Beyond Survival: The US Food and Drug Administration Confirms Surrogate End Points for Patients With Newly Diagnosed Acute Myeloid Leukemia Treated With Intensive Chemotherapy

Midostaurin is a tyrosine multikinase inhibitor approved for the treatment of patients with newly diagnosed acute myeloid leukemia (AML) with mutated Fms-like tyrosine kinase-3. We describe a case report of a 49-year-old AML patient treated with an intensive chemotherapy regimen followed by midostaurin. After achieving complete remission with blood count recovery, he suffered from a serious, rare complication of necrotizing hemorrhagic gastritis with no evidence of infection or malignant infiltration, possibly associated with midostaurin therapy.

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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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Gemtuzumab ozogamicin for acute myeloid leukemia

Blood ◽

10.1182/blood-2017-09-797712 ◽

2017 ◽

Vol 130 (22) ◽

pp. 2373-2376 ◽

Cited By ~ 62

Author(s):

Frederick R. Appelbaum ◽

Irwin D. Bernstein

Keyword(s):

Acute Myeloid Leukemia ◽

Initial Treatment ◽

Myeloid Leukemia ◽

Gemtuzumab Ozogamicin ◽

Newly Diagnosed ◽

Antibody Drug Conjugate ◽

The Us ◽

Human Use ◽

Acute Myeloid ◽

Antibody Drug

Abstract On 1 September 2017, the US Food and Drug Administration (FDA) approved gemtuzumab ozogamicin (GO) for the treatment of adults with newly diagnosed CD33+ acute myeloid leukemia and for patients aged ≥2 years with CD33+ acute myeloid leukemia who have experienced a relapse or who have not responded to initial treatment. This signals a new chapter in the long and unusual story of GO, which was the first antibody–drug conjugate approved for human use by the FDA.

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Phase I Study of Clofarabine (JC0707) in Adult Japanese Patients with Acute Myeloid Leukemia (AML)

Blood ◽

10.1182/blood.v118.21.4295.4295 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4295-4295

Author(s):

Takahiro Yamauchi ◽

Tatsuya Suzuki ◽

Kiyoshi Ando ◽

Tadashi Nagai ◽

Kazuhiko Kakihana ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Phase I ◽

Myeloid Leukemia ◽

The United States ◽

World Health ◽

Plasma Samples ◽

Newly Diagnosed ◽

The Us ◽

Grade 3 ◽

Acute Myeloid

Abstract Abstract 4295 Background and Purpose: Although cytarabine plus anthracycline (7+3 or 7+5) regimens are commonly used for induction therapy in patients (pts) with acute myeloid leukemia (AML) and there have been improvements in the treatment of AML in younger adults, there is no standard of care in pts with relapsed or refractory (R/R) AML. Treatment options for older pts and those with R/R disease remain limited. Clofarabine (JC0707) is a purine nucleoside analog approved in the United States (US) and European Union for the treatment of pediatric pts with R/R acute lymphocytic leukemia (ALL). In a phase II study from the US, single-agent clofarabine showed activity and acceptable toxicity in pts ≥ 60 years with untreated AML and adverse prognostic factors (Kantarjian, J Clin Oncol 2010;28:549–55). The purpose of this phase I open-label, multi-center study is to assess the safety, tolerability, and pharmacokinetics of clofarabine monotherapy in elderly Japanese pts with newly diagnosed AML for whom standard induction chemotherapy is unlikely to be of benefit or Japanese adult pts with R/R AML. Method: Adult pts (20–74 years) with R/R AML according to World Health Organization (WHO) criteria and elderly pts (60–74 years) with newly diagnosed AML were eligible to participate. Additional inclusion criteria included Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 and no prior hematopoietic stem cell transplant. The study utilized a standard 3 + 3 dose escalation method; 3 pts enrolled in each dosing cohort, 3 additional pts were added to cohorts where dose-limiting toxicities (DLTs) were observed. The maximum tolerated dose (MTD) was defined as the dose level below that for which 2 DLTs were observed. Based on prior clinical trials in the US, pts were to be treated with clofarabine 20 mg/m2/day (IV over 1 hr), 30 mg/m2/day, or 40 mg/m2/day for one 5 day cycle in cohorts 1, 2 and 3, respectively. Pts with evidence of hematologic response after one cycle could receive up to a maximum of 3 cycles. The primary endpoints of this study were MTD, safety, and pharmacokinetic (PK) parameters. Result: Until June 2011, 14 pts were enrolled and treated in this trial: cohort 1 (n=3), cohort 2 (n=6), and cohort 3 (n=5). Bioanalytical determination of clofarabine concentrations in plasma samples showed an increased concentration with increased dosage. No DLTs were noted in cohort 1 (20 mg/m2). Among the first 3 pts in cohort 2 (30 mg/m2), only 1 patient experienced DLT (reversible, grade 4 elevated ALT). Additionally, 2 pts in cohort 3 (40 mg/m2) experienced DLTs (grade 3 elevated ALT [n=1]; grade 3 elevated amylase [n=1]). Thus, the MTD was determined to be 30 mg/m2. Preliminary safety and efficacy data are available for 9 of these pts and presented herein. Overall, the most common all cause, non-hematologic toxicities were nausea and headache (89% each), rash and elevated ALT and AST (78% each), malaise (56%), pneumonia and hypokalemia (44% each), and elevated bilirubin and vomiting (33% each). Grade 3 or 4 toxicities were primarily hematologic and infectious occurring in 89% and 67% of patients, respectively. Only one patient developed a treatment-related serious adverse event (SAE) (herpes zoster). There were no AE related deaths and no patients discontinued therapy as a result of an AE. Two patients achieved complete remission (CR) and 2 patients achieved CR without platelet recovery (CRp), for an overall response rate (ORR) of 44% (Table 1). Additionally, plasma samples were obtained from all patients for PK evaluation; plasma concentration data from all 14 patients will be presented. Conclusion: Clofarabine monotherapy was well tolerated at doses up to 30mg/m2 and showed preliminary evidence of activity with 44% ORR in elderly newly diagnosed AML or adult Japanese pts with R/R AML, warranting further investigations. Disclosures: Off Label Use: Clofarabine (JC0707) is an investigational agent in Japan; this abstract assesses its use in adult AML patients. Ewesuedo:Sanofi Oncology: Employment. Tabata:Genzyme (a Sanofi company): Employment.

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A Real World Study of Venetoclax Combined with Azacitidine in 64 Chinese Patients Newly Diagnosed Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2021-149523 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4414-4414

Author(s):

Jiejing Qian ◽

Jieyu Xu ◽

Qing Hong ◽

Yinjun Lou ◽

Liping Mao ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Adverse Events ◽

Myeloid Leukemia ◽

Conflicts Of Interest ◽

Univariate Analysis ◽

Chinese Patients ◽

Combination Regimen ◽

Intensive Chemotherapy ◽

Newly Diagnosed ◽

Acute Myeloid

Abstract Background: Venetoclax combined with azacitidine has been demonstrated to have a favorable overall response rate and tolerable safety in acute myeloid leukemia (AML) patients who are unfit for intensive chemotherapy. Methods: This study retrospectively recruited 64 Adults (≥18 years) with newly diagnosed AML ineligible for intensive chemotherapy who had received at least one cycle of treatment with venetoclax plus azacitidine. The primary endpoint was overall survival (OS). Secondary endpoints were remission rates. Safety was evaluated based on the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. Results: The median age of the enrolled patients was 69 years. The median OS for the cohort was 15.5 months, with 21.2 months for complete responders as opposed to 13.3 months for those who did not achieve a complete response. 39 (60.9%) patients achieved composite complete remission (complete remission (CR) + CR with incomplete count recovery (CRi)) and 7/64 (10.9%) achieved morphologic leukemia-free state (MLFS) with a median follow-up time of 14.7 months. The median CR+CRi duration was 10.9 months. It is noteworthy that 43/64 (67.2%) patients achieved the best response after one cycle with a median time of 1.2 months. Normal karyotype (P=0.015) was significantly associated with extended OS in multivariate analysis, while higher white blood cell count (P=0.032), lower platelet count (p=0.018) and antifungal drug combination (P=0.013) were predictors of shortened OS in univariate analysis. Common grade 3/4 Adverse Events (AEs) included infection (68%) and hematological AEs consisting of neutropenia (93%), anemia (90%), leukopenia (86%), thrombocytopenia (77%) and febrile neutropenia (52%). The median neutropenia duration was 16 days. Conclusions: The novel venetoclax-azacitidine combination regimen showed prolonged survival period, promising efficacy, sound and rapid response, and superior tolerance in Chinese patients newly diagnosed AML. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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