safety monitoring committee
Recently Published Documents
TOTAL DOCUMENTS
H-INDEX
Fixed Duration Combination Therapy with Ibrutinib (ibr) and Venetoclax (ven) Leads to Deep Responses in Relapsed/Refractory (rel/ref) Chronic Lymphocytic Leukemia (CLL): Results of a Phase 2 Study
Abstract Introduction: Ibr and ven are 1 st generation BTK and BCL2 inhibitors respectively that are approved for use in patients with CLL. They are both oral agents that have been shown to work synergistically together with no unexpected toxicities beyond what is already known about each of them. Their combination is very effective in the frontline treatment of CLL including fixed duration therapy for 15 cycles which produces high complete remissions (CR) and undetectable minimal residual disease (uMRD) rates as well as high progression free survival (PFS) and overall survival (OS) independent of high-risk features [Allen JH, et al. EHA virtual annual meeting 2021; Jain N, et al N Engl J Med 2019]. There is also data to support the use of this combination in the rel/ref setting [Hillmen P, et al. J Clin Oncol 2019] and here we present results of a phase 2 trial of fixed duration therapy with ibr+ven in rel/ref CLL (NCT03045328). Methods: Patients with rel/ref CLL with indications for treatment were enrolled at Stanford Cancer Institute and City of Hope National Medical Center. Treatment was initiated with ibr monotherapy (420mg daily) for 8 weeks after which ven ramp up was introduced. Ven was escalated to full dose (400mg daily) over 5 weeks and the combination of ibr+ven was then continued for a total of 2 years. Treatment was stopped in all patients at week 118 and all patients were evaluated 30 days later to complete study follow up. The primary endpoint was the assessment of CR rate at week 62. Secondary endpoints included overall response rate (ORR), duration of response (DOR), PFS, OS, evaluation of adverse events (AEs), as well as rate of uMRD in the bone marrow at week 62 and week 117 of treatment by flow cytometry (10 -4 sensitivity [uMRD4]) and Clonoseq sequencing (10 -6 sensitivity [uMRD6]). Results: A total of 22 patients were enrolled. Median age of the patients was 68 (range 39-82 years). Median prior treatment regimens were 1 (range 1-3). Eleven patients received prior FCR as 1 st line therapy, 9 received BR, 1 received FR, and 1 had received rituximab alone. None had prior BTK inhibitor or ven. Baseline characteristics are shown in Table 1. Twenty-one patients initiated ven. One patient withdrew consent prior to the start of ven. Eighteen patients completed full trial treatment. Three patients discontinued treatment for these reasons: Hodgkin's transformation, kidney failure, need for a coronary stent. Five patients interrupted dosing due to toxicity and five patients had dose reductions. Three patients reduced ibrutinib, 2 due to rash and 1 due to recurrent atrial fibrillation, and 5 patients reduced ven due to fatigue, neutropenia (2), or diarrhea (2). CR rate (intention to treat [n=22]) at week 62 was 55% while the ORR was 91%. PFS and OS were 95% and 100% at 2 years. After 1 year of combination therapy, 13 of 20 (65%) evaluable patients had achieved bone marrow uMRD4 (5 positive and 2 not done) and 4 of 20 (20%) achieved bone marrow uMRD6. After 2 years, 2 additional patients achieved bone marrow uMRD4 (15 of 20 [75%]). Bone marrow flow and Clonoseq MRD data were available in 13 patients at the end of study. Eight were undetectable by flow and Clonoseq (uMRD6), 3 by flow only (uMRD4), and 2 were positive with both (MRD+). Seven patients experienced 11 serious AEs attributed to treatment: 3 with sepsis, 3 pneumonia, 2 atrial fibrillation, and 1 each diarrhea, dehydration, and pulmonary embolism. AEs ≥ Grade 3 are shown in Table 2. There were no TLS events. Conclusions: Ibr+ven combination for a fixed duration of 2 years after initial ibrutinib lead in is a well-tolerated, effective, oral, targeted therapy regimen for patients with rel/ref CLL. Most patients achieve an uMRD4 response in the bone marrow. The effect of poor risk features of disease and dose interruptions on depth of response will be reported. Figure 1 Figure 1. Disclosures Siddiqi: Janssen: Speakers Bureau; Oncternal: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kite Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Research Funding. Coutre: Acerta: Other: Data Safety Monitoring Committee, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Data Safety Monitoring Committee, Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
Background/aimRejection is the main cause of graft failure after penetrating keratoplasty (PK). Its prevention by repeated instillation of steroid eye-drops has not evolved in decades. Poor adherence and discontinuous nature of eye-drop treatment may explain some PK failures. In a rabbit model, we previously demonstrated that a subconjunctival dexamethasone implant was well tolerated and prevented rejection efficiently in the first 5–6 weeks. This clinical trial investigates its tolerance and safety after PK.MethodsSingle-centre, phase II non-randomised tolerance and safety pilot study (NCT02834260). Designed to analyse the risk of elevated intraocular pressure (IOP), discomfort and resorption time. Fourteen patients with a low rejection risk indication of PK were enrolled between January 2017 and August 2018. The implant was injected in the 12 o’clock position, 5 mm from the limbus, at the end of PK. A steroid eye-drop treatment was planned when implant resorption was complete. Patients were monitored regularly for 12 months: IOP (main outcome measure at 1 month), discomfort and redness scores, implant status, rejection episode and central corneal thickness by optical coherence tomography. An independent data safety monitoring committee verified safety aspects.ResultsNo increase in IOP or other adverse event related to the implant was observed. Average resorption time was 6 weeks. The switch to steroid eye-drops was uneventful. One patient, included despite preoperative corneal neovascularisation (unintended protocol deviation) experienced a rejection.ConclusionsThis is the first proof of concept that dropless immunosuppression is possible after low rejection risk PK.Trial registration numberNCT02834260.
159 Background: JACCRO GC-07 is a randomized controlled trial to explore postoperative S-1/docetaxel compared to S-1 alone after D2 gastrectomy for pStage III gastric cancer (GC) patients. The second interim analysis demonstrated that the significant improvement of RFS was obtained by S-1/docetaxel compared to S-1 alone. The study was terminated by the recommendation of independent data and safety monitoring committee and the results were reported at ASCO 2018 and published in the Journal of Clinical Oncology (Yoshida K et al. 2019; 37:1296-1304). As 3 years have passed after completion of the enrollment, preplanned analysis was performed with the updated information of the patients. Methods: Patients with pStage III GC were randomly assigned to receive either S-1/docetaxel (S-1 80-120mg/body on days 1-14 with a 7-day rest followed by docetaxel 40mg/m2 on day 1 and S-1 80-120mg/body on days 1-14 every 21 days for 6 cycles followed by S-1 80-120mg/body on days 1-28 every 42 days for 4 cycles) or S-1 (80-120mg/body on days 1-28 every 42 days for 8 cycles) after D2 gastrectomy. Block randomization was performed by a central interactive computerized system stratified by the stage (IIIA, IIIB, IIIC) and histological type (differentiated or undifferentiated). The sample size of 1,100 was necessary to detect a 7% increase in the 3-year RFS. The primary endpoint was 3y RFS and the secondary endpoints were OS, TTF and safety. Results: In the present analysis, 400 recurrences and 324 deaths were confirmed among 912 patients during the median follow-up period of 42.5 months (0.3-85.16). The 3y RFS of 67.7% in the S-1/docetaxel group was significantly superior to 57.4% in the S-1 group (HR 0.715, 95% CI: 0.587-0.871, p = 0.0008) and the 3y OS was 77.7% in the S-1/docetaxel group and that of S-1 group was 71.2%, respectively (HR 0.742, 95% CI: 0.596-0.925, p = 0.0076), confirming the significant improving effect on the survival of the patient. Conclusions: Adjuvant S-1 plus docetaxel is recommended for patients with pStage III gastric cancer who underwent D2 gastrectomy without neoadjuvant chemotherapy. Clinical trial information: UMIN 000010337.
Background: Activation induced cytidine deaminase (AICDA or AID) causes somatic hypermutation (SHM) of the immunoglobulin heavy chain variable genes (IGHV). It has been widely hypothesized that aberrant targeting of AICDA creates additional driver mutations and intra-clonal heterogeneity which enables clonal evolution and thus disease progression. This hypothesis predicts that greater AICDA-mediated intraclonal heterogeneity will be associated with shortened progression free survival (PFS). To definitively test this hypothesis that AICDA-mediated heterogeneity is linked to risk of progression, we evaluated available samples from the largest US-based phase 3 trial of untreated follicular lymphoma patients treated with CHOP-based therapies, SWOG trial S0016. Methods: We have previously shown that ultradeep sequencing of two genes, the expressed IGHV and the 5' UTR of the translocated BCL2 allele, provide unrelated measures of AICDA-mediated genetic heterogeneity (Spence, J Immunol. 2014). Furthermore, the number of AICDA-mediated mutations in the 5' UTR of BCL2, but not in IGHV, correlates with the number of AICDA-mediated mutations at other known AICDA sites throughout the genome (such as PIM1, BCL6, RHOA, etc). Genomic DNA was prepared from all available paraffin-embedded specimens. Ultra-deep, amplicon-based sequencing (~10,000x) with internal controls to establish specimen-specific signal-to-noise parameters allowed sensitive and specific detection of sequence variants at 0.2% (FDR 1%). Results: For subjects with (152) and without (419) available specimens, the median duration of follow-up (11.3 years), the number of patients who progressed (60%), and other patient characteristics (demographics, histology, stage, FLIPI) were indistinguishable. Sequencing data that fulfilled strict quality metrics for low frequency variants were obtained for >75% of the specimens (114 for BCL2; 120 for IGHV); further analysis was restricted to these subjects. The extent of intraclonal variation within both the IGHV and the 5' UTR of BCL2 was highly variable. For BCL2, a median of 7 mutations/case were detected (range 0-61); the mutations were highly skewed to the RCYW motif (p<0.001), the preferred target of AICDA. These mutations defined a median of 5 subclones/case (range 1-22). The clonal IGHV was somatically mutated (<0.98 germline identity) in 94% of samples (median 0.89). For IGHV, a median of 113 subclones/case were detected (range 0-1531). Consistent with our prior study, no correlation was seen between the number of mutations detected in the IGHV and BCL2 or the number of subclones defined by IGHV and BCL2. Neither the number of mutations in nor the number of subclones defined by BCL2 or IGHV were prognostic. Cox regression showed no relationship between PFS and mutation number or subclone count based on either IGHV or BCL2 (hazard ratios are indistinguishable from 1; parameters were treated both as a continuous variables and dichotomized as quartiles). Furthermore, receiver operator curves did not suggest a cut point for any of these measures that would predict disease progression at any time (areas under the curve are indistinguishable from 0.5). Conclusions: Several measures of AICDA-mediated mutation and resulting subclonal heterogeneity were not found to be prognostic in previously untreated, advanced stage FL treated with CHOP-based regimens. In contrast, AICDA-mediated mutations have been reported to accrue during transformation from low grade FL to large cell lymphoma. This paradox calls for a more refined model to explain the role of AICDA in the progression of FL. Support: NIH/NCI grants U10CA180888, U10CA180819, U10CA180821, R21CA198072(WRB); and in part by GlaxoSmithKline. Disclosures Rimsza: NanoSting: Patents & Royalties: Named inventor on a patent licensed to NanoSting [Institution]. Leonard:Bayer Corporation: Consultancy; AstraZeneca: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Sandoz: Consultancy; ADC Therapeutics: Consultancy; Miltenyi: Consultancy; BeiGene: Consultancy; Sutro Biopharma: Consultancy; Celgene: Consultancy; Nordic Nanovector: Consultancy; Gilead: Consultancy; Karyopharm Therapeutics: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Bayer Corporation: Consultancy; Celgene: Consultancy; Epizyme, Inc: Consultancy; Merck: Consultancy; MorphoSys: Consultancy; AstraZeneca: Consultancy; Epizyme, Inc: Consultancy; Akcea Therapeutics: Consultancy; Miltenyi: Consultancy; ADC Therapeutics: Consultancy; BeiGene: Consultancy; Karyopharm Therapeutics: Consultancy; Merck: Consultancy; Sandoz: Consultancy; Gilead: Consultancy; Akcea Therapeutics: Consultancy; MorphoSys: Consultancy; Nordic Nanovector: Consultancy; Sutro Biopharma: Consultancy. Fisher:Celgene: Consultancy; Barclays: Honoraria; AstraZeneca: Consultancy; prIME: Honoraria. Smith:Portola Pharmaceuticals: Research Funding. Friedberg:Bayer: Honoraria, Other: Data & Safety Monitoring Committee; Acerta: Other: Data & Safety Monitoring Committee.
Introduction Older adults with Hodgkin Lymphoma (HL) have markedly poorer outcomes than younger counterparts. This may reflect treatment decisions, age-related factors, and/or disease biology. For younger patients, standard first-line treatment typically consists of dose-dense, multi-agent chemotherapy regimens with or without radiotherapy (RT). In contrast, older patients who are deemed unfit for full-dose chemotherapy may receive reduced or partial chemotherapy regimens or RT alone. We describe the association between first-line treatment in older patients with HL and 3-year overall survival (OS). Methods We analyzed Surveillance, Epidemiology and End Results (SEER)-Medicare data from 1999-2014. Patients diagnosed with incident classical HL at age ≥65 years and enrolled in Medicare Part A and B fee for service were included. First-line treatment within 4 months of diagnosis was determined from inpatient, outpatient, and physician/supplier claims using chemotherapy J-codes, HCPCS codes, and DRG codes. Treatment was categorized as: 1) full chemotherapy regimen (e.g., ABVD/AVD), 2) partial chemotherapy regimen, 3) single chemotherapy drug or RT, or 4) no treatment. No treatment was defined by lack of claims for any treatment, which may result in misclassification. Three-year OS from time of diagnosis was estimated for all patients using the Kaplan-Meier method. Analyses comparing 3-year OS by treatment excluded the no treatment group because of immortal time bias (patients need to survive to treatment initiation) and lack of comparability with the treated groups even after adjustment (e.g., residual confounding by poor prognosis). Unadjusted 3-year OS was plotted by treatment category using the Kaplan-Meier method. A Cox proportional hazards model estimated hazard ratios (HR) and 95% confidence intervals (CIs) for the association between first-line treatment and 3-year OS, adjusted for age at diagnosis, race/ethnicity, Medicaid dual enrollment, comorbidity, frailty, diagnosis year, histology, stage, B symptoms, prior cancer, population density, and region. Adjusted HRs are also reported for patient and disease factors associated with 3-year OS. Results We included 2825 patients with a mean age of 76 years (SD=7). Patients received the following first-line treatments: 1197 (42.4%) full chemotherapy regimen, 503 (17.8%) partial chemotherapy regimen, 397 (14.1%) single chemotherapy or RT, and 728 (25.8%) no treatment. 92.3% of full chemotherapy regimens were ABVD/AVD. By 3 years post-diagnosis, OS for all patients was 46.7%. In unadjusted analysis including only treated patients (n=2097), those receiving full chemotherapy regimens experienced the highest 3-year OS, followed by single chemotherapy or RT, then partial chemotherapy regimens (Figure). In the Cox model adjusted for patient and disease factors, treatment with partial chemotherapy regimens (HR 2.12; 95% CI=1.75, 2.58) or single chemotherapy or RT regimens (HR 1.60; 95% CI=1.26, 2.03) were associated with a higher hazard of mortality by 3 years compared to treatment with full chemotherapy regimens. The adjusted Cox model also identified patient and disease factors associated with 3-year OS. Older patient age (HR 1.03 per year; 95% CI 1.01, 1.04), any comorbidity (HR 1.40; 95% CI 1.09, 1.79), frailty (HR 1.32; 95% CI 1.67), advanced stage (HR 1.45; 95% CI 1.22, 1.74), B symptoms (HR 1.59; 95% CI 1.31, 1.94), and lymphocyte depleted histology (HR 1.75 vs nodular sclerosis; 95% CI 1.17, 2.60) were associated with a higher hazard of mortality by 3 years. Conversely, lymphocyte rich histology (HR 0.57 vs nodular sclerosis; 95% CI 0.32, 1.00) had a lower hazard of mortality. Conclusions In a comprehensive analysis, we confirm poor outcomes of older patients with HL, with a 3-year overall mortality >50%. Although >40% of patients received full chemotherapy regimens, 25.8% had no documented treatment. Patients treated with full chemotherapy regimens had the highest 3-year OS compared to other treatment groups. Patients with no documented treatment may reflect a different subgroup of patients with poor prognosis, extensive comorbidity, or death before treatment initiation. Shared-decision making about treatment choices should consider competing risks of death from non-HL causes. Those who are able to tolerate full chemotherapy regimens, sequential therapy, or novel agents may benefit with significantly longer OS. Figure Disclosures Friedberg: Bayer: Honoraria, Other: Data & Safety Monitoring Committee; Acerta: Other: Data & Safety Monitoring Committee. Evens:Pharmacyclics: Honoraria, Other: DMC; Bayer: Consultancy, Honoraria; Research to Practice: Honoraria; Seattle Genetics: Consultancy, Honoraria; Verastem: Consultancy, Honoraria; Affimed: Consultancy, Honoraria; Takeda: Research Funding; Merck: Research Funding.
Background. In patients with Hodgkin lymphoma (HL) aged ≥60 years, comorbidities and treatment-related toxicities often prevent delivery of optimal intensity and/or duration of standard frontline chemotherapy. Brentuximab vedotin (BV) and nivolumab (Nivo) have two distinct mechanisms of action, tolerability of the combination has been observed in relapsed/refractory HL in a phase 1/2 study (85% objective response rate [ORR]; 62% complete remission [CR] rate) (Herrera 2017); thus, our phase 2 study was amended to evaluate this combination in a cohort of newly diagnosed HL patients aged ≥60 years (NCT01716806). Methods. Eligible subjects have treatment-naive classical HL and are ineligible for or declined initial conventional combination chemotherapy (planned N = 20). Subjects received BV 1.8 mg/kg + Nivo 3 mg/kg as well as prophylactic premedication for infusion-related reactions on Day 1 of each 3-week cycle for ≤16 cycles. CT/PET scans were performed at Cycles 2 (CT only), 4, 8, 12, and 16 (assessed per Lugano Classification Revised Staging System [Cheson 2014] and Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC) [Cheson 2016]). The primary objective is ORR. Results. Twenty-one subjects received BV + Nivo (median age, 72 years [range, 60-88]). The majority had an ECOG performance status of 0/1 (95%), Stage III/IV disease (77%), and presented with B symptoms at baseline (57%). In this elderly population, 48% had bulky disease and 38% had extranodal disease at the initial diagnosis. Of the 21 subjects treated, 7 remain on treatment, 2 discontinued treatment due to progressive disease, 6 completed treatment, 4 withdrew due to subject decision, 1 withdrew due to pneumocystis jiroveci pneumonia, and 1 had an unrelated Grade 3 serious adverse event of acute renal failure and sepsis, resulting in death. The most common treatment-related adverse events (TRAE) of any grade were fatigue (48%), peripheral sensory neuropathy (38%), diarrhea, infusion-related reactions, and pyrexia (24% each). No infusion-related reactions required steroid intervention. Among TRAE ≥Grade 3, the most common were elevated lipase (19%) and peripheral motor neuropathy (14%). Three subjects had immune-related AEs with a maximum severity of Grade 3. Three of the 21 subjects treated were not evaluable for efficacy, defined in the protocol as subjects who had both a baseline and at least one post-baseline disease assessment or who had documented progression of disease any time after receiving any amount of BV. Non-evaluable subjects included 1 who died from renal failure prior to assessment, 1 who withdrew consent prior to assessment, and 1 who had not been assessed at the time of the data cutoff. Based on the 18 evaluable subjects, the ORR was 100%, with a 72% CR rate and a 28% PR rate. Conclusions. Elderly HL remains an unmet clinical need. These data suggest that BV + Nivo is an active treatment with an encouraging CR rate (72%) and appears well tolerated in these patients. These results also suggest that with further follow-up and validation, treatment with BV + Nivo may improve patient outcomes. Enrollment in this cohort is complete (21 subjects), with 7 subjects continuing to receive treatment. Disclosures Yasenchak: BMS: Consultancy; Seattle Genetics: Consultancy. Bordoni:Seattle Genetics, Inc.: Research Funding; Practice Point Communication: Honoraria; Phillips & Gilmore: Honoraria; Merck: Speakers Bureau; Genentech: Speakers Bureau; Deciphera: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Honoraria; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Yazbeck:Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Patel-Donnelly:Seattle Genetics, Inc.: Research Funding. Anderson:Seattle Genetics, Inc.: Research Funding. Larson:Seattle Genetics, Inc.: Research Funding. Newhook:Seattle Genetics, Inc.: Employment. Mei:Seattle Genetics, Inc.: Research Funding. Ho:Seattle Genetics, Inc.: Employment, Equity Ownership. Friedberg:Bayer: Honoraria, Other: Data & Safety Monitoring Committee; Acerta: Other: Data & Safety Monitoring Committee.
Background Wide-necked bifurcation aneurysms (WNBA) are a difficult subset of aneurysms to successfully repair endovascularly, and a number of treatment adjuncts have been designed to improve on the results of coiling, including stenting and flow diversion of the parent vessel. Surgical clipping is commonly performed for certain WNBAs, such as middle cerebral aneurysms, in some centres. Intra-saccular flow diversion (ISFD) using the Woven Endo-Bridge (WEB) or similar devices, has been developed as a new endovascular alternative to coiling for WNBAs. Meta-analyses of case series suggest satisfactory results, both in terms of safety and efficacy, but in the absence of randomized evidence, whether ISFD leads to better outcomes for patients with WNBA remains unknown. There is a need to offer ISFD within the context of a randomized care trial. Methods The proposed trial is a multicentre, randomized controlled care trial comparing ISFD and best conventional management option (surgical or endovascular), as determined by the treating physician prior to randomized allocation. At least 250 patients will be recruited in at least 10 centres over a four-year period, and followed for one year, to show that ISFD can increase the incidence of successful therapy from 75 to 90% of patients, defined as complete or near-complete occlusion of the aneurysm AND a good clinical outcome (mRS ≤ 2) at one year. The trial will be followed by an independent data safety monitoring committee to assure the safety of participants. Conclusion Introduction of intra-saccular flow diversion can be accomplished within a care trial context.
Abstract Introduction: The role of maintenance treatment in patients with high-risk Acute Promyelocytic Leukemia (APL) in the era of ATO/ATRA is unclear. Methods: We retrospectively reviewed electronic medical records of patients with high-risk Acute Promyelocytic Leukemia (APL) and identified patients who did not receive maintenance. Results: We have identified 9 patients with high-risk APL who did not receive maintenance therapy. Five patients were females and 8 were white. The median age was 47-year-old (range 26-77 year old). The median WBC was 41,500 (range 14,700-167,500). The median blast percentage was 81% (range 1%-91%). The median platelet count was 28,000 (range 7,000-60,000). One patient received G-CSF prior to diagnosis of APL but the majority of cells on presentation were blasts. Two patients had additional cytogenetics changes apart from presence of t(15;17)(q22;21). Three patients had FLT3 ITD detected. All patients received ATRA during induction. Moreover, during induction 8 patients received Arsenic and all but one received Idarubicin. Seven of the 8 received Idarubicin according to Australasian APLM4 study. Bone marrow biopsies following induction were negative for PML/RARA by FISH analysis. RT-PCR for PML/ RARA was obtained at the time of the bone marrow (BM) biopsy in 8 patients and was negative. One patient had assessment close to the time of BM biopsy from peripheral blood and was negative. The median time from diagnosis to post Induction bone marrow was 49 days (range 32-56 days). All patients received 4 cycle of consolidation with ATRA and ATO according to Italian-German APL 0406 trial ( Lo-Coco et al., NEJM 2013). Three patients received Intrathecal chemotherapy for prophylaxis. Six of 9 had end-of-treatment bone marrow, which were negative for relapse. All patients were subsequently followed by RT-PCR for PML/RARA for molecular relapse. At last follow-up, all patients are alive and were in molecular remission. The median follow-up from diagnosis was 916 day (range 429-1674). Conclusion: We report our experience of high-risk APL patients in our institution who did not receive maintenance. None of the patients relapsed and our data suggest that patients that do not undergo maintenance in the era of ATO/Arsenic consolidation may remain in remission. Table. Table. Disclosures Erba: Takeda/Millenium: Research Funding; Pfizer: Consultancy, Other: grant; Celgene: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Takeda/Millenium: Research Funding; Pfizer: Consultancy, Other: grant; Incyte: Consultancy, Speakers Bureau; Amgen: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas: Research Funding; Incyte: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Astellas: Research Funding; Seattle Genetics: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Amgen: Research Funding; Novartis: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Astellas: Research Funding; Agios: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Novartis: Consultancy, Speakers Bureau; Amgen: Research Funding; Amgen: Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Astellas: Research Funding; Seattle Genetics: Consultancy, Research Funding; Janssen: Research Funding; Janssen: Research Funding; MacroGenics: Consultancy; MacroGenics: Consultancy; Pfizer: Consultancy, Other: grant; Juno: Research Funding; Juno: Research Funding; Pfizer: Consultancy, Other: grant; Agios: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Incyte: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Incyte: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Takeda/Millenium: Research Funding; Immunogen: Consultancy, Research Funding; Jazz: Consultancy, Speakers Bureau; Takeda/Millenium: Research Funding; Celgene: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding; MacroGenics: Consultancy; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; MacroGenics: Consultancy; Celgene: Consultancy, Speakers Bureau; Juno: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Juno: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding; Jazz: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding. Papadantonakis:Agios pharmaceuticals: Honoraria, Other: advisory board.
Abstract Introduction: The optimum number of cycles and dose of Cytarabine consolidation in older patients (age 60 and above) with AML in first remission remains unclear. Methods: We retrospectively reviewed electronic medical records of patients. We identified 81 patients that were diagnosed with AML ( at age 60 and above) and received induction chemotherapy followed by Cytarabine consolidation between 2008 and 2017. Results: We reviewed the outcomes of 81 patients and report overall survival (OS) and relapse free survival (RFS) for the 69 patients reaching a landmark of 120 days from diagnosis without relapse or death (to exclude patients who would not be amenable to extended consolidation). Median follow up was 19.4 months (range 4.2-105.7). The median age at diagnosis was 65 (range 60-77); 86% were White. The majority were men (66%) ; 60% received daunorubicin-based induction [dose range 45 mg - 90 mg/m2] and 19% received re-induction chemotherapy. The cytogenetics based on ELN 2017 criteria were 71% intermediate, 13% favorable,10% adverse and for 6% not available (N/A.) From the 69 patients 16 were documented to be FLT3 ITD positive and 17 NPM1 positive. Twenty out of 69 patients (29%) received allogeneic hematopoietic cell transplantation (alloHCT). From those transplanted 5 patients were transplanted at CR2, one patient with relapse disease and the rest at CR1. Thirty patients relapsed and 27 patients died. At time of last follow up or death 56% of patients were on CR1, 13% on CR2 while the rest had relapsed disease [up to 3 relapses]. The median number of Cytarabine consolidation cycles was 2 (range 1-4 cycles) with Cytarabine total dose per cycle ranging between 6 gr/m2-18 gr/m2. The median cumulative dose from all cycles of consolidation was 18 gr/m2. We considered a cumulative dose ≤18 gr/m2 to be "low intensity (LI)" and > 18 gr/m2 "high intensity (HI)". OS was superior for HI patients [(Median not reached vs. 20.3 months, P=0.04), Figure 1a]. However there was no difference in RFS between groups [ median 14.3 Vs 14.8 months, p=0.6, Figure 1b]. When data were censored at the time of alloHCT, the OS advantage for HI was no longer statistically significant (p=0.07). In multivariate analysis for OS HI consolidation, intermediate and favorable risk cytogenetics had a favorable impact. Black race was associated with inferior OS. Since HI was associated with improved OS but not RFS we hypothesized that HI had better post relapse survival. In fact, there was a trend towards better post relapse survival among HI patients (N=15) compared to LI patients (N=15) [( median 12.4 vs. 5.2 months, p=0.070), Figure 1c]. Conclusion: The intensity of Cytarabine consolidation for older AML patients in CR1 was associated with improved OS but not RFS. Although the selection of LI or HI by the treating physician did not affect risk of relapse, our data suggest that HI consolidation is likely a surrogate for factors that make patients more amenable to successful post relapse therapy. Figure 1. Figure 1. Disclosures Costa: Amgen: Honoraria, Research Funding; Abbvie: Research Funding; Janssen: Research Funding; Karyopharm: Research Funding; BMS: Research Funding; Celgene: Honoraria, Research Funding; Sanofi: Honoraria. Erba:Janssen: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; MacroGenics: Consultancy; Seattle Genetics: Consultancy, Research Funding; Astellas: Research Funding; Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Juno: Research Funding; Immunogen: Consultancy, Research Funding; Takeda/Millenium: Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Seattle Genetics: Consultancy, Research Funding; MacroGenics: Consultancy; MacroGenics: Consultancy; Celgene: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Astellas: Research Funding; Juno: Research Funding; Seattle Genetics: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Takeda/Millenium: Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Jazz: Consultancy, Speakers Bureau; Janssen: Research Funding; Jazz: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding; Pfizer: Consultancy, Other: grant; Novartis: Consultancy, Speakers Bureau; Takeda/Millenium: Research Funding; Seattle Genetics: Consultancy, Research Funding; Pfizer: Consultancy, Other: grant; Agios: Consultancy, Speakers Bureau; Amgen: Research Funding; Agios: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Amgen: Research Funding; Incyte: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding; Novartis: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Pfizer: Consultancy, Other: grant; Immunogen: Consultancy, Research Funding; Pfizer: Consultancy, Other: grant; Celgene: Consultancy, Speakers Bureau; Takeda/Millenium: Research Funding; MacroGenics: Consultancy; Juno: Research Funding; Juno: Research Funding; Agios: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Celgene: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy, Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Daiichi Sankyo: Consultancy, Research Funding. Papadantonakis:Agios pharmaceuticals: Honoraria, Other: advisory board.
Abstract Introduction: The initial response to standard induction chemotherapy for acute myeloid leukemia (AML) is commonly assessed with day 14 bone marrow evaluation; patients with residual disease may receive re-induction chemotherapy. The benefit of re-induction chemotherapy in patients with indeterminate day 14 bone marrow results (defined in our study as ≤ 20% cellularity and 5-20% blasts) remains unclear. We report our experience of AML patients with indeterminate day 14 bone marrow treated with and without re-induction chemotherapy. Methods: A retrospective chart review was performed to evaluate adult patients with newly diagnosed AML treated with and without re-induction chemotherapy for indeterminate day 14 bone marrow results between January 2010 and April 2018 at our institution. All patients included in the analysis received induction chemotherapy with cytarabine and an anthracycline. Approval for the study was obtained from the Institutional Review Board. Results: We identified 50 patients with indeterminate day 14 bone marrow results (Table 1). Twenty five patients (50%) received re-induction therapy and 25 (50%) did not. Flow cytometry data on day 14 bone marrow samples were available for 15 patients (60%) who received re-induction and 18 (72%) who did not. All flow cytometry samples, when performed, were reported as persistent/residual disease. The median age at diagnosis was 56 years (range 19-70) in patients who received re-induction and 59 years (range 23-73) in those who did not. There were 12 patients (48%) with poor risk disease, both in the re-induction arm (10 abnormal karyotype, 2 normal karyotype with molecular abnormalities) as well as in the no re-induction arm (6 abnormal karyotype, 6 normal karyotype with molecular abnormalities). FLT3-ITD mutation was positive at diagnosis in 2 cases (8%) in the re-induction arm and in 8 cases (32%) not receiving re-induction. The most commonly used chemotherapy regimen in the re-induction arm was fludarabine, high dose cytarabine and granulocyte-colony stimulating factor (FLAG, 56%). Fifteen patients (60%) in the re-induction arm and 17 (68%) in the no re-induction arm received post-remission consolidation therapy. High-dose cytarabine was the preferred consolidation regimen (96%). The overall response rate [complete remission (CR) + CR with incomplete count recovery (CRi)] was similar in both arms (80% vs. 80%). There was no statistically significant difference in median overall survival (OS) and relapse free survival (RFS) between the re-induction and no re-induction arms (Figure 1). In univariate analysis, no statistically significant difference in OS was found for age at diagnosis (≥ 60 years vs. < 60 years; p=0.06), white blood cell count at diagnosis (≥ 50,000 vs. < 50,000; p=0.48), disease risk status (poor risk vs. favorable/intermediate risk; p=0.81) and performance of transplant (yes vs. no; p=0.13) in the entire population. Conclusion: Our study did not find a statistically significant difference in overall response rates, as well as for OS and RFS in AML patients with indeterminate day 14 bone marrow receiving re-induction or not. Our findings question the utility of immediate re-induction chemotherapy and raise the concern for over treatment in this patient population. Larger studies investigating similar outcomes are warranted to validate these clinical findings. Table 1. Table 1. Disclosures Costa: Celgene: Honoraria, Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding; Janssen: Research Funding; Karyopharm: Research Funding; Sanofi: Honoraria; BMS: Research Funding. Saad:Actinium: Consultancy. Papadantonakis:Agios pharmaceuticals: Honoraria, Other: advisory board. Erba:Janssen: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; MacroGenics: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Incyte: Consultancy, Speakers Bureau; Juno: Research Funding; Amgen: Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Daiichi Sankyo: Consultancy, Research Funding; Agios: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Astellas: Research Funding; Takeda/Millenium: Research Funding; Janssen: Research Funding; Celgene: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Juno: Research Funding; Amgen: Research Funding; Immunogen: Consultancy, Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Celgene: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Pfizer: Consultancy, Other: grant; Astellas: Research Funding; Agios: Consultancy, Speakers Bureau; MacroGenics: Consultancy; Immunogen: Consultancy, Research Funding; Juno: Research Funding; Celgene: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Takeda/Millenium: Research Funding; Astellas: Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Takeda/Millenium: Research Funding; Amgen: Research Funding; Amgen: Research Funding; Novartis: Consultancy, Speakers Bureau; Janssen: Research Funding; Jazz: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Takeda/Millenium: Research Funding; Janssen: Research Funding; Immunogen: Consultancy, Research Funding; MacroGenics: Consultancy; Pfizer: Consultancy, Other: grant; Agios: Consultancy, Speakers Bureau; Juno: Research Funding; MacroGenics: Consultancy; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy, Other: grant; Celgene: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Pfizer: Consultancy, Other: grant; Jazz: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding; Astellas: Research Funding; Incyte: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau.
