Q1 2021 : Additional information and data in acute leukemia

March 3, 2021

Here is a retrospective on additional data and information published in the first quarter of 2021. 

AML and ALL:

Researchers develop a pediatric disease risk index (DRI)  capable of stratifying children with AML and ALL into clinically distinct risk groups based on pre-transplant clinical characteristics, including age, cytogenetics, and disease status. The ability to assign a risk group for any patient prior to hematopoietic cell transplantation is invaluable as it helps in counseling the patient and family and also facilitates discussion on whether a patient at higher risk may benefit from an alternative novel therapy prior to transplantation, or in some cases, may benefit from a planned novel treatment targeted toward leukemia control after transplant. (Ref. Qayed M, Ahn KW, Kitko CL, et al. A validated pediatric disease risk index for allogeneic hematopoietic cell transplantation. Blood. 2020 November 18)


The FDA has granted fast track designation to devimistat for the treatment of AML, clearing its manufacturer, Rafael Pharmaceuticals, to begin the phase III ARMADA 2000 trial. Devimistat is designed to target enzymes that are involved in cancer cell energy metabolism and are located in the mitochondria of cancer cells, increasing their sensitivity to chemotherapies and allowing for effective treatment with lower doses of toxic drugs. (Source: Rafael Pharmaceuticals press release, December 15, 2020)

The FDA cleared Vor Biopharma’s IND application for its hematopoietic cell therapy VOR33. This decision allows the company to initiate a phase I/IIa clinical trial evaluating tolerability and feasibility of VOR33 in patients with CD33-positive AML who are at high risk of relapse. VOR33 consists of hematopoietic cells engineered to lack the CD33 protein. Following treatment with VOR33, patients will be eligible to receive the FDA-approved CD33-directed antibody drug conjugate gemtuzumab ozogamicin to prolong leukemia-free survival and determine if VOR33 protects against the myelosuppression that typically accompanies treatment with gemtuzumab ozogamicin. (Source: Vor Biopharma press release, January 14, 2021.)

Following early-stage results showing 87% of patients with NPM1-mutated AML who were treated with a combination of entospletinib and standard chemotherapy experienced complete remission, Kronos Bio is launching phase III clinical trial evaluating its selective spleen tyrosine kinase inhibitor entospletinib for the treatment of patients with NPM1-mutated AML with a primary endpoint of MRD negativity. (Source: STAT, March 4, 2021)

Ivosidenib, an inhibitor of the mutant isocitrate dehydrogenase 1 (IDH1) enzyme, was well tolerated and associated with deep and durable responses in combination with azacitidine in patients with newly diagnosed AML, according to findings published in the Journal of Clinical Oncology. (ref. DiNardo CD, Stein AS, Stein EM, et al. Mutant isocitrate dehydrogenase 1 inhibitor ivosidenib in combination with azacitidine for newly diagnosed acute myeloid leukemia. J Clin Oncol. 2020 October 29.)

Isocitrate dehydrogenase 1/2 (IDH1/2) mutations occur in around 20% of patients with acute myeloid leukemia (AML) and  venetoclax (VEN) in combination with a hypomethylating agent (HMA), such as decitabine or azacitidine, is a promising therapeutic option for IDH-mutated AML. (Source: Hammond D, Loghavi S, Konopleva M, et al. Response patterns and MRD by flow cytometry and NGS in patients with mutant-IDH acute myeloid leukemia treated with venetoclax in combination with hypomethylating agents. Oral abstract #590. 62nd American Society of Hematology (ASH) Annual Meeting and Exposition; Dec 7, 2020; Virtual)

A study looking at the prognostic impact of complete remission (CR) with MRD negativity showed that among patients with relapsed/refractory AML receiving first salvage chemotherapy, both CR and MRD negativity were independently associated with a lower risk of relapse and longer RFS. Patients who achieved CRMRD– had the best outcomes, which were driven in part by an increased ability to undergo subsequent HSCT. Given the superior outcomes in patients who achieve CRMRD–, this response end point should be considered in clinical trials evaluating novel agents and combinations in relapsed/refractory AML. (Ref. https://ashpublications.org/bloodadvances/article/4/24/6117/474429/Prognostic-impact-of-complete-remission-with-MRD?utm_source=newsletter&utm_medium=email&utm_campaign=adv_not_4_24)

CPX-351 demonstrated longer median overall survival (OS) vs 7+3 among older adults with newly diagnosed high-risk/secondary AML who achieved remission according to Phase 3 post-hoc analyses. The OS benefit was observed across the evaluated patient subgroups and irrespective of subsequent hematopoietic cell transplantation (Ref. https://ashpublications.org/bloodadvances/article/5/6/1719/475487/Older-adults-with-newly-diagnosed-high-risk?utm_source=newsletter&utm_medium=email&utm_campaign=adv_not_5_6)

New technologies like next-generation karyotyping increases precision for ELN-defining gene alterations but warrants special caution for lowly expressed fusions in AML. (Ref. https://ashpublications.org/bloodadvances/article/5/4/1003/475203/Challenging-conventional-karyotyping-by-next?utm_source=newsletter&utm_medium=email&utm_campaign=highlights_3_2_21)

Unfortunately, some trials have failed:

– Maintenance treatment with single-agent azacitidine at a dose of 32 mg/m2 daily for five days did not lead to improved survival in patients with high-risk myelodysplastic syndromes (MDS) or AML who had undergone allogeneic hematopoietic cell transplantation (HCT), according to findings from a phase III randomized controlled trial published in Blood Advances (ref. Oran B, de Lima M, Garcia-Manero G, et al. A phase 3 randomized study of 5-azacitidine maintenance vs observation after transplant in high-risk AML and MDS patients. Blood Adv. 2020;4:5580-5588.)

–  Phase III LACEWING trial (NCT02752035) failed to meet its primary endpoint of a statistically significant improvement in overall survival with gilteritinib plus azacitidineversus azacitidine alone, in patients with newly diagnosed, FLT3-mutated AML, who were ineligible for intensive induction chemotherapy.  Therefore the study has terminated and enrolement has ceased. (Source: Astellas https://www.astellas.com/en/news/16296. Published Dec 21, 2020.)