Cyclophosphamide Regimen Research Articles

Abstract P1-01-04: Comparing the Effects of TC and Anthracycline-based Chemotherapy in Women with Breast Cancer HER2 Negative Treated in the Adjuvant Setting – An individual Patient Meta-Analysis

Abstract Background: Among women, breast cancer is the most common diagnosis of non-skin cancer and the fifth cause of oncological-related death worldwide. Adjuvant chemotherapy has been shown to extend overall survival (OS) and disease-free survival (DFS). Anthracyclines are cytotoxic regimens largely used in breast cancer, mainly in patients with risk factors or high burden of disease. The docetaxel and cyclophosphamide (TC) regimen is a Taxane-based treatment, and is an alternative option when anthracyclines are not indicated. However, anthracyclines have a myriad of adverse effects including alopecia, cardiac-related side effects and myelotoxicity. The question that remains is in which breast cancer population anthracycline chemotherapy should be omitted. Methods: A literature search was performed in Embase, Medline, and the Cochrane Libraries up to February 28 2022. We conducted an individual patient-level meta-analysis of 11,902 participants of 7 randomised controlled trials. The target population was adult women, with a histologically confirmed HER2 negative, stage I-III breast cancer who were treated with TC versus anthracycline-based chemotherapy in adjuvant setting under randomised-controlled trials. To analyse OS and DFS, we utilized the generic inverse variance method for time-to-event outcomes using hazard ratio (HR). A sensitivity analysis of risk of bias (ROB) was undertaken to examine the effects of high/moderate risk studies on each study endpoint. The assessment of certainty of evidence was conducted based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria. Results: With a median follow up of 60 months, the pooled analysis from 7 studies with available data on OS, and from 6 studies on DFS. From a total of 11,778 there was a total of 288 and 281 events of death in the TC and in the anthracycline-based chemotherapy groups, respectively. The analysis of OS revealed HR 1.01, 95% CI (0.86 – 1.19), p = 0.88; high certainty of evidence. From a total of 11,902 participants, there were 639 and 595 recurrence events in the TC and in the anthracycline-based chemotherapy groups, respectively. The analysis of DFS revealed HR 1.07, 95% CI 0.95-1.22, p=0.26; moderate certainty of evidence. No relevant absolute risk of death or recurrence events were found between the two treatments. In the quality of evidence assessment, the heterogeneity across all the studies is likely not more than what is due to chance (i2< 14%). The risk of bias was not a serious concern, and the publication bias was undetected for the endpoints OS and DFS. Conclusion: In this study population, TC chemotherapy likely results little to no difference in OS or DFS compared to anthracyclines-based chemotherapies. Despite the large number of participants and minimum heterogeneity across all the studies, there was no evidence of significant benefit or harm between the treatments. Overall, there is a high to moderate quality of evidence that adjuvant TC chemotherapy does not increase OS or DFS when compared to anthracycline-based chemotherapy in patients with breast cancer HER2-negative. Albeit the choice between the two chemotherapies would need to be balanced considering the specific side-effects that each treatment is likely to cause. Citation Format: Danilo Giffoni M. M. Mata, Mary Smowton. Comparing the Effects of TC and Anthracycline-based Chemotherapy in Women with Breast Cancer HER2 Negative Treated in the Adjuvant Setting – An individual Patient Meta-Analysis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-01-04.

Half Dose Pegfilgrastim for Patients With Breast Cancer During Chemotherapy: A Case-series.

This study aimed to show the trend of neutrophil counts and frequency of febrile neutropenia after changing pegfilgrastim from 3.6 mg to 1.8 mg. This case-series study was performed between April 2016 and December 2021 at Hyogo Prefectural Amagasaki General Medical Center. All patients who reduced their normal dose of 3.6 mg pegfilgrastim to 1.8 mg due to adverse events or markedly elevated neutrophil counts were included. Any type of chemotherapy was acceptable. Patients who dropped out within 1 month of receiving 1.8 mg pegfilgrastim were excluded. The primary outcome was the neutrophil counts after receiving 1.8 mg pegfilgrastim. The secondary outcome was febrile neutropenia, which was evaluated by the Common Terminology Criteria for Adverse Events v5.0. The study included seven patients who used a regimen of dose-dense epirubicin and cyclophosphamide, trastuzumab, pertuzumab, and docetaxel, docetaxel, or docetaxel and cyclophosphamide. After using 1.8 mg pegfilgrastim, neutrophil counts changed from a mean of 18,944 [standard deviation (SD)=-7,768] to only 4,447 (SD=1,224). The patients experienced grades 1 to 3 adverse events during the use of 1.8 mg and 3.6 mg pegfilgrastim doses, including febrile neutropenia, and pain. Four patients (57%) complained of grade 1 or 2 fatigue and anorexia. After switching from 3.6 mg pegfilgrastim to 1.8 mg, three patients (42%) experienced adverse events. In patients who experienced adverse events due to markedly elevated neutrophil counts with pegfilgrastim, reducing the dose of pegfilgrastim by half may reduce adverse events.

Relativity and the fine art of quality of life estimation

Nuclear protein of the testis (NUT) carcinoma (NC) is a rare type of poorly differentiated carcinoma. The median overall survival is 6.7–9.5 months. Surgery and radiotherapy are the main modalities of treatment. The efficacy of chemotherapy is often overlooked.A 7-year-old pediatric patient was diagnosed with recurrent NC of the submandibular gland, an uncommon site of NC. The tumor split and contracted following chemotherapy with cyclophosphamide, pirarubicin, cisplatin, ifosfamide, and etoposide. Subsequently, surgery was performed to excise the tumor with negative margins. Three months after the end of the multimodality treatment, the imaging did not show signs of recurrence or metastasis.The chemotherapy regimen of cyclophosphamide, pirarubicin, cisplatin, ifosfamide, and etoposide may be a new attempt to treat NC.

Long-Term Safety, Clinical and Immunological Outcomes in Primary Membranous Nephropathy with Severe Renal Impairment Treated with Cyclophosphamide and Steroid-Based Regimen

Introduction and Aims: Therapy of primary membranous nephropathy (PMN) with progressive advanced kidney dysfunction is challenging with limited literature and no clear therapeutic strategies. This is due to the scant evidence of effectiveness and uncertainty around the risk-benefit profile of immunosuppression (ImS) when eGFR is less than 30 mL/min. We aimed to determine long-term clinical outcomes in patients with PMN and severe renal impairment treated with combined cyclophosphamide and steroids. Methods: The study is a single-center retrospective longitudinal cohort study. All patients (between 2004 and 2019) with biopsy confirmed PMN who initiated combination therapy with steroids and cyclophosphamide and had an eGFR of ≤30 mL/min/1.73 m² at the time of initiation of therapy were included for analysis. Clinical and laboratory parameters including anti-PLA₂R-Ab were monitored as per standard clinical guidance. Primary outcome was achievement of partial remission. Secondary outcomes included immunological remission, need for renal replacement therapy, and adverse effects. Results: Eighteen patients with median age of 68 (IQR 58–73) years and 5:1 M:F ratio received the combination therapy when eGFR was ≤30 mL/min/1.73 m² (CKD-EPI). At time of ImS, median eGFR and uPCR were 23 (IQR 18–27) mL/min/1.73 m² and 8.4 (IQR 6.9–10.7) g/g, respectively. Median follow-up was for 67 (IQR 27–80) months. 16 patients (89%) achieved partial remission and 7 (39%) achieved complete remission. eGFR increased by 7 mL/min/1.73 m² (27%) after 1 year of starting ImS treatment and 12 mL/min/1.73 m² at end of follow-up. Two patients (11%) developed end-stage renal disease needing renal replacement therapy. 67% achieved both immunological and clinical remission. At the end of the follow-up period, 2 (11%) patients required hospitalization secondary to infections, 4 (22%) patients developed cancer and 4 patients died (22%). Conclusion: Combination therapy with cyclophosphamide and steroids is effective in achieving partial remission and improving renal function in PMN with advanced renal dysfunction. Prospective controlled studies are required to provide further evidence to rationalize treatment and improve outcomes in such patients.

Physical function, nutritional status, and quality of life before and after chemotherapy in patients with malignant lymphoma.

This study investigates the efficacy of and gender differences in exercise therapy in patients with malignant lymphoma undergoing chemotherapy. Twenty-six patients (13 men, 13 women) received physical therapy (based on the Borg Scale 13) during hospitalization. Physical function was measured using grip and knee extension strength, 6-minute walking distance, and body composition; nutritional status assessed via Mini Nutritional Assessment (MNA®); and serum albumin levels analyzed. Fatigue was evaluated using the Brief Fatigue Inventory, and health-related quality of life was assessed with the Medical Outcome Study 36-Item Short-Form Health Survey (SF-36v2). The analysis of all patients indicated that the right grip strength, skeletal muscle mass, skeletal muscle index, and leg muscle mass significantly decreased, whereas the serum albumin level, MNA® score, and scores of many items of the SF-36v2 significantly increased after chemotherapy. In a gender-specific analysis, only men showed significant declines in the skeletal muscle mass and skeletal muscle index, and improvement in the MNA® score after chemotherapy. In the SF-36v2, there were significant improvements in general health and physical component summary scores among men, and general health and mental component summary scores among women. Exercise therapy at a Borg Scale intensity of 13 may not prevent muscle mass decline in patients with malignant lymphoma, especially male patients. In addition, this study revealed that there is a gender difference in the effect of exercise therapy on quality of life. Thus, gender should be considered in exercise therapy for patients with malignant lymphoma.

Estradiol Levels and Chemotherapy in Breast Cancer Patients: A Prospective Clinical Study.

Breast cancer remains a global health issue, including in Indonesia, which has a relatively high incidence of breast cancer. Several theories have proved the role of estrogen in breast cancer carcinogenesis, but there is yet to be a preventive measure against breast cancer. Chemotherapy is one of the therapeutic modalities for breast cancer that disturbs ovarian function in producing estrogen due to damaged ovarian granulosa cells. Chemotherapy becomes an alternative option to decreasing circulating estradiol levels through interventions in ovarian functions, either by surgery, such as oophorectomy, or medications that disturb the ovarian functions. This study aimed to observe the estradiol levels in breast cancer patients before and after chemotherapy. This was a prospective cohort study. We observed the estradiol levels before and after adjuvant chemotherapy in breast cancer patients. Subjects' characteristics are presented in mean ± standard deviation, distribution frequency, and percentage. Subjects' characteristics based on chemotherapy were tested using an independent t-test, Mann-Whitney U, and Chi-square/Fisher exact test. Effects of chemotherapy on estrogen levels were tested using the Wilcoxon rank test and Kruskal-Wallis test. A total of 194 research subjects were included. There were changes in estradiol levels before and after therapy. The decrease of estradiol levels in patients who did not receive chemotherapy was -6.9% (P > 0.05). Patients who received anthracycline cyclophosphamide (AC) regimen, paclitaxel and anthracycline (TA) regimen, paclitaxel, anthracycline and trastuzumab (TA + H) regimen, and platinum regimen experienced a significant decrease in estradiol levels (-21.4% (P < 0.05), -20.2% (P < 0.001), -31.7% (P < 0.01), and -23.7% (P < 0.05), respectively). Among chemotherapy groups, the estradiol levels before and after chemotherapy did not have significant differences (P = 0.937 and P = 0.730, respectively). There are no significant differences in estradiol levels between chemotherapy and hormonal therapy groups. Patients in both groups have decreased estradiol levels after therapy, although patients in hormonal therapy do not experience as much decrease as those in chemotherapy.

A phase I study of GPC3 targeted CAR-T cell therapy in advanced GPC3-expressing hepatocellular carcinoma (HCC).

TPS624 Background: The mortality of hepatocellular carcinoma (HCC) is increasing worldwide, but outcome of systemic treatments in advanced HCC is suboptimal. Adoptive T-cell transfer therapy represents a promising field that exploits the ability of T-cells to recognize and eliminate their target. Targeting the tumor-associated antigen glypican- 3 (GPC3) through chimeric antigen receptors (CAR) engineered T cells is a mechanistically rational novel treatment for advanced HCC. This study aims to determine the dose and early signals of GPC3 targeted (CAR)-T cells in advanced GPC3 expressing HCC (NCT05003895). Methods: This phase I first in human dose escalation trial will study the safety and feasibility of CAR (hYP7)- T cells in advanced HCC patients expressing GPC3. Eligibility criteria includes advanced HCC, not candidates for curative interventions, progressed on first line systemic treatment, tumor GPC3 positivity of ³ 25% by IHC, Child-Pugh Class A, ³1 measurable lesion, ECOG 0 or 1, adequate organ and marrow function. ParticipantsÕ T cells collected through leukapheresis will be transduced with a lentivirus encoding the CAR construct to generate CAR expressing T cells. Patients receive a conditioning chemotherapy regimen of cyclophosphamide and fludarabine prior to the infusion of the GPC3 directed CAR-T cells (Table). The trial has a 4-level modified Fibonacci dose escalation with a minimum of 3 patients at each level and a 28-day interval between the first three patients. Response will be assessed by imaging every two months during the first year. Patients undergo close monitoring with safety assessments during the first year and are followed for life. The primary objective is to determine the MTD, DLT, safety and feasibility of anti-GPC3 CAR expressing T- cells in patients with GPC3-expressing advanced HCC. Secondary objectives include best overall response and overall survival. Exploratory objectives are multiple and include studies to evaluate the persistence and peak levels of anti-GPC3 CAR-T cells after infusion. Recruitment began in December 2021 and the two patients at dose level -1 has been treated; the planned sample size is 38 patients. Table 1 Dose Level Anti-GPC3 CAR-T Cyclophosphamide (mg/m2) Fludarabine (mg/m2) Level -1 0.3x106 CAR-T per kg bw 200 30 Level 1 0.3x106 CAR-T per kg bw 300 30 Level 2 1x106 CAR-T per kg bw 300 30 Level 3 3x106 CAR-T per kg bw 300 30. Clinical trial information: NCT05003895 .

A phase I/IIa open label, nonrandomized, multicenter study of CYNK-101 in combination with trastuzumab and pembrolizumab in patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (G/GEJ) adenocarcinoma.

TPS478 Background: CYNK-101 is a human placental hematopoietic stem/progenitor cell derived NK cell product, that is genetically modified to express a variant of CD16, FcγRIII, via lentiviral vector transduction. The CD16 variant has amino acid modifications to enable high affinity and proteolytic cleavage-resistance for ADCC enhancement. Results from preclinical studies demonstrated enhanced ADCC activity of CYNK-101 in combination with trastuzumab against HER2+ gastric cancer cell lines in vitro, ex vivo and in vivo. Methods: A Phase I/IIa study is a first-line treatment of patients with locally advanced unresectable or metastatic HER2 positive gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. Patients are required to have confirmation of HER2 positivity defined as either IHC 3+ or IHC 2+ with a positive FISH or FISH + alone. Following the completion of screening assessments, patients are enrolled to the initial induction period of the trial and receive pembrolizumab, trastuzumab and a fluoropyrimidine/platinum based-chemotherapy for up to six 21-day cycles. In Phase I, patients may skip the initial induction period if they had previously been treated with pembrolizumab or, trastuzumab and a fluoropyrimidine/platinum based-chemotherapy and have not achieved an adequate response. Patients complete a disease assessment and then proceed to a lymphodepletion regimen of cyclophosphamide 900 mg/m2 and fludarabine 30 mg/m2 with MESNA for 3 days. Following 2 days of rest, the NK-cell re-induction period of the study begins with pembrolizumab 200 mg and trastuzumab 6 mg/kg on Day 1 of that cycle and 6M IU of rhIL-2 with CYNK-101 on days 1, 8, 15. CYNK-101 will be administered based on the calculated number of transduced cells per body weight as measured in kilograms (kg). Two dose levels of CYNK-101 (36 x 106 transduced cells/kg, and 72 x 106 transduced cells/kg) will be evaluated for the NK-Cell reinduction period during the Phase 1 portion of the study in a standard “3+3” dose escalation fashion. Once the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) is determined in Phase I, the designated dosing Cohort level of the NK-Cell re-induction period will be used for the Phase IIa Expansion portion of the study. Both study periods will contain maintenance dosing of pembrolizumab 200 mg, trastuzumab 6 mg/kg and 6M IU rhIL-2 with 3.6 x 106 transduced cells/kg of CYNK-101 on Day 1 of a 21-day cycle. Endpoints: Primary endpoints for Phase I, include the incidence of adverse events defined as dose-limiting toxicities (DLTs). Phase IIa will evaluate efficacy as measured by overall response rate and a complete response rate as determined by RECIST 1.1. Approximately 52 patients are planned for this Phase I/IIa study. Clinical trial information: NCT05207722 .

Thiotepa, Busulfan, Cyclophosphamide: Effective but Toxic Conditioning Regimen Prior to Autologous Hematopoietic Stem Cell Transplantation in Central Nervous System Lymphoma.

In primary central nervous system lymphoma, two-year progression-free survival rates of up to 63 percent have been reported for first-line autologous stem cell transplantation after conditioning with the thiotepa busulfan cyclophosphamide regimen. However, 11 percent of the patients died due to toxicity. Besides conventional survival, progression-free survival and treatment related mortality analyses, a competing-risk analysis was applied to our cohort of twenty-four consecutive patients with primary or secondary central nervous system lymphoma who underwent autologous stem cell transplantation after thiotepa busulfan cyclophosphamide conditioning. The two-year overall survival and progression-free survival rates were 78 percent and 65 percent, respectively. The treatment-related mortality rate was 21 percent. The competing risks analysis demonstrate that age 60 or over and the infusion of less than 4.6 × 106/kg CD34+ stem cells were significant adverse prognostic factors for overall survival. Autologous stem cell transplantation with thiotepa busulfan cyclophosphamide conditioning was associated with sustained remission and survival. Nevertheless, the intensive thiotepa busulfan cyclophosphamide conditioning regimen was highly toxic, especially in older patients. Thus, our results suggest that future studies should aim at identifying the subgroup of patients who will really benefit of the procedure and/or to reduce the toxicity of future conditioning regimen.

Treatment Resulting Changes in Volumes of High-18F-FDG-Uptake Adipose Tissues over Orbit and Epicardium Correlate with Treatment Response for Non-Hodgkin's Lymphoma.

A regimen of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the standard treatment for non-Hodgkin's lymphoma. Brown adipose tissue possesses anti-cancer potential. This study aimed to explore practical biomarkers for non-Hodgkin's lymphoma by analyzing the metabolic activity of adipose tissue. Twenty patients who received R-CHOP for non-Hodgkin's lymphoma were reviewed. Positron emission tomography/computed tomography (PET/CT) images, lactate dehydrogenase (LDH) levels, and body mass index (BMI) before and after treatment were collected. Regions with a high standardized uptake value (SUV) in epicardial and orbital adipose tissue were selected and analyzed by a PET/CT viewer. The initial measurements and changes in the high SUV of epicardial and orbital adipose tissues, LDH levels, and BMI of treatment responders and non-responders, and complete and partial responders, were compared. The volumes of high-SUV epicardial and orbital adipose tissues significantly increased in responders after R-CHOP (p = 0.03 and 0.002, respectively). There were significant differences between changes in the high-SUV volumes of epicardial and orbital adipose tissues (p = 0.03 and 0.001, respectively) and LDH levels (p = 0.03) between responders and non-responders. The changes in high-SUV epicardial adipose tissue volumes were greater among complete responders than partial responders (p = 0.04). Poorer treatment responses were observed in patients with lower high-SUV epicardial adipose tissue volumes and higher LDH levels after R-CHOP (p = 0.03 and 0.03, respectively). The preliminary results of greater changes in high-SUV epicardial and orbital adipose tissue volumes among responders indicate that brown adipose tissue could be considered a favorable prognostic biomarker.

Plasma Cytokine Levels and Cytokine Genetic Polymorphisms in Patients with Metastatic Breast Cancer Receiving High-Dose Chemotherapy

Differences in the baseline levels of serum cytokines or in single-nucleotide polymorphisms (SNPs) in cytokine genes may be useful to predict outcomes for patients being treated for metastatic breast cancer. We have measured the plasma levels and characterized individual SNPs for IL-1RA, IL-1β, IL-2, IL-6 and TNFα in 130 patients with metastatic breast cancer treated with high-dose chemotherapy. Patients were treated with high-dose cyclophosphamide (Group 1, 74 patients) or high-dose paclitaxel-containing regimens (Group 2, 56 patients). A high plasma level of IL-1RA and a SNP in the IL-1RA gene indicated a better prognosis for patients in Group 1 (but not Group 2). However, the level of plasma IL-1RA did not correlate with the SNP genotype. A high plasma level of IL-6 or TNFα indicated a poorer outcome for patients in Group 1 although the SNP genotypes for the IL-6 and TNFα SNPs were not associated with differences in outcome. The plasma levels of IL-1β and IL-2 and the genotype of the IL-1β SNPs did not indicate differences in outcome. Although, individually, plasma levels of cytokine or “risk” SNP genotypes may not indicate outcome, in combination there was an increased trend to predict outcome for patients treated with high-dose cyclophosphamide but not high-dose paclitaxel. These results suggest that the immune cytokines may be useful as prognostic biomarkers in the treatment of patients with metastatic breast cancer treated with different types of chemotherapy.

Treatment options in primary mediastinal B cell lymphoma patients, retrospective multicentric analysis; a Turkısh oncology group study.

Primary mediastinal B-cell lymphomas (PMBL) are aggressive B- cell lymphomas. Although the initial treatment models vary in PMBL, appropriate treatment methods are not known. We aim to show real-life data on health outcomes in adult patients with PMBL who received various type of chemoimmunotherapies in Turkey. We analyzed the data of 61 patients who received treatments for PMBL from 2010 to 2020. The overall response rate (ORR), overall survival (OS) and progression-free survival (PFS) of the patients were evaluated. 61 patients were observed in this study. The mean age of the study group was 38.4 ± 13.5 years. From among them, 49.2% of the patients were female (n = 30). For first-line therapy, 33 of them had received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen (54%). Twenty-five patients had received rituximab, etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (DA-EPOCH-R) regimen. The ORR was 77%. The median OS and PFS were as follows: 25 months (95% CI: 20.4-29.4) and 13 months (95% CI: 8.6-17.3), respectively. The OS and PFS at 12 months were 91.3% and 50%, respectively. The OS and PFS at five years were 64.9% and 36.7%, respectively. Median follow-up time period was 20 months (IQR 8.5-38.5). R-CHOP and DA-EPOCH-R showed good results in PMBL. These remain one of the best determined systemic treatment options for first-line therapy. Also, the treatment was associated with good efficacy and tolerability.

Non-Hodgkin’s Lymphoma Presenting Section as a Soft Tissue Mass on Right Thigh

Non-Hodgkin’s Lymphomas (NHL) are a heterogeneous group of lymphoproliferative malignancies with a greater preference for disseminating to extranodal locations. Prevalence of extranodal involvement in NHL has increased in the past decade, and the sites involved are the stomach, spleen, waldeyer’s ring, Central Nervous System (CNS), lungs and skin. This is a rare case of NHL in a 48-year-old female who presented with solitary exophytic mass with ulceration over the right thigh and erythematous plaque over postaxillary region and enlarged right inguinal and left axillary lymph nodes. Magnetic Resonance Imaging (MRI) of the right thigh showed lobulated mass involving skin and subcutaneous soft tissues without any intramuscular extension suggestive of neoplastic mass. Fine needle aspiration cytology of the inguinal node and biopsy of the right thigh lesion showed features suggestive of NHL. She was treated with three cycles of Cyclophosphamide, Hydroxydaunorubicin, Oncovin and Prednisone (CHOP) regimen, but the patient succumbed to death after six months of chemotherapy

Serum miR-146a level is a potential biomarker in predicting the outcome of diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma with heterogenicity in clinical manifestation and prognosis. Some microRNAs can influence the development of tumors and may be related to the response of therapy or prognosis. This study aims to explore the role of serum miR-146a in predicting the prognosis of DLBCL. A total of 72 de novo DLBCL patients received 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or rituximab combined CHOP (R-CHOP) regimen, and their serum samples were collected before treatment and after 4 cycles of chemotherapy. The results show that a high level of miR-146a is significantly associated with a good outcome in baseline and is more obvious in post-chemotherapy. In addition, a high level of miR-146a was associated with better progression-free survival and overall survival in patients treated with R-CHOP but has not been related to a superior outcome in patients treated with CHOP. Rituximab may improve the efficacy of therapy, especially in patients with high miR-146a levels. The level of miR-146a decreased in more patients after chemotherapy, and it seems patients with a decreased expression of miR-146a after chemotherapy tended a better outcome, but it is not statistically significant. Our results suggest that the level of serum miR-146a can serve as a potential prognostic biomarker for DLBCL patients.

Anti-glomerular basement membrane disease: Treatment outcome of cyclophosphamide vs. rituximab induction therapy regimen.

To study the clinical profile of anti-glomerular basement membrane (anti-GBM) disease and its outcome with two different treatment regimens comprising either cyclophosphamide (CYC) or rituximab (RTX). A retrospective analysis of anti-GBM crescentic glomerulonephritis patients admitted to our hospital over 5 years. 14 patients were diagnosed with anti-GBM crescentic glomerulonephritis. The mean duration of symptoms was 3.6±1.9 weeks. All patients presented with rapidly progressive glomerulonephritis (RPGN). Five (35.7%) patients had concomitant urinary tract infection (UTI), 2 (14.3% had underlying type 2 diabetes mellitus, 5 (35.7%) patients also had positive anti-neutrophil cytoplasmic antibodies (ANCA), and 9 (64.3%) were dialysis-dependent at presentation. Four (28.6%) patients developed diffuse alveolar hemorrhage (DAH). All patients received baseline corticosteroids, and 7 (50%) patients also received plasmapheresis. Nine (64.3%) patients were treated with CYC, and 3 (21.4%) patients received RTX. In the CYC arm, 2 (28.6%) patients died, 3 had end-stage kidney disease (ESKD) at 3 months, and 2 had chronic kidney disease (CKD) stage III at 3 months of follow-up. Two patients were lost to follow-up. In the RTX arm, all 3 patients survived with no incidence of DAH, 1patient each had ESKD and CKD stage III, and 1 dialysis-dependent patient achieved normal kidney function at the end of 3 months. Most patients presented late with dialysis-dependent renal failure, and many had concomitant UTI. Concomitant infection causes diagnostic confusion with RPGN and DAH, which delays diagnosis and treatment. RTX as an alternative to CYC in addition to baseline corticosteroids and/or plasmapheresis and is associated with favorable outcomes.

Risk factors for fatal cardiac complications after allogeneic hematopoietic cell transplantation: Japanese Society for Transplantation and Cellular Therapy transplant complications working group.

Fatal cardiac complications can occur from the early to late phases after hematopoietic cell transplantation (HCT). Herein, the Japanese transplant registry database was used to retrospectively analyze health records of 33,791 allogeneic HCT recipients to elucidate the pathogenesis and risk factors involved. Overall, 527 patients died of cardiac complications at a median of 130 (range 0-3924) days after HCT. The cumulative incidence of fatal cardiac complications was 1.2% (95% confidence interval [CI]: 1.0-1.3) and 1.6% (95% CI: 1.5-1.8) at 1 and 5years after HCT, respectively. Fatal cardiovascular events were significantly associated with an HCT-specific comorbidity index (HCT-CI) score of ≥1 specific to the three cardiovascular items, lower performance status, conditioning regimen cyclophosphamide dose of >120mg/kg, and female sex. Cardiovascular death risk within 60days after HCT was associated with the type of conditioning regimen, presence of bacterial or fungal infections at HCT, and number of blood transfusions. Contrastingly, late cardiovascular death beyond 1year after HCT was associated with female sex and older age. Lower performance status and positive cardiovascular disease-related HCT-CI were risk factors for cardiac complications in all phases after HCT. Systematic follow-up may be necessary according to the patients' risk factors and conditions.

Phase II Study of Myeloablative 8/8- or 7/8-Matched Allotransplantation with Post-Transplant Cyclophosphamide, Tacrolimus, and Mycophenolate Mofetil: Marked Reduction in Gvhd Risk without Increased Relapse Risk Compared to Historical Cyclosporine/Methotrexate

Introduction Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative treatment for many high-risk hematologic malignancies. Myeloablative conditioning (MAC) is currently the standard of care for young and fit patients; however, graft-versus host disease (GVHD) continues to be a major limitation to the success of HCT, increasing post-transplant morbidity and mortality. An ideal HCT is one that combines strategies to reduce the incidence and severity of GVHD, without compromising graft versus-tumor effect. We hypothesized that the GVHD prophylaxis regimen consisting of post-transplant cyclophosphamide (PTCy), tacrolimus (Tac) and mycophenolate mofetil (MMF) would reduce the incidence of chronic GVHD in patients receiving a standard MAC HCT without an increase in risk of malignant relapse. Methods This is an analysis of a phase II study at the University of Minnesota using a MAC regimen of either: 1. total body irradiation (TBI, total dose 1320 cGy administered twice a day from days -4 to -1) or 2. Busulfan 3.2mg/kg daily (cumulative AUC 19,000 - 21,000 μmol/min/L) plus fludarabine 160mg/m2 days -5 to -2 for patients unable to receive further radiation, followed by a GVHD prophylaxis regimen of PTCy (50mg/kg days +3 and +4), Tac and MMF (beginning day +5). The primary endpoint is cumulative incidence of chronic GVHD requiring systemic immunosuppressive treatment at 1 year post-transplant. Eligibility included: age ≤ 60 years, malignant or non-malignant diagnosis, matched related (MRD) or unrelated (MUD) donor with either a bone marrow (BM) or filgrastim-mobilized peripheral blood (PB) graft. We compared those results to our previous MAC protocol which utilized a regimen of either cyclophosphamide (60mg/kg days -6 and -5)/TBI (1320 cGy administered twice a day from days -4 to -1) or busulfan (0.8 mg/kg/dose IV in 4 daily doses days -9 to -6 [total 12.8 mg/kg])/ cyclophosphamide (50 mg/kg days -5 to -2) and GVHD prophylaxis consisted of cyclosporine and methotrexate. Results Through June 2022, we treated 125 patients with a median follow up of 472 days post-transplant. Of those, 48% were female and 22 (17.6%) were ≤ 18 years old with median age at HCT of 38 years (range, 1-59 yrs; Interquartile range [IQR], 22-50 yrs). Donor source was 8/8 MRD in 69 patients (55.2%), 8/8 MUD in 44 (35.2%), and 7/8 MUD in 12 (9.6%). Graft source was bone marrow in 43 patients (34.4%) and PB in 82 (65.6%). Preparative regimen was TBI in 89.6% of patients. 124 of 125 patients achieved primary neutrophil engraftment by 42 days, median 16 days (range, 13-30). 119 of 125 achieved platelet engraftment by 6 months, median 25.5 days (range, 14-98). 91 patients (72.8%) required total parenteral nutrition (TPN) for oral mucositis and regimen-related toxicities during their initial transplant admission. Cumulative incidence of Grade II-IV acute GVHD by day +100 was 16% (95% confidence interval (CI): 9-23%); Grade III-IV acute GVHD was 4% (CI: 0-8%). No patients experienced grade IV GVHD and there were no deaths due to GVHD. At 1 year, only 3 of 105 patients developed chronic GVHD requiring immune suppression, for a cumulative incidence of 4% (CI: 0-8%). Two-year cumulative incidence of relapse was 25% (CI: 15-36%). Two-year overall survival was 80% (CI: 69-87%) and two-year GVHD-free relapse free survival (GRFS) was 57% (CI: 45-67%). Kaplan-Meier curves comparing overall survival and GRFS between this cohort and our previous MAC protocol without PTCy are shown in Figure 1. Figure 2 shows the comparison between these two consecutive cohorts in incidence of acute and chronic GVHD, transplant-related mortality (TRM) and relapse. Discussion Myeloablative HCT with a TBI or Busulfan/Fludarabine-based preparative regimen, followed by a GVHD prophylaxis regimen of PTCy, Tac, and MMF results in extremely low incidence of chronic GVHD, the primary objective of this clinical trial. Importantly, this regimen is feasible and effective for pediatric and adult patients. Further improvement in outcomes could potentially be achieved by incorporating post-transplant relapse mitigating strategies as well as supportive care measures to decrease regimen-related toxicities. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Phase I Clinical Trial of Point-of-Care Manufactured Fresh Anti-CD19/20/22 Chimeric Antigen Receptor T Cells for Treatment of Relapsed or Refractory Lymphoid Malignancies (Non-Hodgkin Lymphoma, Acute Lymphoblastic Leukemia, Chronic Lymphocytic Leukemia, B Prolymphocytic Leukemia)

Background: CD19-targeted CAR-T cells have transformed the treatment of relapsed/refractory B-cell malignancies. However, relapse occurs in over 50% of patients treated with commercial CD19 directed CAR-T due to antigen escape from selective immune pressure either on the target antigen or due to exhaustion and lack of persistence of CAR-T cells. Hence there is an unmet need for next-generation CAR-Ts that have broad antigen recognition and novel costimulatory domains to promote survival and decrease exhaustion of CAR-Ts. Targeting three B-cell antigens simultaneously is a novel approach to prevent antigen-negative relapse while inclusion of the OX40 domain will promote CAR-Ts persistence and expansion. Whether targeting three commonly expressed antigens is feasible or safe and will result in durable remissions is not known. We hypothesize that this trispecific targeting of CD19/20/22 CAR-T construct will be safe and effective in patients with relapsed, refractory B-cell malignancies. Study Design and Methods: This parallel group phase 1 study follows a 3+3 phase 1 design to determine the safety of the infusion of point-of-care manufactured fresh CAR-T cells targeting CD19/20/22 and to find the recommended phase II dose for this cellular therapy. CAR-T cells will be manufactured over 6 days. Patients will be enrolled in one of the two cohorts: Cohort A (single infusion): Non-Hodgkin's Lymphoma (NHL) with lesions <= 5 cm; Indolent lymphomas; B-PLL (B-Pro lymphocytic leukemia); Chronic Lymphocytic Leukemia -CLL (without Richter's transformation), Cohort B (split infusion): B-ALL (B-Acute lymphoblastic leukemia); Lymphoid blast crisis of Chronic myeloid leukemia; CLL (with Richter's transformation); NHL with lesions > 5 cm and/or lymphoblastic lymphoma, or NHL with circulating lymphoma cells. Patients who are CAR-naïve will be enrolled in this study. The study involves infusion of anti-CD19/20/22 CAR-T cells administered after an immunosuppressive conditioning regimen of fludarabine and cyclophosphamide. Cyclophosphamide 60 mg/kg will be infused intravenously over 60 minutes on day -6. Fludarabine 25 mg/m2 will be infused intravenously daily over 30 minutes on days -5 to -3. In each group, patients will be enrolled sequentially to each dose level, starting with dose level 1. Three CAR-T dose-levels: 5x105, 1x106 & 2x106 cells/kg/dose will be explored to determine MTD. For cohort B patients, the total CAR-T cell dose infused, will be divided in two doses, dose 1 (day 0) is 40% of the total dose and dose 2 (day 7) is 60% of total dose. The minimum number of subjects enrolled in the complete study will be 18 (9 per cohort) and the maximum number in dose escalation will be 36 (18 per cohort). Patients in each cohort will be monitored for 30 days before enrollment of next patientTwo patients have been enrolled in the trial and received fresh infusion of Anti CD19/20/22 CAR-T cells and accrual is ongoing. Updates on the initial cohort of patients will be presented at the meeting. ClinicalTrials.gov NCT: NCT05418088 Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Orelabrutinib, Fludarabine, Cyclophosphamide, and Obinutuzumab (OFCG) for First-Line Treatment of Chronic Lymphocytic Leukemia: A Multicenter, Investigator-Initiated Study (cwCLL-001 study)

Background: Fludarabine, cyclophosphamide and rituximab (FCR) regimen was previously recommended as standard chemoimmunotherapy for young fit patients (pts) with CLL prior to the advent of novel target drugs. Orelabrutinib, a highly selective BTK inhibitor, had approved for relapsed/refractory (RR) CLL treatment. Obinutuzumab, a glycoengineeredtype II CD20 mAb, had shown to be superior to rituximab in CLL treatment.Pts achieving minimal residual disease (MRD)-negative status in peripheral blood (PB) or bone marrow (BM) had a better progression free survival (PFS) and overall survival (OS) outcome irrespective of treatment received compared to those who could not achieve MRD negativity (CRISTALLO endorsed). Methods: This is an investigator-initiated phase II trial (NCT 05322733). Eligible pts had previously untreated CLL/SLL with ECOG PS 0-2, 18-65 years old, Cumulative disease score ≤ 6, and Creatinine clearance rate ≥ 70 ml / min (N=25). Patients with IGHV unmutated, del (17p) and/or TP53 Mutation are included. Enrolled patients will receive 7-day lead-in therapy of Orelabrutinib 150 mg once daily. Then all Pts receive three cycles of OFCG. After the 3 cycles, following evaluation by MRD in BM detected by multi-color flow cytometry (FCM) at 10-4 sensitivity according to ERIC methodology. Patients will continue to receive 3 cycles of OFCG regimen if the MRD is positive. Otherwise, the patients will continue to receive 3 cycles of OG regimen if the MRD is negative. At the 7th-12th cycles, Based on the achievement of uMRD in BM at the end of Cycle 6, patients would be decided to received O monotherapy (with uMRD) or OG regimen (without uMRD). Similarly, at the 13rd-24th cycles, patients would be decided whether to discontinue treatment based on the evaluation results of Cycle 12. (Figure 1) We set every 28 days as a dosing cycle. Obinutuzumab, 1000mg, D1/D8/D15 in C1, D1 in other cycles, (first dosing: 100 mg in D1 and 900 mg in D2). Orelabrutinib: 150 mg, QD. Fludarabine: 25 mg/m2, D1-3, per cycle. CTX: 250 mg/m2, D1-3, per cycle. The primary endpoint is the percentage of undetectable MRD in BM after 6 cycles of treatment. The percentage of MRD negativity by NGS is an exploratory endpoint (at 10-6 sensitivity). Results: By the end of July 2022, 13 patients were screened, of which 7 patients have begun treatment with the combination regimen, and 1 patient completed 2 cycles treatment and the first efficacy evaluation who with undetectable BM MRD after 3 cycles treatment. We will update the first efficacy evaluation reporting of 10 patients at this ASH. Conclusions: Enrollment, treatment and follow up continues. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Cost-Effectiveness Analysis of Frontline Treatment with Polatuzumab Vedotin in Diffuse Large B-Cell Lymphoma

Introduction: The POLARIX trial (NCT03274492) recently demonstrated that substituting polatuzumab vedotin (pola), a CD79b-targeted antibody-drug conjugate, for vincristine in standard R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemoimmunotherapy for first-line therapy can prolong progression-free survival in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). However, the medication cost of pola-R-CHP (pola, rituximab, cyclophosphamide, doxorubicin, and prednisolone) regimen is substantially higher than that of R-CHOP treatment. It remains unknown whether the lower rate of treatment failure with pola-R-CHP can be translated into reduced subsequent healthcare costs, increased life years (LYs), and improved quality of life, which may offset the higher medication cost. This study aimed to investigate the cost-effectiveness of substituting pola for vincristine in first-line therapy for patients with newly diagnosed DLBCL from a US payer perspective. Methods: We developed a decision analytic model to project lifetime quality-adjusted life years (QALYs) gained, LYs gained, and direct healthcare costs in newly diagnosed DLBCL patients. The model utilized a hypothetical cohort of patients at 65 years (the median age of disease onset). Direct healthcare costs were adjusted to 2021 US dollars, and an annual rate of 3% was used to discount future costs and benefits. Incremental cost-effectiveness ratios (ICERs) were calculated, and a willingness-to-pay (WTP) threshold of USD 150,000 per QALY gained was used as the acceptable level for determining cost-effectiveness. Sensitivity analyses and scenario analyses were conducted to assess the uncertainty of the base-case scenario and input parameters. Results: Pola-R-CHP, compared to standard R-CHOP, was associated with an incremental cost of USD 90,439, an improvement of 0.89 QALYs and 1.14 LYs, leading to an ICER of USD 101,510/QALY. The model was most sensitive to the survival benefit provided by pola-R-CHP, the age of the patients at initial treatment, and the price of pola. The ICER would increase significantly if pola-R-CHP is ineffective in providing long-term remissions. Furthermore, the ICER value increased as patients were older at the beginning of the treatment. When patients were older than 76.5 years at initial treatment, the ICER would exceed the WTP threshold of USD 150,000/QALY. To make the pola-R-CHP regimen cost-effective in all age groups (up to 80 years old), the current price of pola, which was estimated to be USD 19,307 for 170 mg per treatment cycle, needed to be reduced by 20%. In the probabilistic sensitivity analysis, 48% and 73% of the iterations produced ICERs below WTP thresholds of USD 100,000/ QALY and USD 150,000/ QALY, respectively. Conclusion: Our study findings suggest that pola-R-CHP, compared to the standard R-CHOP regimen, could be a cost-effective strategy in treatment-naïve DLBCL patients aged 65 years from a US payer perspective. However, several noticeable factors that could affect the cost-effectiveness profile of pola-R-CHP therapy should be considered in decision-making. The follow-up period of the POLARIX trial was relatively short, and mature survival data would be required to fully evaluate the value of pola in the treatment of newly diagnosed DLBCL.