Therapeutic Challenges in Patients with Gynecologic Carcinosarcomas: Analysis of a Multicenter National Cohort Study from the French Prospective TMRG Network

Background: Gynecological carcinosarcomas are rare and aggressive diseases, with a poor prognosis. The rarity of these tumors explains the lack of robust and specific data available in the literature. The objective of this study was to investigate the impact of initial adjuvant treatment and recurrent therapeutic strategies. Patients and methods: A multicentric cohort study within the French national prospective Rare Malignant Gynecological Tumors (TMRG) network was conducted. Data from all included carcinosarcomas diagnosed between 2011 and 2018 were retrospectively collected. Results: 425 cases of uterine and ovarian carcinosarcomas (n = 313 and n = 112, respectively) were collected and analyzed from 12 participating centers. At diagnosis, 140 patients (48%) had a FIGO stage III–IV uterine carcinosarcoma (UCS) and 88 patients (83%) had an advanced ovarian carcinosarcoma (OCS) (FIGO stage ≥ III). Two hundred sixty-seven patients (63%) received adjuvant chemotherapy, most preferably carboplatin-paclitaxel regimen (n = 227, 86%). After a median follow-up of 47.4 months, the median progression-free survival (mPFS) was 15.1 months (95% CI 12.3–20.6) and 14.8 months (95% CI 13.1–17.1) for OCS and UCS, respectively. The median overall survival for OCS and UCS was 37.1 months (95% CI 22.2–49.2) and 30.6 months (95% CI 24.1–40.9), respectively. With adjuvant chemotherapy followed by radiotherapy, mPFS was 41.0 months (95% CI 17.0–NR) and 18.9 months (95% CI 14.0–45.6) for UCS stages I–II and stages III–IV, respectively. In the early stage UCS subgroup (i.e., stage IA, n = 86, 30%), mPFS for patients treated with adjuvant chemotherapy (n = 24) was not reached (95% CI 22.2–NR), while mPFS for untreated patients (n = 62) was 19.9 months (95% IC 13.9–72.9) (HR 0.44 (0.20–0.95) p = 0.03). At the first relapse, median PFS for all patients was 4.2 months (95% CI 3.5–5.3). In the first relapse, mPFS was 6.7 months (95% CI 5.1–8.5) and 2.2 months (95% CI 1.9–2.9) with a combination of chemotherapy or monotherapy, respectively (p < 0.001). Conclusions: Interestingly, this vast prospective cohort of gynecological carcinosarcoma patients from the French national Rare Malignant Gynecological Tumors network (i) highlights the positive impact of adjuvant CT on survival in all localized stages (including FIGO IA uterine carcinosarcomas), (ii) confirms the importance of platinum-based combination as an option for relapse setting, and (iii) reports median PFS for various therapeutic strategies in the relapse setting.

Clofarabine with topotecan, vinorelbine, and thiotepa reinduction regimen for children and young adults with relapsed AML

Effective reinduction regimens are needed for children with relapsed and refractory acute myeloid leukemia (AML) as outcomes remain poor. Therapeutic options are limited in this heavily pre-treated patient population, many of whom have reached lifetime recommended doses of anthracycline chemotherapy. The development of effective non-anthracycline based salvage regimens is crucial to these patients who are at significant risk of life-threatening cardiotoxicity. We previously reported results of a phase 2 trial of a clofarabine-based regimen with topotecan, vinorelbine, and thiotepa (TVTC) in patients with relapsed acute leukemias. Here we report on an expanded bicenter cohort of 33 patients, &lt;25 years of age, with relapsed/refractory (R/R) AML treated with up to 2 cycles of the TVTC reinduction regimen from 2007 to 2018. The overall response rate (ORR), defined as complete remission (CR) or CR with partial recovery of platelet count (CRp), was 71.4% (95%CI: 41.9 to 91.6%) for those patients in first relapse (n=14) and 47.4% ( 95%CI: 24.4 to 71.1%) for patients in 2nd or greater relapse or refractory disease. Responses were seen across multiple high risk cytogenetic and molecular subtypes, with 84% of responders successfully bridged to allogeneic stem cell transplantation. The 5-year OS for patients in first relapse was 46.2% (95%CI: 19.1 to 73.3%) and 50.0% (95%CI: 26.9 to 73.1%) for patients who responded to TVTC. For pediatric and young adult patients with R/R AML, TVTC reinduction compares favorably with currently used salvage regimens and warrants further exploration.

LUMOS - Low and Intermediate Grade Glioma Umbrella Study of Molecular Guided TherapieS at relapse: Protocol for a pilot study

IntroductionGrades 2 and 3 gliomas (G2/3 gliomas), when combined, are the second largest group of malignant brain tumours in adults. The outcomes for G2/3 gliomas at progression approach the dismal outcomes for glioblastoma (GBM), yet there is a paucity of trials for Australian patients with relapsed G2/3 gliomas compared with patients with GBM. LUMOS will be a pilot umbrella study for patients with relapsed G2/3 gliomas that aims to match patients to targeted therapies based on molecular screening with contemporaneous tumour tissue. Participants in whom no actionable or no druggable mutation is found, or in whom the matching drug is not available, will form a comparator arm and receive standard of care chemotherapy. The objective of the LUMOS trial is to assess the feasibility of this approach in a multicentre study across five sites in Australia, with a view to establishing a national molecular screening platform for patient treatment guided by the mutational analysis of contemporaneous tissue biopsiesMethods and analysisThis study will be a multicentre pilot study enrolling patients with recurrent grade 2/3 gliomas that have previously been treated with radiotherapy and chemotherapy at diagnosis or at first relapse. Contemporaneous tumour tissue at the time of first relapse, defined as tissue obtained within 6 months of relapse and without subsequent intervening therapy, will be obtained from patients. Molecular screening will be performed by targeted next-generation sequencing at the reference laboratory (PathWest, Perth, Australia). RNA and DNA will be extracted from representative formalin-fixed paraffin embedded tissue scrolls or microdissected from sections on glass slides tissue sections following a review of the histology by pathologists. Extracted nucleic acid will be quantified by Qubit Fluorometric Quantitation (Thermo Fisher Scientific). Library preparation and targeted capture will be performed using the TruSight Tumor 170 (TST170) kit and samples sequenced on NextSeq 550 (Illumina) using NextSeq V.2.5 hi output reagents, according to the manufacturer’s instructions. Data analysis will be performed using the Illumina BaseSpace TST170 app v1.02 and a custom tertiary pipeline, implemented within the Clinical Genomics Workspace software platform from PierianDx (also refer to section 3.2). Primary outcomes for the study will be the number of patients enrolled and the number of patients who complete molecular screening. Secondary outcomes will include the proportion of screened patients enrolled; proportion of patients who complete molecular screening; the turn-around time of molecular screening; and the value of a brain tumour specific multi-disciplinary tumour board, called the molecular tumour advisory panel as measured by the proportion of patients in whom the treatment recommendation was refined compared with the recommendations from the automated bioinformatics platform of the reference laboratory testing.Ethics and disseminationThe study was approved by the lead Human Research Ethics Committee of the Sydney Local Health District: Protocol No. X19-0383. The study will be conducted in accordance with the principles of the Declaration of Helsinki 2013, guidelines for Good Clinical Practice and the National Health and Medical Research Council National Statement on Ethical Conduct in Human Research (2007, updated 2018 and as amended periodically). Results will be disseminated using a range of media channels including newsletters, social media, scientific conferences and peer-reviewed publications.Trial registration numberACTRN12620000087954; Pre-results.

Characteristics and Outcomes of Locally Recurrent Retroperitoneal Sarcoma After First Relapse in a Single Tertiary Asian Centre and Applicability of the Sarculator

ObjectiveRetroperitoneal sarcomas (RPS) comprise of 15% of soft tissue sarcomas where five-year overall survival rate is about 50%. Locoregional recurrences are observed in up to 50% of patients within the first five years following resection. Various factors have been shown to influence survival outcomes, such as histological subtype and tumour size. A nomogram for first relapse locally recurrent RPS was developed using 602 patients from 22 centres. The recurrent RPS Sarculator is available in an electronic interface and includes variables of age, size, margins of re-resection, radiotherapy, chemotherapy and histology to predict for 6-year disease-free survival (DFS) and overall survival (OS). It has not been validated externally. This study aims to validate the Sarculator recurrence nomogram in predicting the survival outcomes of recurrent RPS in an Asian population as well as examine relapse patterns.MethodsPatients diagnosed with first recurrent RPS from 1 January 2000 to 31 December 2017 with first local relapse and eligible for curative re-resection were retrospectively analysed. The type of surgery was unique for individual patients and suggestions of adjuvant therapy were based on globally recognised standards. Patients were followed up every 3 to 4 months post-operatively for the first 2 to 3 years and 6-monthly to a year thereafter. A R0 or R1 margin is deemed as complete resection, including a microscopically negative margin (R0) and microscopically positive but macroscopically clear margin (R1). R2 is classified as an incomplete resection with tumour rupture or remaining disease. Harrell’s C concordance index was used to determine the nomogram’s discriminative ability and calibration plots were used to assess accuracy. For the calibration, the patients were divided into 3 groups. Death data was retrieved from the National Birth and Death registry for accuracy.ResultsThere were 53 patients included in this study. Patient and tumour characteristics have been summarised in Table 1. All patients had their second resection at a single centre. 66.0% had their first resection at the same centre. The median age was 53 (range 21- 79) at diagnosis, median tumour size was 17cm (12cm to 28cm) and median follow-up duration was 44.1 months. The most commonly encountered subtypes were de-differentiated liposarcoma (DDLPS) (56.6%), well-differentiated liposarcoma (WDLPS) (20.8%) and leiomyosarcoma (LMS) (11.3%) with a majority being high-grade (75.5%). The median disease-free interval was 2.9 years (2- 5.3 years) from the first surgery. The median age at second surgery was 56 (21- 79) and all patients had a complete resection (R0/R1). Recurrence patterns differed with subtypes where 90.9% and 9.1% of WDLS, 76.7% and 16.7% of DDLPS and 83.3% and 16.7% of LMS had local and distant relapses respectively from the second surgery. 62.5% of distant relapses was in the lung followed by nodes (18.8%) and liver (12.5%). The 5-year OS from the second surgery was 66.2% (95% CI: 54.3%- 80.8%). The 1-year, 3 years and 6 years DFS were 50.2% (95% CI: 38.2% - 65.9%), 10.4% (4.26% - 25.5%) and 3.91% (0.684% - 22.4%) respectively. Overall, 32 patients (60.4%) had passed away from sarcoma. The concordance indices for 6-year OS and DFS were 0.7 and 0.65 (Figure 1) respectively which represents a fairly accurate prediction by Sarculator.ConclusionOur study has shown the Sarculator nomogram for primary recurrent was applicable in our cohort and its potential application in an Asian setting. The Sarculator nomogram will be a useful tool in clinical practice to improve risk stratification and facilitate prognosis-based decision-making. Moving forward, novel therapeutic strategies are required to enhance the prognosis of patients with recurrent RPS.

Risk factors analysis and establishment of a clinical predictive model for recurrence after first attack of myasthenia gravis: a single-center retrospective study

Background Myasthenia gravis (MG) is a rare and recurrent disease. The purpose of this study was to investigate the risk factors for relapse in MG patients after their first attack and establish a clinical predictive model. We conducted a retrospective study of 86 MG patients, followed and reviewed the clinical data of patients from the first onset to the first relapse, including age of onset, site of first symptom, MGFA at onset, thymoma, surgical resection of the thymoma, infection history, irregular drug use, combination of other autoimmune diseases, AChR antibody, and anti-Musk antibody, etc. The R software was used for statistical analysis. Univariate analysis and multivariate analysis were used to analyze risk factors. The clinical predictive model was established by Logistic regression analysis. Results Within 2 years after the first attack, 61.2% of MG patients relapsed. MGFA at onset, irregular drug use and infection history were independent risk factors for MG relapse within 2 years after the first attack ( p < 0.05). The clinical prediction model has good discrimination and calibration. Conclusion The relapse of MG is affected by a variety of factors. The clinical predictive model that was established in this study can help clinicians predict the probability of relapse in MG patients, identify early high-risk relapse patients, and serve for high-quality clinical management.

Prognostic Impacts of Additional Cytogenetic Abnormalities Acquired at the First Relapse in Adult Patients with Acute Myeloid Leukemia Undergoing Allogeneic Stem Cell Transplant in Second Complete Remission

Background: Additional cytogenetic abnormalities (ACA), the most frequent form of cytogenetic changes, are considered as a result of genetic instability and clonal evolution of leukemia cells. Recently, we described that ACA at the first relapse was associated with the significantly lower second complete remission (CR2) rate and poor survival in adult acute myeloid leukemia (AML) patients (Hematol Oncol. 2018;36:252-257). However, the prognostic impact of ACA after allogeneic stem cell transplant (allo-SCT) has not been elucidated in adult AML patients. Patients and methods: Of the 145 adult AML patients who underwent the first allo-SCT in CR2 between 1997 and 2019, 98 patients whose cytogenetic abnormality data both at diagnosis and at the first relapse were available were included in this study. Cytogenetic changes between at diagnosis and the first relapse were classified into four groups: (1) no change, (2) ACA was acquired at the first relapse, (3) cytogenetic abnormalities observed at diagnosis were reduced or had disappeared at the first relapse, and (4) cytogenetic abnormalities observed at diagnosis were reduced or had disappeared, and completely different ACA was acquired at the first relapse. In this study, groups 2 and 4 were defined as ACA acquisition. Overall survival (OS) was defined as the interval from the date of transplant to the date of death. Fisher's exact test was used to compare binary variables. The cumulative incidence (CI) of non-relapse mortality (NRM) and relapse were evaluated with Gray's test, considering relapse and NRM as a competing risk, respectively. OS was estimated with the Kaplan-Meier method and compared using the log-rank test. Factors associated with at least borderline significance (p &lt; 0.20) in univariate analyses were subjected to multivariate analysis. The Cox and Fine-Gray proportional hazard model were used for multivariate analysis of prognostic and risk factors, respectively. Values of p &lt; 0.05 were considered to indicate statistical significance. Results: Of the 98 patients included in this study, 57 were male, and 41 were female. The median age at transplant was 45 years (range, 17-71 years). The median duration of CR1 was 12.4 months (range, 1.3-70.3 months) and cytogenetic risk groups were good, intermediate, and poor in 26 (27%), 70 (71%), and two patients (2%), respectively. Donor types were related, unrelated, and cord blood in 23 (24%), 59 (60%), and 16 patients (16%), respectively, and 86 (87%) and 61 patients (62%) were conditioned with myeloablative and total body irradiation-containing regimens, respectively. According to the definition described above, 20 patients (20%) acquired ACA at the first relapse. There was no significant difference in baseline characteristics and transplant procedures between patients with and without ACA acquisition. The OS rates were not significantly different between two groups (55% vs. 72% at three years after transplant; p = 0.28). The CI of relapse was significantly higher in patients with ACA acquisition than those without ACA acquisition (59% vs. 15%; p &lt; 0.01), while the CI of NRM were not significantly different between two groups (5% vs. 19%; p = 0.17). Multivariate analysis for OS revealed that age over 50 years (hazard ratio [HR] = 2.4; p &lt; 0.01), but not ACA acquisition, was identified as an independent prognostic factor. ACA acquisition (HR = 4.7; p &lt; 0.01) was extracted as an independent risk factor of relapse, while use of reduced intensity conditioning regimens (HR = 3.1; p = 0.03) and more than or equal to 1 of performance status at transplant (HR = 2.7; p = 0.04) showed independent risks of NRM. The similar OS rates between two groups might resulted from an offset of the lower relapse rate with the higher NRM rate in patients without ACA acquisition despite not reaching statistical significance. This increasing NRM rates in those without ACA acquisition was potentially associated with use of reduced intensity conditioning regimens in larger proportion (0% vs. 15%; p = 0.12). Conclusion: These findings suggested that ACA acquisition at the first relapse was associated with a higher risk of relapse even after allo-SCT in CR2 in adult AML patients. As AML cells with ACA acquisition was resistant to not only chemotherapy but also graft-versus-leukemia effect, innovative therapeutic strategy is warranted. Disclosures Handa: Janssen: Honoraria; Kyowa Kirin: Research Funding; Takeda: Honoraria, Research Funding; BMS: Honoraria; Chugai: Research Funding; Ono: Honoraria; Sanofi: Honoraria, Research Funding; Abbvie: Honoraria; MSD: Research Funding; Shionogi: Research Funding; Celgene: Honoraria, Research Funding; Daiichi Sankyo: Research Funding.

Outcomes after First Rescue Treatment in Patients with Relapsed or Refractory Multiple Myeloma in Colombia

Background Proteasome inhibitors (PIs) are approved for treating newly diagnosed and relapsed multiple myeloma (MM) in Colombia. This propensity score matching (PSM) analysis using data from the real-world, was designed to establish the role PIs (bortezomib or carfilzomib) at first relapsed or refractory MM. The primary endpoint was overall response rate (ORR) and secondary endpoint included was overall survival (OS). Moreover, an analysis of OS was done regarding response attained. On Behalf of RENEHOC-GRIMMCO (Colombian Registry for Hemato-Oncological Diseases and Colombian Mieloma Múltiple study group). Methods PSM by nearest neighbor analysis to evaluate the role of PIs used at first relapse in multiple myeloma of patients belonging to RENEHOC registry, between 2010 and 2020. Results 390 patients were identified in the first relapse of the Colombian registry, 269 patients with PI and 121 patients without PI. One hundred and ten patients were included in each group after PSM. Patients were matched for age, ISS, extramedullary disease, and use of lenalidomide to define the influence of this immunomodulatory drug in the PI group. A difference was found in the use of lenalidomide because only 1 patient was treated with PI and lenalidomide concomitantly (0.91%) compared to 31 patients in the group without PI (28.18%), (p &lt;0, 0001). Regarding ORR, no differences were found between the 2 groups 38.18% in PIs vs 37.27% in non-PIs group (p = 0.801). A trend towards better OS was found in the PIs group with a median of 58 months versus 39 months (p = 0.179). Overall survival in patients who achieved at least PR was better compared to those who did not reach 79 months versus 32 months in non-responders (p = 0.0001). Conclusion In this study, we found that the use of PI has a tendency to improve overall survival in real-world in MM patients when used in the first relapse and that this effect could possibly be enhanced with the combination with lenalidomide. Regardless of the treatment used, better responses are associated with better survival. Figure 1 Figure 1. Disclosures Abello: Janssen: Honoraria; Amgen: Honoraria; Dr Reddy's: Research Funding. Sossa: Amgen: Research Funding.

Inferior Outcomes of Patients with Quad and Penta-Refractory Multiple Myeloma (MM) Compared to Those of Patients Who Have Been Quad and Penta Exposed

Background: Despite significant advancements in MM therapies, patients with quad-refractoriness (refractory to proteasome inhibitors: bortezomib and carfilzomib, and immunomodulatory drugs: lenalidomide and pomalidomide) and penta-refractoriness (additional refractoriness to CD-38+ monoclonal antibody daratumumab) have a poor prognosis in terms of short progression-free survival (PFS) and overall survival (OS). This is a retrospective, single institutional study comparing the outcomes of patients with quad and penta-refractory MM to patients who were quad and penta-exposed, but not refractory. Methods: Consecutive patients from the John Theurer Cancer Center at Hackensack Meridian School of Medicine who were quad and penta-exposed and/or refractory between the dates of 1/1/2015 and 3/1/2021 were identified. Quad-exposed was defined as having had prior exposure to bortezomib, carfilzomib, lenalidomide and pomalidomide. Penta-exposed was defined as having prior exposure to bortezomib, carfilzomib, lenalidomide and pomalidomide and daratumumab. Penta or quad refractory was defined as having stable disease (as best response) or progressive disease while on all of the above drugs, per International Myeloma Working Group (IMWG) definition of refractory. Patients were excluded if they had missing data or if they did not meet the above definitions. Baseline characteristics, high-risk status, ISS, treatment history, treatment response, drugs at first relapse and survival outcomes were obtained retrospectively from the electronic medical record and entered into database. High-risk cytogenetics were defined as the presence of t(4;14), t(14;16) or del 17p; 1q21 gain or amplification; 1p del; t(6;14); t(14;20). Baseline patients' characteristics were summarized descriptively by quad and penta-exposed groups. PFS and OS were estimated using the Kaplan-Meier method. Univariate and multivariable adjusted Cox proportional hazard regression models examined factors affecting OS. Results: A total of 162 patients met the inclusion criteria: 18/162 (11%) were quad or penta-exposed, 32/162 (20%) were quad-refractory, and 112/162 (69%) were penta-refractory. Median age was 62 (55-69), IgG subtype (59%), and 62/162 (38.5%) had high-risk cytogenetics. The median number of lines prior was 6 (range 4-8) among all patients, and 7 (range 5-9) in the penta-refractory group. 133/162 (82.1%) had prior autologous-stem cell transplant (ASCT). Extramedullary disease was present in 40/162 (25.2%). Plasma cell leukemia was present in 14/162 (8.8%). For those who were penta-refractory, the median time from quad to penta-refractory status was 10.2 months (95% confidence interval (CI), 3.57-16.57). See Table 1. Figure 1 shows PFS and OS from the time of becoming quad or penta-exposed or refractory (T0 ). The median PFS after T0 was 11.86 months (95% CI, 6.5-26.6) for combined quad and penta-exposed, compared to 3.88 months (95% CI, 2.99-5.17) for quad and penta-refractory patients. With a median follow-up of 5.14 months (Range, 0-52.4), the median OS for all patients was 7.43 months (95% CI, 5.8- 12.94). (Figure 1A). With a median follow-up time of 4.45 months (Range, 0-52.38), the median OS for patients who were quad or penta-refractory was 5.97 months [95% CI. 4.44-8.23], compared to OS not reached (NR) for quad or penta-exposed, with a median follow-up of 11.86 months. (Figure 1B). At least one subsequent treatment regimen was employed after T0 in 85% of the patients. (Figure 1C). Multivariable adjusted analysis (Table 2) revealed that patients ≥62 had inferior OS compared to those &lt; 62 (p -value=0.046). Furthermore, patients who had ≤10 months between becoming quad- and penta-refractory had inferior OS compared to patients with &gt;10 months (p=0.031). OS was not significantly affected by high risk versus standard cytogenetics or drugs used at first relapse. Conclusion: MM patients with quad and penta-refractory disease have significantly worse outcomes compared to patients with quad and penta-exposed MM: older age (&gt; 62 years) and a short interval (&lt; 10 months) between becoming quad and penta-refractory confer an adverse prognosis. Prospective studies are required to confirm these findings. Penta and quad-refractory multiple myeloma continues to represent a vulnerable population with an unmet need for therapeutic approaches. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.