Non-hematologic Adverse Events Research Articles

Target trial emulation of carfilzomib safety among patients with relapsed/refractory multiple myeloma using a nationwide observational data in Korea

PurposeCarfilzomib, commonly used for relapsed/refractory multiple myeloma (RRMM), has been associated with various adverse events in randomized controlled trials (RCTs). However, real-world safety data for a more diverse population are needed, as carfilzomib received expedited approval. This study aimed to evaluate carfilzomib’s safety in Korea by comparing new users of KRd (carfilzomib, lenalidomide, and dexamethasone) to Rd (lenalidomide and dexamethasone) using a nationwide administrative claims database.MethodsThe retrospective cohort study utilized target trial emulation, focusing on adverse events in various organ systems similar to the ASPIRE trial.ResultsThis study included 4,580 RRMM patients between 2007 and 2020, and the KRd group showed significantly higher risks of hematologic adverse events (anemia, neutropenia, thrombocytopenia) and some non-hematologic adverse events (cough, hypokalemia, constipation, hypertension, heart failure) compared to the Rd group. Among non-hematologic adverse events, cardiovascular events (heart failure [HR 2.04; 95% CI 1.24–3.35], hypertension [HR 1.58; 95% CI 1.15–2.17]) had the highest risk in the KRd group.ConclusionThe safety profile of carfilzomib in Korean patients was similar to previous RCTs. Therefore, caution should be exercised when using carfilzomib in Asian individuals with RRMM due to the increased risk of cardiovascular adverse events.

Treatment outcome of the tyrosine kinase inhibitor (bosutinib) in previously treated chronic myeloid leukemia patients (sample of Iraqi patients)

Abstract BACKGROUND: Chronic myeloid leukemia (CML) is a type of myeloproliferative neoplasm characterized by the excessive accumulation of malignant myeloid cells in the bone marrow and peripheral blood. This condition is primarily triggered by a specific chromosomal translocation known as t(9;22) (q34.13;q11.23), which leads to the formation of the BCR-ABL fusion gene. The treatment landscape for CML has undergone significant changes with the approval of tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL1 kinase activity. One such inhibitor is bosutinib, which has been available for several years to treat patients with chronic, accelerated, and blast-phase CML who have shown resistance or intolerance to previous therapies. OBJECTIVES: The aim of this study was to assess efficacy and safety of Bosutinib as a 2nd line therapy in CML patients, in addition to effect of adherence to treatment on patients response. PATIENTS AND METHODS: Eighty-five patients with CML were enrolled in a prospective cohort study from October 2021 to October 2022 at Hematology Center in Medical City Complex – Baghdad. All patients failed to at least one TKI, and all of them started escalated dose of bosutinib. The patients were followed-up by assessing molecular and cytogenetic response at 3 and 6 months and monitored carefully for adverse events (AEs) which were graded by common terminology IX criteria for AEs version 5. Adherence to bosutinib was also monitored by a specific adherence scale to optimize the response rate to treatment. RESULTS: The mean age of patients was 47.3 ± 14.9 (range: 18–77), with male:female ratio 1.4:1. Status of CML patients showed that 89.4% were in the chronic phase, 5.8% in accelerated phase, and 4.7% in blast phase. Regarding the number of previous TKIs before bosutinib, 72.9% of patients failed to prior one TKI (imatinib). At 6 months (72.3%), patients achieve optimal response according to European Leukemia Net criteria 2013. Gastrointestinal symptoms and dermatological manifestations were the most common nonhematological AEs of bosutinib. According to 9-item Morisky Medication Adherence Scale, 42% of patients were adherent to medication which showed a significant association with a higher number of optimal response (P = 0.0001). CONCLUSION: Bosutinib is effective with a high and promising response as a subsequent line treatment in CML patients, and it is generally safe and associated with mild-to-moderate tolerable and manageable AEs. Adherence to the drug plays a significant role in optimal response to bosutinib.

Polatuzumab vedotin, venetoclax, and an anti-CD20 monoclonal antibody in relapsed/refractory B-cell non-Hodgkin lymphoma.

The Phase 2 portion of this study evaluated safety and efficacy of polatuzumab vedotin 1.8 mg/kg and venetoclax 800 mg, plus fixed-dose obinutuzumab 1000 mg or rituximab 375 mg/m2 in patients with relapsed/refractory (R/R) follicular lymphoma (FL) or diffuse large B-cell lymphoma (DLBCL), respectively. Patients with complete response (CR) or partial response (PR)/stable disease (FL) or CR/PR (DLBCL) at end of induction (EOI; six 21-day cycles) received post-induction therapy with venetoclax and obinutuzumab or rituximab, respectively. Primary endpoint was CR rate at EOI. Safety-evaluable populations included 74 patients (FL cohort; median age 64 years; progression of disease within 24 months on first-line treatment, 25.7%; FL International Prognostic Index 3-5, 54.1%; ≥2 previous therapies, 74.3%) and 57 patients (DLBCL cohort; median age 65 years; International Prognostic Index 3-5, 54.4%; ≥2 previous therapies, 77.2%). The most common non-hematologic adverse events (mostly Grades 1-2) in the FL and DLBCL cohorts were diarrhea (55.4% and 47.4%, respectively) and nausea (47.3% and 36.8%); neutropenia was the most common Grades 3-4 toxicity (39.2% and 52.6%). Efficacy-evaluable populations included patients treated at the recommended Phase 2 dose (FL, n = 49; DLBCL, n = 48). CR rates at EOI were 59.2% (FL) and 31.3% (DLBCL); median progression-free survival was 22.8 months (95% confidence interval [CI], 14.5-not evaluable) and 4.6 months (95% CI, 3.6-8.1), respectively. Polatuzumab vedotin plus venetoclax and obinutuzumab/rituximab had acceptable safety in patients with R/R FL or DLBCL, with promising response rates in R/R FL, including high-risk patients.

Abstract PO3-18-12: Results from a first-in-human study of DAN-222, a novel high-capacity drug conjugate in metastatic breast cancer as monotherapy and in combination with a PARPi [NCT05261269

Abstract Background: Topoisomerase I inhibitors (Topo I) have been shown to be highly effective across a broad range of tumors including breast cancer. Poly (ADP-ribose) polymerase inhibitors (PARPi) have been shown to be effective in BRCAm breast cancers. The combination of Topo I plus PARPi is known to be synergistic beyond the BRCAm subtype but overlapping myelotoxicities have prohibited successful clinical combinations. DAN-222 is a novel therapeutic HDC (High-capacity drug conjugate) whose payload is the topoisomerase 1 inhibitor camptothecin (CPT). Our previously published preclinical data demonstrates synergy of DAN-222 plus a PARPi regardless of BRCA or HRD status. Furthermore, DAN-222 demonstrates reduced bone marrow exposure enabling clinical combinations. Herein we present data for the first-in-human study of DAN-222 as mono- and combination therapy with a PARPi. The expectation is clinical benefit with this complimentary combination for patients with HRD+ and HRD- tumors, and not restricted to BRCAm, while minimizing overlapping myelotoxicities. Methods: A phase 1 study of DAN-222 as monotherapy and in combination with niraparib is being conducted in heavily pretreated patients with metastatic breast cancer. The objectives are to evaluate the safety, tolerability, and pharmacokinetics of DAN-222, and initial clinical activity based on RECIST v1.1 criteria to determine the recommended phase 2 dose. PK will be characterized for the total conjugated and the unconjugated CPT. Adults (≥18 years) with HER2-negative metastatic breast cancer that progressed on standard therapies were enrolled, without restriction on BRCA or HRD status. Results: As of June 2023, 30 patients had enrolled in dose escalation of monotherapy (2-16 mg/m2) or combination therapy with niraparib (100 mg). The median age was 61.5 years old (range, 36-75). The median number of prior treatment lines was 6. All patients were PARPi naïve and BRCAwt. In the monotherapy cohorts, the hematological adverse events (AEs) were neutropenia (28%; grade [Gr] ≥3: 17%), thrombocytopenia (22%; Gr ≥3: 6%) anemia (17%; Gr ≥3: 0%), and lymphopenia (11%; Gr ≥3: 0%), the non-hematologic adverse events Gr ≥3 was one case of cystitis. In the combination cohorts, the hematological AEs were anemia (25%; Gr ≥3: 17%), thrombocytopenia (17%; Gr ≥3: 8%), neutropenia (8%; grade Gr ≥3: 8%), and lymphopenia 8%; Gr ≥3: 0%) and there was no Gr ≥3 non-hematologic adverse events. The exposure of DAN-222 was linear and increased in a dose-proportional manner. The mean half-life ranged from 25.2 to 33.5 hours across all cohorts. Clinical activity during dose escalation was demonstrated with stable disease in 28% of patients with monotherapy and 67% of patients with combination therapy across all dose levels. Conclusions: No DLTs were observed in monotherapy or combination therapy in the dose escalation phase of this study. This study demonstrates the feasibility for DAN-222 to be combined with a PARPi at clinically relevant doses. The reduced myelotoxicity of DAN-222 will also enable combination with other therapies to treat patients with other types of cancer. The promising antitumor activity seen with DAN-222 in combination with PARPi in BRCAwt, supports continued clinical development. Citation Format: Sara Hurvitz, Erika Hamilton, Timothy Pluard, Aki Morikawa, Hatem Soliman, Kay Yeung, Adam Brufsky, Amy Tiersten, Wajeeha Razaq, Kristen Foye, Timothy Hagerty. Results from a first-in-human study of DAN-222, a novel high-capacity drug conjugate in metastatic breast cancer as monotherapy and in combination with a PARPi [NCT05261269] [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-18-12.

Abstract RF02-04: A phase III study comparing trastuzumab emtansine with trastuzumab, pertuzumab, and docetaxel in older patients with metastatic HER2-positive breast cancer. (JCOG1607 HERB TEA study)

Abstract Background A combination of trastuzumab, pertuzumab, and docetaxel (HPD) is recommended as first-line treatment for patients with HER2-positive metastatic breast cancer. For older patients, it is difficult to maintain a relative dose intensity, which often impairs their quality of life. A new standard treatment option for older patients is required with less toxicity and non-inferior efficacy compared to HPD. Methods The eligibility criteria were as follows: age 65 years and older, HER2-positive metastatic breast cancer, no previous systemic treatment with chemotherapy and anti-HER2 targeted drugs, ECOG PS 0–2 for 65–74 years or 0–1 for 75 years or older, and adequate organ function. Treatment consisted of trastuzumab emtansine (T-DM1) 3.6 mg/kg every 3 weeks or HPD (trastuzumab 8 mg/kg, then 6 mg/kg, pertuzumab 840 mg, then 420 mg/body, and docetaxel 60 mg/m2, could be escalated to 75 mg/m2 if there were no unmanageable toxicity) every 3 weeks after a 1:1 ratio randomization. The trial was designed to achieve 70% power to confirm the non-inferiority of T-DM1 to HPD at a one-sided alpha of 5% with a non-inferiority margin of 1.35 in terms of the hazard ratio (HR) for overall survival (OS) as the primary endpoint. With a median OS of 30 months in both arms, 6.5 years of accrual, and 5 years of follow-up, the planned sample size was 250. Secondary endpoints were progression-free survival (PFS), response rate (RR), adverse events, cumulative breast cancer-specific mortality (BCSM), safety, and deterioration of activities of daily living. (Clinical Trial Information: UMIN000030783). Results In total, 148 patients were enrolled between January 2018 and March 2023. A total of 135 patients were assessed in the preplanned first interim analysis. The median patient age was 72 years (range 65-88) in the T-DM1 arm and 71 (65-84) in the HPD arm. The proportion of estrogen receptor-positive (10%) patients was well balanced between both arms (49.3 and 55.6%, respectively). Of these patients, 64.8% had stage IV disease and 35.2% had recurrent disease. T-DM1 was not non-inferior to HPD (HR 1.487; 99.9% CI, 0.288 to 7.678) in terms of OS. The median PFS was 9.8 months in the T-DM1 arm and 18.4 months in the HPD arm (HR 1.749; 95%CI, 1.124-2.723). Response rates were lower in the T-DM1 arm than that of the HPD arm (52.7% [95% CI, 38.8-66.4] and 76.8% [95% CI, 63.6-87.0], respectively) (p=0.099). BCSM was higher in the T-DM1 arm than that of the HPD arm (HR 1.617; 95% CI, 0.764-3.425). Grade 3 and higher neutropenia were less common in the T-DM1 arm than in the HPD arm (0 vs. 30.4%); however, thrombocytopenia was more common in the T-DM1 arm than in the HPD arm (16.9 vs. 0%). Grade 3 or more non-hematological adverse events were less common and lower in the T-DM1 arm (35.2%) than in the HPD arm (58.6%), including fatigue (5.6% vs. 22.9%), diarrhea (0% vs. 11.4%), appetite loss (8.5% vs. 11.4%), and febrile neutropenia (0% vs. 10.0%), which reduced the quality of life in older patients with HER2-positive metastatic breast cancer. Conclusion T-DM1 was not non-inferior to HPD in terms of OS. However, T-DM1 showed better tolerability in terms of frequency and severity of adverse events. HPD will continue to be the standard of care as the first-line treatment for older patients with HER2-positive metastatic breast cancer. Older patients with breast cancer have heterogeneous health conditions. A subset analysis according to age or geriatric assessment may identify the subpopulation of older patients with HER2-positive metastatic breast cancer for whom T-DM1 is an optional treatment. Citation Format: Akihiko Shimomura, Kenji Tamura, Keita Sasaki, Ryo Sadate, Akihiko Suto, Masataka Sawaki, Naohito Yamamoto, Tomoyuki Yoshiyama, Takako Hayashi, Eriko Tokunaga, Takashi Yamanaka, Chikako Shimizu, Tadahiko Shien, Hiroji Iwata. A phase III study comparing trastuzumab emtansine with trastuzumab, pertuzumab, and docetaxel in older patients with metastatic HER2-positive breast cancer. (JCOG1607 HERB TEA study) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr RF02-04.

Abstract PS11-05: Trastuzumab Deruxtecan in patients with HER2[+] or HER2-Low Advanced Breast Cancer and Pathologically Confirmed Leptomeningeal Carcinomatosis: Results from Cohort 5 of the DEBBRAH Study

Abstract Background: Leptomeningeal carcinomatosis (LMC) occurs in approximately 5-15% of patients (pts) with advanced breast cancer (ABC) and is associated with poor survival and a significant reduction in quality of life. The antibody-drug conjugate trastuzumab deruxtecan (T-DXd) has shown remarkable intracranial and extracranial activity, leading to its widespread clinical use. DEBBRAH is evaluating the efficacy and safety of T-DXd in pts with HER2[+] and HER2-low ABC with a history of brain metastases (BM) and/or LMC. Here, we report results from cohort 5 that included pts with pathologically confirmed LMC. Methods: DEBBRAH (NCT04420598) is a single-arm, open-label, five-cohort, phase 2 study conducted across 18 sites in Spain and Portugal. A total of 39 pts aged ≥18 years with pretreated HER2[+] or HER2-low ABC with stable, progressing, or untreated BM and/or LMC were enrolled in 5 cohorts: (1) HER2[+] ABC with non-progressing BM after radiotherapy and/or surgery; (2) HER2[+] or HER2-low ABC with asymptomatic untreated BM; (3) HER2[+] ABC with progressing BM after local treatment; (4) HER2-low ABC with progressing BM after local treatment; (5) HER2[+] or HER2-low ABC and LMC with positive cerebrospinal fluid cytology. Pts received 5.4 mg/kg T-DXd intravenously once every 21 days until disease progression, unacceptable toxicity, or consent withdrawal. Primary endpoint for cohort 5 was overall survival (OS). Secondary endpoints included progression-free survival (PFS), overall response, clinical benefit rate (CBR) according to RANO-BM (intracranial lesions) and RECIST v.1.1 (extracranial and overall lesions); and safety and tolerability as per NCI-CTCAE v.5.0. OS was tested with the maximum likelihood exponential method (H0: median OS ≤2 months; H1: median OS≥6 months). We estimate that 7 pts are needed to attain an 80% power at the nominal level of one-sided α of 0.05. Results: Between Apr 14, 2021, and Apr 5, 2022, 7 pts were allocated into cohort 5. Median age was 57 (range, 42–69) years, 3 (42.9%) pts were HER2[+], 6 (85.7%) pts had synchronous extracranial metastases, 2 of whom (28.6%) also presented BM, and 3 (42.9%) pts had measurable disease. Median number of previous lines of therapy for advanced disease was 4 (range, 1-8) and no patient received prior local treatment for central nervous system involvement. At data cut-off (Apr 4, 2023), median follow-up was 12 months (range, 2.5-18.6). Median duration of treatment was 9.0 months (range, 2.1-18.6). Two (28.6%) pts remained on treatment: 1 HER2[+] and 1 HER2-low, after 18.6 and 12.0 months, respectively. Median OS rate was 13.3 months (95% CI, 5.7-NA, p< 0.001) meeting the primary endpoint. Among 5 pts with disease progression, none had intracranial progression. A total of 4 (57.1%) pts presented extracranial progression and 1 (14.3%) patient had clinical worsening. No objective responses were observed, but 5 out of 7 pts had prolonged stabilization (≥24 weeks) for an overall CBR of 71.4% (95% CI, 29.0-96.3) and a median PFS of 8.9 months (95% CI, 4.9-NA) according to RECIST v.1.1. The most common non-hematological treatment emergent adverse events (TEAEs) of any grade (G) were nausea (57.1%; 14.3% G3), fatigue (42.9%; 0% G3), vomiting (42.9%; 0% G3), headache (42.9%; 0% G3), and urinary tract infection (42.9%; 0% G3). Anemia (42.9%; 0% G3) and thrombocytopenia (28.6%; 14.3% G3) were the most frequent hematological TEAEs. No cases of interstitial lung disease/pneumonitis were reported. Serious unrelated TEAEs occurred in 4 (57.1%) of 7 pts, and 1 patient experienced a related serious TEAE (nausea G3). No treatment-related deaths were reported. Conclusions: T-DXd showed promising activity with no new safety concerns in HER2[+] and HER2-low pts with previously untreated, pathologically confirmed LMC. These encouraging data warrant further investigation to address the unmet need in this difficult-to-treat condition. Citation Format: Marta Vaz Batista, José Manuel Pérez-García, Laia Garrigós, José Ángel García-Sáenz, Patricia Cortez-Castedo, Fabriccio Racca, Salvador Blanch, Manuel Ruíz - Borrego, Adela Fernández, María Fernández-Abad, Vega Iranzo, Maria Gion, Griselda Martrat, Daniel Alcalá-López, Jhudit Pérez-Escuredo, Miguel Sampayo-Cordero, Antonio Llombart-Cussac, Sofía Braga, Javier Cortés. Trastuzumab Deruxtecan in patients with HER2[+] or HER2-Low Advanced Breast Cancer and Pathologically Confirmed Leptomeningeal Carcinomatosis: Results from Cohort 5 of the DEBBRAH Study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS11-05.

First-line therapy with palbociclib in patients with advanced HR+/HER2- breast cancer: The real-life study PALBOSPAIN.

To evaluate the efficacy and safety of first-line therapy with palbociclib in a Spanish cohort treated after palbociclib approval. PALBOSPAIN is an observational, retrospective, multicenter study evaluating real-world patterns and outcomes with 1L palbociclib in men and women (any menopausal status) with advanced HR+/HER2- BC diagnosed between November 2017 and November 2019. The primary endpoint was real-world progression-free survival (rw-PFS). Secondary endpoints included overall survival (OS), the real-world response rate (rw-RR), the clinical benefit rate, palbociclib dose reduction, and safety. A total of 762 patients were included. The median rw-PFS and OS were 24 months (95% CI 21-27) and 42 months (40-not estimable [NE]) in the whole population, respectively. By cohort, the median rw-PFS and OS were as follows: 28 (95% CI 23-39) and 44 (95% CI 38-NE) months in patients with de novo metastatic disease, 13 (95% CI 11-17) and 36 months (95% CI 31-41) in patients who experienced relapse < 12 months after the end of ET, and 31 months (95% CI 26-37) and not reached (NR) in patients who experienced relapse > 12 months after the end of ET. rw-PFS and OS were longer in patients with oligometastasis and only one metastatic site and those with non-visceral disease. The most frequent hematologic toxicity was neutropenia (72%; grade ≥ 3: 52.5%), and the most common non-hematologic adverse event was asthenia (38%). These findings, consistent with those from clinical trials, support use of palbociclib plus ET as 1L for advanced BC in the real-world setting, including pre-menopausal women and men. NCT04874025 (PALBOSPAIN). Date of registration: 04/30/2021 retrospectively registered.

A real-world retrospective-prospective analysis of efficacy and safety of combined ixazomib, lenalidomide, and dexamethasone in relapsed/refractory multiple myeloma: The northern Italy experience.

Ixazomib, lenalidomide, and dexamethasone (IRd) have been approved for the treatment of relapsed/refractory multiple myeloma (RRMM) based on the results of the TOURMALINE-MM1. We conducted a retrospective-prospective analysis of 106 RRMM patients (pts) treated with IRd in 21 centers in Northern Italy, with the aim to evaluate the efficacy and safety of IRd in real life. At IRd initiation, 34% of pts were aged ≥75 (median 72.5), 8.5% had an ECOG performance status ≥2, 54.7% of evaluable pts carried high-risk cytogenetic abnormalities [del17p and/or t(4;14) and/or t(14;16) and/or 1 g gain/amp], 60.2% had received ≥2 prior lines of therapy (pLoT), 57.5% were lenalidomide (Len)-exposed (including both Len-sensitive and Len-refractory pts), and 22% were Len-refractory. Main G ≥3 adverse events (AEs) were thrombocytopenia (16%) and neutropenia (12.3%). G ≥3 non-hematologic AEs included infections (9.4%) and GI toxicity (diarrhea 5.7%, hepatotoxicity 2.8%), VTE, skin rash, and peripheral neuropathy were mainly G1-2. The overall response rate was 56.4% (≥VGPR 30%). With a median follow-up of 38 m, median PFS (mPFS) was 16 m and the 1-year OS rate was 73%. By subgroup analysis, an extended PFS was observed for pts achieving ≥VGPR (mPFS 21.2 m), time from diagnosis to IRd ≥5 years (26.2 m), 1 pLoT (34.4 m), Len-naïve (NR), age ≥70 (20 m). In pts exposed to Len, non-refractory in any prior line and immediately prior to IRd, mPFS was 16 and 18 m, respectively. An inferior PFS was seen in Len-refractory pts (4.6 m). By multivariate analysis, independent predictors of PFS were age ≥70 (HR 0.6), time from diagnosis ≥5 years (HR 0.32), refractoriness to Len in any prior line (HR 3.33), and immediately prior (HR 4.31). IRd might be effective and safe in RRMM pts with an indolent disease, in early lines of treatment, and who proved Len-sensitive, independent of age, and cytogenetic risk.

Efficacy and Safety of Anti-CD38 Monoclonal Antibodies in Patients with Relapsed or Refractory Multiple Myeloma: A Meta-Analysis of Randomized Clinical Trials.

The benefit of associating anti-CD38 monoclonal antibodies to proteasome inhibitor (PI)/immunomodulatory agent (IA) and dexamethasone in the treatment of patients with relapsed or refractory multiple myeloma (MM) remains unclear. PubMed, Embase, and Cochrane Library databases were searched for randomized controlled trials that investigated the addition of anti-CD38 monoclonal antibodies to a therapy composed of PI/IA and dexamethasone versus PI/IA and dexamethasone alone for treating relapsed or refractory MM. Hazard ratios (HRs) or risk ratios (RRs) were computed for binary endpoints, with 95% confidence intervals (CIs). Six studies comprising 2191 patients were included. Anti-CD38 monoclonal antibody significantly improved progression-free survival (HR 0.52; 95% CI 0.43-0.61; p < 0.001) and overall survival (HR 0.72; 95% CI 0.63-0.83; p < 0.001). There was a significant increase in hematological adverse events, such as neutropenia (RR 1.41; 95% CI 1.26-1.58; p < 0.01) and thrombocytopenia (RR 1.14; 95% CI 1.02-1.27; p = 0.02), in the group treated with anti-CD38 monoclonal antibody. Also, there was a significant increase in non-hematological adverse events, such as dyspnea (RR 1.72; 95% CI 1.38-2.13; p < 0.01) and pneumonia (RR 1.34; 95% CI 1.13-1.59; p < 0.01), in the group treated with anti-CD38 monoclonal antibody. In conclusion, the incorporation of an anti-CD38 monoclonal antibody demonstrated a promising prospect for reshaping the established MM treatment paradigms.

Efficacy and safety of venetoclax combined with hypomethylating agents in the treatment of 83 patients with higher-risk myelodysplastic syndromes

Objective: This study aimed to evaluate the efficacy and safety of venetoclax (VEN) combined with hypomethylating agents (HMA) in the treatment of higher-risk myelodysplastic syndromes (HR-MDS) and analyze the factors influencing their therapeutic effect. Methods: The clinical data of 83 patients with HR-MDS who were diagnosed at the First Affiliated Hospital of Zhengzhou University between November 2019 and May 2023 were retrospectively analyzed. All patients were treated with VEN combined with HMA. The Kaplan-Meier method was used to depict the survival curves, and the log-rank test was used to compare survival between the groups. Results: The median age was 57 (15-82) years old, and 51 patients (61.4%) were male. Forty-five patients (54.2%) were initially treated with HMA, 23 (27.7%) received ≤4 cycles of HMA, and 15 (18.1%) demonstrated HMA failure. At the median follow-up of 10.3 (0.6-34.4) months, the overall response rate (ORR) was 62.7% (52/83), including 18 patients (21.7%) with a complete response (CR), 14 (16.9%) with a bone marrow CR (mCR) with hematological improvement, and 20 (24.1%) with a mCR. The ORR of patients with initial treatment, ≤4 HMA cycles, and HMA failure were 66.7%, 60.9%, and 53.3%, respectively (P=0.641). The median overall survival time was 14.6 (95% CI 7.2-22.0) months, and the median progression-free survival time was 8.9 (95% CI 6.7-11.1) months. The multivariate analysis showed that serum alkaline phosphatase (ALP) ≥90 U/L (OR=14.574, 95% CI 3.036-69.951, P=0.001), TP53 mutation (OR=13.052, 95% CI 1.982-85.932, P=0.008), and U2AF1 mutation (OR=7.720, 95% CI 1.540-38.698, P=0.013) were independent risk factors for poor efficacy of VEN combined with HMA. Hematological toxicity occurred in all patients, and the incidence of treatment-induced grade 3-4 leukopenia was 48.2% (40/83). Infection was the most common non-hematological adverse event, mainly pulmonary infection (31.3%) . Conclusion: VEN combined with HMA had a high response rate in patients with HR-MDS, both at initial treatment and with HMA failure. ALP ≥ 90 U/L, TP53 mutation, and U2AF1 mutation were independent risk factors for non-response to treatment.

Efficacy and safety of bispecific antibodies therapy for relapsed or refractory multiple myeloma: a systematic review and meta-analysis of prospective clinical trials.

Bispecific antibody (BsAbs) therapy represents a promising immunotherapeutic approach with manageable toxicity and noteworthy preliminary efficacy in treating patients with relapsed or refractory multiple myeloma (RRMM). The objective of this systematic review and meta-analysis was to compare the efficacy and safety of B-cell maturation antigen (BCMA)-targeted BsAbs and non-BCMA-targeted BsAbs in the treatment of RRMM patients. PubMed/MEDLINE, Web of Science, EMBASE, Cochrane Library and meeting libraries were searched from inception to August 16th, 2023. The efficacy evaluation included the complete objective response rate (ORR), complete response (CR) rate, stringent CR (sCR) rate, partial response (PR) rate, and very good PR (VGPR) rate. The efficacy evaluation included any grade adverse events (AEs) and grade ≥ 3 AEs. Fourteen studies with a total of 1473 RRMM patients were included. The pooled ORR of the entire cohort was 61%. The non-BCMA-targeted BsAbs group displayed a higher ORR than the BCMA-targeted BsAbs group (74% vs. 54%, P < 0.01). In terms of hematological AEs, BCMA-targeted BsAbs therapy exhibited higher risks of neutropenia (any grade: 48% vs. 18%, P < 0.01; grade ≥ 3: 43% vs. 15%, P < 0.01) and lymphopenia (any grade: 37% vs. 8%, P < 0.01; grade ≥ 3: 31% vs. 8%, P = 0.07). Regarding non-hematological AEs, there were no significant differences in the risks of cytokine release syndrome (CRS, any grade: 64% vs. 66%, P = 0.84; grade ≥ 3: 1% vs. 1%, P = 0.36) and infections (any grade: 47% vs. 49%, P = 0.86; grade ≥ 3: 24% vs. 20%, P = 0.06) between the two groups. However, non-BCMA-targeted BsAbs therapy was associated with a higher risk of immune effector cell-associated neurotoxicity syndrome (ICANS, any grade: 11% vs. 2%, P < 0.01) and lower risks of fatigue (any grade: 14% vs. 30%, P < 0.01) and pyrexia (any grade: 14% vs. 29%, P < 0.01). This analysis suggest that non-BCMA-targeted BsAbs therapy may offer a more favorable treatment response and tolerability, while BCMA-targeted BsAbs therapy may be associated with diminished neurotoxic effects. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42018090768.

Clinical Efficacy and Safety of Flumatinib in the Treatment of Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase

To explore the clinical efficacy and safety of flumatinib mesylate produced in China in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). 32 newly diagnosed CML-CP patients admitted to the Hematology Department of the Affiliated Hospital of Southwest Medical University from March 1, 2020 to March 31, 2022, who had never received any tyrosine kinase inhibitor (TKI) were included in the study. The patients were treated by flumatinib mesylate 600mg once daily. The hematologic, cytogenetic and molecular responses were assessed at 3-, 6- and 12-month, and adverse effects of the drug were evaluated. 31 patients were treated with flumatinib for≥3 months, of which 24 patients were treated for ≥6 months and 14 patients were treated for≥12 months. At 3rd month of treatment, 30 out of 31 patients achieved complete hematologic response (CHR); 24 patients underwent cytogenetic testing and 22 cases achieved major cytogenetic response(MCyR), of which 21 cases achieved complete cytogenetic response (CCyR); Among 25 patients who underwent molecular testing, 22 patients had BCR-ABLIS≤10%, including 10 patients with BCR-ABLIS≤0.1%, and 6 patients with BCR-ABLIS≤0.01%. At 6th month of treatment, 23 out of 24 patients achieved CHR; 17 patients underwent cytogenetic testing and all achieved CCyR; Among 23 patients who underwent molecular testing, 20 patients had BCR-ABLIS≤1%, including 16 patients with BCR-ABLIS≤0.1% and 12 patients with BCR-ABLIS≤0.01%. At 12nd month of treatment, all 14 patients achieved CHR and CCyR; Among them, 10 patients had BCR-ABLIS≤0.1%, including 9 patients with BCR-ABLIS≤0.01%. The grade Ⅲ/Ⅳ leukopenia, thrombocytopenia and anemia rates in the patients were 13.3%, 20.0% and 3.3%, respectively. One patient stopped flumatinib therapy due to severe and persistent hematologic toxicity. The major non-hematologic adverse events were abnormal liver function (20%), diarrhea (10%), bone/joint pain (10%), muscle spasm (10%), rash (6.7%), acute kidney injury (6.7%) and nausea(3.3%), most of which were grade I-II. No patient experienced grade Ⅳ non-hematologic adverse events. No drug toxicity-related death occurred. Flumatinib mesglate, as the first-line treatment for newly diagnosed CML-CP, can enable the patients to achieve early and deep molecular and cytogenetic responses, and shows good safety.

Phase 2 study of add-on parsaclisib for patients with myelofibrosis and suboptimal response to ruxolitinib: final results

AbstractRuxolitinib reduces spleen volume, improves symptoms, and increases survival in patients with intermediate- or high-risk myelofibrosis. However, suboptimal response may occur, potentially because of signaling via the phosphoinositide 3-kinase (PI3K)/protein kinase B pathway. This phase 2 study evaluated dosing, efficacy, and safety of add-on PI3Kδ inhibitor parsaclisib for patients with primary or secondary myelofibrosis with suboptimal response to ruxolitinib. Eligible patients remained on a stable ruxolitinib dose and received add-on parsaclisib 10 or 20 mg, once daily for 8 weeks, and once weekly thereafter (daily-to-weekly dosing; n = 32); or parsaclisib 5 or 20 mg, once daily for 8 weeks, then 5 mg once daily thereafter (all-daily dosing; n = 42). Proportion of patients achieving a ≥10% decrease in spleen volume at 12 weeks was 28% for daily-to-weekly dosing and 59.5% for all-daily dosing. Proportions of patients achieving ≥50% decrease at week 12 in Myelofibrosis Symptom Assessment Form and Myeloproliferative Neoplasms Symptom Assessment Form symptom scores were 14% and 18% for daily-to-weekly dosing, and 28% and 32% for all-daily dosing, respectively. Most common nonhematologic treatment-emergent adverse events were nausea (23%), diarrhea (22%), abdominal pain and fatigue (each 19%), and cough and dyspnea (each 18%). New-onset grade 3 and 4 thrombocytopenia were observed in 19% of patients, each dosed daily-to-weekly, and in 26% and 7% of patients dosed all-daily, respectively, managed with dose interruptions. Hemoglobin levels remained steady. The addition of parsaclisib to stable-dose ruxolitinib can reduce splenomegaly and improve symptoms, with manageable toxicity in patients with myelofibrosis with suboptimal response to ruxolitinib. This trial was registered at www.clinicaltrials.gov as #NCT02718300.

Azacitidine, Venetoclax, and Gilteritinib in Newly Diagnosed and Relapsed or Refractory FLT3-Mutated AML.

Azacitidine plus venetoclax is a standard of care for patients with newly diagnosed AML who are unfit for intensive chemotherapy. However, FLT3 mutations are a common mechanism of resistance to this regimen. The addition of gilteritinib, an oral FLT3 inhibitor, to azacitidine and venetoclax may improve outcomes in patients with FLT3-mutated AML. This phase I/II study evaluated azacitidine, venetoclax, and gilteritinib in two cohorts: patients with (1) newly diagnosed FLT3-mutated AML who were unfit for intensive chemotherapy or (2) relapsed/refractory FLT3-mutated AML (ClinicalTrials.gov identifier: NCT04140487). The primary end points were the maximum tolerated dose of gilteritinib (phase I) and the combined complete remission (CR)/CR with incomplete hematologic recovery (CRi) rate (phase II). Fifty-two patients were enrolled (frontline [n = 30]; relapsed/refractory [n = 22]). The recommended phase II dose was gilteritinib 80 mg once daily in combination with azacitidine and venetoclax. In the frontline cohort, the median age was 71 years and 73% of patients had an FLT3-internal tandem duplication (ITD) mutation. The CR/CRi rate was 96% (CR, 90%; CRi, 6%). Sixty-five percent of evaluable patients achieved FLT3-ITD measurable residual disease <5 × 10-5 within four cycles. With a median follow-up of 19.3 months, the median relapse-free survival (RFS) and overall survival (OS) have not been reached and the 18-month RFS and OS rates are 71% and 72%, respectively. In the relapsed/refractory cohort, the CR/CRi rate was 27%; nine additional patients (41%) achieved a morphologic leukemia-free state. The most common grade 3 or higher nonhematologic adverse events were infection (62%) and febrile neutropenia (38%), which were more frequent in the relapsed/refractory cohort. The combination of azacitidine, venetoclax, and gilteritinib resulted in high rates of CR/CRi, deep FLT3 molecular responses, and encouraging survival in newly diagnosed FLT3-mutated AML. Myelosuppression was manageable with mitigative dosing strategies.

Biweekly gemcitabine plus nab-paclitaxel as first-line therapy for older adult patients with unresectable pancreatic cancer: A prospective study.

672 Background: Although the number of older adult patients (aged ≥ 75 years) with pancreatic cancer (PC) is increasing, there are still limited data regarding chemotherapy for these patients, who experience adverse events more frequently than younger patients with PC. In this study, we evaluated the efficacy and safety of biweekly gemcitabine plus nab-paclitaxel (GnP) as first-line therapy for older adult patients with unresectable PC. Methods: We conducted a single-center prospective study. Patients aged ≥ 75 years with pathologically proven unresectable pancreatic adenocarcinoma were enrolled after obtaining written informed consent. Patients were treated with a modified regimen of gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) on days 1, 15 of every 28-day cycle. The primary endpoint was the overall response rate. Secondary endpoints included disease control rate, overall survival, progression-free survival, 1-year survival rate, 2-year survival rate, and adverse events. Results: From August 2018 to March 2021, 17 patients were enrolled (locally advanced 4; metastatic 13). Five patients (29.4%) were men, and the median age was 77 years (range: 75-81). The median Geriatric 8 score was 13 points (range 6-17). Biliary drainage was performed in three patients. The overall response rate was 47.1% (8/17). Disease control rate was 82.4% (14/17). Median overall survival was 16.8 months (95% confidence interval (CI) 5.9-24.6) and median progression-free survival was 8.3 months (95% CI: 4.9-10.1), respectively. The 1-year survival rate and 2-year survival rates were 58.8% and 29.4%, respectively. Grade 3 or 4 hematologic adverse events and non-hematologic adverse events were observed in 17.6% (3/17) and 29.4% (5/17), respectively. No deaths was observed in association with biweekly GnP regimen. Conclusions: Biweekly GnP as first-line therapy can provide favorable treatment outcomes with tolerable toxicity in older adult patients with unresectable PC. Clinical trial information: jRCTs051190038 .

A retrospective analysis of the efficacy and safety of imatinib in elderly patients with advanced gastrointestinal stromal tumor.

730 Background: Gastrointestinal stromal tumor (GIST) is a rare mesenchymal tumor arising from the gastrointestinal tract, characterized by a high predominance of the elderly population. Imatinib is the standard first-line therapy for advanced GIST with a median survival of around 4 years in pivotal clinical trials. However, clinical data for the elderly population is not known well. The aim of this study is to evaluate the efficacy and safety of imatinib for advanced GIST in the elderly population in comparison with the non-elderly population. Methods: We extracted clinical data of patients with advanced GIST treated with imatinib as first-line therapy at our institution between January 2010 and July 2023. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and adverse events (AEs) were assessed and compared between the elderly group (age: ≥ 70 years, E group) and the non-elderly group (age: &lt; 70 years, NE group). Multivariable analyses were performed using Cox proportional hazard models to evaluate the prognostic significance of age groups. Results: A total of 91 patients were included in this analysis with 32 patients in the E group and 59 patients in the NE group with a median follow-up duration of 39.8 months. Patient characteristics were as follows (the E group vs. the NE group): median age 76 (70–90) vs. 54 (29–69) years, male: 50% vs. 56%, performance status 0: 19% vs. 63%, disease status (: 47% vs. 44%), stomach primary 44% vs. 34%, KIT mutation (exon 11: 50% vs. 61%), and maximum tumor diameter (≥8cm: 66% vs. 51%). The proportion of patients with a reduced starting dose of imatinib was significantly higher in the E group (34% vs. 2%, p &lt;0.0001). Median PFS in the E group and the NE group were 29.4 months and 60.0 months (HR=2.04, log-rank p=0.035). Median OS in the E group and the NE group were 91.5 months and not reached (HR=2.74, log-rank p=0.02). ORR was 53% in the elderly group and 66% in the non-elderly group (p=0.32). In for OS, age was not an independent prognostic factor (HR=2.09, p=0.14) with a significant independent prognostic factor of disease status (unresectable/initially metastatic vs. recurrent (reference): HR=3.58, p=0.03). The occurrence of ≥ grade 2 non-hematologic AEs was more common in the elderly group compared to the non-elderly group (78% vs. 32%, p&lt;0.001). Conclusions: The elderly population with advanced GIST may achieve a survival period comparable to that observed in pivotal trials with imatinib. Even with reduced doses of imatinib, careful monitoring is necessary because of the high frequency of non-hematologic ≥ grade 2 AEs in the elderly population.

A phase 1/2 study of mini-hyper-CVD plus venetoclax in patients with relapsed/refractory acute lymphoblastic leukemia

AbstractPreclinical studies suggest that Bcl-2 inhibition with venetoclax has antileukemic activity in acute lymphoblastic leukemia (ALL) and may synergize with conventional chemotherapy. We designed a phase 1/2 clinical trial to evaluate the safety and efficacy of low-intensity chemotherapy in combination with venetoclax in adults with relapsed or refractory ALL. Patients received the mini-hyper-CVD regimen (dose-attenuated hyperfractionated cyclophosphamide, vincristine, and dexamethasone alternating with methotrexate and cytarabine) in combination with venetoclax (200 mg or 400 mg daily) on days 1 to 14 in cycle 1 and on days 1 to 7 in consolidation cycles. Twenty-two patients were treated. The median number of prior therapies was 2 (range, 1-6). Thirteen patients (59%) had undergone prior allogeneic stem cell transplant (allo-SCT), and 7 of 18 patients (39%) with B-cell ALL had previously received both inotuzumab ozogamicin and blinatumomab. The recommended phase 2 dose of venetoclax in the combination regimen was 400 mg daily. The composite complete remission (CR) and CR with incomplete hematologic recovery (CRi) rate was 57% (CR, 43%; CRi, 14%), and 45% of responders achieved measurable residual disease negativity by multiparameter flow cytometry. Four patients proceeded to allo-SCT. The median duration of response was 6.3 months. The median overall survival was 7.1 months, and the 1-year overall survival rate was 29%. The most common grade ≥3 nonhematologic adverse events were infection in 17 patients (77%) and febrile neutropenia in 4 patients (18%). Overall, the combination of mini-hyper-CVD plus venetoclax was active in heavily pretreated relapsed/refractory ALL. Further development of venetoclax-based combinations in ALL is warranted. This trial is registered at www.clinicaltrials.gov as #NCT03808610.

Tolerability of Daratumumab Amongst Asian Patients with Plasma Cell Dyscrasias – A Single Centre Experience.

Daratumumab is increasingly incorporated into the standard treatment regimens for patients with plasma cell dyscrasias in Asia, especially with cost-containment measures implemented by various regional health authorities. This analysis aimed to study daratumumab’s tolerability amongst Asian patients. This is a retrospective medical records review of patients who received daratumumab between November 2016 and August 2021 as part of routine clinical care. Sixty-two patients were included in the study: 62.9% had renal impairment, and 27.4% had creatinine clearance (CrCl) &lt;30ml/min. Forty-five patients (72.6%) received daratumumab combination therapy, with a median 1 line of prior therapy. The median duration of follow-up was 12.4 months, and the median duration patients were on treatment with daratumumab was 12.3 months. Twenty-one of 62 (33.9%) patients experienced infusion-related reactions (IRRs) after the first dose of intravenous daratumumab. Seven developed mostly grades 1 and 2 respiratory events, and 14 showed grades 1 and 2 non-respiratory IRRs. Only one patient experienced a grade 1 IRR with the second infusion, with none developing any IRRs in the third or subsequent infusions. Eight (12.9%) patients were affected by hematological adverse events (AEs), mostly grades 2 and 3, with one experiencing grade-4 neutropenia without sepsis. Six (9.7%) patients experienced non-hematological AEs, the commonest being pneumonia and other infections, with one developing Nocardia pneumonia (grade 4) 14 months after the initiation of daratumumab. In conclusion, daratumumab is tolerable amongst Asian patients, including the elderly, and patients with severe renal impairment and chronic lung diseases.

Hypofractionated radiotherapy for refractory or relapsed aggressive B-cell lymphoma in the rituximab era

BackgroundRadiotherapy (RT) is an effective and available local treatment for patients with refractory or relapsed (R/R) aggressive B-cell lymphomas. However, the value of hypofractionated RT in this setting has not been confirmed.MethodsWe retrospectively analyzed patients with R/R aggressive B-cell lymphoma who received hypofractionated RT between January 2020 and August 2022 at a single institution. The objective response rate (ORR), overall survival (OS), progression-free survival (PFS) and acute side effects were analyzed.ResultsA total of 30 patients were included. The median dose for residual disease was 36 Gy, at a dose per fraction of 2.3–5 Gy. After RT, the ORR and complete response (CR) rates were 90% and 80%, respectively. With a median follow-up of 10 months (range, 2–27 months), 10 patients (33.3%) experienced disease progression and three died. The 1-year OS and PFS rates for all patients were 81.8% and 66.3%, respectively. The majority (8/10) of post-RT progressions involved out-of-field relapses. Patients with relapsed diseases, no response to systemic therapy, multiple lesions at the time of RT, and no response to RT were associated with out-of-field relapses. PFS was associated with response to RT (P = 0.001) and numbers of residual sites (P < 0.001). No serious non-hematological adverse effects (≥ grade 3) associated with RT were reported.ConclusionThese data suggest that hypofractionated RT was effective and tolerable for patients with R/R aggressive B-cell lymphoma, especially for those that exhibited localized residual disease.

Efficacy of continuous arterial perfusion chemotherapy combined with transarterial chemoembolization regional arterial thermal perfusion in the treatment of pancreatic cancer with liver metastases

Abstract Background The aim of the study was to investigate the efficacy of continuous transcatheter arterial infusion chemotherapy combined with transarterial chemoembolization (TACE) for the treatment of advanced pancreatic cancer with liver metastasis. Methods Sixty patients with advanced pancreatic cancer and liver metastases were enrolled in this study. In the treatment group, 31 patients underwent continuous transcatheter arterial infusion chemotherapy combined with TACE regional arterial thermal perfusion, whereas 29 patients included in the control group received intravenous chemotherapy with gemcitabine and S-1. All patients received maintenance chemotherapy with S-1 after 4 cycles of the study regimen. Treatment efficacy, quality of life, survival, and toxicity were evaluated. Results Efficacy was better in the treatment group than in the control group, as reflected by the objective remission, partial remission, and disease progression rates (all P &lt; 0.05). The Eastern Cooperative Oncology Group and Numerical Rating Scale pain scores were also higher in the treatment group (both P &lt; 0.05). In survival analysis, the 1-year overall survival rates in the treatment and control groups were 64.516% and 10.345%, respectively, whereas the median overall survival times were 16 and 6 months, respectively (both P &lt; 0.05). The 6-month progression-free survival rates in the treatment and control groups were 77.419% and 13.790%, respectively, and the median progression-free survival times were 12 and 3 months, respectively (both P &lt; 0.05). The rates of hematological and nonhematological toxicological adverse effects were also lower in the treatment group (both P &lt; 0.05). Although the rate of liver dysfunction was higher in the treatment group, this finding had no adverse effects on prognosis. Conclusions Continuous transcatheter arterial infusion chemotherapy combined with TACE regional arterial perfusion chemotherapy resulted in better efficacy and safety outcomes in patients with pancreatic cancer and liver metastasis, suggesting its utility as a reference method for the clinical treatment of advanced pancreatic cancer.