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Outcomes of Induction with Venetoclax in Combination with Decitabine, Azacitidine, or Low-Dose Cytarabine for Treatment of AML: A Real-World Retrospective Analysis
Abstract Background: The addition of venetoclax to a hypomethylating agent (HMA) backbone has been shown to augment responses when compared to HMA monotherapy or to low-dose cytarabine in the treatment of acute myeloid leukemia (AML). The aim of this retrospective analysis was to characterize venetoclax-based regimens in both the first-line and relapsed/refractory settings to determine efficacy and safety outcomes. Patients & Methods: We retrospectively analyzed 74 patients treated with venetoclax in combination with decitabine, azacitidine, or low-dose cytarabine treated from June 2018 to December 2020. This analysis included 41 patients in the upfront setting and 33 patients in the relapsed/refractory setting. Baseline patient demographics were obtained alongside ECOG performance status at diagnosis, cytogenetics and molecular profiling, dates and doses of induction, toxicity, responses, MRD analysis, and allogeneic hematopoietic stem cell transplant (HSCT) outcomes. The event for calculating the overall survival was the date of death and patients were otherwise censored at the date of last contact. Results: In the upfront setting of 41 patients, 25 (61%) were male and 16 (39%) were female, the median age was 72 (range: 37 - 85), the median ECOG score was 2 (range: 0 - 3), and the median Charlson Comorbidity Index (CCI) score was 6 (range: 3 - 12). There were four patients with favorable-risk cytogenetics (9.8%), six (14.6%) with intermediate cytogenetics, and 29 (70.7%) with adverse cytogenetics. Two (4.9%) patients had cytogenetics unknown at diagnosis. Eight (19.5%) had mutations in TP53. Thirty-three (80.5%) received venetoclax with 5-day decitabine, one (2.4%) with 10-day decitabine, six (14.6%) with azacitidine, and one (2.4%) with low-dose cytarabine. In the entire cohort, 37 (90.2%) experienced at least one grade 1 non-hematological toxicity during induction. Non-hematological adverse events were infection (58.5%), neutropenic fever (53.7%), and acute kidney injury (26.8%). Six (14.6%) patients had tumor lysis syndrome defined by Cairo-Bishop criteria and all six were spontaneous rather than therapy-induced. One (2.4%) died within 30 days of induction, nine (22.0%) died within 60 days, and 29 (70.7%) had no death during induction. Three (7.3%) achieved CR and 13 (31.7%) achieved CRi for an ORR of 39.0%. Two patients (4.9%) went on to receive HSCT. The median OS was 416 days (13.7 months) in the intermediate category and 281 days (9.2 months) in the adverse category. In the relapsed/refractory setting, 20 (60.6%) were male and 13 (39.4%) were female. The median age was 63 (range: 23 - 76), the median ECOG score was 1 (range: 0 - 4), and the median CCI score was 5 (range: 2 - 11). At the time of initial diagnosis, two patients (6.1%) had favorable cytogenetics, three (9.1%) had intermediate cytogenetics, 27 (81.8%) had adverse cytogenetics, and one had unknown cytogenetics. Seven (21.2%) patients had a TP53 mutation at initial diagnosis. Twenty-five (75.8%) received venetoclax with 5-day decitabine, 6 (18.2%) with azacitidine, one (3.0%) with low-dose cytarabine, and one with an unknown duration of decitabine. Common non-hematological toxicities included 13 (39.4%) with infection, 11 (33.3%) with neutropenic fever, and 3 (9.1%) with acute kidney injury. Five patients (15.2%) achieved CR and 5 (15.2%) achieved CRi for an ORR of 30.3%. Four (12.1%) died within 30 days, 3 (9.1%) within 60 days, and 25 (75.8%) with no death during induction. The median OS was 251 days (8.25 months). Conclusion: The combination of venetoclax with decitabine, azacitidine, or low-dose cytarabine demonstrates an ORR of 39.0% in the upfront setting and the OS was 13.7 months and 9.2 months in the intermediate and adverse categories, respectively. The relapsed/refractory setting featured a shorter OS at 8.25 months and an ORR of 30.3%, which does not appear to be substantially different from historical data with HMA monotherapy in relapsed disease (mOS = 6.7 months). These findings raise the question regarding the benefit of venetoclax in the relapsed setting for selected patients. Additionally, our findings augment the small sample of available data on the utility of HMA/venetoclax, particularly in the treatment of relapsed disease, with recent retrospective data showing a CR/CRi rate of 24% and a mOS of 6.1 months. Prospective trial designs are needed to confirm these findings. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
Abstract Introduction Treatment with the BCL-2 inhibitor Venetoclax (VEN) in combination with hypomethylating agents (HMA) or low-dose cytarabine (LDAC) has shown encouraging results in patients with acute myeloid leukemia (AML). In contrast to the FDA, EMA approval for unfit AML patients was given only recently, and VEN combinations have therefore often been used as off-label treatment for relapsed/refractory (r/r) AML patients. We conducted a retrospective study of 73 unfit or r/r AML patients treated with a VEN combination between 2017 and 2021 at two German university hospitals. Methods Data was collected by medical chart review and included genetics, ELN2017 risk classification, previous treatment lines, courses of VEN treatment as well as outcome. All statistical tests were performed with GraphPad Prism. The median time of follow-up was 8.3 months. Results At beginning of VEN treatment, the median age was 73 (20-85) years (Table 1). The majority of patients had a secondary (s) AML [n=34 (47%)] and was assigned to the adverse ELN2017 risk group [n=32 (44%)]. Mutations in isocitrate-dehydrogenase 1/2 genes (IDH1/2) were the most frequent alteration [n=19 (26%)]. Before VEN treatment, a total of n=58 (79%) patients had received prior treatment including intensive chemotherapy [n=36 (49%)] and allogeneic stem cell transplantation (allo-HSCT) [n=26 (36%)]. Twenty-five (34%) patients were treated with >4 cycles HMA or LDAC before VEN initiation. VEN was given as first-line treatment in n=15 (21%) patients and started during the first or second treatment cycle of HMA/LDAC. The initial VEN dosage after ramp-up during cycle 1 was in median 400mg (50-800mg). Patients received VEN in combination with azacytidine [n=34 (47%)], decitabine [n=18 (25%)] or LDAC [n=20 (28%)]. In median, patients had received 3 (1-17) VEN cycles at data cut-off. VEN was initiated after progression on HMA/LDAC treatment (>2 cycles) in n=35 (48%) patients. In most patients VEN was discontinued or dose-adjusted during treatment [cycle 1 n=37 (51%), after cycle 1 n=43 (59%)]. Response assessment was available for n=58 (79%) patients, of which n=18 (25%) achieved complete remission (CR) or CR with incomplete hematologic recovery (CRi), n=24 (33%) a partial remission (PR) or stable disease (SD), and n=16 (22%) were refractory to VEN combination treatment. The overall response rate (ORR) including CR/CRi/PR patients was 47% and not influenced by age or previous treatments including allo-HSCT and HMA pretreatment. Achievement of CR/CRi was significantly better in patients with IDH1/2 and/or NPM1 mutations (Figure 1). The median overall survival (OS) of the entire cohort was 6.5 months. OS was significantly better in patients achieving a CR/CRi (20.3 months) as compared to patients with PR/SD/RD. (p<0.0001; Figure 2 A). OS was shorter in patients with more than two prior treatment lines (p=0.01, Figure 2 B) and in patients who had received allo-HSCT (p=0.05, Figure 2 C). There was no significant impact on OS with respect to age (>=65 years), ELN2017 risk group or previous HMA treatment. OS was however significantly longer in patients harboring NPM1 and/or IDH1/2 mutations (p=0.016; Figure 2 D). Conclusions Our real-world analysis demonstrates that VEN combination treatment is feasible and effective also in r/r AML patients. Response rates and survival were lower than in patients treated with VEN combinations in first line (DiNardo, NEJM 2020) and in our cohort highly influenced by the number of previous treatment lines. As in patients treated with VEN combinations at fist line, the NPM1 and IDH1/2 genotype was associated with better response and survival. Further studies with larger cohorts are needed to investigate the role of VEN combinations in r/r AML. Figure 1 Figure 1. Disclosures Westermann: Abbvie: Consultancy, Honoraria; Astellas: Honoraria; Novartis: Consultancy, Honoraria; BMS: Honoraria; Amgen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Stem Cell Line: Consultancy, Honoraria. Bullinger: Seattle Genetics: Honoraria; Bayer: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Astellas: Honoraria; Amgen: Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Gilead: Consultancy; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Menarini: Consultancy; Sanofi: Honoraria; Celgene: Consultancy, Honoraria; Hexal: Consultancy. Keller: Abbvie: Other: Advisory Role. Krönke: BMS/Celgene: Other: Advisory board; Abbvie: Other: Advisory board. Goetze: Abbvie: Other: Advisory Board; BMS/Celgene: Other: Advisory Board, Research Funding. OffLabel Disclosure: Venetoclax was used "off-lable" in unfit and relapsed/refractory AML patients in combination with HMA/LDAC.
Abstract Background: Many patients with Acute Myeloid Leukemia (AML) diagnosed after 60 years of age are not considered suitable for intensive remission induction chemotherapy, either due to co-morbidities or frailty associated with advanced age. Despite treatment with either a hypomethylating agent or low-dose cytarabine arabinoside (LDAC), survival is usually poor, with 1-year survival after LDAC of 24-37% in NCRI AML16 and historical arms of LI-1. Combination therapy with additional agents represents an attractive option, and has the potential to improve patient outcomes without substantially increasing toxicity. Lenalidomide (Revlimid TM) is an immunomodulatory drug, used to treat myeloma, and some cases of myelodysplastic syndrome, and has potent antineoplastic, anti-angiogenic, anti-inflammatory and pro-erythropoietic properties. Early-phase trials of lenalidomide in AML have demonstrated clinical activity with acceptable toxicity. Aim: To assess the efficacy and tolerability of LDAC+lenalidomide versus LDAC alone in patients aged 60+ unsuitable for intensive therapy. The aim was to double 2-year survival from 11% to 22% (HR 0.69). Methods: LI-1 was an international multicentre, multi-arm, randomised phase II trial developed to study the efficacy and tolerability of novel non-intensive therapies in AML using a "pick a winner" design. LDAC was given at 20mg BD SC on days 1-10 of each course. Lenalidomide was administered orally once daily in a flat 10mg dose for 21 days, where day 1 is day 1 of LDAC with courses occurring at 5-week intervals for courses 1-4. Patients considered to be benefitting after 4 courses, i.e. in remission or stable disease, could continue to receive treatment until disease progression, either with LDAC+lenalidomide at 6-week intervals, or lenalidomide only at 4-week intervals if patient had experienced significant toxicity. Toxicities were recorded using CTCAEv3. Primary objectives included overall survival (OS), complete remission (CR + CRi) achievement, reasons for failure, duration of response (CR/CRi), relapse rates and deaths in first CR. Secondary objectives included toxicity, supportive care requirements, and Quality of Life assessments (measured using EORTC QLQ-30, EQ5D and HADS tools). Results: Between Jan-17 and Jun-19, 202 patients from Denmark (8%), New Zealand (16%) and the UK (76%) were randomised. Median age was 78 years (range 62-89). Overall, 58% were male; 76% de novo AML, 20% secondary AML, and 4% high risk MDS; 1% favourable, 66% intermediate, 19% adverse and 14% unknown cytogenetics; WHO performance status 0 for 15%, 1 for 58%, 2 for 22% and 3 for 5%. Median of 2 courses (range 0-24; mean 3.28) was delivered in LDAC arm and 1 course in LDAC+lenalidomide arm (range 0-25; mean 3.48). Overall response (CR/CRi) was achieved in 40/202 patients (20%), (LDAC+lenalidomide 25%, LDAC 14%, OR 0.45 (0.22, 0.93), P=0.031). 30-day mortality was not significantly increased (19% in both arms); and 2-year OS showed no significant difference (14% vs 11.5%, HR 0.94 (0.69, 1.29, P=0.719). Median OS was 3.5 vs 4.6 months; HR 0.96 (0.71, 1.30), P=0.80. 1-year OS for patients that didn't enter CR/CRi was 6.8% for LDAC+lenalidomide vs 16.9% for LDAC (P=0.028). Cause of death for the majority of patients was resistant/recurrent disease: 45(53%) vs 47(58%). Most adverse events (AEs) were grade 1/2 in both arms. During cycle 1, there were 78 vs 51 grade 3/4 AEs in the LDAC+lenalidomide and LDAC arms, respectively (P=0.02). This included 5 thrombotic events in the LDAC+lenalidomide arm (4 grade 3 and 1 grade 4) and none in the LDAC arm. In course 1, supportive care requirements were higher in terms of both days of antibiotics (7 vs 3; p=0.001) and hospitalisation days (11 vs 6.5; p=0.005) for the LDAC+lenalidomide arm. There was no difference in transfusion requirements. Conclusions: Despite improving the CR/CRi rate, the combination of lenalidomide+LDAC did not improve OS, relapse-free survival or time in remission in elderly patients with AML. The addition of lenalidomide to LDAC resulted in increased toxicity, including episodes of thrombosis, as well as increased supportive care requirements. Alternative strategies to improve survival for elderly patients with AML remain a significant clinical need. Acknowledgements: We are grateful to Blood Cancer UK for funding the trial and Celgene for providing drug and additional support for this IIS. Fig 1: OS All patients Figure 1 Figure 1. Disclosures Copland: Astellas: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Incyte: Honoraria, Research Funding, Speakers Bureau; Jazz: Honoraria, Speakers Bureau; Cyclacel Ltd: Research Funding. Russell: Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees; Jazz: Research Funding, Speakers Bureau. OffLabel Disclosure: Off label use of lenalidomide in combination with low dose cytarabine will be discussed in the setting of elderly unfit AML.
Abstract Background Venetoclax based therapies have produced varying results in the relapsed or refractory acute myeloid leukemia (R/R AML) setting. Highest response rates were demonstrated after Venetoclax in combination with high dose chemotherapy. However, this approach is feasible mainly in fit, younger patients. Herein, we present a lower intensity combination therapy consisting of Venetoclax, low dose Cytarabine and Actinomycin D (ACTIVE) in patients with R/R AML administered in real-life clinical practice setting. Methods We performed an observational, retrospective, single centre study. The patients were at least 18 years of age and had R/R AML. All patients provided informed consent for treatment as well as data collection. Venetoclax ramp-up was administered over either 3 or 5 days until the daily dose of 600mg/d was reached. The ACTIVE regimen consisted of Venetoclax 600mg/d p/o on days 1-28, Cytarabine 20mg/m 2 s/c on days 1-10, Actinomycin D 12.5 µg/kg i/v on days 1, 2 and 3 (on days 1 and 2 for patients ≥65 years). Strong/moderate CYP3A inhibitors/inducers or Venetoclax dose reductions were not allowed. Indications for stopping Venetoclax before Day 28 were life threatening infectious complications or faster hematological recovery with the addition of G-CSF in responders. A second ACTIVE cycle was administered in non-responders without evidence of progressive disease after Cycle 1 or in responders with positive minimal residual disease (MRD). We evaluated baseline characteristics, composite CR (CRc = CR + CRi + CRp), overall response (ORR = CRc + MLFS), MRD negativity rates, overall survival (OS), relapse-free survival (RFS), event-free survival (EFS), Grade 3-5 non-hematological toxicities and Day 30 and Day 60 mortality rates. Results Fifty R/R AML patients were treated with ACTIVE and 56% (28/50) were male. The median age was 65 years (20-84). The median Eastern Cooperative Oncology Group (ECOG) status was 1 (0-3) and 40% (20/50) had ECOG status of 2 or 3. Secondary AML was confirmed in 48% (24/50) of cases. Adverse cytogenetics were identified in 28% (14/50) of patients whereas 60% (30/50) were stratified to adverse risk group in accordance with ELN 2017 guidelines. The most common gene mutations were IDH1/2 30% (15/50), FLT3 28% (14/50), ASXL1 22% (11/50), NPM1 14% (7/50), N/KRAS 12% (6/50) and RUNX1 12% (6/50). The median number of prior therapies was 2 (1-5). Intensive chemotherapy was administered in 80% (40/50) of whom 38% (15/40) had primary refractory disease and 48% (19/40) had previously received Fludarabine + Cytarabine + Idarubicin (FLAG-Ida) or Cytarabine + Mitoxantrone (HAM). Eight percent (4/50) had had prior Venetoclax exposure. Thirty-six percent (18/50) had relapsed after allogeneic stem cell transplantation (alloSCT) with a median time of 7.4 months (1.6-37.3) from transplant to relapse. One cycle of ACTIVE therapy was administered in 76% (38/50) of cases, whereas 24% (12/50) received 2 cycles. The median number of Venetoclax 600mg/d days per cycle was 18 (8-28). Additional FLT3/RAS/BCR-ABL1 inhibitors Gilteritinib, Trametinib or Dasatinib were administered in 12% (6/50). Forty-nine patients were evaluable for response and one patient died of sepsis before response evaluation (Table 1). The ORR was 73% (36/49) and the CRc rate was 67% (31/46). MRD negativity was confirmed in 61% (19/31) of CRc patients. Sixteen patients had undergone additional early bone marrow evaluations. Blast count reduction to <5% was observed in 50% (8/16) after Venetoclax ramp-up and in 88% (14/16) on Day 4. Half of the ACTIVE responders (18/36) continued maintenance therapy with Venetoclax + low dose Cytarabine and optional DLI, whereas 36% (13/36) proceeded to either first or second alloSCT. After 16.4 months of median follow-up, the median OS, RFS and EFS were 13.1, 7.2 and 4.5 months, respectively (Figure 1A). Median OS was not reached in MRD negative patients (Figure 1B). In multivariable Cox regression analysis, adverse cytogenetics (HR 3.48, 95% CI 1.39 -8.55) and primary refractory disease (HR 2.54, 95% CI 1.05-6.12) were associated with worse OS. The most common grade 3-5 non-hematological adverse events were febrile neutropenia (54%, 27/50) and bacteremia/sepsis (34%, 17/50). Day 30 and Day 60 mortality rates were 8% (4/50) and 16% (8/50), respectively. Conclusions ACTIVE was effective and well tolerated in this unselected prognostically unfavourable older R/R AML patient population. Figure 1 Figure 1. Disclosures Zucenka: Jannsen: Honoraria, Other: Travel-expenses; Takeda: Other: Travel Expenses; Novartis: Honoraria, Other: Travel Expenses; Pfizer: Honoraria, Other: Travel Expenses; Astellas: Honoraria; Abbvie: Honoraria, Other: Travel Expenses. Maneikis: Abbvie: Honoraria. Pileckytė: Abbvie: Honoraria, Other: Travel Expenses. Griškevičius: Abbvie: Other: Travel Expenses. OffLabel Disclosure: Venetoclax has been used off-label for the treatment of R/R AML
Abstract Background: It is difficult for AML-MRC patients to achieve complete remission (CR) and these patients develop recurrence and die of either disease progression or associated complications. The CAG regimen (cytarabine, aclarubicin and G-CSF) has been widely used in treating patients with AML-MRC in Asia. Decitabine (DAC) was approved to the treatment of MDS and reported to achieve higher response rate (67%) in AML with unfavorable-risk cytogenetics. Several studies reported low dose DAC in combination with chemotherapy to treat AML. Purpose:To evaluate the clinical efficacy and safety of low-dose decitabine in combination with small-dose CAG regimen (D-CAG regimen) in the treatment of AML-MRC, compared to CAG regimen. Methods:A total of 80 patients with newly diagnosed AML-MRC from September 2015 to January 2020 in our center were included in the study. 43 cases were initially treated with G-CSF for priming, in combination with cytarabine of 10-mg/ m 2q12h for 14 days and aclarubicin of 20 mg/day for 4 days (CAG regimen) and other 37 cases were initially treated with decitabine of 20 mg/m 2 for 5 days and small-dose CAG regimen (cytarabine of 10-mg/ m 2q12h for 7 days, aclarubicin of 10 mg/day for 4 days, and G-CSF for priming (D-CAG regimen). After induction chemotherapy, the patients who achieved CR received consolidation chemotherapy or hematopoietic stem cell transplantation (HSCT). Results:Among a total of 80 patients, the median age was 55 years (18-69 years) and 32 of them were male. Baseline characteristics of patients between D-CAG group and CAG group showed no significant differences (table 1). For the overall AML-MRC patients, the MLFS rate of D-CAG group was higher than the MLFS rate of CAG group after two courses of D-CAG regimen (62.2% v. s. 48.8%, χ2 =8.727, P=0.013, bilateral). Seven patients in CAG group did not response and then received D-CAG regimen as induction therapy, and five of them achieved MLFS (5/7) and one achieved PR (1/7). Among the population with less than 9 months of AML-MRC and/or MDS history, the MLFS rate (74.1%, 20/27) of D-CAG group was statistically higher than the MLFS rate (42.9% 15/35) of CAG group (74.1% v. s. 42.9%, χ 2 =1.909, p=0.008). Compared to the CAG group, the high-risk patients classified according to SWOG criteria in D-CAG group achieved a better MLFS rate (80.0% v. s. 26.1%, χ 2 =11.392, P=0.003, bilateral). Except patients receiving HSCT, the probability of OS and LFS for patients between D-CAG group and CAG group did not show any significant difference, but among the population with less than 9 months of AML-MRC and/or MDS history, the DCAG group showed a better probability of OS than the CAG group (58.3%±18.6% v. s. 11.3%±10.3%, p=0.006). Conclusion: In conclusion, patients with AML-MRC have a poor prognosis, and might benefit from D-CAG regimen as the induction therapy. For patients with less than 9 months of AML-MRC/MDS history or with poor karyotypes, the MLFS rate for patients in D-CAG group was higher than patients in CAG group. Disclosures No relevant conflicts of interest to declare.
Abstract Introduction Venetoclax, a BCL-2 specific inhibitor, used in combination with azacitidine in patients with newly-diagnosed acute myeloid leukemia (AML) who were ineligible for intensive chemotherapy treatment, has shown high response rate and overall survival compared with azacitidine monotherapy (Di Nardo et al. N Engl J Med 2020; 383:617-629). Moreover, venetoclax in combination with hypomethylating agents or with low-dose cytarabine is being explored in other settings being frequently used in relapsed/refractory (R/R) AML. Aims: We performed a retrospective study of patients diagnosed with R/R AML receiving azacitidine combinations in the Catalan Institute of Oncology (ICO) in order to determine the efficacy and safety of the combination. Methods We analyze 35 patients diagnosed with R/R AML at 4 hospitals belonging to ICO in Spain, treated with venetoclax (400mg/24h; initial daily dose of 100mg with a 3-day ramp-up to target dose of 400mg) in combination with hypomethylating agents (azacitidine 75mg/m 2 or decitabine 20mg/m 2) or low-dose cytarabine (20mg/m 2) from May 2019 to Agost 2021. Event was defined as death, refractoriness to treatment or progressive disease. Results Median age was 72 years (range 44-82). Seventeen (43%) patients had high-risk AML according to ELN 2017. Five (14%) patients received venetoclax in combination with decitabine, 20 (57%) patients with azacitidine, and 10 (29%) patients with low-dose cytarabine. The median number of cycles received was 3 (range 1-25). Early mortality in the first 30 days was 5.7% (2 patients). Overall response rate (ORR) was 58%. Complete remission (CR) rate was 48% and 10% partial remission. Seventeen patients (43%) needed venetoclax dosage adjustments due to hematologic toxicity. Median time to response was 2 months. Four patients (10%) were transitioned to allogeneic stem cell transplantation. The median OS was 9.5 months (95% C.I. 2.6-16.2). Response to treatment after 3-4 cycles, discriminate two groups patients with an OS of 13.57 months in those patients who achieved CR or PR vs 2.1 months in non-responders (p<0001). Thirteen patients died as a result of infection (8.2%), disease progression (4.1%), and bleeding (1.3%) Summary/Conclusions Our study showed that real-world experience of treating patients with R/R AML with venetoclax in combination with hypomethylating agents or low-dose cytarabine is feasible, well tolerated with a rapid and promising response rate and low toxicity profile. Moreover, rapid responses shown with the combination, allow us to identify those patients who may benefit from this approach. Figure 1 Figure 1. Disclosures Sureda: Mundipharma: Consultancy; Bluebird: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Support for attending meetings and/or travel; GSK: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau.
Abstract Introduction Venetoclax, a selective b-cell lymphoma 2 (BCL2) inhibitor, has changed the landscape of treatment in newly diagnosed acute myeloid leukemia (AML) elderly patients. In addition, it has shown promising efficacy in treatment-naive and relapsed/refractory (r/r) myelodysplastic syndrome (MDS) as well as r/r AML. Unique toxicities of venetoclax include tumor lysis syndrome (TLS) due to the rapid apoptotic effect by BCL2 inhibition. Although TLS is less frequently reported in AML, due to the fatalities from TLS reported in chronic lymphocytic leukemia patients, inpatient hospitalization during initial venetoclax dose ramp up is recommended. Hydroxyurea or leukapheresis can also be used to achieve a white blood cell (WBC) count of less than 25,000 prior to initiating venetoclax. At NYU Langone Health (NYULH), patients are initiated on venetoclax dose ramp up in the outpatient setting regardless of WBC count due to the low incidence of TLS. The aim of this study is to assess the safety of outpatient venetoclax dose escalation in our AML and MDS patients. Methods/Results This was an institutional review board approved, descriptive, retrospective medical chart review of 60 adult patients who received venetoclax dose ramp up in the outpatient setting at NYULH and NYU Long Island from March 1, 2017 to March 01, 2021. Patients were included if they were 18 years and older, received venetoclax in combination with either hypomethylating agents (HMA) or low-dose cytarabine in the outpatient setting, and had a documented diagnosis of either de novo AML, r/r AML, newly diagnosed high-risk MDS, or r/r MDS. The primary endpoint was the number of patients demonstrating laboratory or clinical TLS as defined by Cairo-Bishop Criteria described by Howard and colleagues. Secondary endpoints included hospital admission within two weeks of initiating venetoclax therapy. If patients did not have laboratory values obtained within one week of starting venetoclax, but had continued hematology follow-up with the NYU health system, it was assumed that these patients did not experience laboratory or clinical TLS. One patient was counted as two individual patients because venetoclax was initiated as initial frontline AML treatment, followed by re-trial for relapsed disease. The median age was 74 years (IQR, 66-83). Most patients (24) had newly diagnosed AML (40%) followed by 17 patients (28.3%) with newly diagnosed MDS, 14 patients (23.3%) with r/r AML, and 5 patients (8.3%) with r/r MDS. The median total WBC count prior to initiating venetoclax was 2.25 x 10^3 cells/uL (IQR, 1.40-7) with a median blast count in the bone marrow of 25% (IQR, 11.5-53). Two patients had an initial WBC count of greater than 25. Thirty-six (60%) patients had a Carlson Comorbidity Index score of 5 or greater. Decitabine was the most common combination agent used (50%), followed by azacitidine (48.3%), and low-dose cytarabine (1.7%). The majority of patients, 39 (65%) were prescribed the standard dosing ramp up schedule, with 15 patients (25%) had venetoclax initiated during cycle two or thereafter. Thirty-seven (61.7%) patients ramped up to the full venetoclax dose (either 400mg or 600mg). The most common reasons for dose reductions included drug-drug interactions (7 patients), neutropenia or anemia (7 patients), and general tolerance (5 patients). Thirty-seven (61.7%) patients were prescribed allopurinol prophylaxis. No patients received rasburicase prior to initiating venetoclax. Only 1 patient (1.67%) experienced both laboratory and clinical tumor lysis and required intravenous hydration in outpatient clinic. Three additional patients (5%) required TLS directed treatment, but did not meet TLS definition. Of note, 8 patients (13.3%) did not have any laboratory values checked between days 1-7 of starting venetoclax. No patients were hospitalized within two weeks of venetoclax initiation due to TLS. Conclusion Administering venetoclax dose ramp up in the outpatient setting avoids need for hospitalization and appears to be safe in patients with AML and MDS. Limitations of this study include the heterogeneous population and the retrospective nature of the study. Although 35% of our patients were not prescribed the standard venetoclax ramp up dose, this highlights the existing challenges of treating elderly AML and MDS patients. Disclosures Abdul Hay: Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Speakers Bureau. OffLabel Disclosure: To assess the safety of outpatient venetoclax ramp up in both newly diagnosed & relapsed/refractory acute myeloid leukemia & myelodysplastic syndrome
Abstract Background Overall survival remains poor in older patients with acute myeloid leukemia (AML) with less than 10% being alive after 5 years. In recent studies, a significant improvement in event-free, relapse-free and overall survival was shown by adding gemtuzumab ozogamicin (GO), a humanized antibody-drug conjugate directed against CD33, to intensive induction therapy once or in a sequential dosing schedule. Glasdegib, the small-molecule inhibitor of smoothened (SMO), also showed improved overall survival in patients not eligible for intensive chemotherapy when combined with low-dose cytarabine compared to low-dose cytarabine alone. These findings warrant further investigations in the phase III GnG trial. Methods/Design This is a randomized phase III trial with measurable residual disease (MRD) after induction therapy and event-free survival (EFS) as primary endpoints. The two research questions are addressed in a 2 by 2 factorial design. Patients age 60 years and older are upfront randomized 1:1 in one of the two induction arms: GO administered to intensive induction therapy on days 1,4, and 7 versus GO administered once on day 1 (GO-147 versus GO-1), and double-blinded 1:1 in one of the subsequent treatment arms glasdegib vs. placebo as adjunct to consolidation therapy and as single-agent maintenance therapy for six months. Chemotherapy backbone for induction therapy consists of standard 7 + 3 schedule with cytarabine 200 mg/m2 continuously days 1 to 7, daunorubicin 60 mg/m2 days 1, 2, and 3 and high-dose cytarabine (1 g/m2, bi-daily, days 1, 2, and 3) for consolidation therapy. Addressing two primary endpoints, MRD-negativity after induction therapy and event-free survival (EFS), 252 evaluable patients are needed to reject each of the two null hypotheses at a two-sided significance level of 2.5% with a power of at least 85%. Ethics and dissemination Ethical approval and approvals from the local and federal competent authorities were granted. Trial results will be reported via peer-reviewed journals and presented at conferences and scientific meetings. Trial status Protocol version: 1st version 20.10.2020, no amendments yet. Study initiation on February 16, 2021. First patient was recruited on April 1st. Trial registration ClinicalTrials.govNCT04093505; EudraCT 2019-003913-32. Registered on October 30, 2018.
For patients with newly diagnosed acute myeloid leukemia (AML) who are candidates for intensive induction regimens, all therapies include anthracycline- and cytarabine-based backbones. Core-binding factor AML is typically treated with gemtuzumab ozogamicin and 7 + 3 chemotherapy. Patients with FLT3-mutated (ITD or TKD) disease should have midostaurin + 7 + 3 and consolidation, and those with secondary or therapy-related AML should be considered for CPX-351. For patients ineligible for intensive induction regimens, venetoclax has changed the game and should be used in combination with hypomethylating agents or cytarabine. Glasdegib is also approved in combination with low-dose cytarabine. Patients with IDH1/2-mutated disease can be treated with ivosidenib and enasidenib, respectively. Although enasidenib has yet to secure its spot in the up-front setting, data support its use in newly diagnosed AML. An ongoing question in the field concerns how to treat patients with TP53-mutated AML, because most patients do not respond well to currently available therapies and continue to have poor overall outcomes.
CADTH reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class. The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada's federal, provincial, and territorial governments, with the exception of Quebec. This review assesses venetoclax (Venclexta), 10 mg, 50 mg, and 100 mg oral tablets. Indication: In combination with azacitidine or low-dose cytarabine for the treatment of patients with newly diagnosed AML who are 75 years or older, or who have comorbidities that preclude the use of intensive induction chemotherapy.
