First Reported Case Series of Combined Treatment with CLAG and Venetoclax for Acute Myeloid Leukemia (AML)

Author Type(s)

Faculty

Document Type

Abstract

Publication Date

11-15-2022

Journal Title

Blood

Department

Medicine

Abstract

Background: Since the 1970s, the standard of care for patients with AML has been a "7+3" induction regimen consisting of 7 days of cytarabine and 3 days of anthracycline. CLAG has been demonstrated to be effective in patients with newly diagnosed, high-risk AML. Venetoclax is a Bcl2 inhibitor FDA approved to treat AML in elderly patients in combination with hypomethylating agents. Here we describe two patients who received both CLAG and venetoclax to treat R/R AML. Both patients were heavily treated (unsuccessfully), and this novel combination therapy was administered near the end of their treatment.

Patient #1 was a 54 year old female with AML. Genetic analysis revealed a FLT3-ITD mutation. Patient was treated with cytarabine 3mg/m2 x 5 and mitoxantrone 60 mg/m2 on day 1 of cycle 1. She went into morphologic remission and then received 2 cycles of HIDAC. Unfortunately, patient relapsed 5 months after starting chemotherapy, thus was not a candidate for allo-SCT. At relapse, the patient had mutations of FLT3-ITD, DNMT3A, NPM1, and WT1. The patient was then treated with CLAG -Idarubicin. Venetoclax was added on day 3 of the cycle, in combination to the CLAG regimen, and she received the venetoclax for 7 days (titrated on day 1 at 50 mg, then 100 mg on day 2, and 200 mg for the next 5 days). She also received midostaurin starting day 6 of the CLAG cycle at a dose of 50 mg and received it for 14 days.

Patient #2 was a 71 year old female with AML. Patient Karyotype was 45, XX, add(5)(q11), der(6;7)(p10;q10)[20]. Analysis did not detect a targetable mutation, but an NRAS mutation was detected. The patient began cycle 1 of CLAG-Ida, and on day 23 bone marrow biopsy showed myeloid hyperplasia without increased blasts. The patient then received two more cycles of CLAG-Ida at approximate 1 month intervals. 4 months after diagnosis, the patient underwent an allo-SCT. Patient developed skin lesions and on day +96 biopsy revealed leukemia cutis. Bone marrow biopsy showed no morphologic evidence of AML but abnormal karyotype was noted 45,XX,del(5)(q13q33), dic(6;7)(q11;p11.2)[4]/46,XX[16]. On day +103 the patient began decitabine-venetoclax 200 mg. She received 2 more cycles of decitabine-venetoclax. A right axillary lymph node biopsy was done day on day +238 and showed an abnormal immature population expressing CD34, CD117, MPO, CD4, and CD56. Patient then started on GO 4.5mg and then HIDAC. Patient did not respond to these regiments and received CLAG and Venetoclax starting day +307. She completed this cycle but progressed further. She then received hydrea. This was followed by vyxeos on day+357. Patient did not respond and elected to go to hospice; she died day+381 post SCT.

Discussion: To our knowledge, this is the first reported case series of concomitant treatment with CLAG and Venetoclax. During the literature review, we looked at FLAG, which is similar to CLAG but uses a different purine analogue fludarabine instead of cladribine. We also saw that FLAG and venetoclax have been combined to treat AML patients as they transition into SCT. When compared to FLAG, CLAG has been shown to be more effective in treating patients with high risk AML. Although in both cases the patients ultimately succumbed to AML, this was a proof of concept, and we suspect the CLAG venetoclax combination will be more efficacious than FLAG-venetoclax in treating high risk patients. This case series is intended to show that these two therapies can be combined, and we propose a further, more complete investigation into the concomitant use of CLAG and venetoclax to treat patients with AML.

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