Toxicity Of Regimen Research Articles

Prospective Evaluation of Limited Stage Small Cell Lung Cancer (LS-SCLC) Fractionation Regimen Usage and Toxicity in a Large Statewide Quality Collaborative

<h3>Purpose/Objective(s)</h3> National guidelines on LS-SCLC treatment give preference to a hyperfractionated regimen of 45 Gy in 30 fractions (Fx) delivered twice-daily (BID) but allow for daily fractionation (QD) to 60-70 Gy in certain circumstances. Use of the BID regimen has been reportedly low, however this is based upon small retrospective series, national databases that lack radiation treatment specifics, or survey data. We sought to characterize the fractionation regimens used to treat LS-SCLC in actual practice across academic and community settings and analyze factors associated with fractionation and toxicity. <h3>Materials/Methods</h3> As part of a quality improvement initiative, the Michigan Radiation Oncology Quality Consortium prospectively collects clinical, dosimetric, and physician- and patient-reported outcomes data from patients treated for lung cancer at 29 institutions, which represent about 60% of the radiation oncology volume in the state. Between 2012 and 2021, 3,962 lung cancer cases were enrolled. Of those, 680 (17%) had SCLC histology and the 502 patients with LS-SCLC and known fractionation regimen represent the population studied here. <h3>Results</h3> Among the 502 LS-SCLC patients, 98% were current or former smokers (50 pack-year mean) and 98% received chemotherapy. In total, 73 (15%) were treated BID to a median dose of 45 Gy / 30 Fx (IQR same) and 429 (85%) were treated QD to a median dose of 60 Gy / 30 Fx (IQR 60-64.8 Gy / 30-36 Fx). The proportion of patients treated BID did not vary by practice setting or demographics except those treated BID were significantly more likely to be married or living with someone (64% vs 51%, p=0.035). There was no difference between the groups in baseline clinical factors such as performance status, weight loss, comorbidities, or pulmonary function. QD treated patients were more likely to experience a treatment break due to toxicity (24% vs 6%, p<0.01) despite no differences in physician-reported toxicity or patient-reported swallowing difficulty at the end of treatment. However, BID treated patients did report twice the rate of difficulty swallowing solids at 1 month (42% vs 19%, p<0.01). <h3>Conclusion</h3> Despite evidence in its favor, the twice-daily fractionation regimen for LS-SCLC remains infrequently prescribed (15%) in a large multicenter prospectively collected cohort. BID treated patients were more likely to be married or living with someone, perhaps relating to the logistic burden of BID treatment. Despite similar end of treatment toxicity, QD treated patients had more treatment breaks. However, BID treated patients had twice the rate of swallowing difficulty at 1 month suggesting BID toxicity may peak later than QD toxicity, which is consistent with prior reports. Analysis of late toxicity, chemotherapy specifics, and additional physician- and patient-reported outcomes is ongoing.

Comparative assessment of the toxicity of different induction chemotherapy regimens for oropharyngeal squamous cell carcinoma

<h3>ЦЕЛЬ ИССЛЕДОВАНИЯ</h3> Улучшить результаты лечения пациентов с местно-распространенным ВПЧ-позитивным плоскоклеточным раком ротоглотки путем оптимизации режима индукционной химиотерапии, в частности, использования двухкомпонентной схемы. <h3>МАТЕРИАЛ И МЕТОДЫ</h3> С 2021 г. в исследование включено 13 пациентов с местно-распространенным ВПЧ-позитивным плоскоклеточным раком ротоглотки. Всем больным на первом этапе комбинированного лечения проводилось 3 курса индукционной химиотерапии (ИХТ) по схеме ТР (доцетаксел 75 мг/м2 + цисплатин 75 мг/м2, цикл 21 день). Далее всем пациентам было запланировано использование химиолучевой терапии в СОД 70 Гр на фоне радиомодификации карбоплатином AUC 2,0. Первичными конечными точками после ИХТ являлась оценка объективного ответа и токсичности. Вторичные конечные точки: оценка частоты объективного ответа после второго этапа комбинированного лечения, 1-годичной общей выживаемости и выживаемости без прогрессирования. <h3>РЕЗУЛЬТАТЫ</h3> В настоящее время произведена оценка частоты объективного ответа и токсичности для всех пациентов. Полный ответ отмечен у 2 (15%) пациентов, частичный — у 5 (38%), стабилизация заболевания — у 5 (38%). Оценка токсичности проводилась по шкалам CTC — NCIC V5.0. Не было отмечено ни одного случая лейкопении 3—4-й степени. Анемия 1—2-й степени наблюдалась 4 (31%) пациентов, тромбоцитопения 1—2-й степени — у 2 (15%). <h3>ЗАКЛЮЧЕНИЕ</h3> Предложенный режим двухкомпонентной ИХТ продемонстрировал приемлемый профиль токсичности. В случае достижения сопоставимых показателей выживаемости в сравнении с существующим стандартом данная схема ИХТ может рассматриваться как новый стандарт для реальной клинической практики лечения пациентов с местно-распространенным плоскоклеточным ВПЧ-позитивным раком ротоглотки.

Age-Dependent Hematologic Toxicity Profiles and Prognostic Serologic Markers in Postoperative Radiochemotherapy Treatment for Uterine Cervical Cancer.

Introduction: In the adjuvant setting for cervical cancer, classical risk factors for postoperative radiochemotherapy have been established. However, data on laboratory changes during therapy and the prognostic value of serological markers are limited and further knowledge is needed to optimize the toxic trimodal regimen. Methods: We retrospectively identified 69 women who underwent weekly postoperative radiochemotherapy with 40 mg/m2 of cisplatin for cervical cancer between 2010 and 2021 at a single center. Laboratory parameters were recorded before, at each cycle and after radiochemotherapy. Kaplan-Meier and log-rank analyses were used to calculate and compare survival, groups were compared using the Mann–Whitney U, χ2, and variance tests. Results: With a median follow-up of 17.7 months, the 1- and 5-year local control rates were 94.0% and 73.7%, respectively, with significantly better rates for more chemotherapy cycles and negative resection margins. Only 68.1% of patients completed all cycles. The most common reasons for early discontinuation were persistent asymptomatic leukopenia in women aged ≤ 50 years, and limiting infections in women aged > 50 years. Leukopenia was more likely to occur after the third cycle. Significantly worse survival was observed for post-radiochemotherapy elevated C-reactive-protein and lactate dehydrogenase levels, low pre-radiochemotherapy nutritional index, and raised C-reactive-protein-levels; the latter were also predictable for local control. The Glasgow prognostic score did not reliably predict survival. Conclusion: Incomplete application of simultaneous chemotherapy leads to inferior local control, and age-dependent limiting factors should be identified at an early stage. In addition to classical risk factors, serological markers (C-reactive-protein, lactate dehydrogenase, nutritional index) show prognostic significance.

Current leishmaniasis drug discovery.

Leishmaniasis is a complex protozoan infectious disease and, associated with malnutrition, poor health services and unavailability of prophylactic control measures, neglected populations are particularly affected. Current drug regimens are outdated and associated with some drawbacks, such as cytotoxicity and resistance, and the development of novel, efficacious and less toxic drug regimens is urgently required. In addition, leishmanial pathogenesis is not well established or understood, and a prophylactic vaccine is an unfulfilled goal. Human kinetoplastid protozoan infections, including leishmaniasis, have been neglected for many years, and in an attempt to overcome this situation, some new drug targets were recently identified, enabling the development of new drugs and vaccines. Compounds from new drug classes have also shown excellent antileishmanial activities, some of the most promising ones included in clinical trials, and could be a hope to control the disease burden of this endemic disease in the near future. In this review, we discuss the limitations of current control methods, explore the wide range of compounds that are being screened and identified as antileishmanial drug prototypes, summarize the advances in identifying new drug targets aiming at innovative treatments and explore the state-of-art vaccine development field, including immunomodulation strategies.

Efficacy and Safety of FOLFOX in Advanced Gastric Cancer Initially Presenting With Disseminated Intravascular Coagulation.

Advanced gastric cancer (AGC) rarely presents with disseminated intravascular coagulation (DIC) at the time of diagnosis. Chemotherapy should be selected in consideration of hematological toxicities because these patients are at high risk of hemorrhagic complications. The leucovorin, fluorouracil, and oxaliplatin (FOLFOX) regimen is an effective and less toxic regimen for patients with AGC and poor performance status. The present study assessed overall survival of all patients receiving first-line chemotherapy with and without DIC using Kaplan-Meier methods and examined the clinicopathological factors, DIC parameters, response, and survival of five patients with AGC and DIC who received FOLFOX in the first-line setting between February 2017 and February 2020. Among the patients, four patients (80%) recovered from DIC after a median of 12 days of FOLFOX therapy (range=12-25), and their platelet count gradually increased within 1 week after the start of chemotherapy. The median progression-free survival and overall survival were 46 (range=22-296) and 115 days (range=83-324), respectively. No patients experienced adverse events necessitating treatment discontinuation, including gastrointestinal bleeding and thrombocytopenia. Moreover, all patients received second-line treatment after progression, and one patient exhibited improvement of DIC symptoms following nab-paclitaxel and ramucirumab treatment. FOLFOX therapy is well tolerated and effective in patients with AGC initially presenting with DIC and subsequent second-line treatment might be crucial for better prognosis.

Incorporation of FLT3 Inhibitors Into the Treatment Regimens for FLT3 Mutated Acute Myeloid Leukemia: The Case for Total Therapy.

Therapeutic outcomes for acute myeloid leukemia patients with Fms-like tyrosine kinase 3 (FLT3) mutations have improved substantially since the discovery of small molecule tyrosine kinase inhibitors. Today, use of FLT3 inhibitors is standard in frontline intensive chemotherapy as well as patients with relapsed or refractory acute myeloid leukemia and FLT3 mutations and increasingly used as for prolonged remission maintenance posttransplant and/or postconsolidation. Yet, FLT3 inhibitors alone are not curative, and best outcomes are seen when the drugs are used as part of combination regimens. Optimizing therapy for patients with FLT3 mutations remains a work in progress. Overall, modern therapeutic approaches generate cure rates for this group at levels that argue against considering these mutations adverse risk. Still, such survivals require intensive therapy and often transplant. Therefore, efforts are underway to determine if lower toxicity regimens can attain comparable outcomes, at least for patients responding optimally. This review will review the various FLT3 inhibitors that are approved or in development, highlight the areas where they have been shown to add value, and identify areas where their use remains controversial.

Pre-operative Carboplatin/Paclitaxel Versus 5-Fluorouracil (5-FU)-based Chemoradiotherapy for Older Adults With Esophageal Cancer

This study aimed to compare the efficacy and tolerability of pre-operative platinum/5-fluorouracil (P5F) and carboplatin/paclitaxel (CP), in combination with radiation therapy in older adults with locally advanced, stage I-III esophageal cancer. We retrospectively reviewed 51 patients aged ≥70 years who underwent chemoradiotherapy followed by esophagectomy for stage I-III esophageal cancer between 2008 and 2018. Pathological complete response (pCR) and survival rates were compared across the two chemotherapy regimen arms. Treatment completion (p=0.28), pCR (p=0.89), and partial response rates were similar across both chemotherapy groups. Overall survival (OS) and disease-free survival (DFS) were similar across both groups with HR=0.80 (p=0.62) and HR=0.72 (p=0.72) respectively. The lesser toxic CP regimen may be used in older patients with locally advanced esophageal cancer, with tumor response and survival rates similar to P5F chemotherapy.

The role of pharmacogenetics in Efficacy and safety of protease inhibitor based therapy in human immunodeficiency virus type (HIV) infection.

Antiretroviral therapy has markedly reduced morbidity and mortality for persons living with human immunodeficiency virus (HIV). HIV can now be classified as a chronic disease; until a cure is found, patients are likely to require life-long therapy. However, despite these undoubted advances, there are many issues that need to be resolved, including the problems associated with long-term efficacy and toxicity. Moreover, pharmacotherapy of patients infected with HIV is challenging because a great number of comorbidities increase polypharmacy and the risk for drug-drug interactions. There is considerable interindividual variability in patient outcomes in terms of drug disposition, drug efficacy and adverse events. The basis of these differences is multifactorial, but host genetics are believed to play a significant part. HIV-infected population consists of ethnically diverse individuals on complex and potentially toxic antiretroviral regimens on a long-term basis. These individuals would benefit greatly from predictive tests that identify the most durable regimens. Pharmacogenetics holds that promise. Thus, detailed understanding of the metabolism and transport of antiretrovirals and the influence of genetics on these pathways is important. To this end, this review provides an up-to-date overview of the metabolism of antiHIV therapeutics of the protease inhibitors Lopinavir and Ritonavir and the impact of genetic variation in drug metabolism and transport on the treatment of HIV.

Comparison of efficacy and toxicity of chemoradiation regimens for head and neck squamous cell carcinoma primary treatment.

The best chemoradiation regimen to treat locally and regionally advanced head and neck squamous cell carcinoma (HNSCC) is yet to be established. We compared overall survival (OS) and adverse events following chemoradiation regimens (high-dose [HDC] or low-dose [LDC] cisplatin, or carboplatin [CB]) in HNSCC cases selected from SEER-Medicare linked database. Of the 1335 cases who underwent radiotherapy, 264 received HDC, 259 received LDC, and 353 received CB, concurrently. Compared to chemoradiation with HDC, using LDC or CB, or radiotherapy alone were associated with an increasingly worse OS; hazard ratios were 1.33, p=0.03; 1.35, p=0.02; and 2.12, p < 0.001; respectively. There were no differences in the rates of adverse events between the three chemoradiation regimens. Chemoradiation regimen using HDC appears to be the best primary treatment for locally and regionally advanced HNSCC. Nonetheless, prospective large studies are warranted to further determine its absolute benefit.

O-P04 Sonodynamic Therapy Complements PD-L1 Immune Checkpoint Inhibition in a Murine Model of Pancreatic Cancer

Abstract Background The emergence of immune checkpoint inhibitors (ICI’s) in the past decade has proven transformative in the area of immuno-oncology. The PD-1 / PD-L1 axis has been particularly well studied and monoclonal antibodies developed to block either the receptor (anti PD-1) or its associated ligand (anti PD-L1) can generate potent anti-tumour immunity in certain tumour models. However, many “immune cold” tumours remain unresponsive to ICI’s. Sonodynamic therapy (SDT) is a targeted anti-cancer treatment that uses ultrasound to activate a sensitiser with the resulting generation of reactive oxygen species (ROS) causing direct cell death. SDT has also been shown to stimulate the adaptive immune system in a pre-clinical cancer model. We investigate the ability of combining ICI and microbubble mediated SDT at controlling tumour growth in a bilateral pancreatic cancer model. Methods Preparation of O2MB-RB are shown below (scheme 1). Cytotoxicity of SDT and immunotherapy in-vivo are illustrated below (Figure 1). Figure 1 highlights that T110299 cells were subcutaneously implanted in the right and left dorsum of C57 mice. Group 1 received an IP injection of anti-mouse PD-L1 antibody (10mg/kg). After 2 hours, mice in this group received an IV injection of O2MB-RB suspension while receiving ultrasound applied to the right-hand-side (target) tumour. Group 2 received the same as Group 1 but no anti PD-L1 antibody; Group 3 received anti-PD-L1 antibody alone and Group 4 remained untreated. Flow cytometry analysis were carried out to investigate tumour infiltrating CD4+ and CD8+ T-lymphocytes. Results The results demonstrated a significant 287% decrease in tumour volume when compared to untreated animals 11 days following the initial treatment with SDT, which reduced further to 369% when SDT was combined with anti-PD-L1 ICI treatment. Analysis of residual tumour tissues remaining after treatment revealed increased levels of infiltrating CD4+ and CD8+ T-lymphocytes (respectively 4.65 and 3.16-fold more) in the off-target tumours of animals where the target tumour was treated with SDT and anti-PD-L1, when compared to untreated tumours. These results suggest that SDT treatment elicits an adaptive immune response that is potentiated by the anti-PD-L1 ICI in this particular model of pancreatic cancer. Conclusions In conclusion, microbubble mediated SDT treatment of a target tumour in a bilateral tumour model of pancreatic cancer, enables growth control at both the target and off-target tumours which is further enhanced when combined with anti-PD-L1 ICI treatment. Combining SDT with anti-PD-L1 ICI treatment, which is also well tolerated, could provide an attractive treatment option for pancreatic cancer, particularly for patients with advanced disease who may not be physically capable of undertaking a toxic chemotherapy regimen.

Pediatric immune deficiencies: current treatment approaches.

To summarize the currently available definitive therapies for patients with inborn errors of immunity (IEIs) with a strong focus on recent advances in allogeneic hematopoietic cell transplantation (HCT) and gene therapy, including the use of alternative donors, graft manipulation techniques, less toxic approaches for pretransplant conditioning and gene transfer using autologous hematopoietic stem cells. In the absence of a matched sibling or a matched related donor, therapeutic alternatives for patients with IEIs include alternative donor transplantation or autologous gene therapy, which is only available for selected IEIs. In recent years, several groups have published their experience with haploidentical hematopoietic cell transplantation (HHCT) using different T-cell depletion strategies. Overall survival and event free survival results, although variable among centers, are encouraging. Preliminary results from autologous gene therapy trials with safer vectors and low-dose busulfan conditioning have shown reproducible and successful results. Both strategies have become valid therapeutic options for patients with IEIs. A new promising and less toxic conditioning regimen strategy is also discussed. Definitive therapies for IEIs with HCT and gene therapy are in stage of evolution, not only to refine their efficacy and safety but also their reach to a larger number of patients.

All You Need to Know About UGT1A1 Genetic Testing for Patients Treated With Irinotecan: A Practitioner-Friendly Guide.

Irinotecan is an anticancer agent widely used for the treatment of solid tumors, including colorectal and pancreatic cancers. Severe neutropenia and diarrhea are common dose-limiting toxicities of irinotecan-based therapy, and UGT1A1 polymorphisms are one of the major risk factors of these toxicities. In 2005, the US Food and Drug Administration revised the drug label to indicate that patients with UGT1A1*28 homozygous genotype should receive a decreased dose of irinotecan. However, UGT1A1*28 testing is not routinely used in the clinic, and specific reasons include lack of access to concise information on this wide issue as well as mixed recommendations by regulatory and professional entities. To assist oncologists in assessing whether and when to use UGT1A1 genetic testing in patients receiving irinotecan-based therapies, this article provided (1) essential knowledge of UGT1A1 polymorphisms; (2) an update on the impact of UGT1A1 polymorphisms on efficacy and toxicity of contemporary irinotecan-based regimens; (3) dosing adjustments based upon the UGT1A1 genotypes, and (4) recommendations from currently available guidelines from the US and international scientific consortia and major oncology societies.

Optimising recruitment to a late-phase tuberculosis clinical trial: a qualitative study exploring patient and practitioner experiences in Uzbekistan

BackgroundAddressing the global burden of multidrug-resistant tuberculosis (MDR-TB) requires identification of shorter, less toxic treatment regimens. Médecins Sans Frontières (MSF) is currently conducting a phase II/III randomised controlled clinical trial, to find more effective, shorter and tolerable treatments for people with MDR-TB. Recruitment to the trial in Uzbekistan has been slower than expected; we aimed to study patient and health worker experiences of the trial, examining potential factors perceived to impede and facilitate trial recruitment, as well as general perceptions of clinical research in this context.MethodsWe conducted a qualitative study using maximum variation, purposive sampling of participants. We carried out in-depth interviews (IDIs) and focus group discussions (FGDs) guided by semi-structured topic guides. In December 2019 and January 2020, 26 interviews were conducted with patients, Ministry of Health (MoH) and MSF staff and trial health workers, to explore challenges and barriers to patient recruitment as well as perceptions of the trial and research in general. Preliminary findings from the interviews informed three subsequent focus group discussions held with patients, nurses and counsellors. Focus groups adopted a person-centred design, brainstorming potential solutions to problems and barriers. Interviews and FGDs were audio recorded, translated and transcribed verbatim. Thematic analysis, drawing on constant comparison, was used to analyse the data.ResultsHealth system contexts may compete with new approaches especially when legislative health regulations or policy around treatment is ingrained in staff beliefs, perceptions and practice, which can undermine clinical trial recruitment. Trust plays a significant role in how patients engage with the trial. Decision-making processes are dynamic and associated with relationship to diagnosis, assimilation of information, previous knowledge or experience and influence of peers and close relations.ConclusionsThis qualitative analysis highlights ways in which insights developed together with patients and healthcare workers might inform approaches towards improved recruitment into trials, with the overall objective of delivering evidence for better treatments.

Hematopoietic stem cell transplantation for Inborn Errors of Immunity

Hematopoietic stem cell transplantation for Inborn Errors of Immunity

Determinants of medication adherence in childhood nephrotic syndrome and associations of adherence with clinical outcomes.

Pediatric patients with nephrotic syndrome take medications long-term with significant toxicity and complex regimens, yet data on medication adherence are limited. In a multicenter observational study of patients with nephrotic syndrome, NEPTUNE (NCT01209000), we surveyed caregivers of patients <19 years old and adolescent patients on medication adherence during longitudinal follow-up beginning in June 2015. Data extraction was in October 2020. We described the proportion of nonadherent patients at first survey. Participant social and economic factors, condition-related factors, therapy-related factors, and patient-related factors were examined for relationships with nonadherence by generalized linear mixed models using the longitudinal data. In exploratory fashion, we assessed the relationship between adherence and subsequent steroid response classification by binary logistic regression and adherence with healthcare utilization by Poisson regression. A total of 225 participants completed a median of 3 surveys during follow-up (IQR, 2-5), with a total of 743 surveys. Overall, 80 (36%) reported nonadherence with medications. In adjusted analysis, older age (per 1 year; OR 1.08; 95% CI, 1.03 1.12), lower maternal educational level (≥ high school vs. < high school; OR 0.47; 95% CI 0.25 to 0.89), and increased parent and self-identification of medications barriers (per 1 point; OR 1.57; 95% CI, 1.15-2.15) were significantly associated with nonadherence. No relationship between nonadherence and subsequent frequency of healthcare utilization was observed. A trend toward increased subsequent steroid resistance classification was seen with nonadherence, though not statistically significant. Medication nonadherence is common in pediatric nephrotic syndrome. Investigations into the use of surveys in the clinic setting to identify at-risk patients and ways to support families over time are needed. A higher resolution version of the Graphical abstract is available as Supplementary information.

Rituximab, Methotrexate, Carmustine, Etoposide, and Prednisone (RMBVP) for the treatment of relapsed/refractory primary central nervous system lymphoma: a retrospective single-center study

Relapsed/refractory Primary Central Nervous System Lymphoma (R/R PCNSL) has a poor prognosis with no established preferred treatment. We report the efficacy and toxicity of a combination chemotherapy regimen: methotrexate, carmustine, etoposide, and prednisone with or without rituximab (RMBVP). This retrospective study included thirty patients who received a median of two 28-day cycles (0.5–5). The median age was 66 years (23–81); median KPS was 70 (30–90); 14 (46.7%) were women. Patients received a median of 2 prior lines of therapy and all received prior methotrexate. Of 29 evaluable patients, the overall response rate was 73.3% (n = 22). Median progression-free survival (PFS) was 15.6 months. Patients who recurred or progressed <12 months since last chemotherapy had a shorter median PFS (7.6 vs 37.6 months). Toxicity was moderate with 20% rates of severe myelosuppression. RMBVP is a tolerable treatment option for R/R PCNSL, with favorable response rates in those with recurrent disease.

Clinical Impact of the Administration of FOLFIRINOX Beyond Six Months in Advanced Pancreatic Adenocarcinoma: A Cohort Study.

BackgroundAlthough a toxic regimen, FOLFIRINOX is one of the most efficient chemotherapy regimens in advanced pancreatic adenocarcinoma. There is no standard number of cycles in locally advanced or metastatic stages.Materials and methodThe present retrospective study reports the experience of a single center with this regimen administered until disease progression or unacceptable toxicity. The authors of this retrospective study analyzed the data on patients with this diagnosis treated in our clinic during 2017-2021. Forty-two patients were included in the study, 21 who received six courses or less and 21 who received more than six courses. Progression-free survival (PFS) and overall survival (OS) were analyzed according to this stratification. The oncological response was also reported according to dose reduction and treatment delay, irrespective of the number of courses administered.ResultsMedian PFS was 7.5 months, and median OS was 13.6 months in the entire studied population. When patients were compared according to the number of courses received (under six vs. over six), there were obvious differences (PFS: 5.17 months vs. 11.2, p = 0.8, OS: 8 months vs. 17.3 months, p = 0.6). However, when stratifying survival by treatment delay and the presence or absence of dose reduction, better results were seen with lower doses (p<0.001) and treatment temporization (p=0.03). The general incidence of hematologic and neurologic toxicity was higher than the ones reported in the literature.ConclusionThe study revealed that patients benefit from the administration of FOLFIRINOX for more than six months, but that the administration of full dose and the maintaining dose intensity does not necessarily favor the patient.

A Comprehensive Toxicity and Efficacy Analysis of Different Bridging Therapies Prior to Anti CD19-CAR-T Cell Therapy in Patients with DLBCL- a National Multi-Center Cohort Study

Introduction - Data regarding efficacy and toxicity of different bridging strategies prior to CAR-T therapy are scanty. Tisagenlecleucel (Kymriah TM, Novartis) and axictagene ciloleucel (Yescarta TM, Kite/Gilead) were commercially approved for relapsed/refractory (R/R) DLBCL since 2019. We analyzed real-life data of CAR-T therapy among all consecutive patients who were treated in 4 different CAR-T centers in Israel.Methods - From May 2019, 144 R/R DLBCL patients underwent apheresis and continued to receive bridging therapy that included chemo/immunotherapy (n=78, 54%), radiation (n=11, 7.6%), chemoradiation (n=22, 15%), steroids only (n=5, 3.5%) and none (n=28, 19.4%). All patients were evaluated after bridging therapy and prior to CAR-T infusion by PETCT (96%) or CT scan (4%).Results - Median age was 68 (20-88) years and Median follow-up was 13 (4-26) months. All 144 patients underwent successful apheresis. Reasoning for choosing specific bridging therapy was based on low tumor mass (n= 23, 16%), high tumor mass (n=73, 51%), frailty of the patient (n=27, 19%), ongoing significant prior regimen's toxicities (n=14, 10%) and local disease (n=7, 4%). In patients given radiation therapy median dose was 23 (range, 8-30) Gy. In patients given chemo/immunotherapy or chemoradiation, sepsis was the main complications (9% of all patients) during bridging therapy. However, none of the patients had a fatal event. 14 patients (9.7%) did not proceed to CAR-T infusion; 6 (4.2%) had disease progression and died; 8 (5.6%) had manufacture failure). Among the 130 patients that received CAR-T infusion, PET-CT prior to preparative regimen demonstrated CR/PR status in 38%, 50%, 40%, 17%, and 16% of patients given chemotherapy, radiation, chemoradiation, steroids only, or no bridging therapy, respectively (p=.15), Figure 1. Any bridging therapy was associated with a better disease control compared to either steroids only or no treatment (p=.012). There were no differences in the incidences of overall CRS (p=.692), grade 3-4 CRS (p=.196), overall ICANS (p=.941), grade 3-4 ICANS (p=.281), acute kidney disease (p=.244), and liver dysfunction (p=.45) between the 5 different bridging strategies. Cardiovascular complications were more common after chemoradiation (36%), chemotherapy (19%) and radiation (13%), compared with steroids (0%) or no bridging therapy (4%), p=.05. Non-relapse mortality was 0 in all subgroups. PETCT at 1-month post CAR-T infusion demonstrated an increase in CR status percentage across all subgroups with no statistically significant difference in the incidence between the subgroups (p=.27), Figure 1. There was no difference in both progression-free survival (Figure 2) and overall survival between the 5 subgroups (p=.7, and p=.23). Cox regression model identified preinfusion lower ECOG status (HR=0.8, p=.04), preinfusion CR/PR status (HR=.46, p=.037) and 1-month post infusion CR status as a time dependent co-variate (HR=.14, p<.01) to be associated with better progression-free survival, while age and type of bridging therapy did not predict survival.Conclusions - Bridging to CAR-T should be tailored based on patient's and disease's characteristics with the aim to achieve the best disease control prior to CAR-T. However the chosen strategy per-se does not impact long-term outcomes. Intensive bridging therapy is associated with more cardiovascular events after CAR-T infusion. A prospective-controlled-trial allocating patients to different bridging strategies is needed to verify these results. [Display omitted] DisclosuresRam: Gilead: Honoraria; Novartis: Honoraria. Yehudai-Ofir: Novartis: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees. Avivi: Novartis: Speakers Bureau; Kite, a Gilead Company: Speakers Bureau. Zuckerman: Cellect Biotechnology: Honoraria; Gilead Sciences: Honoraria, Speakers Bureau; Novartis: Honoraria; Janssen: Honoraria; BioSight Ltd: Honoraria; Orgenesis Inc.: Honoraria; AbbVie: Honoraria. Yeshurun: Astellas: Consultancy; Janssen: Consultancy. Gurion: Medison; Gilead Sciences; Takeda Pharmaceuticals: Consultancy; JC Health CARE; Roche: Honoraria. Levi: AbbVie: Consultancy, Research Funding.

Applicability of the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) to Predict Outcomes of Acute Myeloid Leukemia Patients Older Than 60 Years Undergoing Non-Myeloablative Allogeneic Stem Cell Transplantation

Background: For most acute myeloid leukemia (AML) patients an allogeneic hematopoietic stem cell transplantation (HSCT) offers the highest chance of cure and long-term survival. Higher age and/or comorbidities may confine this option in a considerable number of AML patients due to toxic myeloablative preparation regimens. Non-myeloablative conditioning (NMA) regimes were developed to allow HSCT in these patients. The HSCT comorbidity index (HCT-CI) has been shown to predict outcome after allogeneic HSCT in cohorts of unselected patients. However, there is no separate evaluation of its prognostic significance in older (> 60 years) AML patients undergoing less-toxic NMA-HSCT. We evaluated the prognostic impact of the HCT-CI in a large, homogenously treated AML patient cohort that received NMA-HSCT.Methods: We retrospectively analyzed 289 AML patients older than 60 years (median age 66, range 60-77 years) at the time of NMA-HSCT. The conditioning regimen consisted of fludarabine 30 mg/m 2 for 3 consecutive days in addition to 2 (n=278) or 3 Gy (n=6) total body irradiation (TBI), five patients received 2 Gy TBI alone. Graft versus host disease prophylaxis contained cyclosporine and mycophenolate mofetil, none of the patients received in vivo or in vitro T-cell depletion. Disease risk at diagnosis was assessed according to the European LeukemiaNet (ELN) 2017 classification. In patients transplanted in morphologic remission, measurable residual disease (MRD) at HSCT was assessed based on NPM1 mutations and BAALC, MN1, and WT1 expression levels. The pre-transplant HCT-CI was calculated prior to the start of the conditioning regimen. Median follow up after HSCT was 3.8 years.Results: 97% of the patients (n=281) engrafted. 36% of the patients (n=104) had a low risk (0 points), 31% (n=90) an intermediate risk (1-2 points), and 33% (n=95) a high risk (≥3 points) HCT-CI score. The performance score at HSCT (ECOG, 0/1 vs. 2/3) was not different between HCT-CI risk groups (P=.86). Incidences of chronic graft-versus-host disease (GvHD) were 16% limited and 52% extensive disease. The non-relapse mortality (NRM) did not differ significantly between HCT-CI risk groups after NMA-HSCT (P=.56, Figure 1A, at 5 years HCT-CI low 24% vs. HCT-CI intermediate 20% vs. HCT-CI high 27%, respectively). Likewise, neither the cumulative incidence of relapse (P=.88, Figure 1B, at 5 years 46% vs. 45% vs. 43%) nor the overall survival (P=.70, Figure 1C, at 5 years 40% vs. 44% vs. 41%) differed according to the HCT-CI risk groups. The HCT-CI also did not impact outcomes in separate analyses according to ELN2017 risk at diagnosis (OS, P=.20, P=.30, and P=.70 for favorable, intermediate, and adverse, respectively) or MRD status prior to HSCT (OS, P=1 and P=.30 for MRD-negative and MRD-positive patients, respectively). In the favorable risk subgroup of patients being MRD-negative at the time of NMA-HSCT, the median overall survival reached 49% at 5 years after NMA-HSCT, irrespective of the HCT-CI.Conclusion: In the here presented cohort of older AML patients a higher HCT-CI did not have a negative impact on NRM or survival. In general, the NRM following NMA-HSCT was relatively low. Our data indicates that comorbidities per se - reflected by a higher HCT-CI score - should not impede NMA-HSCT. Independently from the HCT-CI score MRD-negative patients had notably good survival of 49 % at 5 years following NMA-HSCT. As the incidences of chronic graft-versus host disease were relatively high, alternative immunosuppressive strategies may help to further improve outcomes. Our data aid in informed clinical decisions regarding HSCT consolidation in older AML patients since we show that HSCT with this reduced toxicity regimen represents a feasible treatment option in older and comorbid AML patients also with higher HCT-CI scores. [Display omitted] DisclosuresBackhaus: Bayer: Other: Current Employment of Family Member. Jentzsch: Astellas: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria. Vucinic: Janssen: Honoraria, Other: Travel Sponsoring; Novartis: Honoraria; Gilead: Honoraria, Other: Travel Sponsoring; Abbvie: Honoraria, Other: Travel Sponsoring; MSD: Honoraria. Franke: BMS: Honoraria; Gilead: Honoraria, Other: Travel Sponsoring; Jazz Pharmaceuticals: Honoraria, Other: Travel Sponsoring; MSD: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Platzbecker: Celgene/BMS: Honoraria; AbbVie: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Geron: Honoraria; Takeda: Honoraria. Schwind: Novartis: Honoraria, Research Funding; Pfizer: Honoraria.

A Randomized Study of Bortezomib, Cyclophosphamide and Dexamethasone Induction (VCD) Versus VCD and Daratumumab Induction Followed By Daratumumab Maintenance (VCDD) for the Initial Treatment of Transplant-Ineligible Patients with Multiple Myeloma (AMaRC 03-16)

A Randomized Study of Bortezomib, Cyclophosphamide and Dexamethasone Induction (VCD) Versus VCD and Daratumumab Induction Followed By Daratumumab Maintenance (VCDD) for the Initial Treatment of Transplant-Ineligible Patients with Multiple Myeloma (AMaRC 03-16)