Salvage Chemotherapy In Patients Research Articles

High-dose chemotherapy as initial salvage chemotherapy in patients with relapsed or refractory testicular cancer: a systematic review and meta-analysis.

The role of high-dose chemotherapy followed by autologous hematopoietic cell transplantation in the management of patients with relapsed/refractory germ-cell tumors has not been established in prospective studies. Our aim was to estimate the benefits and harm of this treatment in men with relapsed/refractory germ-cell tumors. Electronic databases, conference proceedings, and trial registers until April 30, 2023, were searched. Randomized and non-randomized prospective controlled trials were included. Risk of bias assessments were performed using either RoB2 or ROBINS-I tools. The certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach. Time-to-event data were analyzed using the hazard ratio. The primary outcome was overall survival, and a meta-analysis was not conducted to assess it because non-randomized trials were judged to have a critical risk of bias. Categorical data were analyzed using a risk ratio. All results are presented with the corresponding 95% confidence interval. Four out of 3,824 records met the inclusion criteria, and three out of four were used to assess primary and secondary outcomes. Based on the IT94 study (N = 263 participants), single high-dose chemotherapy followed by autologous hematopoietic cell transplantation may have little to no effect on overall survival [hazard ratio (HR) 0.98, 95%CI 0.68 to 1.42; p = 0.916]. Non-randomized trials (N = 43 participants) showed contrasting results, which may be explained by the number of cycles of high-dose chemotherapy administered in each study. Regarding secondary outcomes, information was only provided for event-free survival, response rate, and acute toxicities. Based on prospective data, there is insufficient evidence to support or refute the proposal that high-dose chemotherapy with autologous hematopoietic cell transplantation improves survival in men with relapsed/refractory germ-cell tumors. If this treatment is considered essential, the choice should be made by experienced clinicians at high-volume cancer centers.

Blinatumomab-induced macrophage activating syndrome (MAS) in adult with B-cell acute lymphoblastic leukemia (B-ALL)

Blinatumomab as a single agent has demonstrated superiority over salvage chemotherapy in patients with relapsed and refractory B-cell acute lymphoblastic leukemia (B-ALL), with manageable safety and efficacy. Though known to have anticipated drug toxicities including cytokine release syndrome (CRS) and neurotoxicity, there is only one prior report of macrophage activating syndrome (MAS) due to blinatumomab. Case Presentation: We report the first case of blinatumomab-induced MAS in an adult. The patient presented with fever, cough, and weakness on the second cycle of blinatumomab. Complete blood count was notable for severe leukopenia, with comprehensive metabolic panel notable for elevated alkaline phosphatase, AST, ALT, LDH, and hyperferritinemia consistent with MAS. The patient was already in MRD-negative remission at presentation with MAS. She responded rapidly to withholding the drug and administration of both tocilizumab and dexamethasone. She was able to restart therapy with blinatumomab dosed at 9 mcg/day with no recurrence of symptoms. Though MAS is not an expected association with blinatumomab, the risk for CRS is. Secondary MAS in this case likely shares a mechanism with other hyperinflammatory conditions. Management includes holding the offending agent, like blinatumomab, and administering tocilizumab and dexamethasone. Future research will be needed to predict which patients are at highest risk to develop MAS after similar T-cell therapies.

Response to ifosfamide, carboplatin, etoposide (ICE) vs. dexamethasone, cytarabine cisplatin (DHAP) as salvage chemotherapy in patients with relapsed/refractory lymphoma.

Non-Hodgkin's lymphomas are the eighth-most prevalent malignancy in females and the eleventh in males. No research has been conducted comparing dexamethasone, cytarabine cisplatin (DHAP) vs. ifosfamide, carboplatin, etoposide (ICE) as salvage chemotherapy regimens for relapsed or refractory lymphomas in Pakistan. This study aims to compare the response of ICE vs. DHAP as salvage chemotherapy in patients with relapsed/refractory lymphomas. A prospective follow-up study was conducted at the tertiary care hospital in Karachi, Pakistan, from 2019 to 2020. A total of 58 lymphoma patients after first-line chemotherapy were included in the study. The treatment response was evaluated after two cycles of salvage chemotherapy using WHO assessment criteria, and Cox regression was used to determine the hazard ratios considering the P value ≤0.05 significant. Of 58 patients, 19 (32.8%) patients achieved complete response (CR), and 8 (13.8%) patients achieved partial response (PR), with an overall response rate of overall response rate of 46.6%. In the ICE group, the response was assessed in 19 patients. Overall response was 42.1%, CR was 31.6% and PR was 10.5%. In the DHAP group, response was evaluated in 39 patients, the overall response rate was 48.7%, CR was 33.3% and PR was 15.4%. The hazard ratio for survival in patients with relapsed/refractory lymphomas who received DHAP was 1.40 times (95% CI: 1.27-3.63, P=0.001) compared to patients who received ICE as salvage chemotherapy. DHAP seems to have a marginally better overall response rate than the ICE regimen in patients with refractory or relapsed lymphoma. However, the toxicity profile of patients in both groups was similar.

Neutrophil-to-lymphocyte ratio as an early marker of outcomes in patients with recurrent oral squamous cell carcinoma treated with nivolumab

The immune checkpoint inhibitor (ICI), nivolumab, has revolutionised the treatment of recurrent and metastatic oral cancer. However, the response rate to ICIs remains low, and identifying predictors of nivolumab response is critical. Although the neutrophil-to-lymphocyte ratio (NLR) has been suggested as a predictive marker of nivolumab response in patients with various types of cancer, its utility in oral squamous cell carcinoma (OSCC) has not been elucidated. In this retrospective multicentre cohort study, we evaluated the association between NLR and outcome of nivolumab treatment in 64 patients with OSCC treated between 2017 and 2020. The objective response and disease control rates were 25.1% and 32.9%, respectively. The rates for complete and partial responses were 15.7% (10/64) and 9.4% (6/64), respectively; stable and progressive disease rates were 7.8% (5/64) and 67.1% (43/64), respectively. Complete and partial responses were classified as responders, and stable and progressive diseases were classified as non-responders. The median (range) pre-treatment NLR among responders was 4.3 (2.8–8.0), which decreased to 4.0 (2.6–6.3) after nivolumab treatment, and the median (range) pre-treatment NLR among non-responders was 5.1 (2.7–7.9), which increased to 6.4 (4.0–14.0) with tumour growth. Moreover, overall survival was significantly worse in the group with a higher post-treatment NLR (≥5) than in the group with a lower NLR (<5). Patients with a post-treatment NLR of ≥6 had worse outcomes for salvage chemotherapy following nivolumab treatment. Thus, post-treatment NLR could be a useful marker for predicting the response to nivolumab treatment or salvage chemotherapy in patients with OSCC.

Virtual clinical trials: A tool for predicting patients who may benefit from treatment beyond progression with pembrolizumab in non-small cell lung cancer.

Enrolling patients in immunotherapy clinical trials is becoming increasingly competitive. Virtual clinical trials can help investigators answer key questions despite this. For example, pembrolizumab is the recommended first-line treatment for non-small cell lung cancer (NSCLC) with no driver alterations and a programmed death ligand 1 (PD-L1) Tumor Proportion Score ≥50%. Salvage therapies for relapsed/refractory patients are limited. Retrospective studies suggest that a subset of patients may benefit from pembrolizumab beyond progression; these results have not been validated in a prospective study. We constructed digital twins of patients and simulated clinical trials to predict the best salvage therapy after progressive disease (PD) on pembrolizumab. Response dynamics were evaluated at the lesion level to represent patients who experience systemic PD while individual lesions continue shrinking. With >25,000 radiographic lesion measurements from >500 patients, we simulated responses to pembrolizumab, chemotherapy, and PD on pembrolizumab followed by either pembrolizumab beyond progression or salvage chemotherapy. Switching all progressors to salvage chemotherapy was suboptimal. Virtual trials predicted progression-free survival (PFS) from pembrolizumab beyond progression to be comparable with salvage chemotherapy in patients whose PD was due to nontarget progression. A PFS-optimized regimen may improve disease control rates ≥15%. Pembrolizumab beyond progression may benefit a subset of patients with PD-L1-high, driver alteration-free NSCLC, but prospective studies are warranted.

Sequential Therapy Vs. Salvage Chemotherapy for Patients with AML Refractory to First Induction Regimen- a Bi-Institutional Retrospective Cohort Analysis

Background: Induction-refractory acute myeloid leukemia (AML) occurs in approximately 30% of AML patients and is mostly associated with inferior outcome. A sequential approach offers shorter time to allogeneic hematopoietic cell transplantation (HCT), reduces salvage-associated toxicities while providing significant anti-leukemic activity. We hypothesized that early intervention with a sequential approach based on the original FLAMSA regimen salvage these patients more effectively as compared with a standard salvage therapy. Methods: We retrospectively compared results between 2 tertiary centers in Israel that apply different therapeutic modalities for first-induction failure: The first (TASMC -"cases" group), employs a transplant-based sequential approach for patients with first-induction-refractory AML, while the second center (RMC - "controls" group), applies mostly conventional salvage regimens. All consecutive patients ≥18 years who were treated in both centers between 2013 and 2021 and given either high-intensity induction chemotherapy or low-intensity venetoclax (VEN)-based regimens were included. Refractory to first induction was defined as either blasts >10% on day 30 marrow after 7+3 regimen, or after 2-3 cycles of a VEN-based regimen. We compared baseline characteristics between the 2 groups and used time-to-event analyses to calculate non-relapse mortality (NRM) and overall survival (OS) with day of allocation (either sequential therapy or non-sequential approach) defined as day 0. Controls who underwent HCT were not censored at transplant. Cox regression analysis was used to identify predictors for survival. This trial was approved by both Institutional Ethic Committees. Results: Between 01/2013 and 12/2021 we identified 91 patients that fulfilled the eligibility criteria (cases, n=55; controls, n=36). Characteristics of cases and controls were similar, except for higher % of patients with metabolic syndrome in the control group, Table. Mean days from diagnosis to HCT in the cases group was 69±25 with longer mean time in patients who were given VEN-based compared to high-intensity induction chemotherapy (94±23 vs. 62±21 days, respectively, p<.001). All patients advanced to transplantation. Median days to neutrophils and platelets engraftment were 10 (range, 7-16) and 16 (range, 9-35), respectively. Incidences of grade 2-4 and 3-4 acute GVHD were 55% (95%CI 47%-63%) and 15% (95%CI 47%-63%), respectively, and incidences of overall and moderate-severe chronic GVHD at 3 years were 64% (95%CI 44%-84%) and 37% (95%CI 25%-49%), respectively. In the controls group, patients were given high-dose cytarabine-based salvage regimens (n=21, 58%), novel targeted therapies (n=5, 14%), HCT (n=4, 11%), VEN-based regimen (n=3, 8%), and palliation (n=2, 6%). Of those patients who were given chemotherapy/other targeted therapies (n=30), 11 (37%) responded and of them, 9 (82%) proceeded to HCT. Five additional patients underwent HCT in active disease. Thus, overall, 18 patients (50%) in the controls group underwent HCT. Percentage of complete remission was higher in the cases group (measured at 1 month after HCT) vs. controls group (measured at any time after allocation) (87% vs. 39%, p<.001). 1-year NRM was higher in the cases group compared to controls group, however this did not reach statistical significance (37% (95%CI 32%-42%) vs. 20% (95%CI 14%-26%), p=0.126). Median OS was similar in patients given intensive induction chemotherapy between the cases and controls groups (8.3 (95%CI 2.74-14.4) months vs. 7.1 (95%CI 2.15-11.4) months, p=0.66), although in patients with adverse ELN risk, OS within the intensive group was better (8.2 (95%5.1-11/7) months vs. 2.4 (95%CI 0-4.8) months, p=0.027). Importantly, OS was better in cases refractory to VEN-based induction regimens compared to controls (22 (95%CI n/a) months vs. 7.8 (95%CI 0-15.9) months, p<.001). Cox regression analysis identified adverse ELN risk group and lower performance status as predictors for mortality (HR=2.5, p=0.02 and p=0.008, respectively). Conclusions: sequential therapy in refractory to induction therapy AML may benefit patients with poor salvage options such as those with adverse risk AML and those with refractory disease to VEN-based induction regimens. Better salvage regimens and improved transplantation techniques may improve both strategies to enhance patients’ outcomes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

P11.63.B Thrombocytopenia limits the feasibility of salvage lomustine chemotherapy in recurrent glioblastoma: a secondary analysis of EORTC 26101

Abstract Background Chemotherapies used for the treatment of primary brain tumors frequently induce hematological toxicity. Thrombocytopenia represents the main cause of stopping chemotherapy for toxicity. Here we explored the incidence, and the consequences for treatment exposure and survival, of thrombocytopenia induced by lomustine chemotherapy at first recurrence of glioblastoma. Methods We performed a retrospective analysis of thrombocytopenia at first recurrence of glioblastoma, its consequences for treatment delivery, and associations with outcome in the phase II and III parts of EORTC 26101, a randomized trial designed to define the role of lomustine versus bevacizumab versus their combination in glioblastoma patients at first relapse. Results 225 patients were treated with lomustine alone (median 1 cycle) (group 1) and 283 patients were treated with lomustine plus bevacizumab (median 3 lomustine cycles) (group 2). Among cycle delays and dose reductions of lomustine for toxicity, thrombocytopenia was the leading cause. Among 129 patients of group 1 and 187 patients of group 2 experiencing at least one episode of thrombocytopenia, 36 patients in group 1 and 93 in group 2 had their treatment modified because of thrombocytopenia. Lomustine was discontinued for thrombocytopenia in 16 patients (7.1%) in group 1 and in 38 patients (13.4%) in group 2. Patients with O6-methylguanine DNA methyltransferase (MGMT) promoter-methylated glioblastoma treated with lomustine alone experienced more interference with study treatment than patients with tumors without MGMT promoter methylation. On adjusted analysis accounting for major prognostic factors, treatment modification by thrombocytopenia was a positive prognostic factor for overall survival, and this effect was entirely driven by patients with tumors without MGMT promoter methylation only. Conversely, thrombocytopenia was associated with inferior progression-free survival in patients with MGMT promoter-methylated tumors, suggesting a link to insufficient lomustine exposure. Conclusion Drug-induced thrombocytopenia is a major limitation to adequate exposure to lomustine salvage chemotherapy in patients with recurrent glioblastoma. Its association with survival suggests that mitigating thrombocytopenia to allow enhanced drug exposure in patients with MGMT promoter methylated tumors might improve outcome.

Successful Mobilization of Autologous Hematopoietic Peripheral Blood Stem Cells after Salvage Chemotherapy in Patients with Low CD34 Blood Cell Counts

A major barrier for proceeding to autologous stem cell transplantation (ASCT) is an inability to mobilize and collect an adequate number of peripheral blood (PB) stem cells (PBSC) for the transplant graft. Plerixafor added to granulocyte colony stimulating factor (G-CSF) alone, without prior chemotherapy, significantly improves the mobilization of autologous PBSC in patients with non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). However, the efficacy of plerixafor and the best timing to give the drug to poorly mobilizing patients with very low PB CD34+ cell counts after salvage chemotherapy and G-CSF are not well defined. We hypothesized that PBSC mobilization and collection might be improved in heavily treated patients who mobilized very poorly after salvage chemotherapy and G-CSF by alternating the days of plerixafor administration and leukapheresis. A day of rest between plerixafor doses, while continuing G-CSF, could allow time for some replenishment of the marrow stem/progenitor cell pool before the next mobilization. A retrospective review of collection results in poorly mobilizing patients at our center was undertaken. Three cohorts were identified: those who got every-other-day plerixafor and leukapheresis, those who got sequential plerixafor and leukapheresis and those who got risk adapted plerixafor. Overall, 69% of patients with NHL and MM with PB CD34+ cell counts <5/µL after salvage chemotherapy and G-CSF were ultimately able to collect adequate CD34+ cells to support ASCT using daily plerixafor and leukapheresis. On the alternating plerixafor and leukapheresis schedule, all 17 patients achieved the cumulative CD34+ cell product goals required for ASCT. This positive observation after salvage chemotherapy and G-CSF led to the incorporation at our center of an alternate-day schedule of plerixafor and leukapheresis into our real-time risk adapted strategy for poor mobilizers.© 2023 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Salvage chemotherapy in patients with nonsmall cell lung cancer after prior immunotherapy: a retrospective, real-life experience study.

Patients with advanced nonsmall cell lung cancer (NSCLC) who progress with immune checkpoint inhibitors (ICIs), salvage chemotherapy remains the only viable option for tumors that do not harbor genomic alterations. Data on the efficacy of salvage chemotherapy after immunotherapy (SCAI) are scarce. Our main objective in the current study was to evaluate the efficacy of SCAI. All consecutive patients who were diagnosed as having metastatic NSCLC and received at least one dose of ICIs were retrospectively reviewed. We computed progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) with SCAI. We also analyzed associations between survival and various clinicopathologic factors. We identified 35 patients with advanced NSCLC who received at least one dose of SCAI. The median age was 66 years. Most of patients were male ( n = 26, 74.3%) and former or current smokers ( n = 33, 94.3%). The majority of the patients were Eastern Cooperative Oncology Group Performance Status (ECOG PS) 2 ( n = 22; 62.9%), and there were no patients with driver mutations. SCAI was administered as second-line therapy in 21 (60.0%) patients and third-line in 14 (40.0%) patients. The ORR to SCAI was 20.0% with median PFS and OS were 2.43 (95% CI, 1.69-3.16) months and 4.40 (95% CI, 2.17-6.62) months, respectively. In multivariate analysis, ECOG PS 2 was confirmed as being independently associated with inferior OS. We demonstrated that patients with NSCLC who progressed to ICIs had limited clinical benefit with salvage chemotherapy, particularly for patients who were ECOG PS 2.

5-Fluorouracil/L-Leucovorin Plus Oxaliplatin (FOLFOX) Regimen as Salvage Chemotherapy for Patients with Unresectable Pancreatic Cancer Receiving Gemcitabine and Nab-Paclitaxel and 5-Fluorouracil/L-Leucovorin Plus Nanoliposomal Irinotecan: Preliminary Results from Clinical Practice.

Salvage chemotherapy for patients with unresectable pancreatic cancer (UR-PC) who have been treated with gemcitabine and nab-paclitaxel (GnP), and 5-fluorouracil (5-FU)/l-leucovorin (LV) plus nanoliposomal irinotecan (nal-IRI), has not been fully established. We retrospectively reviewed data from 17 patients with UR-PC who initiated 5-FU/l-LV plus oxaliplatin (FOLFOX) as salvage chemotherapy at our hospital between June 2020 and August 2021, after treatment with GnP and 5-FU/LV plus nal-IRI. The primary endpoint was tumor response. The secondary endpoints were progression-free survival (PFS) and adverse events (AEs). The response and disease control rates were 5.9% (1/17) and 17.6% (3/17), respectively. The median PFS was 1.8 months (range: 0.4–5.2 months). Eight patients (47.1%) experienced grade 3 nonhematologic AEs, while none experienced grade 3 hematologic AEs. Two patients with controlled disease had homologous recombination deficiency (HRD)-associated gene mutations in cancer panel testing. The FOLFOX regimen benefit for UR-PC patients treated with GnP and 5-FU/LV plus nal-IRI may be limited to patients with HRD-associated gene mutations.

Molecular profile of FLT3-mutated relapsed/refractory patients with AML in the phase 3 ADMIRAL study of gilteritinib

AbstractThe phase 3 Study of ASP2215 Versus Salvage Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With FMS-like Tyrosine Kinase (FLT3) Mutation (ADMIRAL) trial demonstrated the superiority of the FLT3 inhibitor, gilteritinib, to salvage chemotherapy (SC) in patients with FLT3-mutated relapsed or refractory (R/R) AML. Baseline comutations, FLT3-internal tandem duplication (ITD) allelic ratio and length, and treatment-emergent mutations were analyzed in patients in the ADMIRAL trial. Baseline comutations were grouped according to gene subgroups (DNA methylation/hydroxymethylation, transcription, chromatin–spliceosome, receptor tyrosine kinase-Ras signaling, TP53-aneuploidy, NPM1, DNMT3A, DNMT3A/NPM1, WT-1, and IDH1/IDH2). Across all but 1 gene subgroup (TP53-aneuploidy), higher pretransplant response rates and a trend toward longer overall survival were observed with gilteritinib vs SC. Patients with DNMT3A/NPM1 comutations who received gilteritinib had the most favorable outcomes of any molecular subgroup analyzed. Survival outcomes with gilteritinib were not adversely affected by FLT3-ITD allelic ratio, FLT3-ITD length, or multiple FLT3-ITD mutations. Among patients who relapsed on gilteritinib, Ras/mitogen-activated protein kinase (MAPK) pathway and FLT3 F691L gene mutations were the most common mutational events associated with treatment resistance. However, the occurrence of Ras/MAPK pathway gene mutations at baseline did not preclude a clinical benefit from gilteritinib. Acquisition of multiple Ras/MAPK pathway gene mutations at relapse suggests a high level of pathway reactivation is needed to overcome the gilteritinib treatment effect. These findings provide insight into the R/R AML molecular profile and the impact of FLT3 inhibitors on mutational evolution associated with treatment resistance and benefit of gilteritinib across a wide spectrum of molecular and genetic subgroups in FLT3-mutated R/R AML. This trial was registered at www.clinicaltrials.gov as #NCT02421939.

Salvage Chemotherapy in Patients with Previously Treated Thymic Carcinoma.

Simple SummaryThymic carcinoma is identified as thoracic neoplasm having low sensitivity to systemic chemotherapy. As first-line setting, platinum-based chemotherapy is administered, but, it is difficult to achieve long-term survival. Therefore, salvage chemotherapy is clinically considered as second or third line treatment. This study reviewed the therapeutic significance of several kinds of cytotoxic agents and molecular targeting drugs in patients with previously treated thymic carcinoma. The clinical trials of salvage chemotherapy in patients with thymic carcinoma are limited, and we cannot draw an optimal conclusion due to the small sample size. However, S-1, amrubicin, docetaxel, pemetrexed, and paclitaxel, sunitinib and lenvatinib yielded some efficacy to such patients. As S-1 and amrubicin are limited to Japan and East Asian, it remains unclear which regimens are better as second-line setting. Further investigation is warranted to establish the clinical evidence of salvage chemotherapy in advanced or metastatic thymic carcinoma by large-scale study.Thymic carcinoma is a rare neoplasm, and it is difficult to achieve complete remission with systemic chemotherapy. In advanced or recurrent thymic carcinoma, platinum-based chemotherapy is chosen as the first-line setting; however, it remains unclear which regimen is better to improve its outcome. It remains unknown whether salvage chemotherapy should be administered to patients with platinum-based chemotherapy-refractory thymic carcinoma. Currently, several clinical studies have investigated the efficacy of second-line settings for advanced thymic carcinoma. As cytotoxic agents, S-1, amrubicin, pemetrexed, docetaxel, paclitaxel, and gemcitabine have been reported as prospective phase II studies or retrospective studies. The overall response rates (ORRs) of S-1, amrubicin, and pemetrexed were 25–50%, 11–44.4%, and 9–10%, respectively. Molecular targeting drugs, such as sunitinib, everolimus, and lenvatinib, also provide clinical effectiveness with tolerability after the failure of platinum-based regimens. Based on the results of the prospective phase II study, the ORR, median progression-free survival, and median overall survival were 16.6% and 5.6 months, respectively, in everolimus, 26% and 7.2 months, respectively, in sunitinib, and 38% and 9.3 months, respectively, in lenvatinib. Although it is difficult to compare each study, lenvatinib appears to be better in increasing efficacy as a second-line setting. However, each study had a small sample size, which may have biased the results of their studies. Further investigation is warranted to elucidate the therapeutic significance of salvage chemotherapy in advanced thymic carcinoma in a large-scale study.

Hypometilating Agents (HMA) As Salvage Therapy in Relapsed or Refractory AML: A 5-Center Retrospective Study

Introduction: 5-azacytidine and decitabine have been widely studied as first line chemotherapy in acute myeloid leukemia (AML) patients not eligible for allogenic stem cell transplantation, but data on their use as salvage chemotherapy are limited. We tried to define efficacy and feasibility of hypometilating agents (HMA) as salvage chemotherapy in patients without previous allogenic stem cell transplantation.Methods: We retrospectively reviewed clinical records of 35 patients treated with HMA as salvage therapy in our 5 institutions since their introduction in clinical practice for AML patients.Results: Median age was 68 years. 22 patients were men and 13 women. One patient was AML with t(9;11), 18 were AML MRC, 4 were therapy related AML, 12 were AML NOS. Two patients were favorable risk sec ELN 2017, 20 were intermediate, 11 were adverse risk. Cytogenetic risk was not available for 2 patients. 66% of patients received HMA as second line therapy for their disease, 23% as third line and 11% were beyond the third line. 29 patients were treated with azacitidine and 6 with decitabine. Six patients reached CR or morphologic leukemia free state (MLFS) or PR after HMA. All patients underwent intensive chemotherapy (i.e. FLAI or 3+7 like) as first line induction, and we excluded patients who had an HMA as first line chemotherapy and another one as second line. Median number of hospitalization days during HMA therapy was 11(1-78); median number of HMA cycles was 3 (range 1-31). 7 episodes of sepsis demonstrated by positive blood cultures and 3 fungal infections were recorded during HMA therapy. Median OS was 197 days from the starting of HMA and median EFS was 125 days. Median EFS in patients with adverse cytogenetic risk was 68 days, while median EFS in patient with favorable and intermediate risk was 207 days (p=0,0124). Median OS in patients with adverse cytogenetic risk was 181 days, while median OS in patient with favorable and intermediate risk was 307 days (p=0,0401).We did not find significant difference between median OS ed EFS in patients with refractory disease compared to relapsed patients. 31% of patients with adverse cytogenetic risk reached a stable disease with HMA therapy while 64% of patients with favorable/intermediate cytogenetic risk reached a response (CR, PR; MLFS) or a stable disease. We did not find significant differences between transfusion needs before and after salvage therapy but this could be due to the small size of our sample.Conclusion: HMA showed efficacy and a considerable OS in our patients. OS was significantly better in favorable/intermediate risk patients than adverse risk patients. Hospitalization was limited, and we can argue that this could lead to improved costs and quality of life, but further studies are needed. So HMA could be a good clinical option in a selected population of relapsed patients, especially in those not suitable for allogenic bone marrow transplantation, in whom the prognosis is generally extremely poor. Further studies are needed to define if there is a survival or quality of life advantage over other therapies. DisclosuresNo relevant conflicts of interest to declare.

A Single Arm Prospective Pilot Study Examining the Efficacy and Safety of Bevacizumab Single Maintenance Therapy Following Platinum-Based Chemotherapy in Patients with Advanced or Recurrent Cervical Cancer.

Although the addition of bevacizumab to platinum-based combination chemotherapy has been recommended as a standard regimen for patients with advanced or recurrent cervical cancer, there is no clear evidence regarding the effectiveness of bevacizumab monotherapy as salvage chemotherapy. This study prospectively examined the efficacy and safety of switching from platinum-based chemotherapy combined with bevacizumab to single maintenance therapy in patients with advanced or recurrent cervical cancer. Patients were first treated with standard combination chemotherapy. However, if chemotherapy was discontinued because of an adverse event, bevacizumab monotherapy was continued for patients who agreed to participate in this study and provided written informed consent. The study protocol was approved by the Independent Review Board of Tohoku University School of Medicine (reception number 2017-1-540). A total of 15 patients (median age of 55 years, range 33-69 years) participated in this study. The median number of cycles of bevacizumab single maintenance administration was 8, and the main reasons for discontinuation were disease progression and adverse events. Bevacizumab single maintenance therapy had a disease control rate of 53.3% (CR 40%, PR 6.7%, SD 6.7%). The most frequent grade 3/4 clinical adverse events were proteinuria (5/15) and hypertension (4/15). No treatment-related deaths occurred. Bevacizumab single maintenance therapy was effective as salvage chemotherapy in patients with advanced or recurrent cervical cancer, and the safety profile was generally consistent with those reported in previous studies of bevacizumab monotherapy.

Clinical Outcomes in Patients with FLT3-ITD-Mutated Relapsed/Refractory Acute Myelogenous Leukemia Undergoing Hematopoietic Stem Cell Transplantation after Quizartinib or Salvage Chemotherapy in the QuANTUM-R Trial

Despite the substantial clinical activity of fms-related tyrosine kinase 3 (FLT3) inhibitors in relapsed or refractory (R/R) FLT3-ITD‒positive acute myelogenous leukemia (AML), durable remissions and prolonged survival in this population require allogeneic hematopoietic stem cell transplantation (allo-HSCT). Quizartinib, a once-daily oral, highly potent, and selective FLT3 inhibitor, significantly prolonged overall survival (OS) and improved clinical benefit compared with salvage chemotherapy (median OS, 6.2 months versus 4.7 months; hazard ratio [HR], .76; 95% confidence interval [CI], .58 to .98; P=.018; composite complete remission [CRc] rate, 48% versus 27%; median duration of CRc, 2.8 months versus 1.2 months; mortality rate, .8% versus 14% by day 30, 7% versus 24% by day 60) in patients with R/R FLT3-ITD AML in the phase 3 QuANTUM-R trial. In this post hoc analysis, we described the characteristics of and clinical outcomes in patients who underwent on-study HSCT in QuANTUM-R at the investigator's discretion and institutional practices. Of 367 randomized patients, 78 (32%) in the quizartinib arm and 14 (11%) in the salvage chemotherapy arm underwent on-study allo-HSCT without any intervening therapy for AML after quizartinib or study-specified salvage chemotherapy. Pooled data of patients from both treatment arms showed a longer median overall survival (OS) in transplant recipients versus those treated without allo-HSCT (12.2 months versus 4.4 months; HR, .315; 95% CI, .233 to .427). Pooled data also showed a longer median OS in patients with a last recorded response of CRc before allo-HSCT versus patients without a CRc (20.1 months versus 8.8 months; HR, .506; 95% CI, .296 to .864). By treatment arm, the median OS was 25.1 months with quizartinib and 20.1 months with salvage chemotherapy in patients with a last recorded response of CRc before allo-HSCT. Forty-eight patients in the quizartinib arm continued quizartinib treatment after allo-HSCT. In the 31 patients with a last recorded response of CRc before allo-HSCT who continued quizartinib after allo-HSCT, the median OS was 27.1 months. Continuation of quizartinib after allo-HSCT was tolerable, and no new safety signals were identified. These results suggest that post-transplantation survival following salvage chemotherapy and quizartinib treatment are similar. However, quizartinib response occurs more frequently than with salvage chemotherapy, potentially allowing more patients to undergo transplantation and achieve durable clinical benefit. In addition, post-transplant quizartinib was found to be tolerable and may be associated with prolonged survival in some patients, highlighting its potential value in the management of patients with FLT3-ITD R/R AML.

Oncologic Outcomes of Salvage Chemotherapy in Patients with Recurrent or Metastatic Lesions after Radical Nephroureterectomy: A Multi-Institutional Retrospective Study

Background: Radical nephroureterectomy (RNU) is the standard treatment for patients with upper tract urothelial carcinoma (UTUC). However, approximately 25% of patients experience recurrence or metastasis after RNU. This study evaluated the clinical outcome and efficacy of salvage chemotherapy (SC) after recurrence or metastasis. Patients and Methods: Of the 441 nonmetastatic UTUC patients who underwent RNU, 147 patients with recurrent or metastatic lesions were analyzed; patients with bladder cancer recurrence were excluded. Time from disease recurrence or metastasis to cancer-specific survival (CSS) was estimated by the Kaplan-Meier method. Multivariate analyses were performed with the Cox proportional hazards regression model, controlling for the effects of clinicopathological factors. Results: The median time from RNU to disease recurrence or metastasis was 13.2 months. In the recurrent or metastatic sites, 31 cases (21%) were liver. In multivariate analyses, pT stage (≥pT3), time to recurrence (<12 months), and liver metastasis were independently predictive factors. In the risk stratification model for CSS after recurrence, patients were categorized into 2 groups based on pT stage, time to recurrence, and liver metastasis. The low-risk group (0–1 risk factors) included 87 patients, and the high-risk group (2–3 risk factors) included 60 patients. In the high-risk group, 27 patients received SC. The probability of CSS after recurrence or metastasis was higher in patients in the SC group compared to the non-SC group (9.5 vs. 3.7 months; p < 0.001). Conclusion: Two or more risk factors defined the high-risk group for patients with recurrence or metastasis after RNU. SC was associated with improved survival in patients with high-risk UTUC.

Safety and Efficacy of Tyrosine Kinase Inhibitors in Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

Introduction: Five year overall survival for acute myeloid leukemia (AML) is estimated to be less than 30%. Encouraging results seen with the tyrosine kinase inhibitors (TKIs), midostaurin and gilteritinib resulted in the approval of these molecular targeted therapies for patients with FLT3 Mutated AML. Other TKIs like sorafenib and quizartinib, have ongoing clinical trials. In this systematic review and meta-analysis, we assessed the efficacy and safety of TKIs for the treatment of newly diagnosed (ND) and relapsed refractory (R/R) AML. Methods: A search was performed on PubMed, Cochrane, Embase, and clinicaltrials.gov. We used the keywords "tyrosine kinase inhibitors" AND "acute myeloid leukemia" from the inception of literature till 07/10/2020. We screened 3245 articles and included 5 randomized clinical trials (RCTs) (N=1919) in this meta-analysis. We extracted data for efficacy (i-e, OS, CR, ORR, EFS) and safety (≥grade 3 treatment related adverse events (TRAE). We excluded case reports, case series, preclinical studies, review articles, meta-analysis, observational studies, and controlled clinical studies not providing any information about the efficacy or safety of TKI. We used the R programming language (version 4.0.2) to conduct a meta-analysis. Results: In the 5 RCTs (n=1919), the age range was 18-85 years. 1675 participants had FLT-3 mutation (Table 1). In 2 RCTs (N=738), two TKIs (gilteritinib and quizartinib) (N=492) were compared with salvage chemotherapy (N=246). Risk ratio (RR) of overall response rate (ORR) and complete remission (CR) was 2.43 (95% CI=1.97-3.00, I2=0) and 2.09 (95% CI=1.5-2.90, I2=48%), respectively in favor of TKIs. The hazard ratio (HR) for overall survival (OS) was 0.70 (95% CI=0.58-0.84, I2=0) in favor of TKIs. (Fig 1-3). The median OS was 6.2 months in the quizartinib group vs. 4.7 months in the chemotherapy group. Similarly, median OS was 9.3 months in the gilteritinib group vs. 5.6 months in the chemotherapy group. Grade 3 or higher TRAEs (anemia, infections, sepsis, febrile neutropenia, and liver toxicity) were reported more often in the TKI group vs. salvage chemotherapy group. (Fig 4-6). In 3 RCTs (N=1181), two TKIs (midostaurin and sorafenib) (N=597) were compared with placebo (N=582). In the RCT evaluating role of sorafenib in older patients (&amp;gt;60 years) (N=197), RR of CR was 0.75 (95% CI=0.58-0.96) in favor of placebo. Although more patients died in the sorafenib group than the placebo group (23 vs 10 within 60-day period), TRAEs were similar in the two groups. In the remaining 2 RCTs, sorafenib and midostaurin were compared with placebo in younger patients (&amp;lt;60 years old) (N=982). RR of CR was 1.07 (95% CI=0.96-1.19, I2=0) in favor of TKIs and the hazard ratio for OS was 0.80 (95% CI=0.66-0.96, I2=0) in favor of TKIs (Fig 7,8). Median event-free survival (EFS) was 21 months in the sorafenib group vs. 9 months in the placebo group. Similarly, median EFS was 8.2 months in the midostaurin group vs. 3 months in the placebo group. Grade 3 or higher TRAEs (anemia, liver toxicity, infections, and diarrhea) were more common in the TKI group as compared to the placebo group. (Fig 9,10) Conclusion: Gilteritinib and quizartinib were not only better tolerated but also more effective than salvage chemotherapy in patients with FLT-3 mutated AML. In older patients, sorafenib appeared to have lower efficacy and higher toxicity when compared with placebo. In contrast, for younger patients, sorafenib and midostaurin had better efficacy and lower toxicity than placebo. Additional multicenter double-blind randomized clinical trials are needed to confirm these results. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.:Honoraria, Research Funding, Speakers Bureau.

Standard-dose salvage chemotherapy in patients with refractory metastatic germ-cell tumors (mGCT) progressing after high-dose chemotherapy (HDCT) and peripheral-blood stem-cell transplant (PBSCT).

e17061 Background: About 40% of patients with relapsed GCT will progress after HDCT and PBSCT and are generally incurable with further standard dose chemotherapy. We previously evaluated standard dose cisplatin combination chemotherapy in 15 patients following progression from HDCT and observed only a single brief PR ( JCO 18(6), 1181-1186.). We report results of non-platinum standard-dose chemotherapy regimens in refractory mGCT. Methods: Pts with mGCT who progressed after HDCT+PBSCT at Indiana University from 2004-2019 were evaluated. Kaplan-Meier methods and log-rank tests were used to analyze PFS and OS for the regimen directly following HDCT. Results: 78 pts with refractory mGCT were reviewed. 64 pts. (82%) received paclitaxel+gemcitabine (TG), 10 pts. (13%) received daily oral etoposide (E), and 4 pts. (5%) received oxaliplatin-based (O) regimens (oxaliplatin+gemcitabine or oxaliplatin+bevacizumab). Median age was 29 (range, 16-57). Primary site was testis in 62, retroperitoneum in 6, mediastinum in 9. Metastatic sites included retroperitoneal LNs (62), pulmonary (58), liver (23), bone (6), and brain (21). IGCCCG risk was good in 16, intermediate in 5, and poor in 57. HDCT was utilized as 2nd line setting in 72 pts, and ≥3rd line in 6 pts. Median time from HDCT to progression was 4 months (upper limit 16.6 months). PS and OS data is shown in the table, with superior outcomes in TG compared to O and E (p &lt; 0.001). Maintenance oral etoposide after HDCT was administered in 44% (n = 28) of all patients who later progressed and received TG. Among 12 patients (19%) with 12-month PFS on TG, the median overall PFS was 18.3 months with 2 patients alive at the time of last follow-up. The primary site was testis in 11 patients, 67% (n = 8) were platinum refractory, and 83% (n = 10) were IGCCCG poor risk. 10 patients achieved a PR to TG, and two patients achieved CR. Conclusions: Salvage standard-dose chemotherapy with paclitaxel+gemcitabine after progression on HDCT is superior to oral etoposide or oxaliplatin-based regimens and should be the preferred regimen in patients with refractory mGCT. [Table: see text]

PCN306 ESTIMATION OF HEALTH STATE UTILITIES IN FLT3-MUTATED RELAPSED/REFRACTORY ACUTE MYELOID LEUKEMIA

Patients with relapsed or refractory acute myeloid leukemia (R/R AML) have poor health-related quality of life (HRQoL); however, limited evidence is available specifically for FLT3-mutated (FLT3mut+) R/R AML and health states. To date, the phase 3 ADMIRAL study is the only trial to collect comprehensive EuroQoL 5-Dimension (EQ-5D) data as patients progressed through different health states (eg, event-free survival [EFS], post-event). The objective of this analysis was to estimate utilities for clinically distinct health states in patients with FLT3mut+ R/R AML, using data from ADMIRAL. In ADMIRAL, EQ-5D utility scores were estimated based on data from all randomized patients (regardless of treatment arm) with a baseline and ≥1 post-baseline assessment. The UK crosswalk value set was used to map 5-level EQ-5D (EQ-5D-5L) to 3-level EQ-5D (EQ-5D-3L) scores. Observed values were used in the analysis without imputation for missing evaluations. Results were estimated at baseline, for patients in the EFS health state following treatment, and patients alive post-event (defined as relapse or treatment failure), using a generalized estimating equation model with a robust variance estimator to account for correlation within patients' repeated assessments. The analysis included 279 patients with FLT3mut+ R/R AML (208 gilteritinib; 71 salvage chemotherapy). At baseline, the overall mean EQ-5D-3L score was 0.74 (standard error [SE]=0.01). For patients without hematopoietic stem cell transplantation (HSCT) during follow-up, pre- and post-event utility values were 0.80 (SE=0.02) and 0.70 (SE=0.02), respectively, where higher scores imply better HRQoL. For patients who had undergone HSCT, the pre-event utility was 0.82 (SE=0.03) and the post-event utility was 0.75 (SE=0.03). EFS was associated with improved utility scores in patients with FLT3mut+ R/R AML treated with gilteritinib or salvage chemotherapy for patients both with and without HSCT. Therefore, treatments which prolong patients’ time in a pre-progression state are likely to improve HRQoL.

Anti-CD38 Therapy with Daratumumab for Relapsed/Refractory CD20-Negative Diffuse Large B-Cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) is the most common and one of the most aggressive subtypes of non-Hodgkin’s lymphomas. Front-line therapy consists of chemotherapy in combination with anti-CD20 monoclonal antibody rituximab. Relapses after rituximab-based regimen have poor prognosis and call for new treatment options. Immunohistochemistry analysis of relapsed DLBCL often reveal CD20-negative lymphoma, which limits repeated use of rituximab in combination with salvage chemotherapy. CD38 is a surface antigen that binds to CD38, CD31/PECAM-1 and hyaluronic acid. CD38 is an important mediator of signal transmission from the microenvironment into the cell. Anti-CD38 monoclonal antibody daratumumab has been approved for the treatment of multiple myeloma. Expression of CD38 on the surface of DLBCL is highly variable (compared to strong expression on myeloma cells), but can be easily assessed by flow cytometry or immunohistochemistry. A patient-derived xenograft (PDX) model of CD20-negative, CD38-positive DLBCL derived from a patient with rituximab-refractory DLBCL was used for in vivo experiments. We demonstrated that daratumumab suppressed growth of subcutaneous PDX tumours significantly more effectively than rituximab. Analysis of tumours obtained from mice treated with daratumumab revealed down-regulation of surface CD38, suggesting endocytosis of CD38-daratumumab complexes. The results suggest a potential clinical use of daratumumab in combination with salvage chemotherapy in patients with relapses of CD20-negative DLBCL. In addition, daratumumab might potentially serve as a suitable antibody moiety for derivation of antibodydrug conjugates for the targeted delivery of toxic payloads to the lymphoma cells.