Hematologic Toxicity Grade Research Articles

Bone marrow toxicity in patients with locally advanced cervical cancer undergoing multimodal treatment with VMAT/IMRT: are there dosimetric predictors for toxicity?

PurposeFor women with locoregionally advanced cervical cancer, the standard of care treatment is the curatively intended chemoradiation therapy (CRT). A relationship between bone marrow (BM) dose–volume histograms (DVHs) and acute hematological toxicity (HT) has been debated recently. Aim of this study was the evaluation of BM dose constraints and HT in a contemporary patient cohort.MethodsRadiation treatment plans of 31 patients with cervical cancer (FIGO stage IIB–IVB) treated with intensity-modulated radiotherapy and simultaneous chemotherapy were explored retrospective. Pelvic bones (PB) and femoral heads (FH) were contoured and DVHs were correlated with white blood cells (WBC), hemoglobin levels and platelets.ResultsComparing the absolute blood levels with the dose volumes of both FH and PB the data showed a significant correlation between WBC and the median dose of the FH and the median dose, V30Gy, V40Gy and V50Gy of the PB. A correlation between the toxicity grade of anemia and mean dose, maximum dose and V5Gy of the PB was found. Counting the highest grade of HT of all three blood levels of each patient, significant correlations were found for the mean and median dose, V30Gy, V40Gy and V50Gy of the PB.ConclusionThe results show that blood levels may correlate with distinct dosimetric subvolumes of critical bone marrow compartments with a potential impact on therapeutic outcome and treatment-related toxicity. The data presented are in line with the previous findings on the relevance of dosimetric exposure of pelvic bony subvolumes.

Efficacy and safety of apatinib combined with nab-paclitaxel for second-line treatment of metastatic triple negative breast cancer (TNBC): An open-label phase II trial.

e13127 Background: Apatinib is an oral, highly potent tyrosine-kinase inhibitor targeting VEGFR2. Preclinical studies have demonstrated that apatinib can enhance the anti-tumor effect of taxanes in TNBC via promoting apoptosis and suppressing migration and invasion of tumor cells. Previous studies have also shown the role of apatinib in combination with chemotherapy for treating TNBC. However, combinational treatment of apatinib and nab-paclitaxel for metastatic TNBC has not been reported. Therefore, the objective of this study was to evaluate the safety and efficacy of apatinib in combination with nab-paclitaxel as a second-line treatment for TNBC. Methods: This is a single-center, single-arm, and open-label prospective study. The patients enrolled in this study had metastatic TNBC, ECOG PS 0-2, at least one measurable lesion, and had previously received one systemic therapy except apatinib and nab-paclitaxel. They were treated with apatinib (250mg, PO, QD) plus nab-paclitaxel (125mg/m2, IV, day 1, 8 and 15) every 3 weeks as second-line treatment until disease progression, unacceptable toxicity, or consent withdrawal. The study utilized RECIST v1.1 to assess efficacy and NCI-CTCAE 5.0 to report adverse events. The study's primary endpoints were tolerability and progressive free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR) and disease control rate (DCR). Results: Twenty patients were enrolled by the cut-off date of December 1st, 2023. The median age was 55 years (range 31-76) and all had an ECOG PS of 0-1. Ninety percent of the sample had a Ki67 of 30% or higher, while 85% tested negative for PD-L1. All patients had distant metastases, with 35.0% having visceral metastasis and 35% having metastatic sites of 3 or more. 70% of patients had undergone surgery on the primary tumor. All patients received apatinib plus nab-paclitaxel treatment, with a median of 9 cycles (range 2-25), were included in the safety dataset. All patients experienced grade 1-2 treatment-related adverse events (TRAEs). Haematological toxicity of grade 3-4 with neutropenia occurred in 25.0% of patients. In addition, non-haematological toxicities were observed in 10% of patients, including abnormal hepatic function (5.0%) and hypertension (5.0%). No treatment-emergent adverse event (TEAE) resulted in death during the study. Out of the 20 evaluated patients, the median progression-free survival (PFS) was 6.7 months (95% CI: 6.0-NR). The objective response rate (ORR) was 65.0% (13/20), and the disease control rate (DCR) was 90.0% (18/20), according to RECIST v1.1. The median overall survival (OS) has not yet been reached. Conclusions: The combination of apatinib and nab-paclitaxel showed promising antitumor activity in patients with metastatic TNBC as a second-line treatment, with a manageable safety profile. Clinical trial information: NCT05019690 .

Hematologic Toxicity and Bone Marrow-Sparing Strategies in Chemoradiation for Locally Advanced Cervical Cancer: A Systematic Review.

The standard treatment for locally advanced cervical cancer typically includes concomitant chemoradiation, a regimen known to induce severe hematologic toxicity (HT). Particularly, pelvic bone marrow dose exposure has been identified as a contributing factor to this hematologic toxicity. Chemotherapy further increases bone marrow suppression, often necessitating treatment interruptions or dose reductions. A systematic search for original articles published between 1 January 2006 and 7 January 2024 that reported on chemoradiotherapy for locally advanced cervical cancer and hematologic toxicities was conducted. Twenty-four articles comprising 1539 patients were included in the final analysis. HT of grade 2 and higher was observed across all studies and frequently exceeded 50%. When correlating active pelvic bone marrow and HT, significant correlations were found for volumes between 10 and 45 Gy and HT of grade 3 and higher. Several dose recommendations for pelvic bone and pelvic bone marrow sparing to reduce HT were established, including V10 < 90-95%, V20 < 65-86.6% and V40 < 22.8-40%. Applying dose constraints to the pelvic bone/bone marrow is a promising approach for reducing HT, and thus reliable implementation of therapy. However, prospective randomized controlled trials are needed to define precise dose constraints and optimize clinical strategies.

Оптимизация терапии у пациентов с впервые диагностированной диффузной В-крупноклеточной лимфомой: эффективность и безопасность программы R-SD-EPOCH ± HDMTX в рамках одноцентрового нерандомизированного проспективного клинического исследования (предварительные результаты)

Оптимизация терапии у пациентов с впервые диагностированной диффузной В-крупноклеточной лимфомой: эффективность и безопасность программы R-SD-EPOCH ± HDMTX в рамках одноцентрового нерандомизированного проспективного клинического исследования (предварительные результаты)

Phase II study of the novel antifolate agent pralatrexate in combination with the histone deacetylase inhibitor romidepsin for the treatment of patients with mature T-cell lymphoma

Previously, we conducted a Phase I study of the combination of pralatrexate and romidepsin in patients with relapsed/refractory (R/R) lymphomas and subsequently conducted a multicenter Phase II study in patients with untreated or R/R mature T cell lymphomas (MTCL). Patients received pralatrexate 25 mg/m2 and romidepsin 12 mg/m2 every 2 weeks. Fourteen patients were evaluable for efficacy. Overall response rate was 35.7% with CR in 14.3% and disease control in 50%. The mDOR was 8.2 months, mPFS was 3.6 months, and mOS was 20.2 months. Gastrointestinal side effects were most common in up to 33%; there was only one hematologic toxicity of grade 3 anemia. Combining results of MTCL patients from the Phase I and II studies (N = 28), the ORR was 53.5% with CR in 21.4%, disease control in67.8%, and DOR of 7.2 months. The combination was safe however does not out-perform other combination strategies.Trial Registration: www.clinicaltrials.gov (NCT 01947140).

Preliminary results of surgical treatment and neoadjuvant chemotherapy in upper rectal cancer

Introduction: There is a lack of information on the role of neoadjuvant chemotherapy in upper rectal cancer. The aim of our research was to investigate the role of neoadjuvant chemotherapy in upper rectal cancer treatment.Materials and methods: We conducted a retrospective cohort multicenter study to analyze the medical records of patients with upper rectal cancer from 2007 to 2020 obtained from the archive of Research Institute FSBI «N. N. Blokhin Cancer Research Center» of the Ministry of Health of Russia, A. N. Ryzhikh National Medical Research Centre for Coloproctology, Stavropol regional Clinical oncological Dispensary and Kaliningrad oncological Center. All patients were divided into 2 groups: group 1 included patients who underwent neoadjuvant chemotherapy with CAPOX as the first treatment step, and group 2 included patients who underwent upfront surgery. Primary endpoint was 3‑year disease-free survival (DFS) rate. We also estimated the pathological complete response (pCR) rate, treatment toxicity, postoperative morbidity rate (Clavien – Dindo), degree of tumor regression, local recurrence rate, distant metastases rate, 3‑year overall survival (OS) and the neoadjuvant chemotherapy completion rate.Results: 118 patients were included in the neoadjuvant chemotherapy group and 103 patients — in the surgery group. Study groups were well balanced and comparable for gender, the ASA status and the tumor differentiation grade. More patients in the neoadjuvant chemotherapy group had clinically positive lymph nodes (p = 0.002). Median follow-up period was 36 months. There were no significant differences in 3‑year OS and DFS. The local recurrence rate was 3.9 % in the surgery group versus 0 % in the neoadjuvant chemotherapy group (p = 0.046). There were no significant differences between study groups in the distant metastases rate (p = 0.293). Sixteen (13.6 %) patients had a pCR after neoadjuvant chemotherapy. The neoadjuvant chemotherapy completion rate was 91.5 %. The hematological toxicity grade 3–4 was observed in 3.3 % (4 patients), the non-hematological toxicity grade 3–4 in 3.3 % (4 patients).Conclusion: NACT has an acceptable toxicity profile, does not impede oncological treatment results, and can be used in a selected group of patients for early systemic control.

Комбинация Nivo-DHAP с последующей высокодозной химиотерапией и трансплантацией аутологичных гемопоэтических стволовых клеток у пациентов с рецидивами и рефрактерным течением классической лимфомы Ходжкина: результаты многоцентрового проспективного клинического исследования (ClinicalTrials.gov, NCT04091490)

Background. High-dose chemotherapy (HDCT) with autologous hematopoietic stem cell transplantation (auto-HSCT) is currently regarded as a standard treatment for patients with relapsed/refractory classical Hodgkin lymphoma (cHL). The efficacy of transplantation correlates with the depth of antitumor response achieved on pre-transplantation chemotherapy. A combination of PD-1 inhibitors with chemotherapy is a new forward-looking approach ensuring a higher rate of complete responses prior to auto-HSCT as well as better outcomes of the treatment in general.&#x0D; Aim. To assess the efficacy and safety of the combined program with Nivo-DHAP and subsequent HDCT and auto-HSCT in patients with relapsed/refractory cHL.&#x0D; Materials &amp; Methods. From March 2020 to January 2022, 38 patients were enrolled in the study. The Nivo-DHAP program consisted of two stages. At stage 1 nivolumab immunotherapy was administered: two 240 mg/day IV infusions as a monoregimen 14 days apart. Stage 2, Nivo-DHAP immunochemotherapy, started in 14 days after stage 1: nivolumab 480 mg/day IV infusion on Day 1 in combination with DHAP chemotherapy, total of 4 cycles. The efficacy of this therapy was evaluated after 2 nivolumab infusions as well as after 2 and 4 Nivo-DHAP cycles. The program was fully implemented in 36 patients. HSCs were collected after remission had been reported, in most cases it was after 2 Nivo-DHAP cycles. For various reasons, auto-HSCT was performed only in 23 out of 36 patients. The median follow-up of patients after auto-HSCT was 24 months.&#x0D; Results. After completing the pre-transplantation stage of the program to the full extent, which included Nivo, Nivo, and 4 Nivo-DHAP cycles, 36 patients showed a 100 % overall objective response. Complete response was achieved in 27 (75 %) patients, and partial response was reported in 9 (25 %) patients. The signs of hematological toxicity grade 3/4 were manifested in 26 % of patients. In the total cohort of 36 patients with (n = 23) and without (n = 13) auto-HSCT, progression-free survival (PFS) was 81 % with the follow-up of 12 months, 78 % with the follow-up of 24 months, and 74 % with the follow-up of 36 months. Overall survival (OS) in the total cohort with the same follow-up end-points was 95 %. A comparative assessment revealed that PFS was 87 % in the cohort with auto-HSCT with the follow-up of 12, 24, and 36 months and 70 %, 64 %, and 48 % in the cohort without auto-HSCT with the same follow-up end-points, respectively (p = 0.056).&#x0D; Conclusion. A combination of PD-1 inhibitors with chemotherapy as a stage prior to HDCT followed by auto-HSCT is a promising strategy resulting in high PFS and OS rates. Preliminary data on using PD-1 inhibitors combined with chemotherapy cannot yet provide substantial basis for disregarding HDCT with subsequent auto-HSCT which is considered to be the optimal method for remission consolidation.

Venetoclax plus dose-adjusted R-EPOCH (VR-DA-EPOCH) or G-EPOCH bridging to subsequent cellular therapy for the patients with transformed lymphoma a single center clinical experience

Indolent lymphoma, including chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and follicular lymphoma (FL), can undergo histological transformation into an aggressive subtype, typically diffuse large B-cell lymphoma (DLBCL). The prognosis of transformed lymphoma is poor. In this study, we reported the efficacy and toxicity of a combination of venetoclax, dose-adjusted rituximab or obinutuzumab, etoposide, prednisone, vincristine, doxorubicin, and cyclophosphamide (VR-DA-EPOCH or VG-DA-EPOCH) in 11 patients with biopsy-proven histology transformation into DLBCL, including 8 patients with RT and 3 with transformed FL (tFL). The study was conducted between October 2019 and March 2023 at our single center. The median age of participants at enrolment was 53 years. Six patients (85.7%, 6/7) achieved complete remission (CR) at the end of treatment. The best overall response rate (ORR) and CR rate were both 72.7%, respectively. Two patients received autologous hemopoietic stem cell transplant (ASCT) while two patients received ASCT concurrently with CAR-T therapy for consolidation. With a median follow-up of 13.5 (range, 2.4–29.8) months after enrollment, the median event-free survival, progression-free survival, and overall survival were 9.4, 11.5, and 17.5 months, respectively. Hematologic toxicities of grade ≥3 consisted of neutropenia (90.9%, 10/11), thrombocytopenia (63.6%, 7/11), and febrile neutropenia (54.5%, 6/11). In conclusion, VR-DA-EPOCH or VG-DA-EPOCH was a promising strategy to achieve an early remission, bridging to cellular therapy within this population.

Treatment Continuity and Bone Marrow Suppression in Whole-Brain and Whole-Spinal Cord Radiotherapy for Medulloblastoma Patients.

This study investigated the factors influencing treatment continuity and bone marrow suppression in whole-brain and whole-spinal cord radiotherapy for medulloblastoma, providing a clinical reference for mitigating the impact of hematological suppression on radiotherapy continuity. A retrospective analysis was conducted on patients with medulloblastoma who underwent craniospinal irradiation (CSI) radiotherapy at our hospital between August 2019 and December 2023. According to the inclusion and exclusion criteria, a total of 87 patients were enrolled. The bone marrow suppression status, clinical data, and radiotherapy dose data of the enrolled patients were recorded, and correlation analyses were performed. Based on the correlation results, further group comparisons were subsequently conducted. Overall, 22.99% (20 out of 87) of the patients experienced treatment interruption (median duration, 6.5 [5, 8] days), typically during the 12th (7.5, 14.75) radiotherapy session. Treatment continuity was weakly correlated with age and treatment modality, and the timing of interruptions was weakly correlated with dosage and treatment modality. Bone marrow suppression severity was weakly correlated with age, body mass index (BMI), and treatment modality. Treatment modality and age were found to be independent predictors of treatment continuity and the degree of bone marrow suppression, respectively. Subgroup comparisons revealed differences in the severity of bone marrow suppression, grade of hematological toxicity, and timing of interruption depending on the treatment modality, dosage, and sex (P < .05). Timely monitoring of hematological changes, especially in the middle and posterior segments after radiotherapy, is crucial. Treatment with helical tomotherapy, male sex, younger age, and lower BMI during radiotherapy are indicators of greater clinical attention.

Targeted therapy for advanced forms of systemic mastocytosis in real clinical practice

Background. Mastocytosis is a heterogeneous group of diseases that are characterized by excessive proliferation and accumulation of clonal (neoplastic) mast cells in one or more organs. Advanced variants of systemic mastocytosis (aggressive systemic mastocytosis, systemic mastocytosis associated with hematological neoplasm, and mast cell leukemia) are characterized by infiltration of organs by mast cells, which leads to organs dysfunction. Such patients require a more active approach and the use of cytoreductive therapy. Available therapeutic options include imatinib, interferon-alpha, cladribine. Only one of the targeted drugs is registered in Russia – midostaurin. Midostaurin is a potent multikinase inhibitor that is active against KIT regardless of mutation status. Midostaurin has shown its effectiveness in clinical trials, however, we know that data from real clinical practice often differ from clinical studies due to the characteristics of patients (preserved comorbid status, stable disease parameters) traditionally included in clinical trials.Aim. To evaluate the effectiveness and safety of midostaurin in patients with advanced variants of systemic mastocytosis in real clinical practice.Materials and methods. This work analyzed 13 patients (7 (54 %) men and 6 (46 %) women) who received midostaurin therapy for systemic mastocytosis (aggressive systemic mastocytosis – 9 (69 %), systemic mastocytosis associated with a hematological neoplasm – 4 (31 %)). The median age of patients when the diagnosis was verified was 73 (61–87) years, the median age when midostaurin was prescribed was 74 (61–88) years. According to the International prognostic scoring system for mastocytosis (IPSM) based on clinical variables, patients are classified as follows groups: SM1 – 1 (8 %) patient, SM2 – 3 (23 %), SM3 – 8 (61 %), SM4 – 1 (8 %).Results. As a result of therapy, clinical improvement was achieved in 10 (77 %) patients, and stabilization in 3 (23 %) patients. During midostaurin therapy, grade I–II adverse events were noted from the gastrointestinal tract: nausea in 5 patients (38 %), vomiting in 2 (15 %), diarrhea in 6 (46 %). Hematological toxicity of grade I–II was also observed: anemia in 6 (46 %) patients, thrombocytopenia in 5 (38 %) patients. The median overall survival in the group was not achieved. The 2-year overall survival rate was 75 %.Conclusion. The study results suggest the potential efficacy and safety of midostaurin in patients with aggressive systemic mastocytosis and systemic mastocytosis associated with hematological malignancies.

Association of Hypomethylating Agents + Venetoclax in the Real-Life Treatment of Myeloproliferative Neoplasms in Blastic Phase

Background Association of hypomethylating agents (HMA) and venetoclax (VEN) is widely used in elderly patients (pts) with de novo Acute Myeloid Leukemia not eligible for intensive chemotherapy, with improvement of survival. However, very few data are available in pts with Myeloproliferative Neoplasms evolved in blastic phase (MPN-BP). In this setting, the survival is dismal and at present no therapy seems to have a role. Methods Data of 54 pts with MPN-BP treated frontline with HMA+VEN in 19 hematologic Centers in Italy outside clinical trials from 11/2018 to 3/2023 were retrospectively collected and analysed. Composite overall response rate [ORR; complete remission (CR) + CR with incomplete hematologic recovery (iCR) + partial remission (PR) + hematologic improvement (HI)], duration of response and overall survival (OS) were assessed. Results: Baseline features at evolution and starting treatment are reported in the Table. Median interval from initial MPN diagnosis to evolution was 38.4 months [interquartile range (IQR) 15.4-124.5]. Pts were treated for a median of 3 courses (IQR 2-7): HMA were administered at standard dosage, VEN daily doses in the 1 st cycle are reported in the Table. On the whole, 40 pts (74.1%) had at least one hematologic toxicity of grade 3-4: in particular, severe neutropenia (PMN &amp;lt; 0.5 x 10 9/l) was reported in 37 pts (68.5%). Thirty pts (55.5%) had at least one infective episode during the treatment: pulmonary infections were reported in 13 pts (24.0%). Response to treatment is shown in the Table: ORR was 62.7%, with a median response duration of 9.4 months (95%CI 5.8-12.9). After a median follow-up of 6.7 months (IQR 3.2-12.1), 35 pts (64.8%) died, 2 (3.7%) were lost to follow-up and 17 (31.5%) were alive. Median OS of the whole cohort was 10.6 months (95%CI 5.8-15.3), Pts with any response to HMA+VEN had a significantly longer OS compared to pts with progressive/stable disease [11.6 (95%CI 9.4-13.7) versus 5.4 (95%CI 2.1-8.6) months, respectively (p=0.002)] (Figure). Conclusions: Our real-life data confirm that HMA+ VEN combination could have a role in MPN-BP, with ORR &amp;gt; 50% in pts unfit for intensive approaches: however, this treatment is affected by severe hematologic and infective toxicities and the response duration is short, with a persistently poor median OS. Larger cohorts of pts and a longer follow-up are needed to assess factors predictive of CR/iCR achievement, while addition of other targeted therapies should be explored.

Association of Hypometilating Agents (HMA) + Venetoclax (VEN) in the Therapy of Acute Myeloid Leukemias Evolved from Myelodysplastic Syndromes (AML-MDS) Already Treated with Azacytidine

Background Survival of high-risk Myelodysplastic Syndromes (MDS) treated with azacytidine during the dysplastic phase and then evolved in Acute Myeloid Leukemia (AML-MDS) is very poor. While the association of hypometilating agents (HMA) and venetoclax (VEN) is widely used in de novo AML not eligible for intensive chemotherapy, very few data are available in patients (pts) with AML-MDS. Methods Data of 42 pts with AML-MDS treated frontline with HMA+VEN in 19 hematologic Centres in Italy outside clinical trials from 5/2018 to 3/2023 were retrospectively collected and analysed. Composite overall response rate [ORR; complete remission (CR) + CR with incomplete hematologic recovery (iCR) + partial remission (PR) + hematologic improvement (HI)], duration of response and overall survival (OS) were assessed. Results: Baseline characteristics at evolution in AML are reported in the Table. Median interval from initial MDS diagnosis to evolution was 16.7 months [interquartile range (IQR) 8.2-30.1]. Pts were treated for a median of 3 courses (IQR 2-6): HMA were administered at standard dosage, VEN daily doses in the 1 st cycle are reported in the Table. On the whole, 34 pts (81.0%) had at least one hematologic toxicity of grade 3-4: in particular, severe neutropenia (PMN &amp;lt; 0.5 x 10 9/l) was reported in 32 pts (76.1%). Eighteen pts (42.8%) had at least one infective episode during the treatment: pulmonary infections were reported in 9 pts (21.4%). Response to treatment is shown in the Table: ORR was 52.4%, with a median response duration of 17.8 months (95%CI 3.3-32.2). After a median follow-up from AML evolution of 6.1 months (IQR 2.2-11.6), 31 pts (73.8%) died and 11 (26.2%) were alive. Median OS from AML evolution of the whole cohort was 6.9 months (95%CI 4.7-9.1), Pts with any response to HMA+VEN had a significantly longer OS compared to pts with progressive/stable disease [15.6 (95%CI 11.3-19.8) versus 3.3 (95%CI 0.7-5.8) months, respectively (p&amp;lt;0.001)] (Figure). Conclusions: Our real-life data suggested that HMA+ VEN combination could be useful also in AML-MDS already treated with azacytidine in the dysplastic phase, with an ORR of about 50% in pts unfit for intensive approaches: however, hematologic and infective toxicities were severe and the response duration was short, with a persistently poor median OS. As a consequence, addition of other targeted therapies driven by NGS should be explored in the next future.

Zanubrutinib, Polatuzumab Vedotin and Rituximab (ZPR) Combination Regimen for Relapsed/Refractory Patients with Diffuse Large B-Cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous and invasive lymphoma. About 30% of patients are difficult to cure or relapse after R-CHOP treatment, known as relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). Patients who are not suitable for high-dose chemotherapy followed by autologous stem cell rescue, rely more on the discovery of new drugs and proposals of new treatment plans. Polatuzumab vedotin (Pola) is an antibody-drug conjugate that targets the B-cell antigen CD79b and delivers monomethyl auristatin E (MMAE). It is recently available in China and approved in combination with Bendamustine and Rituximab for r/r DLBCL. However, real-world data on Pola-based regimens are limited. Here, we propose ZPR (combination of Zanubrutinib, Polatuzumab vedotin and Rituximab) as a potential salvage treatment in r/r DLBCL patients, aiming to explore its efficacy and safety in our single center. Response characteristics in patients received ZPR therapy There were already eight r/r DLBCL patients treated with ZPR regimen at our institution between April 1 and July 31, 2023. Informed consent and biological sample donation informed consent were both signed by each participant. Patients were 69 years old on median and half of them were non-GCB type. Seven patients are classified as stage IV. The median number of treatment lines is two. Patients were given Zanubrutinib 160mg bid daily; Polatuzumab vedotin 1.8 mg/kg and Rituximab 375 mg/m 2 on the first day of each cycle (every 21 days per cycle). Four patients completed 3 cycles of ZPR and three underwent a mid-term evaluation. Results showed that the complete remission (CR) rate was 100% (Figure 1). In terms of adverse events, hematological toxicity grade is not greater than level 2 of Common Terminology Criteria for Adverse Events (CTCAE). One patient developed a pulmonary infection during the treatment. The Rationale for the combination of Polatuzumab vedotin, Rituximab and Zanubrutinib The combination therapy of bruton's tyrosine kinase inhibitor (BTKi) with anti-CD20 therapy has been used in many B-cell lymphomas. It was proposed that combining these two drugs will target and clear blood lymphocytes and shorten the time to respond in chronic lymphocytic leukemia patients. Compared with the first generation BTKi the new generation BTKi Zanubrutinib has a higher selectivity and fewer off-target effects on BTK. Meanwhile, Natsumi Kawasaki et al discovered that Pola increased the expression of CD20 and sensitized Pola refractory cells to Rituximab-induced complement-dependent cytotoxicity (CDC). While the release of MMAE, a chemical component of Pola, results in microtubule disruption and cycle arrest. These findings provide a scientific rationale for employing the Pola-Rituximab combination therapy to treat DLBCL patients. However, the combination of Pola and Zanubrutinib does not show a clear mutual antagonism effect. The molecular rationale for the combination of these two drugs needs further exploration. Who are suitable for ZPR regimen? Patients who are diagnosed with r/r DLBCL after standard first-line treatment failure: ECOG≥2Age≥70As a bridging therapy for patients waiting for ASCT or CAR-T therapyAge＜70 expect a high quality of life, still need working, or going to schoolUnable to tolerate standard-dose of chemotherapy due to hematological toxicity (need a blood transfusion, treatment delay, or dosage reduction) Prospective study to be continued Due to the good response of our three r/r DLBCL patients, we intended to conduct a “Prospective single-arm, single-center clinical study of Zanubrutinib, Polatuzumab vedotin and Rituximab (ZPR) regimen in relapsed/refractory patients with diffuse large B-cell lymphoma” to learn more about the impact of the ZPR regimen in the treatment of r/r DLBCL. We got the approval from the Investigator-Initiated Trial (IIT) Scientific Review Board of Zhongshan Hospital after discussing the risks and benefits of ZPR regimen with them. This protocol has also been reviewed and approved by the Institutional Review Board (IRB) of Zhongshan Hospital Affiliated to Fudan University (B2023-186R) and will follow the principles of the Helsinki Declaration. The protocol was previously registered on ClinicalTrials. gov (NCT05940051) . We illustrated the flowchart of our study in Figure 2.

Safety and Efficacy of New Drugs Combinations in Newly Diagnosed Multiple Myeloma with Renal Failure at Onset: A Retrospective Multicentric Study

Renal injury at onset of newly diagnosed multiple myeloma (NDMM) is associated with poor outcome. Patients with severe renal failure due to MM are excluded from clinical trials with new drugs. The aim of this retrospective study was to describe the clinical characteristics, the treatment choices, the efficacy and the incidence of treatment-related toxicities of NDMM patients with renal insufficiency. We enrolled all NDMM patients with renal failure due to the disease treated at our Centers from 2012 to present. Fifty-one patients with a median age of 75 years were included; 76% had an International Staging System (ISS) of 3; 76% had anemia, 74% bone lesions and 30% had hypercalcemia; 31% had micromolecular myeloma. Thirty seven percent of patients had severe renal failure requiring dialysis treatment. Thirty-five percent of patients received treatment according to a VMP (Bortezomib, Melphalan and Prednisone) scheme, 20% received a triplet including Bortezomib and an immunomodulatory drugs (IMIDs) and 33% received a regimen including Daratumumab. The remaining 12% received a douplet (lenalidomide-dexamethasone or melphalan-prednisone). Thirty one percent of patients underwent an autograft procedure. Overall response rate (ORR) was 94% with a complete response (CR) rate of 17%. In terms of recovery of renal function, 50% achieved at least minimal renal response according to IMWG criteria, with 40% obtain a complete recovery of renal function. Patients who received more innovative treatment (regimens containing Daratumumab or Bortezomib in combination with IMIDs) achieved a response rate superior than very good partial response (≥ VGPR) of 74% with hematologic, neurologic, and infectious toxicities grade ≥ 3 of 22%, 7%, and 26%, respectively. Patients who received therapy with VMP or douplet had response rates ≥ VGPR of 25% with hematologic, neurologic, and infectious toxicity grade ≥ 3 rates of 29%, 4%, and 21%, respectively. Complete renal response rates in these two groups of patients were 45% and 20%, respectively. No death due to toxicity was registered. Patients with NDMM with renal failure at onset had a high burden of disease with unfavorable prognostic features. Although the small numbers of the cohort and the retrospective nature of this study it can be concluded that these patients can received new drugs combinations treatments with excellent response rates and without increased toxicity.

Alternating Gemcitabine/Nab-Paclitaxel (GA) and 5-FU/Leucovorin/Irinotecan (FOLFIRI) as First-Line Treatment for De Novo Metastatic Pancreatic Cancer (MPC): Safety and Effect

Background: Both gemcitabine- and 5-fluorouracil (5-FU)-based chemotherapy regimens have demonstrated efficacy in metastatic pancreatic cancer (MPC). Alternating these regimens may reduce toxicity, slow resistant cancer biology emergence, and provide a platform for the addition of other therapeutic agents. Alternating gemcitabine/nab-paclitaxel (GA) and 5-FU/leucovorin/irinotecan (FOLFIRI) in MPC has previously been reported at our own institution and elsewhere. An extension of our institutional observations is reported here. Methods: Patient eligibility required the following: biopsy-proven de novo MPC, no prior evidence of disease on CT, ECOG performance status (PS) ≤ 2, and bi-dimensionally measurable disease. Treatment (Tx) entailed gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2 1, (8), 15 alternating every 8 weeks (2 cycles) with FOLFIRI using standard dosing. Patients were radiographically re-staged every 8 weeks. Tx spanned up to 12 cycles. Tx thereafter was decided following patient/physician discussion. Results: Median overall survival (mOS) was 13.2 months (95% CI 10.9–16.5 months). Median progression-free survival (mPFS) was 8.5 months (95% CI, 7.1–9.9). The 6-, 12-, 18-, and 24-month OS rates were 88%, 54%, 36%, and 20%, respectively. The disease control rate at 16 weeks was 83% (37% PR, 46% SD). Hematologic toxicity grade ≥ 3 included 9.3% anemia, 10.2% neutropenia, and 4.6% thrombocytopenia. Neutrophil growth factors were not used in this cohort. Non-hematologic toxicities grade ≥ 3 included neuropathy 0.9%, nausea/vomiting 0.9%, and diarrhea 0.9%. No patients experienced mucositis on this regimen. Conclusions: Alternating GA/FOLFIRI in MPC has a favorable toxicity profile in comparison to current standard regimens. Median OS was at least competitive with standard regimens, and longer-term (18 and 24 months) OS seemed particularly encouraging. Treatment for ≥48 weeks and ECOG PS of zero at the time of treatment initiation were prognostically significant. Further investigation using this regimen including randomized comparisons, the incorporation of molecular data, and use of additional agents is merited.

Results of combined and chemoradiation treatment of patients with thoracic esophageal cancer according to the data of the regional cancer center

Background. esophageal cancer (ec) is one of the most aggressive malignancies of the gastrointestinal tract. chemoradiation therapy is the standard of care for locally advanced ec.The purpose of the study was to evaluate the efficacy of chemoradiation therapy given alone and in combination with surgery in patients with thoracic esophageal cancer.Material and Methods. From January 1, 2012 to december 31, 2021, a total of 940 patients with thoracic esophageal cancer were registered in the regional cancer registry, of which 178 patients were selected for concurrent chemoradiotherapy (CRT) at clinical stages I–III. thirty seven thoracic esophageal cancer patients who received CRT and required treatment interruption due to complications were not included in our analysis. The final analysis included 141 patients.Results. 37 (20.7 %) patients were unable to complete treatment due to intolerance and the development of severe complications of CRT. Hematological toxicity of grade 3-4 was noted in 21 patients (14.8 %). Non-hematological complications of grade 2-4 were noted in 109 patients (77.3 %). The 5-year relapse-free survival rates in patients undergoing and non-undergoing to surgery were 23.0 and 25.0 %, respectively (p=0.018). Overall 5-year survival rates were 24 and 27 %, respectively (p=0.020). The rate of pathological complete response (pcR) was 43.5 % (in 20 of 46 patients who underwent surgery after CRT). The median survival time in patients with clinical complete response (ccR) was 24.0 months and the median survival time in patients with pcR was 29.0 months. The 3-year survival rates were 21 and 45 %, respectively (p=0.050).Conclusion. The combination of chemoradiotherapy and surgery in patients with thoracic esophageal cancer demonstrated an increase in overall survival in our study. if there is a complete clinical response to CRT and contraindications for surgery or the patient’s refusal to undergo surgery, it is advisable to use the “wait &amp; watch” tactic.

Pharmacokinetic Consideration of Venetoclax in Acute Myeloid Leukemia Patients: A Potential Candidate for TDM? A Short Communication.

Venetoclax (VNX)-based regimens have demonstrated significantly favorable outcomes in patients with acute myeloid leukemia (AML) and are now becoming the standard treatment. Tyrosine kinase inhibitors are administered at a fixed dose, irrespective of body surface area or weight. For such orally targeted therapies, real-world data have highlighted a larger pharmacokinetic (PK) interindividual variability (IIV) than expected. Even if VNX PKs have been well characterized and described in the literature, only 1 clinical trial-based PK study has been conducted in patients with AML. This study aimed to evaluate the PK of VNX in AML patients. We retrospectively analyzed all patients treated with a combination of VNX-azacitidine between January and July 2022 at our center, using at least 1 available VNX blood sample. Based on a previously published population PK model, individual PK parameters were estimated to evaluate the exposure and IIV. and Discussion. Twenty patients received VNX in combination with azacitidine, according to the PK data. A total of 93 plasma concentrations were collected. The dose of VNX was 400 mg, except in 7 patients who received concomitant posaconazole (VNX 70 mg). The patients' weight ranged from 49 kg to 108 kg (mean = 78 kg). Mean individual clearance was 13.5 ± 9.4 L/h with mean individual daily area under the concentration-time curves of 35.8 mg.h/L with significant IIV (coefficient of variation = 41.1%). Ten patients were still alive (8 in complete response), but all experienced at least 1 hematological toxicity of grade ≥ 3. Based on the observed large PK variability in the data from our real-world AML patients, the risk of drug interactions and the recommended fixed-dosage regimen of VNX therapeutic drug monitoring may be useful.

A Phase II Study of S-1 plus Oxaliplatin for Patients with Recurrent Non-Squamous Cell Carcinoma of the Uterine Cervix (Tohoku Gynecologic Cancer Unit: TGCU206 Study).

Recurrent non-squamous cell carcinoma (non-SCC) of the uterine cervix is resistant to treatment and has a poor prognosis. The efficacy and safety of S-1/oxaliplatin (SOX) therapy in patients with recurrent non-SCC was examined in a phase II study. Fifteen patients were enrolled between August 2013 and March 2023. S-1 was administered orally at a daily dose of 80-120 mg for 14 days, and oxaliplatin was administered intravenously at a dose of 100 mg/m2 on day 1. Each treatment cycle lasted 21 days. The anti-tumor effects, adverse events, progression-free survival (PFS), and overall survival (OS) were investigated. The median patient age was 54 (41-74) years. The anti-tumor effect was rated as a partial response in five patients, stable disease in four, and progressive disease in 6. The overall response rate was 33% and the disease control rate was 60%. Regarding hematologic toxicities of grade 3 or more severity, leukopenia, neutropenia, anemia, and thrombocytopenia occurred in 26.6-40.0%. None of the patients discontinued the treatment because of adverse events. The median PFS and OS were 6 months (95% confidence interval [CI]: 2-11 months) and 22 months (95% CI: 11-23 months), respectively. No treatment-related deaths occurred. These results suggest that SOX therapy is useful for the treatment of recurrent non-SCC with promising anti-tumor effects and minimal adverse events.

Integrating radiation therapy with CDK4/6 inhibitors for breast cancer: A systematic review and meta-analysis of toxicity.

e13075 Background: Over the past years, the treatment landscape of breast cancer (BC) has significantly evolved. Several new anticancer agents entered clinical use. Among them CDK4/6i have revolutionised both curative and advanced BC scenarios. The availability of new drugs raises the crucial question on how to integrate them with local and regional treatments. Strong levels of evidence on the safety profile of CDK4/6i in combination with different RT techniques or schedules are currently missing. We aim to systematically review and summarise the published data on the safety profile of palliative and ablative RT combined with CDK4/6i in early and metastatic BC settings. Methods: A literature search (PUBMED/MedLine, Embase, and Cochrane databases) was conducted to identify original studies on the safety profile of the combination of CDK4/6i with RT. This systematic review and meta-analysis project is part of the ESTRO Guidelines Committee consensus recommendations on integration of RT with targeted treatments for breast cancer, an initiative developed by a multidisciplinary Core Group and Expert Panel of medical, clinical, radiation oncologists, preclinical specialists, and patient advocates. Results: Eleven articles finally met all eligible criteria and were included in the meta-analysis. Data could not be collected in the adjuvant setting due to lack of data in the current literature. Pooling data of the included studies show a moderate incidence of hematological toxicities grade 3+ (21.0 %) and a very low-grade 3+ non-hematological toxicity were observed. Conclusions: The safety profile of CK4/6i and RT combination is acceptable. However, international consensus guidelines regarding the safety issue of CDK4/6i and RT combination for breast cancer are warranted.

Integration of Consolidation Chemotherapy After Concurrent Chemoradiation in the Treatment of Locally Advanced Uterine Cervical Cancer.

Despite the current standard of concurrent chemoradiation (CCRT), around 30-40% are still dying from locally advanced cervical cancer. Increasing the radiation dose further was not a feasible option, but addition of chemotherapy further was tried due to the different toxicity profiles of it. So, the use of consolidation chemotherapy beyond CCRT has been studied. To evaluate the efficacy, toxicity, tumour response and loco-regional control following consolidation chemotherapy after concurrent chemoradiation in locally advanced carcinoma cervix (LACC). The patients were randomized into two arms: the conventional arm (control arm, n = 30) patients received conventional treatment with weekly injection cisplatin (35mg/m2) concurrently with pelvic external beam radiation (50Gy/25 fraction, 2Gy/fraction, 5 fraction weekly) followed by intracavitary radiotherapy of 21Gy in 3 fractions of 7Gy each by HDR brachytherapy. In the interventional arm (study arm, n = 30), patients received the standard treatment followed by 3 cycles of consolidation chemotherapy (paclitaxel + carboplatin) every three weekly. Haematological toxicity (grade 3 anaemia and grade 1 leucopenia, grade 1 and 2 thrombocytopenia) was higher in the study group. Renal, hepatic and gastrointestinal toxicity was more in the study arm. Peripheral neuropathy was mostly seen in the study arm. Median follow-up was 9months. Treatment response was better, and the rate of recurrence was less in the study arm. Addition of few cycles of consolidation chemotherapy after standard treatment is beneficial in patients with LACC with manageable toxicity and good compliance.