Midostaurin: Nursing Perspectives on Managing Treatment and Adverse Events in Patients With FLT3 Mutation–Positive Acute Myeloid Leukemia and Advanced Systemic Mastocytosis

Background: Acute myeloid leukemia (AML) and myelodysplasia (MDS) are usually associated with poor outcomes, especially in high-risk AML/MDS. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curable option for patients suffering from high-risk AML/MDS. However, there were still many patients relapsed after allo-HSCT, especially for some patients are MRD positive before transplantation. Novel therapy to prevent replase is urgently needed. Both BCL-2 inhibitor, venetoclax (VEN) and hypomethylating agent, decitabine (DEC) possess significant antitumor activity effects against AML/MDS. Administration DEC has been shown to ameliorate GVHD and boost GVL post-transplantation. Several clinical trials have also shown that venetoclax plus decitabine can be a safety and effective salvage treatment for patients with AML/MDS relapsing after allo-HSCT. We therefore conducted a prospective study (ChiCTR1900025374) to exam the tolerability and efficacy of a maintenance therapy low-dose decitabine (LDEC) plus VEN to prevent relapse after allo-HSCT for MRD positive high-risk AML/MDS patients. To our knowledge, this is the first report of venetoclax combined decitabine in this setting. Methods: Six patients with MRD positive high-risk AML (n=5) /MDS(n=1) post transplantation were recruited. Around day 100 post transplantation, all patients received LDEC (15mg/m2 for 3 days) followed by VEN (200mg) on day 1 to 21. Two months is a cycle. 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), incidence of 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 analyzed using Kaplan-Meier analysis Results: Two of the six patients were partial remission (PR) before transplantation, and the remaining 4 patients were MRD+ before transplantation. The median follow-up was 16 (11-26.5) months. Both 2-year OS and 2-year EFS were 83%. The median 2-year EFS time was 16(9-26.5) months, and five patients still EFS alive at the time of this writing. The 2-year cumulative incidence of relapse after LDEC+VEN was 17% and 2-year non-relapse mortality was 0%. No tumor lysis syndrome (TLS) was observed. The most common AEs were neutropenia, anemia, thrombocytopenia, neutropenic fever, and fatigue. Grade 2 or 3 adverse events were observed in 33% (2/6). No grade>3 AEs were observed. Acute (any grade) and chronic (limited or extensive) graft-versus-host disease occurred in 67% and 17% of patients, respectively. The 2-year cumulative incidence of CMV viremia and EBV viremia were 33.3% and 16.7%, respectively. Conclusion: We conclude LDEC+VEN can be administered safely after allo-HSCT, without evidence for increased incidence of GVHD, and this combination demonstrates decreased relapse for MRD positive high-risk AML/MDS patients. This novel maintenance therapy may be a promising way to prevent replase for MRD positive high-risk AML/MDS patients, and the clinical benefits need to be assessed in a comparative prospective trial. Figure Disclosures No relevant conflicts of interest to declare.

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Stone RM, Manley PW, Larson RA, Capdeville R. Midostaurin: its odyssey from discovery to approval for treating acute myeloid leukemia and advanced systemic mastocytosis. Blood Adv. 2018;2(4):444-453.

Blood Advances ◽

10.1182/bloodadvances.2018018481 ◽

2018 ◽

Vol 2 (7) ◽

pp. 787-787 ◽

Cited By ~ 1

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Systemic Mastocytosis ◽

Acute Myeloid

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Venetoclax for the treatment of newly diagnosed acute myeloid leukemia in patients who are ineligible for intensive chemotherapy

Therapeutic Advances in Hematology ◽

10.1177/2040620719882822 ◽

2019 ◽

Vol 10 ◽

pp. 204062071988282 ◽

Cited By ~ 10

Author(s):

Guillaume Richard-Carpentier ◽

Courtney D. DiNardo

Keyword(s):

Clinical Trials ◽

Acute Myeloid Leukemia ◽

Adverse Events ◽

B Cell ◽

Drug Administration ◽

Myeloid Leukemia ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Intensive Chemotherapy ◽

Acute Myeloid

Acute myeloid leukemia (AML) is an aggressive hematological malignancy with a globally poor outcome, especially in patients ineligible for intensive chemotherapy. Until recently, therapeutic options for these patients included low-dose cytarabine (LDAC) or the hypomethylating agents (HMA) azacitidine and decitabine, which have historically provided only short-lived and modest benefits. The oral B-cell lymphoma 2 inhibitor, venetoclax, Venetoclax, an oral B-cell lymphoma 2 (BCL2) inhibitor, is now approved by the USA Food and Drug Administration (FDA) in combination with LDAC or HMA in older AML patients ineligible for intensive chemotherapy. Is now approved by the US Food and Drug Administration for this indication. In the pivotal clinical trials evaluating venetoclax either in combination with LDAC or with HMA, the rates of complete remission (CR) plus CR with incomplete hematological recovery were 54% and 67%, respectively and the median overall survival (OS) was 10.4 months and 17.5 months, respectively, comparing favorably with outcomes in clinical trials evaluating single-agent LDAC or HMA. The most common adverse events with venetoclax combinations are gastrointestinal symptoms, which are primarily low grade and easily manageable, and myelosuppression, which may require delays between cycles, granulocyte colony-stimulating factor (G-CSF) administration, or decreased duration of venetoclax administration per cycle. A bone marrow assessment after the first cycle of treatment is critical to determine dosing and timing of subsequent cycles, as most patients will achieve their best response after one cycle. Appropriate prophylactic measures can reduce the risk of venetoclax-induced tumor lysis syndrome. In this review, we present clinical data from the pivotal trials evaluating venetoclax-based combinations in older patients ineligible for intensive chemotherapy, and provide practical recommendations for the prevention and management of adverse events associated with venetoclax.

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A systematic review and meta-analysis of the efficacy and adverse events of azacitidine-plus-lenalidomide treatment for patients with acute myeloid leukemia, myelodysplastic syndromes and chronic myelomonocytic leukemia

Hematology ◽

10.1080/16078454.2019.1631425 ◽

2019 ◽

Vol 24 (1) ◽

pp. 498-506 ◽

Cited By ~ 1

Author(s):

Chutima Kunacheewa ◽

Pakaporn Thongthang ◽

Patompong Ungprasert ◽

Eakkapol Utchariyaprasit ◽

Weerapat Owattanapanich

Keyword(s):

Systematic Review ◽

Acute Myeloid Leukemia ◽

Adverse Events ◽

Myelodysplastic Syndromes ◽

Myeloid Leukemia ◽

Meta Analysis ◽

Chronic Myelomonocytic Leukemia ◽

Myelomonocytic Leukemia ◽

Acute Myeloid

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Mutant Isocitrate Dehydrogenase 1 Inhibitor Ivosidenib in Combination With Azacitidine for Newly Diagnosed Acute Myeloid Leukemia

Journal of Clinical Oncology ◽

10.1200/jco.20.01632 ◽

2021 ◽

Vol 39 (1) ◽

pp. 57-65

Author(s):

Courtney D. DiNardo ◽

Anthony S. Stein ◽

Eytan M. Stein ◽

Amir T. Fathi ◽

Olga Frankfurt ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Complete Remission ◽

Adverse Events ◽

Isocitrate Dehydrogenase ◽

Myeloid Leukemia ◽

Qt Prolongation ◽

Newly Diagnosed ◽

Isocitrate Dehydrogenase 1 ◽

Grade 3 ◽

Acute Myeloid

PURPOSE Ivosidenib is an oral inhibitor of the mutant isocitrate dehydrogenase 1 (IDH1) enzyme, approved for treatment of IDH1-mutant (m IDH1) acute myeloid leukemia (AML). Preclinical work suggested that addition of azacitidine to ivosidenib enhances mIDH1 inhibition–related differentiation and apoptosis. PATIENTS AND METHODS This was an open-label, multicenter, phase Ib trial comprising dose-finding and expansion stages to evaluate safety and efficacy of combining oral ivosidenib 500 mg once daily continuously with subcutaneous azacitidine 75 mg/m2 on days 1-7 in 28-day cycles in patients with newly diagnosed m IDH1 AML ineligible for intensive induction chemotherapy (ClinicalTrials.gov identifier: NCT02677922 ). RESULTS Twenty-three patients received ivosidenib plus azacitidine (median age, 76 years; range, 61-88 years). Treatment-related grade ≥ 3 adverse events occurring in > 10% of patients were neutropenia (22%), anemia (13%), thrombocytopenia (13%), and electrocardiogram QT prolongation (13%). Adverse events of special interest included all-grade IDH differentiation syndrome (17%), all-grade electrocardiogram QT prolongation (26%), and grade ≥ 3 leukocytosis (9%). Median treatment duration was 15.1 months (range, 0.3-32.2 months); 10 patients remained on treatment as of February 19, 2019. The overall response rate was 78.3% (18/23 patients; 95% CI, 56.3% to 92.5%), and the complete remission rate was 60.9% (14/23 patients; 95% CI, 38.5% to 80.3%). With median follow-up of 16 months, median duration of response in responders had not been reached. The 12-month survival estimate was 82.0% (95% CI, 58.8% to 92.8%). m IDH1 clearance in bone marrow mononuclear cells by BEAMing (beads, emulsion, amplification, magnetics) digital polymerase chain reaction was seen in 10/14 patients (71.4%) achieving complete remission. CONCLUSION Ivosidenib plus azacitidine was well tolerated, with an expected safety profile consistent with monotherapy with each agent. Responses were deep and durable, with most complete responders achieving m IDH1 mutation clearance.

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