOR) by BICR per iwCLL 2018, and safety. OR will be tested via a non-inferiority comparison, while PFS and OS will be tested for superiority. Adverse events will be monitored throughout the trial and graded per NCI CTCAE v5.0 and iwCLL scales. Enrollment in this trial is ongoing. Clinical trial information: NCT06136559 .
BGB-11417-203: An ongoing, phase 2 study of sonrotoclax (BGB-11417), a next-generation BCL2 inhibitor, in patients with Waldenström macroglobulinemia.
Authors: Lee Hui-Peng , Opat Stephen , Hrom John , Kliman David S. , Marlton Paula , Liu Peng , Du Chenmu , Lussier Amber , Zhang Jun , Guo Haiyi , Treon Steven P. 
Published: June 2024

TPS7090 Background: Bruton tyrosine kinase (BTK) inhibitors and anti-CD20 antibody-based systemic therapy are included within the preferred treatment algorithms for Waldenström macroglobulinemia (WM). However, to date, no treatments have been approved for patients with WM that is refractory to both BTK inhibitors and anti-CD20 therapy. Venetoclax, the first-generation BCL2 inhibitor, has demonstrated clinical activity in patients with relapsed/refractory (R/R) WM (Castillo et al. J Clin Oncol. 2022), but it has no regulatory approvals in WM. Sonrotoclax, a next generation BCL2 inhibitor, is more selective and a more pharmacologically potent inhibitor of BCL2 than venetoclax. In a phase 1 trial, sonrotoclax monotherapy was well tolerated at all dose levels tested up to 640 mg and showed promising evidence of antitumor activity in patients with R/R WM (Soumerai et al. Blood. 2022). Based on the data from these earlier studies, a phase 2 study of sonrotoclax monotherapy in patients with WM has been initiated and is currently recruiting. Methods: BGB-11417-203 (NCT05952037) is an open-label, international, phase 2 study. Eligible patients have histologically confirmed WM that is R/R to both BTK inhibitor therapy and anti-CD20–based systemic therapy combined with chemotherapy or a proteasome inhibitor (PI; Cohort 1); R/R to anti-CD20–based systemic therapy combined with chemotherapy or a PI and who are intolerant to BTK inhibitor therapy (Cohort 2); or R/R to a BTK inhibitor and who are unsuitable for chemoimmunotherapy (Cohort 3). Patients who have received previous treatment with a BCL2 inhibitor are ineligible. Approximately 85 patients will be enrolled across cohorts and will receive sonrotoclax until disease progression, death, unacceptable toxicity, patient withdrawal, loss to follow-up, or study termination. The primary endpoint is major response rate (MRR; defined as partial response or better) in Cohort 1 per IWWM-11 criteria, as assessed by independent review committee (IRC). Key secondary endpoints include MRR assessed by investigator (INV) in Cohort 1 and by IRC and INV in both Cohorts 2 and 3; overall response rate, duration of response, and progression-free survival by IRC and INV; overall survival; and safety and tolerability. Patient recruitment is ongoing in Australia, the US, China, and Europe. Clinical trial information: NCT05952037 .
An open label, single arm, multicenter phase II study of the efficacy and safety of LP-168 monotherapy for relapsed or refractory mantle cell lymphoma.
Authors: Song Yuqin , Tang Xiaoqiong , Cai Qingqing , Liu Lihong , Jing Hongmei , Jiang Ming , Sun Xiuhua , Wu Jianqiu , Yang Yu , Wu Huijing , Peng Zhigang , Ding Kaiyang , Yi Shuhua , Yan Xiaojing , Wu Guowu , Wu Yudan , Cui Jie , Ou Pengju , Tan Fenlai , Zhu Jun 
Published: June 2024

TPS7098 Background: Targeting Bruton’s tyrosine kinase (BTK) has demonstrated impressive efficacy in relapsed or refractory mantle cell lymphoma (R/R MCL). Covalent BTK inhibitors (cBTKi) have produced extended disease remission and durable responses in R/R MCL. However, patients with continuous cBTKi treatment tend to develop selection or outgrowth of resistant clones, which triggers disease relapse. Non-covalent binding BTKi has become a treatment option for patients who progressed on cBTKi. LP-168 is a highly selective next-generation inhibitor of BTK that can bind wild-type BTK covalently and C481-mutated BTK non-covalently (reversibly) Here, we propose to evaluate the safety and efficacy of LP-168 monotherapy in patients with R/R MCL. Methods: NCT05716087 is an open-label, multicenter, single-arm, phase II study to assess the efficacy, safety, tolerability, and pharmacokinetics of LP-168 in Chinese patients with R/R MCL who have failed prior cBTKi treatment. Responses were evaluated using Lugano 2014 criteria. Eligible patients with R/R MCL must show evidence of disease progression or intolerance to at least a prior cBTKi. Patients are also required to have adequate bone marrow, liver function, kidney function, and heart function, and an ECOG performance status of 0-2. Moreover, patients must have at least one measurable lesion. Key exclusion criteria include previous non-covalent BTKi or BTK proteolysis-targeting chimeras (PROTAC) treatment, uncontrolled systemic disease, active infection, central nervous system (CNS) involvement, prior history of other malignancies within two years, and current pregnancy or breastfeeding. Concomitant use of strong or moderate CYP3A4 inducers and inhibitors or OATP1B1/OATP1B3 sensitive substrates is prohibited. LP-168 is orally administered at 150mg once daily in 28-day/cycle until progressive disease (PD), unacceptable toxicity, withdrawal of consent, death, or other reasons for treatment discontinuation. In this study, the primary endpoint was ORR according to an independent review committee (IRC) assessment based on the best overall response (BOR) of PR or better per Lugano 2014 criteria. Secondary endpoints include safety evaluation, quality of life assessment, PK parameters, ORR by investigator’s assessment, and other efficacy parameters, such as complete response ratio (CRR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), and time to response (TTR). First patient was enrolled on May 12, 2023. Currently 41 study sites across China are actively enrolling patients. ClinicalTrials.gov Identifier: NCT05716087. Clinical trial information: NCT05716087 .