Progression Related Death Research Articles

Prediction of Early Death and Severe Infections during Novel Agent-Based Induction Therapy in Newly-Diagnosed Multiple Myeloma: An Intergroup Analysis from the German Speaking Myeloma Multicenter Group, the Dutch-Belgian Cooperative Trial Group for Hematology Oncology Foundation and the European Myeloma Network

Prediction of Early Death and Severe Infections during Novel Agent-Based Induction Therapy in Newly-Diagnosed Multiple Myeloma: An Intergroup Analysis from the German Speaking Myeloma Multicenter Group, the Dutch-Belgian Cooperative Trial Group for Hematology Oncology Foundation and the European Myeloma Network

Post-Irradiation Hyperamylasemia Is a Prognostic Marker for Allogeneic Hematopoietic Stem Cell Transplantation Outcomes in Pediatric Population: A Retrospective Single-Centre Cohort Analysis.

Background: Total body irradiation (TBI) is a mandatory step for patients with acute lymphoblastic leukemia (ALL), undergoing allogeneic hematopoietic stem cell transplantation (HSCT). In the past, amylases have been reported to be a possible sign of TBI toxicity. We investigated the relationship between total amylases (TA) and transplant-related outcomes in pediatric recipients. Methods: We retrospectively analyzed the medical records of all the patients who underwent allogeneic HSCT between January 2000 and November 2019. The inclusion criteria were the following: recipient’s age between 2 and 18, diagnosis of ALL, no previous transplantation, and use of TBI-based conditioning. The serum total amylase and pancreatic amylase were evaluated before, during, and after transplantation. Cytokines and chemokines assays were retrospectively performed. Results: 78 patients fulfilled the inclusion criteria. Fifty-seven patients were treated with fractionated TBI, and 21 with a single-dose regimen. The overall survival (OS) was 62.8%. Elevated values of TA were detected in 71 patients (91%). The TA were excellent in predicting the OS (AUC = 0.773; 95% CI = 0.66–0.86; p < 0.001). TA values below 374 U/L were correlated with a higher OS. The highest mean TA values (673 U/L) were associated with a high disease-progression mortality rate. The TA showed a high predictive performance for disease progression-related death (AUC = 0.865; 95% CI = 0.77–0.93; p < 0.0001). Elevated TA values were also connected with significantly higher levels of proinflammatory cytokines, such as TNF-α, IL-6, and RANTES (p < 0.001). Conclusions: this study shows that TA is a valuable predictor of post-transplant OS and increased risk of leukemia relapse.

The 47th Annual Meeting of the European Society for Blood and Marrow Transplantation: Physicians - Oral Sessions (O010 – O169)

Background: Axicabtagen Ciloleucel (axi-cel) is approved in Europe for the treatment of adults with R/R large B-cell lymphoma (LBCL), primary mediastinal B-cell lymphoma (PMBCL) and transformed follicular lymphoma (tFL). In Spain, nationwide CAR-T administration requests are reviewed centrally within the Ministry of Health. We analyzed the real-world outcomes of patients treated with axicel under the commercial label in Spanish centers. Methods: Six designated centers for commercial CAR-T administration collected data on behalf of GETH-GELTAMO. Data were collected retrospectively from consecutive patients in whom apheresis was performed for axi-cel treatment from Febrruary-2019 to November-2020. CRS and ICANS were graded with the ASTCT consensus criteria. Response was assessed according to the Lugano criteria. Results: 106 patients with R/R lymphoma underwent apheresis for axi-cel. At data cutoff, 92 (87%) received infusion. The reasons for not undergoing infusion were progression-related death in 12 (86%), tumor lysis syndrome in 1 (7%) and complete response after bridging therapy in 1 (7%). Of note, 14 patients were conditioned and infused during the peak of COVID-19 epidemic in Spain (March-April 2020). Median time from Ministry approval to infusion was 54 days. Histology consisted of 74% DLBCL with 11% tFL, and 15% PMBCL. Disease status at lymphodepletion was PD in 69%, SD in 22% and PR in 9%. All patients received lymphodepletion. Median time from leukapheresis to start of lymphodepletion was 34 days. Median time from leukapheresis to infusion was 39 days. Median hospitalization period was 21 days. Any grade of CRS occurred in 86% of pts (18% grade 2, 6.5% grades 3-4). Tocilizumab was used in 58% of patients who developed CRS, corticosteroids in 19%. ICANS was diagnosed in 42.5% of pts (10% grade 2, 15% grade 3-4). Treatment for ICANS included corticosteroids in 78%, tocilizumab in 31%, siltuximab in 15%, and anakinra in 21%. ICU admission was needed in 20 patients (22%). 4 patients died in the context of ICANS, 1 due to CRS, and 1 due to infection. Of 80 patients evaluable and restaged at day 30, ORR was 78% with 40% CR, 38% PR, 11% PD and 11% SD or indeterminate. Of 58 patients evaluable at day 100, 66% had ongoing response (CR 48%, PR 18%). Of 23 patients evaluable at day 180, 65% presented CR. Of 39 patients who showed PR/SD at day 30, 9 (23%) converted to CR. After a median follow-up of 6.3 months, EFS and OS were 55.5% and 78%, respectively in the infused population, with an estimated median EFS and OS of 13.1 and 7.3 months. In the intention-to-treat analysis for all patients who underwent apheresis, median estimated OS and EFS were 12.3 (95%CI 8.9-15.7) and 6.6 months (95%CI 4.6-8.5), respectively (Figure 1). Conclusions: This Spanish multicenter retrospective analysis shows encouraging results of axi-cell treatment in patients with R/R aggressive B-cell lymphoma in the real-world setting. Significant toxicity events were less frequent than those reported in the pivotal trial, however events of mortality associated to toxicity occurred. With a limited follow-up time, response outcomes are favorable.

Antitumor activity and safety of sirolimus for solid tumors with PIK3CA mutations: A multicenter, open-label, prospective single-arm study (KM 02-01, KCSG UN17-16).

BackgroundPIK3CA contributes to cell growth via the PI3K-AKT-mammalian target of rapamycin (mTOR) signaling pathway. Mutations in the pathway are frequently observed in solid tumors. We assessed the efficacy and safety of sirolimus, an mTOR inhibitor, in chemotherapy-refractory solid tumors with PIK3CA mutations or amplifications.MethodsThis was an open-label, single-arm, multicenter pilot study. Twenty-four patients with solid tumors harboring a PIK3CA mutation were treated with sirolimus between July 2017 and March 2019. Treatment was continued until disease progression, unacceptable adverse events, or death. The primary end points were the overall response rate (ORR), disease control rate (DCR), and safety.ResultsThe median follow-up time was 6.1 months. Two patients with rapid disease progression-related death, one who withdrew, and one with a non-target lesion only were excluded from the analysis. Among 20 evaluable patients, 6 patients showed stable disease and 14 showed progressive disease (ORR 0%, DCR 30%). The median progression-free survival was 2.39 months (95% confidence interval, 1.97–2.81 months). The most common adverse event was abdominal pain (20.8%), followed by anemia (16.7%) and fatigue (16.7%). The adverse events were generally manageable.ConclusionsAlthough safe, sirolimus monotherapy did not show meaningful antitumor activity in chemotherapy-refractory solid tumors with PIK3CA mutations. Combinations of mTOR inhibitors for stabilization and other antitumor agents with beneficial effects on tumor volume may improve outcomes.

Combination of international scoring system 3, high lactate dehydrogenase, and t(4;14) and/or del(17p) identifies patients with multiple myeloma (MM) treated with front-line autologous stem-cell transplantation at high risk of early MM progression-related death.

To construct and validate among patients with multiple myeloma (MM) who were treated with intensive therapy a prognostic index of early MM progression-related death. Patient-level data from the Intergroupe Francophone du Myélome (IFM) 2005-01 trial (N = 482) were used to construct the prognostic index. The event was MM progression-related death within 2 years from treatment initiation. The index was validated using data from three other trials: the Gruppo Italiano Malattie Ematologiche dell' Adulto (GIMEMA) 26866138-MMY-3006 trial (N = 480), the Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA)-GEMMENOS65 trial (N = 390), and the Hemato-Oncologie voor Volwassenen Nederland (HOVON) -65/German-Speaking Myeloma Multicenter Group (GMMG) -HD4 trial (N = 827). The risk of early MM progression-related death was related to three independent prognostic variables: lactate dehydrogenase (LDH) higher than than normal, International Staging System 3 (ISS3), and adverse cytogenetics [t(4;14) and/or del(17p)]. These three variables enabled the definition of an ordinal prognostic classification composed of four scores (0 to 3). Patients with a score of 3, defined by the presence of t(4;14) and/or del(17p) in addition to ISS3 and/or high LDH, comprised 5% (20 of 387 patients) to 8% (94 of 1,139 patients) of the patients in the learning and validation samples, respectively, and they had a very poor prognosis. When applied to the population of 855 patients who had received bortezomib-based induction therapy in the four trials, the prognostic classification was also able to segregate patients into four categories, with a very poor prognosis attributed to patients with a score of 3. Our model allows the simple definition of a subgroup of MM patients at high risk of early MM progression-related death despite the use of the most modern and effective strategies.

Colorectal neuroendocrine carcinomas and adenocarcinomas share oncogenic pathways. A clinico-pathologic study of 12 cases

Neuroendocrine carcinomas (NECs) are rare neoplasms with an increasing incidence. Oncogenetic pathways of colorectal NEC are still poorly understood, and no treatment standards are available for these rare tumors. We analyzed retrospectively the clinical records and histology of 12 patients with colorectal NEC. KRAS and BRAF mutations were investigated after the dissection of exoendocrine and neuroendocrine components. ALK alterations and EML4-ALK transcripts were detected by in-situ hybridization and determination of fusion transcripts, respectively. At the time of diagnosis, the mean age of the patients was 60 years (40-79) and 10 patients had synchronous metastases. A transient response occurred in two patients and one patient treated with cisplatin-etoposide or fluoropyrimidine-oxaliplatin, respectively. Tumor progression-related death occurred in 11 of 12 patients. Ten tumors contained an exocrine component, accounting for 5-70% of the tumor, and the other two contained an amphicrine component. BRAF/KRAS mutations were found in six of 10 tumors, corresponding to BRAF(V600E) (n=2) or KRAS(G12D) (n=2), KRAS(G12V) or KRAS(G13D). DNA was obtained from both exocrine and endocrine components in seven cases, and the BRAF/KRAS status was identical in all cases. Split of the ALK locus was detected in a minority of tumor cells in two of eight cases, but EML4-ALK transcripts were absent. The association of an exocrine component in all cases and the similar profile of BRAF/KRAS mutations indicate that colorectal NEC may correspond to a high-grade transformation of colorectal carcinoma. New chemotherapy regimens using targeted therapies should be assessed in these tumors.

Upfront Imatinib Therapy in CML Patients with Rapid Switching to Nilotinib for Failure to Achieve Molecular Targets or Intolerance Achieves High Overall Rates of Molecular Response and a Low Risk of Progression - An Update of the TIDEL-II Trial

Abstract Abstract 451FN2 Background: While nilotinib and dasatinib produce faster responses than imatinib as first-line therapy in de novo Chronic Phase Chronic Myeloid Leukemia (CP-CML), an equally effective strategy may be to selectively use these more potent tyrosine kinase inhibitors (TKIs) only in patients who fail to achieve stringent early molecular targets or are intolerant. Aim: To update the molecular outcome and survival of patients in the TIDEL-II study. Method: TIDEL-II is a multicentre, single arm prospective ALLG trial for de novo CP-CML adult patients with two sequential cohorts each of 105 patients. All patients started on imatinib (IM) 600mg OD. Patients with IM trough levels &lt;1000ng/mL on day 22 were dose escalated to 800mg OD (IM800). All patients were monitored for achievement of time-dependent molecular targets - BCR-ABL RQ-PCR of 10%, 1% and 0.1% IS at 3, 6 and 12 months (mo) respectively. Patients in cohort I who failed to meet these targets had dose escalation to IM800. Those patients who again failed to achieve these targets after a further 3 mo were switched to nilotinib 400mg BID (NIL). Patients in cohort 2 who failed their time dependent targets switched to NIL directly without escalating to IM800. In both cohorts, switching to NIL was also permitted for grade III/IV or persistent grade II non-haematological toxicity or loss of response. Primary end point was MMR at 12 mo (BCR-ABL '0.1%IS), with CMR4.5 being a secondary end point (BCR-ABL ≤0.0032%IS). Results: At 12 mo 69% of patients achieved MMR. With median follow up (f/u) of 20mo, AP/BC progression occurred in 5 cases (2.4%) ( Table 1). The 3 mo molecular response was highly correlated with the MMR at 12mo and progression events (table 2). COHORT 1: Using intention to treat analysis (ITT) with median follow-up of 30 mo the rate of MMR at 12 and 24 mo is 66% and 81% respectively (n=105); CMR4.5 was 12% and 24%, respectively. In total, 34/105 (32%) patients switched to NIL, 12 for failure to achieve molecular targets, 19 for intolerance and 3 for loss of response. Only 2/12 patients who failed to meet targets on IM have subsequently achieved MMR on NIL (median f/u on NIL 14 mo). Fourteen patients switched for intolerance when not in MMR, and 9 subsequently gained MMR (64%) (median f/u on NIL 19 mo). Two patients progressed to AP/BC, both in the first 12 mo in patients taking IM. One progression related death and one fatal myocardial infarction (on NIL) have been reported. Fourteen (13%) of patients remain on IM800. COHORT 2: With a median f/u of 12 mo the rates of MMR and CMR4.5 at 12 mo (n=50) were 72% and 16%, respectively (ITT). To date, 35/105 patients, (33%) have switched to NIL, of which 23 switched for failure to meet molecular targets. Subsequently, 3/23 (13%) have achieved MMR (median 6 mo on NIL). Eleven patients have switched to NIL for intolerance, 7 of them not in MMR at time of switch; 6/7 reached MMR in the subsequent 6 mo (median 5 mo on NIL). Seven patients (7%) remain on IM800. Three patients progressed to AP/BC (3%), 2 on IM and 1 on NIL. Three deaths were reported (3%), 1 from cardiac causes and 1 from stroke, both patients on IM at the time; and 1 from CML progression. Relatively short f/u precludes a meaningful comparison of results between the 2 cohorts. Conclusion: The TIDEL-II strategy has achieved a higher rate of MMR at 12 mo of 69% compared to 47% achieved with the strategy of IM intensification previously utilised in the TIDEL-I study. The improvement in molecular response is mostly attributable to improved responses in patients intolerant of IM as deeper responses were uncommon with patients who failed their early molecular targets despite intensification of kinase inhibition. Molecular response at 3 mo is highly correlated with response and progression events, underscoring the importance of early molecular targets. Disclosures: Yeung: Novartis Pharmaceuticals: Research Funding; BMS Oncology: Research Funding. Osborn:Novartis Pharmaceuticals: Research Funding; BMS Oncology: Research Funding. White:Novartis Pharmaceuticals: Research Funding. Branford:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Research Funding; Ariad: Research Funding. Slader:Novartis Pharmaceuticals: Employment, Equity Ownership. Hiwase:CSL: Research Funding. Schwarer:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria; Hospira: Membership on an entity's Board of Directors or advisory committees. Arthur:Novartis Pharmaceuticals: Honoraria; BMS Oncology: Honoraria. Ross:Novartis: Honoraria, Research Funding. Mills:Novartis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Sponsorship to professional meetings; BMS Oncology: Sponsorship to professional meetings. Hughes:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS Oncology: Research Funding.