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Abstract Systemic corticosteroids are not recommended to treat children with acute respiratory tract infections (ARTIs). Using data from a national commercial health care company, we found that corticosteroid treatment occurred in 3.2% of ARTI encounters. The adjusted odds of corticosteroid treatment were highest for bronchitis/bronchiolitis, in emergency departments, and in the South.
Purpose Outsourcing logistical activities have become a widely used approach for firms to avoid high fixed costs and heavy investment requirements and to achieve competitive advantages. Lean six sigma (LSS) has been accepted globally across sectors as a management strategy for achieving process excellence. The purpose of this paper is to feature the application of LSS for improving the supplier selection process (SSP) of outsourced logistics services in a multinational health-care company. Design/methodology/approach This study is based on an action research case study conducted on the SSP of the freight and distribution department in a multinational health-care company. This paper reports on the application of the LSS define-measure-analyze-improve-control (DMAIC) approach for reducing supplier selection lead time. Findings The study features a real-world case study of the LSS DMAIC application to improve the supplier selection process of a large health-care company. The key issues that were identified are lack of information visibility, top-down changes and unclear communication lines. To counteract these three root causes, the lean six sigma techniques that are implemented are the 5S, stakeholder analysis and standard operating procedure. Research limitations/implications This research provided empirical evidence of how practical challenges in SSP can be managed with the use of LSS. It further proposed plausible solutions for reducing and sustaining improved outcomes. As the study is limited to one case, the validity of the results can be improved by including more organisations and more case studies from other similar organisations. Originality/value Research in supplier selection processes rarely links continuous improvement ideology such as LSS to support strategic selection and procurement of logistics services. This paper could serve as a resource for both practitioners to derive useful implications and to academicians as it contributes to the LSS body of knowledge for further theory testing.
Clonal Hematopoiesis Is Associated with Increased Risk for Therapy-Related Myeloid Neoplasms in Chronic Lymphocytic Leukemia Patients Treated with Chemo(immuno)Therapy
Clonal haematopoiesis of indeterminate potential (CHIP) is defined by the detection of somatic mutations in genes recurrently mutated in myeloid neoplasms (MNs), in the blood of healthy individuals with normal blood values and lack of morphological evidence of MN. Recent studies have highlighted the potential association between CHIP and the development of MN, in particular therapy-related MN (t-MN) in patients with lymphoma treated with chemotherapy and/or autologous stem-cell transplantation. In the present study, we investigated whether the presence of CHIP is associated with a higher risk for the development of t-MN in patients with chronic lymphocytic leukemia (CLL) treated with chemo(immuno)therapy, including fludarabine and cyclophosphamide combinations. To this end, we studied 9 patients with CLL who developed a t-MN [acute myeloid leukemia (AML): n=6, myelodysplastic syndrome (MDS): n=3] after the administration of chemo(immuno)therapy (FCR: n=7, other, n=2), with available samples collected both before CLL treatment and at diagnosis of t-MN. The median interval between the two samples was 26 months (range: 9-38months). NGS was performed on DNA extracted from bone marrow mononuclear cells (MNCs) at t-MN diagnosis, using the Trusight Myeloid Sequencing Panel (n=4) and the Archer VariantPlex Myeloid kit (n=5). Backtracking of the variants detected at the t-MN phase was performed by NGS of DNA extracted from peripheral blood MNCs (n=8) or CD19+ selected cells (n=1) in the samples from the CLL phase. In case no variants were detected in the t-MN phase, targeted digital droplet PCR (ddPCR) was also performed in paired CLL samples to confirm the presence of the variants. Moreover, using the Trusight Myeloid Sequencing Panel, we evaluated the prevalence of CHIP in a population cohort of 285 patients with CLL at the time of diagnosis. The variant allele frequency (VAF) cut-off for the detection of the variants was set to 5%. Variants were reported if meeting the following criteria: (i) located within an exonic or splicing region; (ii) be non-synonymous; (iii) not listed in the gnomAD database, if not also recurrently reported in Cosmic v85. Overall, 16 variants were detected in 7/9 cases analyzed at the time of t-MN [NRAS (n=4), DNMT3A (n=3), TET2 (n=2), EH2 (n=2), TP53 (n=2), KRAS (n=1), U2AF1 (n=1) and SF3B1 (n=1)], while no variants were detected in 2 t-MN samples. In 6/7 cases with detectable variants at t-MN diagnosis, the same variants were present at the CLL phase with either lower (n=4) or similar (n=2) VAF. Overall, CHIP was detectable in 6/9 (66.7%) CLL patients who later developed a t-MN. Among the untreated CLL patients, 45 CHIP-related variants were detected in 35/285 cases (12%) as 7 patients harbored more than one variant. The median VAF was 12.7% (5.1-58.6%) with 27/45 (60%) having a VAF<20%. The affected genes were: DNMT3A (n=9), ASXL1 (n=8), KRAS (n=7), BCOR (n=3), NRAS (n=3), TET2 (n=2), U2AF1 (n=2), PTPN11 (n=2), HRAS (n=2), JAK2 (n=1), CBL (n=1), CALR (n=1), IDH2 (n=1), MPL (n=1), PHF6 (n=1) and ETV6 (n=1). CHIP was not associated with advanced age. Subgroup-analysis amongst CHIP-patients revealed: (i) enrichment of additional CHIP-related variants, male gender and younger age in carriers of ASXL1 variants and (p=0.1, p=0.008 and p=0.06; (ii) a bias towards female gender in patients with DNMT3A variants (p=0.008). The difference in the prevalence of CHIP between patients with CLL developing a t-MN (6/7) and those in the untreated cohort (35/285) was statistically significant (p<0.001). In conclusion, CHIP is significantly enriched in patients with CLL developing t-MNs after the administration of chemo(immuno)therapy, with obvious therapeutic implications especially in the era of targeted agents. The significance of CHIP in CLL should be further evaluated in the context of large clinical studies. MTV and TP contributed equally. EF and PB contributed equally. Disclosures Voso: Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Scarfo:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees. Ghia:ArQule: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria; Adaptive, Dynamo: Consultancy, Honoraria; Novartis: Research Funding; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Sunesis: Consultancy, Honoraria, Research Funding; MEI: Consultancy, Honoraria; Lilly: Consultancy, Honoraria; Celgene/Juno: Consultancy, Honoraria. Stamatopoulos:AstraZeneca: Honoraria; Janssen, Gilead, Abbvie: Honoraria, Research Funding.
Introduction For multiple myeloma patients who are eligible for transplant determined by age and physiological reserve, autologous stem cell transplant (ASCT) following induction chemotherapy is considered as frontline treatment due to the better depth of response, progression-free (PFS) and overall survival (OS). Bortezomib is effective as part of a multi-agent induction regimen prior to ASCT as supported by long-term analysis with survival benefit. However, the role of Bortezomib and Thalidomide consolidation remains controversial. In New Zealand, Bortezomib was funded for up to nine cycles in front line setting. To maximise Bortezomib exposure, patients were typically given four to five cycles of Cyclophosphamide-Bortezomib-Dexamethasone (CyBorD) induction and later received the remaining number of cycles as consolidation after ASCT. Here we present our real-world data on patients who had CyBorD induction followed by ASCT and VTD consolidation. Method Data from 3 centres across New Zealand (Waitemata District Health Board, Counties Manukau District Health Board and Northland District Health Board) were extracted from the patient electronic database. All patients with multiple myeloma under the age of 70 who received CyBorD induction and ASCT as frontline treatment between 1 January 2013 and 31 December 2019 were included. Treatment response was determined as per the International Myeloma Working Group criteria and survival time was determined from the time of commencement of CyBorD. All statistical analyses were performed using IBM SPSS version 20.The data cut-off date is 10th October 2019. Result A total of 263 patients were identified from the 3 centres who were aged <70 and received frontline CyBorD. 125 patients did not proceed with frontline ASCT due to comorbidities, patients' choice, or progressive disease. In total, 138 patients received ASCT following CyBorD induction from the 3 centres. The median age was 60.8 (range: 34.2 - 69.8) and 86 (62.3%) were male. 69.6% of the patients were European, 9.4% were New Zealand Maori, 10.9% were Pacific Islanders, and 5.8% were Asians. The international staging system (ISS) was able to be determined in 89.1% of the patients, and 48.0% and 21.1% of them were ISS II and III, respectively. FISH cytogenetic results were available in 91.3% of the cases, and 13.5% of these patients were deemed to have high-risk disease (del(17p) 7.9%, t(4;14) 3.2%, t(14;16) 1.6%, and concurrent del(17p) and t(4;14) 0.8%). The median number of cycles given in induction was 5 (range: 4 - 9). 60.1% of the patients achieved at least a very good partial response after induction, and this was increased to 84.1% after ASCT and 87.7% after consolidation. Complete response was increased from 22.5% after induction to 30.4% after ASCT and 40.6% after consolidation. After a median follow-up of 54.5 months (range: 1.8 - 96.9 months), the median progression-free survival was 47.8 months and the median overall survival was not reached (Figure1). The estimated 2 and 5-year survival were 93% and 84%, respectively. Thalidomide was added to the induction regimen in 19 patients and this was commonly done due to the presence of high risk clinical features or suboptimal clinical response as determined by the treating clinicians. These patients did not appear to have an inferior treatment outcome with a comparable median PFS (median 42.2 vs 49.5 months, p = 0.291). Conclusion Our real-world data shows that Bortezomib-based consolidation following ASCT improves depth of response and results in favourable long-term outcomes. Patients who required the addition of Thalidomide during induction due to suboptimal response do not appear to have an inferior long-term outcome. Figure Disclosures Jackson: Abbvie: Honoraria. Chan:AbbVie: Membership on an entity's Board of Directors or advisory committees; Roche: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Celgene: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau.
Introduction: Secondary immunodeficiency (SID) occurs, among other reasons, as a consequence of hematological malignancies (HM), most commonly in chronic lymphocytic leukemia (CLL) and multiple myeloma. About 25% of patients present with secondary immune deficiency (SID) at diagnosis of CLL and this incidence may increase to 85% during the course of disease. This increase is also due to recent advances in CLL therapy leading to cumulative immunosuppression. Infections are the main cause of morbidity and mortality in CLL patients, causing between 30% and 50% of deaths within the first year after diagnosis. Intravenous immunoglobulin (IVIg) is established as secondary prophylaxis to reduce infectious complications in patients with HM with hypogammaglobulinemia. To date, no large randomized study has established efficacy of IVIg as primary prophylaxis in CLL patients with hypogammaglobulinemia although several small studies suggest an up-to 4-fold reduction of infection rates. Methods: This study is planned as a prospective, double-blind, randomized, placebo-controlled, multicenter, interventional phase 3 study and will be conducted in approximately 50 centers in North America and Europe (EUDRA-CT #: 2019-004375-40). The primary objective is to demonstrate the benefit of IVIg 10% (Panzyga®) compared to placebo as primary infection prophylaxis in patients with CLL and SID who are undergoing antineoplastic therapy. A minimum of 240 adult patients with a diagnosis of CLL will be enrolled and allocated 1:1 to either IVIg 10% (0.4 g/kg) plus standard of care (SoC) prophylaxis or placebo plus SoC prophylaxis. Patients will receive up to 13 infusions of IVIg in 4-weekly intervals. Total duration for each patient will be up to 55 weeks consisting of up to 3 weeks for screening, 48 weeks of treatment and then 4 weeks of follow-up. Main inclusion criteria include: Patients with CLL diagnosis according to International Workshop on CLL (iwCLL) criteria undergoing CLL antineoplastic treatment, and hypogammaglobulinemia with IgG levels <500 mg/dL (5 g/L). Main exclusion criteria include: IgG treatment within the last 3 months, antibiotic prophylaxis and/or treatment within 7 days prior to current CLL treatment start, and current major infection or ˃1 major infection in the previous 6 months before baseline. The primary efficacy outcome will be the occurrence of at least one major infection defined as (•) bacterial or viral infection resulting in death, (•) microbiologically or clinically documented bacterial or viral infection requiring treatment with anti-infectives, or (•) fever of unknown origin requiring hospitalization or hospitalization prolongation. Rate of occurrence of at least one major infection will be compared between treatment groups (IVIg plus SoC or placebo plus SoC). Secondary outcomes include overall infection rate, frequency of SoC prophylaxis with anti-infectives, duration of anti-infective prophylaxis. Exploratory outcomes include: Quality of life measured by EQ-5D, IVIg PK profiles, and resource utilization. The primary efficacy evaluation is based on the comparison of major infections in CLL patients with or without primary infection prophylaxis with IVIg. The difference between these proportions will be statistically tested in the ITT population. The Z approximation will be used for statistical comparison of the proportions observed. One-sided 97.5% confidence interval will be provided. Conclusion: This prospective, placebo-controlled study will evaluate the efficacy and safety of IVIg 10% as primary prophylaxis of infections in CLL patients with SID in a large clinical setting for the first time. Figure 1 Disclosures Cornely: Scynexis: Consultancy, Honoraria, Other, Research Funding; Melinta: Research Funding; Medicines Company: Research Funding; Roche Diagnostics: Consultancy, Honoraria, Other; PSI: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Other, Research Funding; Paratek: Consultancy, Honoraria; Octapharma: Consultancy, Honoraria, Other, Research Funding; Noxxon: Consultancy, Honoraria; Nabriva: Consultancy, Honoraria; Merck/MSD: Consultancy, Honoraria, Other, Research Funding; Mylan: Consultancy, Honoraria; Menarini: Consultancy, Honoraria, Other; MedPace: Consultancy, Honoraria; Matinas: Consultancy, Honoraria, Other; Gilead: Consultancy, Honoraria, Other, Research Funding; F2G: Consultancy, Honoraria, Other: Travel, Accomodation, Expenses, Research Funding; Entasis: Consultancy, Honoraria; DaVolterra: Consultancy, Honoraria, Other: Travel, Accomodation, Expenses, Research Funding; Cidara: Consultancy, Honoraria, Other: Travel, Accomodation, Expenses, Research Funding; Biosys: Consultancy, Honoraria; Basilea: Consultancy, Honoraria, Other: Travel, Accomodation, Expenses, Research Funding; Astellas: Consultancy, Honoraria, Other: Travel, Accomodation, Expenses, Research Funding; Amplyx: Consultancy, Honoraria, Other: Travel, Accomodation, Expenses, Research Funding; Mycoses Study Group Education Research Council: Membership on an entity's Board of Directors or advisory committees; CoRe Consulting GmBH, Cologne, Germany: Current equity holder in private company; Shinogi: Consultancy, Honoraria, Other; German Federal Ministry of Research and Education and DFG: Research Funding; Actelion: Consultancy, Honoraria, Research Funding; Allecra: Consultancy, Honoraria, Other: Travel, Accomodation, Expenses; Janssen: Research Funding. Mato:Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Robak:Sandoz: Consultancy, Honoraria; UTX-TGR: Research Funding; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; GSK: Research Funding; Acerta: Research Funding; Pfizer: Research Funding; AstraZeneca: Honoraria, Research Funding; Bristol Meyers Squibb: Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; Morphosys: Research Funding; Medical University of Lodz: Current Employment; Takeda: Consultancy; Octapharma: Honoraria; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Momenta: Consultancy; UCB: Honoraria, Research Funding; BioGene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Mellinghoff:Octapharma: Consultancy; German Center for Infection Research, University of Cologne, German Society for Mycology: Research Funding. Lavrova:Octapharma Pharmazeutika Produktionsges.m.b.H.: Current Employment.
Background: Acute myeloid leukaemia (AML) is a blood cancer characterised by the expansion of a malignant myeloid progenitor. The estimated age-standardised incidence rate in many western countries has remained static over the last 2 decades at 3-4 per 100,000, whilst long-term survival has improved, especially for the younger individuals. However, disparities remain for the older individuals, people of ethnic minority background, and those who are more socio-economically deprived. Previous evaluation of population data from New Zealand has shown a similar pattern, but a more recent analysis has not been done. Here we present the incidence and long-term survival of patients with AML in New Zealand (NZ), using the New Zealand Cancer Registry (NZCR). Method: The NZCR was established in 1948 and it became mandatory by law to report all new cases of malignancy by 1994. We extracted all AML cases from the registry between 1 January 1997 and 31 December 2016. Cases with an ICD-10-CM code for acute myeloid leukaemia and its subtypes including acute promyelocytic leukaemia (e.g. C92.0) were included. Individuals residing overseas or without an address were excluded, and individuals with a diagnosis of acute promyelocytic leukaemia (APML) were analyzed separately. The socio-economic status of the individual was estimated based on their domicile area using the New Zealand 2013 Index of Deprivation (NZDep2013) which is a geographically based composite measure of deprivation. Overall survival was calculated from the date of diagnosis to the date of death or last follow-up (31 December 2016). Multivariable Cox-proportional hazard models were used to evaluate potential associations with survival time in NZ AML cases. Results: During this 20-year period, 154 cases of APML and 2876 cases of AML (excluding APML) were reported to the registry on individuals residing in New Zealand. Of the AML cases, 53% were male and the median age at the time of diagnosis was 67 (IQR 52-77), with a small positive correlation between year of diagnosis and age at diagnosis (Spearman's rho=0.05, p=0.009). The majority of cases (77%) were of European descent, 12% were New Zealand Maori, and 6% were Pacific Islanders. Individuals of European descent were significantly older at diagnosis compared to other ethnicities (median of 70 vs 51 for Maori, 56 for Pacific Islanders, and 58 for all other ethnicities, p<0.001). AML appeared to disproportionally affect those more socio-economically deprived, with 23% of cases reported in the most deprived 20% of the population, compared with only 16% of the cases in the least deprived 20%. The annual crude incidence remained stable during this period at an average of 3.42 per 100,000 (ranging from 2.57 to 4.29, figure 1), and was significantly higher in the older adults (figure 2). Age-standardised rates were lower (figure 1), with an average of 2.6 (range 1.9 to 3.4) cases per 100,000, and a small but significant average annual decrease over the study period. The estimated 1, 2, and 5-year survival for the entire cohort was 38%, 27%, and 22%, respectively. Age at diagnosis was a significant predictor of inferior survival, with a hazard ratio (HR) for all-cause mortality of 2.06, 3.95, 6.39 and 10.84 for the 50-59, 60-69, 70-79 and >80 age groups, respectively, compared to those aged <50. Shorter overall survival was also noted in individuals in the more socio-economically deprived 50% of the population (HR 1.13, 95% CI 1.03-1.23). Conclusion The incidence of AML in New Zealand has remained static in the last 2 decades, consistent with data from other western countries. Lower age-standardised rates and the small decrease in these observed over the study period are likely to reflect the increasingly and comparatively older population in NZ. Maori and Pacific Islanders appeared to present at a younger age than individuals of European descent. Age at diagnosis and socio-economic deprivation were shown to be an adverse prognostic factor for overall survival. Further in-depth analysis is required to determine the cause of these observations at a population level. Disclosures Chan: AbbVie:Membership on an entity's Board of Directors or advisory committees;Janssen:Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau;Celgene:Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company);Amgen:Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company);Roche:Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company).
Background The primary analysis of the investigator-sponsored randomized multicenter phase II GHSG NIVAHL trial showed feasibility and excellent short-term efficacy of anti-PD1 based 1st-line treatment of early-stage unfavorable classical Hodgkin lymphoma (cHL). Achieving long-term disease control without excessive treatment-related morbidity is of utmost importance when developing innovative 1st-line cHL therapies. Duration of response and development of persisting immune-related toxicities are of concern in the setting of 1st-line anti-PD1 treatment. Methods NIVAHL enrolled treatment naïve early-stage unfavorable cHL patients at 28 German centers and individuals were randomized to either receive fully concomitant 4x Nivo-AVD (group A) or sequential 4xnivolumab, followed by 2x Nivo-AVD and 2x AVD (group B). Both groups received consolidative 30Gy IS-RT and the primary endpoint was complete response (CR) rate at end of study treatment. Detailed methods, patient characteristics and the primary endpoint analysis of NIVAHL have been recently published (Bröckelmann PJ et al. JAMA Oncol 2020). Herein we present extended follow-up of the NIVAHL trial to assess efficacy in terms of 2-year progression-free (PFS) and overall survival (OS) as well as safety with regards to long-term toxicities or organ impairment documented during the first year of follow-up after treatment. Results A total of 109 patients with cHL confirmed by central pathology review were enrolled between 04/2017 - 10/2018 and followed for a median of 20 and 21 months in groups A (n=55) and B (n=54), respectively, for the present analysis. All of the 7 patients deemed in partial remission (PR) at end of study treatment (EOT) converted into an ongoing CR after end of study without additional treatment during follow-up. With no relapse and no death observed since the primary analysis, the 2-year PFS estimates are 100% and 98% (95%CI 88-100%) in groups A and B, respectively, and the 2-year OS is 100% in both groups. With a median observation time for late-toxicities of 14 months after EOT (range 6-26 months) among 103 patients, any potentially treatment-related AE during follow-up was reported in 65% of patients (A: 74%, B: 56%). The highest documented CTCAE grade of late AEs was °I in 33%, °II in 25% and °III in 7% of patients with no °IV-V AEs observed. A total of 54% had at least one late event related to AVD, 47% to nivolumab and 32% to RT, with multiple relations attributable per event. Mean FEV1 and DLCOc did not decrease from baseline (91.1% -> 96.4% and 86.2% -> 83.3%, respectively). Decreased LVEF after EOT was reported in 2/56 patients with available data (4%). After EOT, 18% of patients required medication for adverse events. Corticosteroid ≥ and < 10mg prednisolone equivalent was required in 3% and 2% of patients, respectively, for a toxicity at any time during follow-up. No patient required corticosteroid treatment at last available follow-up. Most frequent toxicities reported after EOT included fatigue (21%), hypothyroidism (17%), respiratory tract disorders (16%), leukopenia (14%) and nervous system disorders (14%). Hypothyroidism was the event most frequently solely attributed to nivolumab during follow-up. The median time to onset after EOT was 5 months and affected patients nearly exclusively female (15/16 [94%]). After median follow-up of 10 months (range 0-21), hypothyroidism remained unchanged in 10 of 16 affected patients and resolved in 3 patients. Conclusion The excellent disease control of concomitant and sequential nivolumab and AVD in early-stage unfavorable cHL is confirmed with the currently available follow-up. Treatment-related toxicities ongoing or emerging during follow-up are predominantly associated with chemo- and/or RT. The most frequent nivolumab-associated late toxicity is hypothyroidism. No patient currently requires chronic corticosteroid treatment. Disclosures Bröckelmann: Bristol Myers Squibb: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; MSD Sharp & Dohme: Research Funding. Keller:Bristol Myers Squibb: Honoraria, Other: Travel support, Speakers Bureau. Meissner:Celgene: Other: Travel support; Bristol Myers Squibb: Other: Travel support; Takeda: Other: Travel support; Merck Sharp & Dohme: Other: Travel support; Hexal: Other: Travel support. Trautmann:Bristol Myers Squibb: Honoraria. Kerkhoff:BMS: Honoraria. Hüttmann:Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Lead Discovery Center GmbH: Consultancy; Seattle Genetics: Research Funding; Gilead: Honoraria; University Hospital Essen, University of Duisburg-Essen, Essen, Germany: Current Employment; Roche: Other: Travel expenses; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Zimmermann:Takeda: Consultancy, Honoraria, Other: Travel Expenses; Bristol-Myers Squibb: Other: Travel Expenses; MSD: Other: Travel Expenses; Novartis: Other: Travel Expenses. Fuchs:Bristol Myers Squibb: Honoraria, Research Funding; Affimed: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Celgene: Honoraria. von Tresckow:Takeda: Honoraria, Other: Travel support, Research Funding; Novartis: Other: Travel support, Research Funding; Takeda: Honoraria, Other: Travel support, Research Funding; MSD Sharp & Dohme: Honoraria, Research Funding; Roche: Honoraria; Kite/Gilead: Honoraria; Pfizer: Honoraria; Amgen: Honoraria. Borchmann:Takeda: Research Funding; Bristol Myers Squibb: Research Funding. Engert:Bristol Myers Squibb: Honoraria, Research Funding; Affimed Therapeutics: Research Funding; Takeda: Honoraria, Research Funding; MSD Sharp & Dohme: Honoraria; AstraZeneca: Honoraria; Sandoz: Honoraria. OffLabel Disclosure: Nivolumab 240mg Q2W alone or in combination with AVD for 1st-line treatment of classical Hodgkin lymphoma.
Introduction: Despite high response rates to initial treatment, relapse is common in CLL. Although newer agents are approved for treatment recently, CLL remains an incurable disease. Tenalisib (RP6530) is a highly specific and orally available PI3K δ/γ+SIK3 inhibitor. In in-vitro studies, Tenalisib was highly effective (62nM) in demonstrating a cytotoxic effect in patient derived CLL cells and showed very good synergism in combination with fludarabine and ibrutinib at very low concentrations in patient derived primary CLL cells. Tenalisib has demonstrated good clinical activity in patients with T cell lymphomas. Previously, a pooled safety analysis of 93 patients treated with tenalisib monotherapy demonstrated a differentiated safety profile which is largely devoid of immune mediated toxicities (Iyer, ASH 2018). Methods: This trial is a Phase II, open label, multi-center, Simon's two stage study design to evaluate the efficacy and safety of Tenalisib in patients with CLL who have relapsed or are refractory after at least one prior therapy. In stage 1, 20 patients were to be enrolled and an additional 41 patients to be enrolled in stage 2 based efficacy results of stage 1 (>8 responders needed to proceed to stage 2). Patients with previously treated CLL with adequate bone marrow, liver, and renal function, ECOG ≤2, and measurable disease are eligible. Patients with prior exposure to drug that specifically inhibits PI3K were excluded. The primary objective was to assess the anti-tumor activity. The secondary objectives were to assess safety and tolerability, and progression free survival (PFS). The responses were assessed using iwCLL criteria (Hallek 2018). Results: A total of 21 CLL patients predominantly male (86%) with median age was 66 years (range 44-79) were enrolled between Dec 2019 and March 2020 in Stage 1 of the study. 67% of patients had an ECOG score of 1, and 43% had Rai Stage III/IV disease with 67% having spleno/hepatomegaly. Patients had a median of 2 (range: 1-3) prior treatment regimens and 16 (76%) were refractory to last therapy. High risk patients included 15% del 17p, 10% del 11q, 5% ZAP and 5% TP53 mutations. In all 21 evaluable pts with a median follow-up of 4.9 months, 7 patients showed partial response (33%) while the remaining 14 patients showed stable disease (67%). 19 patients (90%) were still continuing therapy while 2 patients discontinued due to disease progression after showing a stable response. There was a median reduction in nodal disease to the extent of 54% in responding patients. The data readouts at C8D1 for all patients is currently awaited. The most common AEs which were mild-moderate in severity included transaminitis (19%), GGT elevation (5%) and neutropenia (5%). There was a related Grade 3 AE of neutropenia (5%). None of the related AEs led to study discontinuation. There were no events of diarrhoea/colitis or pneumonitis in patients who were on therapy for more than 6 months. Conclusions: Tenalisib showed promising single agent anti-tumor activity in patients with CLL with a favourable safety profile. Further data is awaited to estimate the response rates and the decision to move to Stage 2 of the study. Disclosures Robak: Momenta: Consultancy; BioGene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Takeda: Consultancy; Pfizer: Research Funding; UCB: Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; UTX-TGR: Research Funding; Acerta: Research Funding; Morphosys: Research Funding; AstraZeneca: Honoraria, Research Funding; Bristol Meyers Squibb: Research Funding; Sandoz: Consultancy, Honoraria; Octapharma: Honoraria; Medical University of Lodz: Current Employment; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; GSK: Research Funding; Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding. Routhu:Rhizen Pharmaceuticals S.A>.: Current Employment. Barde:Rhizen Pharmaceuticals S.A: Current Employment. Nair:Rhizen Pharmaceuticals S.A.: Current Employment.
Background: In Acute Myeloid Leukemia (AML), identification of measurable residual disease (MRD) thresholds with clinical significance is still a matter of debate. For this purpose, multiparametric flow cytometry (MFC) is extensively employed for MRD quantification, due to high sensitivity (down to 1:10-3/10-5 cells) and wide applicability (up to 90% of cases). The identification of 20 clustered residual leukemic cells seems sufficient for the recognition of MRD presence (lower limit of detection [LOD]), whereas a cluster of 50 events may be the minimum threshold for the quantification of a cell population (lower limit of quantitation [LOQ]), provided a sufficient denominator of relevant events (500'000-1'000'000) is acquired. Methods: Using a MFC assay, we assessed the predictive power of a threshold calculated applying the criteria of LOD and LOQ on 261 intensively treated AML patients enrolled in the GIMEMA AML1310 prospective trial.According to the protocol design, patients with a bone marrow residual leukemic cells count (RLCc) equal or above 0.035% of the total no. of mononuclear (MNC) cells qualified as MRDpos,, whileusing LOD and LOQ, we selected the following categories of patients: 1) LODneg if RLCc was below LOD (20x100/total no. of events); 2) LODpos-LOQneg if RLCc was between LOD and LOQ; and 3) LOQpos if RLCc was above LOQ (50x100/total no. of events). Results: The ELN target of 500'000 events was reached in 182/261 (69.6%) patients. Overall, using the predefined AML1310 protocol MRD threshold, 154 (59%) and 107 (41%) were MRDneg and MRDpos, respectively, whereas 74 (28.4%), 43 (16.5%) and 144 (54.4%) patients were classified as LODneg, LODpos-LOQneg and LOQpos, respectively. Two-year overall survival (OS) was 75.4% vs. 79.8% vs. 66.4% for LODneg, LODpos-LOQneg and LODpos, respectively (p=0.1197), and 74.5% vs. 66.4% according to AML1310 protocol 0.035% threshold for MRDneg and MRDpos patients, respectively (p=0.3521). Due to superimposable outcome, LOD-LOQneg and LODpos-LOQneg categories were combined. Accordingly, LODneg/LODpos-LOQneg and LOQpos groups clearly differed in terms of OS (77% vs. 66.4%, p=0.0437) [FIGURE 1A]. Such a figure was challenged in multivariate analysis (p=0.048, HR 0.628, 95% CI 0.396-0.997) that confirmed the independent role of LOD-LOQ approach in influencing OS. To enhance the predictivity of LOD-LOQ estimate, we then focused on samples acquisition of which passed the 500'000 events, according to ELN guidelines. Among 182/261 (69.7%) cases with > 500'000 MNC events as denominator, LODneg/LODpos-LOQneg and LOQpos subgroups were clearly distinct in terms of OS (2-years OS of 83.5% vs. 69.4%, p=0.009). [FIGURE 1B] Similarly, also when selecting those patients (158/261 [60.5%]) whose acquisition passed 500'000 CD45+ events, LODneg/LODpos-LOQneg and LOQpos showed a different behavior with 2-years OS of 86.7% vs. 69.0%, respectively (p=0.004). [FIGURE 1C] Finally, when considering the interaction of the 3 LOD-LOQ categories with possible post-remissional strategies, LODneg/LODpos-LOQneg patients submitted to autologous stem cell transplant showed the best 2-years OS (88.9%) as compared to all the other categories (allogeneic stem cells transplant and no graft-based treatments) (p=0.026). Summary/Conclusion: In conclusion, the use of LOD-LOQ method results in a more sensitive detection of MRD that, in turn, translates in a more accurate recognition of patients with different prognosis. Actually, such an approach allowed to dissect even further the category of patients called MRDneg according to the AML1310 protocol definition, since MRDneg subjects who belonged to a "true negative" LOD-LOQ sub-group [LODneg/LODpos-LOQneg] had a better outcome than the other MRDneg ones. This MRD approach could serve as a useful tool to personalize post-remission strategy in intensively treated AML patients, through selection of high-quality remission patients who may benefit from less intensive post-consolidation therapies. Disclosures Voso: Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Venditti:Novartis: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Pfizer: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Amgen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Jazz: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company).
