A phase 3b study of venetoclax and azacitidine or decitabine in an outpatient setting in patients with acute myeloid leukemia.

Venetoclax, a highly selective BCL-2 inhibitor, combined with hypomethylating agents (HMAs) azacitidine or decitabine, is approved for the treatment of newly diagnosed acute myeloid leukemia (ND AML) in patients who are ineligible to receive intensive chemotherapy. Previous clinical studies initiated venetoclax plus HMA in an inpatient setting owing to concerns of tumor lysis syndrome (TLS). This study (NCT03941964) evaluated the efficacy and safety of venetoclax plus HMA in a United States community-based outpatient setting in patients with ND AML (N = 60) who were treatment naïve for AML, ineligible to receive intensive chemotherapy, had no evidence of spontaneous TLS at screening, and were deemed as appropriate candidates for outpatient initiation of venetoclax plus HMA by the investigator. Patients received venetoclax in combination with azacitidine (75 mg/m2) or decitabine (20 mg/m2) for up to 6 cycles during the study. With a median time on study of 18.3 weeks, the best response rate of composite complete remission was 66.7%, and the overall post-baseline red blood cell (RBC) and platelet transfusion independence rate was 55.0%, consistent with results of studies in which treatment was initiated in an inpatient setting. Key adverse events included nausea, anemia, thrombocytopenia, neutropenia, and white blood cell count decrease of any grade (≥50% of patients). The observed safety profile was generally consistent with that of venetoclax plus HMA observed in inpatient AML studies. With close monitoring, 2 cases of TLS were identified, appropriately managed, and the patients were able to continue study treatment. CLINICAL TRIALS REGISTRATION: This study is registered at ClinicalTrials.gov. The registration identification number is NCT03941964.

Oral decitabine and cedazuridine plus venetoclax for older or unfit patients with acute myeloid leukaemia: a phase 2 study.

BACKGROUND: Hypomethylating agents combined with venetoclax are effective regimens in patients with acute myeloid leukaemia who are ineligible for intensive chemotherapy. Decitabine and cedazuridine (ASTX727) is an oral formulation of decitabine that achieves equivalent area-under-curve exposure to intravenous decitabine. We performed a single centre phase 2 study to evaluate the efficacy and safety of ASTX727 plus venetoclax. METHODS: This study enrolled patients with newly diagnosed (frontline treatment group) acute myeloid leukaemia who were ineligible for intensive chemotherapy (aged ≥75 years, an Eastern Cooperative Oncology Group [ECOG] performance status of 2-3, or major comorbidities) or relapsed or refractory acute myeloid leukaemia. Being aged 18 years or older and having an ECOG performance status of 2 or less were requirements for the relapsed or refractory disease treatment cohort, without any limits in the number of previous lines of therapy. Treatment consisted of ASTX727 (cedazuridine 100 mg and decitabine 35 mg) orally for 5 days and venetoclax 400 mg orally for 21-28 days in 28-day cycles. The primary outcome was overall response rate of ASTX727 plus venetoclax. Living patients who have not completed cycle one were not evaluable for response. Safety was analysed in all patients who started treatment. This study was registered on ClinicalTrials.gov (NCT04746235) and is ongoing. The data cutoff date for this analysis was Sept 22, 2023. FINDINGS: Between March 16, 2021, and Sept 18, 2023, 62 patients were enrolled (49 frontline and 13 relapsed or refractory) with a median age of 78 years (IQR 73-82). 36 (58%) were male; 53 (85%) were White, 4 (6%) Black, 2 (3%) Asian and 3 (5%) other or did not answer. 48 (77%) of 62 patients were European LeukemiaNet 2022 adverse risk, 24 (39%) had antecedent myelodysplastic syndromes, 12 (19%) had previously failed a hypomethylating agent, ten (16%) had therapy-related acute myeloid leukaemia, and 11 (18%) had TP53 mutations. The median follow-up time was 18·3 months (IQR 8·8-23·3). The overall response rate was 30 (64%) of 47 patients (95% CI 49-77) in frontline cohort and six (46%) of 13 patients (19-75) in relapsed or refractory cohort. The most common grade 3 or worse treatment-emergent adverse events were febrile neutropenia in 11 (18%) of 62 patients, pneumonia in eight (13%), respiratory failure in five (8%), bacteraemia in four (6%), and sepsis in four (6%). Three deaths occurred in patients in remission (one sepsis, one gastrointestinal haemorrhage, and one respiratory failure) and were potentially treatment related. INTERPRETATION: ASTX727 plus venetoclax is an active fully oral regimen and safe in most older or unfit patients with acute myeloid leukaemia. Our findings should be confirmed in larger multicentric studies. FUNDING: MD Anderson Cancer Center Support Grant, Myelodysplastic Syndrome/Acute Myeloid Leukaemia Moon Shot, Leukemia SPORE, Taiho Oncology, and Astex Pharmaceuticals.

Venetoclax with decitabine or azacitidine in relapsed or refractory acute myeloid leukemia.

Relapsed or refractory acute myeloid leukemia (AML) is associated with poor outcomes and resistance to therapy. The addition of venetoclax, a BCL-2 antagonist, to lower-intensity therapies results in improved survival in the first-line setting compared to monotherapy with a hypomethylating agent or low-dose cytarabine. Despite this, much remains unknown about the performance of venetoclax with a hypomethylating agent following the first-line setting. Additionally, while the ELN 2022 guidelines appear to improve the prognostication of AML, clarification is needed to determine how the revision applies to lower-intensity strategies. To investigate this, we retrospectively analyzed the performance of venetoclax with decitabine or azacitidine in relapsed or refractory AML under the ELN 2022 guidelines. We demonstrated that the ELN 2022 revision is not optimized for lower-intensity venetoclax-based strategies. To refine the prognostication schema, we showed significantly improved response and survival benefits for patients with mutated NPM1 and IDH. Relatively, patients with mutated NRAS, KRAS, and FLT3-ITD were associated with inferior response and survival. Furthermore, there is an unmet clinical need for tools to improve the selection of lower-intensity therapy candidates with borderline functional status. Using an incremental survival computation method, we discovered that a CCI score threshold of 5 distinguishes patients at an elevated risk of death. Together, these novel findings highlight areas of refinement to improve survival in relapsed or refractory AML.

Venetoclax combined with decitabine induced tumor lysis syndrome in a young patient with acute myeloid leukemia: a case report and literature review.

Venetoclax, in combination with hypomethylation agents (HMAs), is a novel treatment for leukemia patients with low chemotherapy tolerance. However, it has been reported to be a risk of causing tumor lysis syndrome (TLS) in chronic lymphocytic leukemia (CLL) and elderly acute myeloid leukemia (AML) patients. Here we report a rare case of a young adult AML patient who induced TLS after receiving a combination therapy of venetoclax with decitabine (DEC). A 36-year-old male patient presented with an unexplained fever and was diagnosed with AML-M5a. The patient was first treated with a combination of antibiotics, including voriconazole 300 mg Q12h. After the infection was relieved, he was treated with 100 mg venetoclax in combination with 75 mg/m 2 DEC. However, 12 h after the first treatment, he developed diarrhea, fatigue and other symptoms, and the laboratory results were consistent with the laboratory TLS. The patient stopped chemotherapy immediately, and TLS gradually improved after receiving rehydration, diuresis, dialysis and other treatments. Finally, the patient achieved complete remission. Based on the experience of this case and related studies, we recommend the prevention of TLS should not be limited to elderly patients taking venetoclax, and it is equally important in young patients. And reduce the dosage of venetoclax when using azole antifungal drugs.

Oral decitabine-cedazuridine versus intravenous decitabine for myelodysplastic syndromes and chronic myelomonocytic leukaemia (ASCERTAIN): a registrational, randomised, crossover, pharmacokinetics, phase 3 study.

BACKGROUND: The DNA methyltransferase inhibitors azacitidine and decitabine for individuals with myelodysplastic syndromes or chronic myelomonocytic leukaemia are available in parenteral form. Oral therapy with similar exposure for these diseases would offer potential treatment benefits. We aimed to compare the safety and pharmacokinetics of oral decitabine plus the cytidine deaminase inhibitor cedazuridine versus intravenous decitabine. METHODS: We did a registrational, multicentre, open-label, crossover, phase 3 trial of individuals with myelodysplastic syndromes or chronic myelomonocytic leukaemia and individuals with acute myeloid leukaemia, enrolled as separate cohorts; results for only participants with myelodysplastic syndromes or chronic myelomonocytic leukaemia are reported here. In 37 academic and community-based clinics in Canada and the USA, we enrolled individuals aged 18 years or older who were candidates to receive intravenous decitabine, with Eastern Cooperative Oncology Group performance status 0 or 1 and a life expectancy of at least 3 months. Participants were randomly assigned (1:1) to receive 5 days of oral decitabine-cedazuridine (one tablet once daily containing 35 mg decitabine and 100 mg cedazuridine as a fixed-dose combination) or intravenous decitabine (20 mg/m2 per day by continuous 1-h intravenous infusion) in a 28-day treatment cycle, followed by 5 days of the other formulation in the next treatment cycle. Thereafter, all participants received oral decitabine-cedazuridine from the third cycle on until treatment discontinuation. The primary endpoint was total decitabine exposure over 5 days with oral decitabine-cedazuridine versus intravenous decitabine for cycles 1 and 2, measured as area under the curve in participants who received the full treatment dose in cycles 1 and 2 and had decitabine daily AUC0-24 for both oral decitabine-cedazuridine and intravenous decitabine (ie, paired cycles). On completion of the study, all patients were rolled over to a maintenance study. This study is registered with ClinicalTrials.gov, NCT03306264. FINDINGS: Between Feb 8, 2018, and June 7, 2021, 173 individuals were screened, 138 (80%) participants were randomly assigned to a treatment sequence, and 133 (96%) participants (87 [65%] men and 46 [35%] women; 121 [91%] White, four [3%] Black or African-American, three [2%] Asian, and five [4%] not reported) received treatment. Median follow-up was 966 days (IQR 917-1050). Primary endpoint of total exposure of oral decitabine-cedazuridine versus intravenous decitabine was 98·93% (90% CI 92·66-105·60), indicating equivalent pharmacokinetic exposure on the basis of area under the curve. The safety profiles of oral decitabine-cedazuridine and intravenous decitabine were similar. The most frequent adverse events of grade 3 or worse were thrombocytopenia (81 [61%] of 133 participants), neutropenia (76 [57%] participants), and anaemia (67 [50%] participants). The incidence of serious adverse events in cycles 1-2 was 31% (40 of 130 participants) with oral decitabine-cedazuridine and 18% (24 of 132 participants) with intravenous decitabine. There were five treatment-related deaths; two deemed related to oral therapy (sepsis and pneumonia) and three to intravenous treatment (septic shock [n=2] and pneumonia [n=1]). INTERPRETATION: Oral decitabine-cedazuridine was pharmacologically and pharmacodynamically equivalent to intravenous decitabine. The results support use of oral decitabine-cedazuridine as a safe and effective alternative to intravenous decitabine for treatment of individuals with myelodysplastic syndromes or chronic myelomonocytic leukaemia. FUNDING: Astex Pharmaceuticals.

Efficacy and safety of an HDACi- and HMA-based protocol in adults with acute myeloid leukemia of intermediate- and adverse-risk categories: a retrospective study.

OBJECTIVE: Anthracyclines and cytarabine have comprised standard induction therapy for acute myeloid leukemia (AML) for decades. Low overall survival of AML is due to non-remission or relapse after remission. Hypomethylating agent (HMA) decitabine combined with low-dose chemotherapy or other targeted agents has shown promising effect for AML in clinical trials, especially in t(8;21) acute myeloid leukemia. We previously investigated histone deacetylase inhibitor (HDACi) chidamide could regulate Wnt/ß-catenin signaling pathway in leukemia cell lines. METHODS: Adult patients with de novo or relapsed/refractory AML who were treated with chidamide and decitabine in combination with chemotherapy (chidamide group, n = 23) or only decitabine combination with chemotherapy (decitabine group, n = 17) were analyzed. RESULTS: Chidamide group represented higher complete response rate (82.6% and 52.9%, p = 0.0430, vs. decitabine group), progression-free survival and overall survival rates (p = 0.0088 and p = 0.0139, respectively), especially for patients with de novo AML. Hematological toxicity and infections were the most common adverse events (AEs) in both groups, and they were manageable by supportive treatments. CONCLUSIONS: This HDACi- and HMA-based protocol is an effective and tolerable therapy for patients with AML. The comprehensive mechanism and effects of chidamide in combination with decitabine are worth to be further explored in AML.

A 7-Day Decitabine-Included Conditioning Regimen Accelerated Donor Hematopoietic Engraftment while Reduced the Occurrence of Mucositis without Interfering with Prognosis.

INTRODUCTION: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the standard and curative treatment strategy for patients with hematologic malignancies. Recently, decitabine-included regimens have been investigated by several studies including ours, which may prevent relapse of primary malignant diseases. METHODS: This study was to retrospectively evaluate a 7-day decitabine-included regimen with reduced dose of idarubicin for patients with hematologic malignancies who underwent allo-HSCT. RESULTS: A total of 84 patients were enrolled, including 24 cases in 7-day and 60 cases in 5-day decitabine groups, respectively. Patients conditioned with 7-day decitabine regimen showed accelerated neutrophil (12.05 ± 1.97 vs. 13.86 ± 3.15; u = 9.309, p < 0.001) and platelet (16.32 ± 6.27 vs. 21.37 ± 8.57; u = 8.887, p < 0.001) engraftment compared with those treated with 5-day decitabine regimen. Patients in the 7-day decitabine group showed a significantly lower incidence rate of total (50.00% [12/24] versus 78.33% [47/60]; χ2 = 6.583, p = 0.010) and grade III or above (4.17% [1/24] vs. 31.67% [19/60]; χ2 = 7.147, p = 0.008) oral mucositis compared to those in the 5-day decitabine group. However, the occurrence of other major complications post-allo-HSCT and outcomes of patients in these two groups were comparable. CONCLUSION: These results demonstrate that this 7-day decitabine-contained new conditioning regimen seems to be feasible and safe for patients with myeloid neoplasms who receive allo-HSCT, and a large-scale prospective study is needed to confirm the findings of this study.

Decitabine combined with RDHAP regimen in relapsed/refractory diffuse large B cell lymphoma.

BACKGROUND: There is an urgent need for effective treatment of patients with relapsed/refractory diffuse large B-cell lymphoma (R/R-DLBCL). This trial investigated the efficacy of decitabine in combination with rituximab, cisplatin, cytarabine, dexamethasone (RDHAP) in R/R-DLBCL. METHODS: 56 patients were divided into two groups (decitabine-RDHAP group. n = 35; RDHAP group, n = 21). The primary endpoints were the overall response rate (ORR) and duration of remission (DOR). Secondary objectives were toxicity, progression-free survival (PFS), and overall survival (OS). RESULTS: The ORR was 40% and 33% for decitabine-RDHAP and RDHAP groups, respectively, with no difference between the groups. The DOR for the decitabine-RDHAP regimen was higher than that for the RDHAP regimen (p = 0.044). After a median follow-up of 12.0 months, the median PFS and OS were 7.0 and 17.0 months for in the decitabine-RDHAP group and 5.0 and 9.0 months in the RDHAP group with no significant differences between the two groups (p = 0.47, 0.17). The incidence of adverse events was not significantly different between groups. CONCLUSION: The decitabine-RDHAP regimen is effective and well tolerated, and is a promising salvage regimen for R/R-DLBCL.

Hypomethylating agents combined with low-dose chemotherapy for elderly patients with acute myeloid leukaemia unfit for intensive chemotherapy: a real-world clinical experience.

This study aimed to assess the efficacy and safety of hypomethylating agent (HMA)-based regimens in the treatment of older adult patients with acute myeloid leukaemia (AML), unfit for standard induction chemotherapy. Treatment outcomes and prognostic factors of 140 older adult patients with AML who were unfit for intensive chemotherapy and were treated with HMA-based therapies were retrospectively analysed. The median age of the group was 70 years, and poor-risk cytogenetics and secondary/treatment-related AML (s/t-AML) accounted for 45.6% and 34.3% of these patients, respectively. The overall response rate was 48.6%, and 40.1% for patients who achieved complete remission (CR) or CR with incomplete blood count recovery. The median overall survival (OS) was 10.4 months, and the 1-, 2-, and 5-year OS rates were 42.6%, 19.9%, and 4.9%, respectively. Early mortality accounted for 4.3% of all cases, and infection occurred in 87.1% of all patients during induction therapy. Patients who received HMA and low-dose chemotherapy presented with significantly superior response and long-term survival rates compared to those who received HMA alone. They also showed comparable outcomes to those treated with the azacitidine plus venetoclax protocol. Low-dose chemotherapy in combination with decitabine or azacitidine showed a similar response rate and prognosis. Age ≥ 75years and a white blood cell (WBC) count ≥ 10 × 109 cells/L were identified as independent adverse prognostic factors for OS, while poor-risk cytogenetics, percentage of bone marrow blasts, and s/tAML had no significant impact on OS when patients were treated with HMA-based regimens. In conclusion, HMA combined with low-dose chemotherapy was effective and safe in older adults with AML who were unfit for intensive chemotherapy, and no difference was observed between decitabine and azacitidine.

Venetoclax and Hypomethylating Agents as First-line Treatment in Newly Diagnosed Patients with AML in a Predominately Community Setting in the US.

BACKGROUND: Treatment with venetoclax + hypomethylating agents (HMAs) is standard-of-care for newly diagnosed (ND) patients with acute myeloid leukemia (AML) aged ≥75 years, or with comorbidities precluding intensive chemotherapy. We describe real-world venetoclax + HMA treatment practices and outcomes in patients with ND AML in the US. PATIENTS AND METHODS: This retrospective cohort study used an electronic health record-derived, US nationwide, de-identified database, and included adults with ND AML, initiating venetoclax + HMA treatment ≤30 days from diagnosis (June 1, 2018-January 31, 2020). Venetoclax treatment variables included dosing information, schedule modifications, and drug-drug interactions. The median venetoclax + HMA treatment duration and overall survival (OS) from venetoclax initiation to discontinuation, death, or end of follow-up (August 31, 2020) were examined by Kaplan-Meier analyses. RESULTS: Overall, 169 patients were included. The median age at diagnosis was 77 years; 85.2% of patients were treated in community practice. Ninety-five of 169 patients (56.2%) had evaluable bone marrow response data following the start of treatment; 53.7% were assessed approximately at the end of cycle 1. Following the first treatment cycle, treatment schedule modifications were recorded in 101 patients and dose changes in 56, primarily due to toxicity. The median treatment duration was 5.2 months; the median OS was 8.6 months (median follow-up was 7.2 months). Venetoclax dose changes did not modify efficacy outcomes, but longer median OS was associated with venetoclax treatment schedule modifications (P = .02). CONCLUSIONS: This study reflects early real-world experience with venetoclax + HMAs in a predominantly community setting and emphasizes the importance of appropriate venetoclax management in optimizing patient outcomes.

Costs per patient achieving remission with venetoclax-based combinations in newly diagnosed patients with acute myeloid leukemia ineligible for intensive induction chemotherapy.

BACKGROUND: Venetoclax, in combination with azacitidine, decitabine, or low-dose cytarabine (LDAC), received confirmatory approval in 2020 by the US Food and Drug Administration for the treatment of newly diagnosed acute myeloid leukemia (AML) in patients aged 75 years or older or who are ineligible for intensive induction chemotherapy. The economic value associated with response to venetoclax combinations compared with other treatments for this patient population has not been comprehensively evaluated. OBJECTIVE: To assess the cost per patient achieving remission with venetoclax combination therapies, compared with other therapies for newly diagnosed patients with AML who are ineligible for intensive induction chemotherapy, from a US third-party payer perspective. METHODS: The analysis used treatment effect estimates (ie, complete remission [CR] + CR with incomplete blood count recovery [CRi]) from a network meta-analysis and annual cost estimates from a prior budget impact model. The model considered the total cost of care including the costs of drug and administration, adverse events, hospitalization, disease monitoring, blood transfusions, and subsequent AML management when patients discontinued active treatment. Costs per patient achieving CR + CRi associated with venetoclax + azacitidine, venetoclax + LDAC, azacitidine, decitabine, LDAC, and best supportive care (ie, treatment given with the intent to maximize quality of life without specific antileukemic intent, such as blood transfusion products and antibiotics) were calculated as the annual total cost of care per patient divided by the CR + CRi rate. All costs were adjusted to 2020 US dollars. RESULTS: Venetoclax combination therapies were estimated to have substantially lower costs per patient achieving CR + CRi (venetoclax + azacitidine: $473,960; venetoclax + LDAC: $428,071) than alternative treatments. Azacitidine was estimated to have the the highest cost per patient achieving CR + CRi ($1,197,438), followed by best supportive care ($869,849), LDAC ($689,101), and decitabine ($594,074). A pair-wise matrix of the difference between therapies estimated that both venetoclax + azacitidine and venetoclax + LDAC were associated with significantly lower costs per patient achieving CR + CRi than azacitidine (by $723,477 and $769,367, respectively) and LDAC (by $215,141 and $261,030; all P < 0.05). CONCLUSIONS: From a US third-party payer perspective, venetoclax in combination with azacitidine or LDAC was estimated to be associated with a significantly lower cost per patient achieving CR + CRi than azacitidine or LDAC among newly diagnosed patients with AML ineligible for intensive chemotherapy. DISCLOSURES: This research was supported by AbbVie Inc. and Genentech. The sponsors helped design the study, interpret the data, and draft the manuscript. Drs Bui and Kapustyan are employees of and have equity ownership in AbbVie; Dr Choi was an employee of AbbVie during the study's conduct and has equity ownership. Ms Ma and Dr Montez are employees of and have equity ownership in Genentech. Drs Song and Chai, Ms Yin, and Dr Betts are employees of Analysis Group, Inc., which has received funding from AbbVie and Genentech for the conduct of this research. Dr LeBlanc reports personal fees for consulting or advisory boards from AbbVie, Agios/Servier, AstraZeneca, Amgen, Astellas, BlueNote, CareVive, BMS/Celgene, Daiichi-Sankyo, Flatiron, Genentech, GSK, Pfizer, and Seattle Genetics; royalties from UpToDate; speakers bureau fees from Agios/Servier, AbbVie, and BMS/Celgene; and grants and/or research contracts from the American Cancer Society, AstraZeneca, BMS, Jazz Pharmaceuticals, and Seattle Genetics.

A real-world study of infectious complications of venetoclax combined with decitabine or azacitidine in adult acute myeloid leukemia.

PURPOSE: The purpose of this study was to identify the incidence, sites and main pathogens, and risk factors for infectious complications occurring in patients with adult acute myeloid leukemia (AML) during the first course of venetoclax combined with decitabine or azacitidine. METHODS: A retrospective cohort analysis was performed of 81 patients with AML older than 14 years who received the first cycle of venetoclax combined with a hypomethylating agent (HMA) between March 2018 and March 2021 at our institution. Infectious complications, if any, were documented. RESULTS: Among a total of 81 cases of AML, 59 (72.8%) patients occurred infections, including fever without an identifiable source (28.8%), clinically documented infections (40.7%), and microbiologically documented infections (30.5%). The most commonly isolated organism in culture was Candida albicans, followed by Klebsiella pneumonia, and Pseudomonas aeruginosa. The 4-week and 8-week mortality rates were 3.7% and 7.4%, respectively. In multivariate analysis, a high proportion of blasts in bone marrow, decreased hemoglobin level, and fever with or without a documented infection at baseline were significant independent risk factors for infectious complications. CONCLUSION: Compared with conventional chemotherapy, the incidence of infectious complications of venetoclax combined with decitabine or azacitidine significantly decreased. Pretreatment high leukemia burden and fever were independent risk factors for infections.

FDA Approval Summary: Decitabine and Cedazuridine Tablets for Myelodysplastic Syndromes.

On July 7, 2020, the Food and Drug Administration approved Inqovi (Otsuka Pharmaceutical Co.), an oral fixed-dose combination tablet comprising 35 mg decitabine, a hypomethylating agent, and 100 mg cedazuridine, a cytidine deaminase inhibitor (abbreviated DEC-C) for treatment of adult patients with myelodysplastic syndromes (MDS). Evidence of effectiveness of DEC-C was established in phase III ASTX727-02 (N = 133) in adults with MDS. The study involved a two-sequence crossover comparing DEC-C and intravenous (IV) decitabine 20 mg/m2 once daily for the first 5 days of each 28-day cycle in the first 2 cycles. From cycle 3 onward, patients received DEC-C. Five-day cumulative area under the curve (5-d AUC) of decitabine for DEC-C was similar to that of IV decitabine, with geometric mean ratio 0.99 (90% confidence interval: 0.93-1.06). Clinical benefit was supported by study ASTX727-02 and the similarly designed phase II study ASTX727-01-B (n = 80), with complete remission (CR) of 21% and 18% and median duration of CR 7.5 and 8.7 months, respectively. Adverse reactions were consistent with IV decitabine. Postmarketing assessments were issued to address the effect of cedazuridine on QT prolongation, food effect, moderate and severe hepatic impairment, and severe renal impairment on the pharmacokinetics and safety of DEC-C.

A phase II study of sequential decitabine and rapamycin in acute myelogenous leukemia.

A phase II study was conducted to ascertain whether sequential exposure to decitabine followed by rapamycin, an mTOR (mechanistic target of rapamycin) inhibitor would result in better responses than decitabine alone. Newly diagnosed acute myelogenous leukemia (AML) patients who were >65 years old and not eligible for intensive induction regimens or patients with relapsed or refractory AML received 10 days of decitabine followed by 12 days of rapamycin in cycle 1 and 5 days of decitabine followed by 17 days of rapamycin in subsequent cycles. The composite complete remission rate (CR) was 33 % (CR plus CR with incomplete count recovery). Median overall survival was 7.7 months in newly diagnosed elderly AML patients and 6.6 months in relapsed/refractory AML patients. Twenty-four evaluable patients were enrolled, and the study did not meet its primary endpoint of demonstrating a significant improvement in composite CR rate with the combination as compared to an established historical CR rate of 25 % with decitabine alone. Despite that, the survival rates in relapsed/refractory cases appear comparable to what is reported with other salvage regimens, and no significant patterns of non-hematologic toxicity were noted. 50 % of subjects in the de novo group achieved a composite CR which is significantly higher (p = 0.02) than the rate of 25 % with decitabine alone. This trial is registered at clinical trials.gov as NCT02109744.

Outcomes of TP53-mutant acute myeloid leukemia with decitabine and venetoclax.

BACKGROUND: TP53 mutation (TP53mut ) confers an adverse prognosis in acute myeloid leukemia (AML). Venetoclax with hypomethylating agents is a current standard for older patients; however, recent reports suggest that TP53mut confers resistance to venetoclax. The authors investigated the outcomes of patients with TP53mut AML who were treated with a 10-day decitabine and venetoclax (DEC10-VEN) (ClinicalTrials.gov identifier NCT03404193). METHODS: Patients with newly diagnosed AML received decitabine 20 mg/m2 for 10 days every 4 to 6 weeks for induction, followed by decitabine for 5 days after response. The venetoclax dose was 400 mg daily. TP53mut was identified in bone marrow samples using next-generation sequencing, with sensitivity of 5%. Outcomes were analyzed according to European LeukemiaNet 2017 guidelines. RESULTS: Among 118 patients (median age, 72 years; age range, 49-89 years), 63 (53%) had secondary AML, 39 (33%) had AML with complex karyotype, and 35 (30%) had TP53mut AML. The median TP53 variant allele frequency was 32% (interquartile range, 16%-65%), 8 patients (23%) had only a single TP53 mutation, 15 (43%) had multiple mutations, and 12 (34%) had mutation and deletion. Outcomes were significantly worse in patients who had TP53mut AML compared with those who had wild-type TP53 AML, with an overall response rate of 66% vs 89% (P = .002), a complete response/complete response with incomplete hematologic recovery rate of 57% vs 77% (P = .029), and a 60-day mortality of 26% vs 4% (P < .001), respectively. Patients with TP53mut versus wild-type TP53 had shorter overall survival at 5.2 versus 19.4 months, respectively (hazard ratio, 4.67; 95% CI, 2.44-8.93; P < .0001), and shorter relapse-free survival at 3.4 versus 18.9 months (hazard ratio, 4.80; 95% CI, 1.97-11.69; P < .0001), respectively. Outcomes with DEC10-VEN in patients with TP53mut AML were comparable to historical results with 10-day decitabine alone. CONCLUSIONS: Patients with TP53mut AML have lower response rates and shorter survival with DEC10-VEN.

Predictive Value of High ICAM-1 Level for Poor Treatment Response to Low-Dose Decitabine in Adult Corticosteroid Resistant ITP Patients.

Primary immune thrombocytopenia (ITP) is an autoimmune hemorrhagic disease. Endothelial cell activation/injury has been found in some autoimmune diseases including SLE, systemic sclerosis, and rheumatoid arthritis, but its role in ITP pathogenesis remains unclear. This study attempted to elucidate the correlation between endothelial dysfunction and disease severity of ITP and find related markers to predict response to low-dose decitabine treatment. Compared with healthy volunteers, higher plasma levels of soluble intercellular adhesion molecule-1 (ICAM-1), vascular endothelial growth factor (VEGF), and Angiopoietin-2 were found in adult corticosteroid resistant ITP patients. Notably, ICAM-1 levels were negatively correlated with the platelet count, and positively associated with the bleeding score. Recently, we have reported the efficacy and safety of low-dose decitabine in adult patients with ITP who failed for the first line therapies. Here, we evaluated the correlation of plasma ICAM-1 level with the efficacy of low-dose decitabine therapy for corticosteroid resistant ITP. A total of 29 adult corticosteroid resistant ITP patients who received consecutive treatments of low-dose decitabine were enrolled in this study. Fourteen patients showed response (nine showed complete response and five showed partial response). The levels of ICAM-1 before and after treatment were significantly higher in the non-responsive ITP patients than in the responsive patients. As shown in the multivariable logistic regression model, the odds of developing no-response to low-dose decitabine increased by 36.8% for per 5 ng/ml increase in plasma ICAM-1 level [odds ratio (OR) 1.368, 95% confidence interval (CI): 1.060 to 1.764]. In summary, this was the first study to elucidate the relationship between endothelial dysfunction and corticosteroid resistant ITP and identify the potential predictive value of ICAM-1 level for response to low-dose decitabine.

Low-dose decitabine plus venetoclax is safe and effective as post-transplant maintenance therapy for high-risk acute myeloid leukemia and myelodysplastic syndrome.

Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are usually associated with poor outcomes, especially in high-risk AML/MDS. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative option for patients suffering from high-risk AML/MDS. However, many patients relapse after allo-HSCT. Novel therapy to prevent relapse is urgently needed. Both the BCL-2 inhibitor venetoclax (VEN) and the hypomethylating agent decitabine (DEC) possess significant antitumor activity effects against AML/MDS. Administration of DEC has been shown to ameliorate graft-versus-host disease (GVHD) and boost the graft-versus-leukemia (GVL) effect post-transplantation. We therefore conducted a prospective study (ChiCTR1900025374) to examine the tolerability and efficacy of a maintenance therapy of low-dose decitabine (LDEC) plus VEN to prevent relapse after allo-HSCT for high-risk AML/MDS patients. Twenty patients with high-risk AML (n = 17) or high-risk MDS (n = 3) post-transplantation were recruited. Approximately day 100 post-transplantation, all patients received LDEC (15 mg/m2 for 3 d) followed by VEN (200 mg) on d 1-21. The cycle interval was 2 mo, and there was 10 cycles. The primary end points of this study were rates of overall survival (OS) and event-free survival (EFS). The secondary endpoints included adverse events (AEs), cumulative incidence of relapse (CIR), nonrelapse mortality (NRM), incidences of acute GVHD (aGVHD) and chronic GVHD (cGVHD), and incidences of viral infection after allo-HSCT. Survival outcomes were assessed using Kaplan-Meier analysis. The median follow-up was 598 (149-1072) d. Two patients relapsed, 1 died, and 1 is still alive after the second transplant. The 2-y OS and EFS rates were 85.2% and 84.7%, respectively. The median 2-y EFS time was 525 (149-1072) d, and 17 patients still had EFS and were alive at the time of this writing. The most common AEs were neutropenia, anemia, thrombocytopenia, neutropenic fever, and fatigue. Grade 2 or 3 AEs were observed in 35% (7/20) and 20% (4/20) of the patients, respectively. No grade >3 AEs were observed. aGVHD (any grade) and cGVHD (limited or extensive) occurred in 55% and 20% of patients, respectively. We conclude that LDEC + VEN can be administered safely after allo-HSCT with no evidence of an increased incidence of GVHD, and this combination decreases the relapse rate in high-risk AML/MDS patients. This novel maintenance therapy may be a promising way to prevent relapse in high-risk AML/MDS patients.

Improved clinical outcome in a randomized phase II study of anti-PD-1 camrelizumab plus decitabine in relapsed/refractory Hodgkin lymphoma.

BACKGROUND: Programmed death-1 (PD-1) blockade monotherapy induced durable remission in a subset of patients with relapsed/refractory classical Hodgkin lymphoma (cHL). We asked whether the anti-PD-1 agent, camrelizumab, combined with the DNA demethylating agent, decitabine, improves progression-free survival (PFS) in patients with relapsed/refractory cHL over camrelizumab alone. METHODS: This extended follow-up of an ongoing randomized phase II trial analyzed PFS among patients enrolled from January 2017 through July 2018. Sixty-one patients with relapsed/refractory cHL who were clinically naïve to PD-1 blockade and had received ≥2 previous therapies were randomized 1:2 to receive either camrelizumab (200 mg) monotherapy or camrelizumab (200 mg, day 8) combined with decitabine (10 mg/day, days 1-5) every 3 weeks. RESULTS: With a median follow-up of 34.5 months, complete remission was 79% (95% CI 63% to 90%) in the decitabine-plus-camrelizumab group versus 32% (95% CI 13% to 57%) in the camrelizumab group (p=0.001). Median duration of response was not reached in the decitabine-plus-camrelizumab group, with an estimated 63% (95% CI 46% to 75%) of patients maintaining a response at 24 months. Median PFS with decitabine-plus-camrelizumab therapy was 35.0 months (95% CI not reached) and 15.5 months (95% CI 8.4 to 22.7 months) with camrelizumab monotherapy (HR, 0.46; 95% CI 0.21 to 1.01; p=0.02). Female gender, lower tumor burden, and fewer previous therapies were favorable prognostic factors for durable remission with camrelizumab monotherapy. The PFS benefits of decitabine-plus-camrelizumab versus camrelizumab were observed in most subgroups, especially in patients with relative larger tumor burdens and those treated with ≥3 prior therapies. After decitabine-plus-camrelizumab treatment, the percentage increase of circulating peripheral central memory T-cells correlated with both improved clinical response and PFS, suggesting a putative biomarker of decitabine-plus-camrelizumab therapy for cHL. CONCLUSIONS: Decitabine-plus-camrelizumab results in longer PFS compared with camrelizumab alone in patients with relapsed/refractory cHL. TRIAL REGISTRATION NUMBERS: NCT02961101 and NCT03250962.

The path to approval for oral hypomethylating agents in acute myeloid leukemia and myelodysplastic syndromes.

Two oral hypomethylating agents, oral azacitidine (CC-486) and decitabine/cedazuridine (ASTX727), have recently entered the clinical domain. CC-486 has been shown to improve overall survival as maintenance therapy for older patients with acute myeloid leukemia in complete remission, whereas the combination of decitabine with cedazuridine, a cytidine deaminase inhibitor, is indicated for the treatment of adult patients with myelodysplastic syndromes and chronic myelomonocytic leukemia with intermediate-1, or higher, International Prognostic Scoring System risk. This article briefly summarizes the clinical development of both drugs, the pivotal studies that led to their approval and some of the issues faced in extending the use of these drugs to other indications.

Lay abstract One of the key challenges in treating acute myeloid leukemia is to prevent relapse after remission has been achieved. This means that developing an effective maintenance treatment is very important. Maintenance treatment is given for a prolonged period and so it needs to be easy to give and well tolerated. Oral azacitidine is an example of this type of treatment and is the first drug that has been shown to improve survival as maintenance therapy for acute myeloid leukemia patients. This article describes the key studies that led to the approval of this important therapy.