Editor’s Note:

Acute Myeloid Leukemia (AML) is a malignant clonal disease originating from hematopoietic stem cells. Affected myeloid cells (leukemic cells) undergo uncontrolled proliferation, differentiation disorders, and blocked apoptosis, accumulating in the bone marrow and other hematopoietic tissues. This inhibits normal hematopoietic function and infiltrates organs such as lymph nodes, liver, and spleen, leading to clinical features including anemia, infections, bleeding, and leukemic cell infiltration. As the most common hematologic malignancy, research in the field of AML, both basic and clinical, has never ceased, yielding continuous breakthroughs. So, what significant advancements has the AML field witnessed in the past year? “Oncology Frontier” has invited Professor Jianxiang Wang from the Institute of Hematology, Chinese Academy of Medical Sciences, to meticulously review various developments in the AML domain. The summary is compiled below.

Part One

AML Basic Research Section

In the realm of basic research, there were not many major breakthroughs in the field of AML in the fiscal year 2021. However, it is worth noting that in the LBA-4 abstract presented at the 2021 ASH conference, researchers conducted a comprehensive analysis of 136 pediatric patients with relapsed AML using RNA sequencing (RNA-seq), whole-genome sequencing, and targeted capture sequencing. The aim was to identify the spectrum of genetic alterations commonly observed in pediatric AML patients at the time of relapse. The results revealed that, apart from well-described fusion genes such as KMT2A and NUP98, 8.8% of relapsed AML pediatric patients in the cohort exhibited somatic mutations in the UBTF (Upstream Binding Transcription Factor) gene. These alterations were characterized as heterozygous exon 13 frame-shift insertions, termed UBTF-TD, including the 3′ end of exon 13 and the entire exon 13 of UBTF.

In the AAML1031 cohort (n=1035) of this study, the mutation rate of UBTF-TD was 4.3%. It was found to be often mutually exclusive with known AML molecular subtypes, co-occurring with FLT3-ITD (66.7%) and WT1 (40.0%) mutations, as well as having a normal karyotype or trisomy 8. Analysis revealed a correlation between UBTF-TD in the AAML1031 cohort, poor survival outcomes (refer to Figure 1 below), and positive minimal residual disease (MRD). This suggests that UBTF-TD and WT1 are independent risk factors for overall survival in FLT3-ITD-positive AML, indicating that the newly discovered UBTF-TD defines a unique subtype of acute myeloid leukemia (AML).

Part Two

Advancements in AML Clinical Research

In the realm of AML clinical research for the fiscal year 2021, the primary focus was on novel drug treatments, with notable progress in targeted therapies taking the forefront and dominating the landscape of AML treatment advancements. Immunotherapy closely followed, unleashing another wave of innovation in the treatment of newly diagnosed and relapsed AML. Additionally, there were noteworthy developments in the chemotherapy aspect of AML.

• IDH1/2 Inhibitors

Ivosidenib, a novel IDH1 inhibitor, has shown remarkable progress in the past year, demonstrating efficacy in both newly diagnosed and relapsed/refractory AML patients.

At the 2021 ASH conference, abstract 875 reported the efficacy of Ivosidenib in combination with azacitidine in the induction treatment of elderly AML patients with newly diagnosed IDH1 mutations. Nineteen elderly AML patients with IDH1 mutations were enrolled, all receiving Ivosidenib + azacitidine for six treatment cycles. The results showed: ① After six treatment cycles, 13 patients achieved complete remission or complete remission with incomplete blood count recovery (CR/CRi). ② In terms of survival, the 12-month disease-free survival (DFS) was 96%, with the median overall survival (mOS) not reached. The 12-month and 18-month OS rates were 100% and 73%, respectively. This study indicated that Ivosidenib in combination with azacitidine has a favorable efficacy in the induction treatment of newly diagnosed elderly AML patients with IDH1 mutations.

Similarly, in the AGILE study (an international multicenter, phase III trial), the efficacy of Ivosidenib + azacitidine (AZA) vs. placebo + azacitidine (AZA) in newly diagnosed AML patients with IDH1 mutations was compared. The results showed: ① Compared to the placebo + azacitidine group, the Ivosidenib + azacitidine (AZA) group exhibited a significantly prolonged median OS, with 24 months vs. 7.9 months (p=0.0005, see Figure 2 below). ② Additionally, the complete remission rate (CR) in the Ivosidenib + azacitidine (AZA) group reached 47.2%, significantly higher than the 14.9% in the placebo + azacitidine group (p<0.0001).

It should be noted that Ivosidenib (Ivosidenib), either as a monotherapy or in combination with other drugs, also demonstrates remarkable efficacy in the treatment of relapsed/refractory acute myeloid leukemia (R/R-AML). In a study from China, Ivosidenib monotherapy for mIDH1-type R/R-AML patients achieved a CR+CRh rate of 36.7%, with a median overall survival (mOS) reaching 9.1 months, and a median event-free survival (mEFS) of 5.52 months. In another study, Ivosidenib in combination with two or three drugs for IDH1-mutant R/R-AML achieved a complete remission rate (CRc) of 62.5%, with a 1-year OS rate of 50%.

• BCL-2 Inhibitors

Based on previous research findings, BCL-2 inhibitors, targeting pathways involved in metabolism or signaling, have gained increasing importance in AML treatment. Abstract 798 from the 2021 ASH conference presented an international multicenter retrospective study involving 87 elderly AML patients unfit for chemotherapy and harboring FLT3 mutations. They received either a dual-drug combination (demethylating agent + FLT3 inhibitor, i.e., HAM+FL3Ti) or a triple-drug combination (demethylating agent + FLT3 inhibitor + BCL-2 inhibitor venetoclax, i.e., HMA+FL3Ti+VEN). The results showed: ① Compared to the dual-drug combination, the triple-drug combination achieved a higher CR/CRi rate (93% vs. 70%, P=0.02, see Figure 3 below) and FLT3-PCR negativity rate (96% vs. 54%, P<0.01). ② Follow-up revealed a significantly superior median overall survival (OS) for the triple-drug combination compared to the dual-drug combination (NR vs. 9.5 months, P<0.01).

In another study, the BCL-2 inhibitor venetoclax, in combination with the demethylating agent azacitidine (AZA), was employed to treat newly diagnosed AML patients with cytogenetically low-risk TP53 mutations. The results indicated a significant improvement in the complete remission rate, with a CRc rate reaching 41%, significantly higher than the 17% achieved with azacitidine monotherapy.

It is noteworthy that in a real-world study, the BCL-2 inhibitor venetoclax combined with low-dose cytarabine and daunorubicin (ACTIVE) demonstrated impressive efficacy and good tolerability in elderly relapsed/refractory AML (R/R-AML) patients with poor prognosis. Among the 49 evaluable R/R-AML patients, the objective response rate (ORR) was as high as 73%, and the CRc rate was 67%, with 61% of CRc patients achieving negative minimal residual disease (MRD).

• FLT-3 Inhibitors

FLT3 mutations are one of the most common genetic mutations in AML, significantly impacting patient prognosis. Therefore, targeted inhibitory treatment against FLT3 holds great significance in addressing the unmet needs in AML therapy. In a real-world study, it was confirmed that the FLT3 inhibitor midostaurin, when combined with intensive therapy, significantly improved the prognosis of FLT3 mutation-positive patients. Follow-up revealed that the overall survival (OS) in the midostaurin + intensive therapy group had not been reached (NR), significantly surpassing the 19 months in the intensive therapy group (p=0.022). The 2-year OS rates were 79.2% vs. 54.2% (p=0.026), respectively.

In the 2021 ASH conference’s abstract 695 study (COMMODORE), 234 relapsed/refractory AML patients with FLT3 mutations were enrolled and evenly assigned to receive treatment with the FLT3 inhibitor gilteritinib or salvage chemotherapy (SC). The aim was to assess differences in effectiveness and safety. The results showed: ① Patients in the gilteritinib group had a significantly higher median OS than those in the salvage chemotherapy group (SC), with 9 months vs. 4.7 months (HR=0.549, P=0.00126, see Figure 4 below); the 1-year survival rates were 33.3% vs. 23.2%. ② The median event-free survival (EFS) in the gilteritinib group was significantly longer than in the salvage chemotherapy group (SC), with 2.8 months vs. 0.6 months (HR=0.551, P=0.00004). ③ The complete remission rate (CR) in the gilteritinib group was 16.4%, higher than the 10.2% in the salvage chemotherapy group (SC), and the CRc rate was 50% vs. 20.3% (P<0.0001).

In another study presented at the 2021 ASH conference (abstract 700), a total of 123 relapsed/refractory AML patients with FLT3 mutations were enrolled. They received either gilteritinib (gilteritinib) + azacitidine (AZA) or azacitidine (AZA) monotherapy, aiming to compare the efficacy differences between the two treatment regimens. The results revealed that the complete remission rate in the gilteritinib+AZA group was 58.1%, significantly higher than the 26.5% in the AZA group (P<0.001). Regarding survival outcomes, the median overall survival (OS) in the gilteritinib+AZA group was 9.82 months, while the AZA group’s median OS was 8.87 months (HR=0.916, p=0.753).

• AML Immunotherapy

In the field of immunotherapy for AML, progressive drugs include Sabatolimab, Cusatuzumab, CD47 monoclonal antibody Magrol, and CAR-T therapy, which has demonstrated certain efficacy. In a study utilizing the Sabatolimab, targeting the TIM-3 receptor in combination with demethylating agents (HMA) for the treatment of newly diagnosed AML patients (ND-AML), the objective response rate (ORR) reached 40% in the evaluable 40 ND AML patients, with an estimated 12-month progression-free survival (PFS) rate of 27.9%. Furthermore, in a study involving 44 patients, the use of the monoclonal antibody Cusatuzumab + VEN + AZA for the treatment of elderly newly diagnosed AML patients achieved a complete remission rate (CR) of 45.5%, and CR+CRh+Cri reached 77.3%. Additionally, CAR-T therapy has shown some progress in the treatment of relapsed/refractory AML. In a clinical study involving 11 relapsed/refractory AML patients, CAR-T therapy achieved an objective response rate (ORR) of 90.9% in pediatric R/R AML patients.

• AML Chemotherapy Advancements

At the 2021 ASH conference, abstract 871 reported the latest results from the QUAZARAML-001 study, investigating the effectiveness differences between oral azacitidine and placebo in AML patients achieving first remission. After a median follow-up of 51.7 months, the azacitidine group maintained a significant advantage in OS over the control group, with 24.7 vs. 14.8 months (P=0.0008). The estimated 3-year OS rates were 37.4% vs. 27.9%. The study suggests that maintenance therapy with oral azacitidine provides significant benefits for long-term survival in AML patients after strengthening chemotherapy and achieving first remission.

Chief Physician, Professor, Ph.D. Supervisor

Deputy Director of the Institute, Hematology Hospital, Chinese Academy of Medical Sciences

Chairman of the 10th Committee, Hematology Branch, Chinese Medical Association

Vice President, Hematology Physicians Branch, Chinese Medical Doctor Association

Vice President, Internal Medicine Physicians Branch, Chinese Medical Doctor Association

Director, National Clinical Research Center for Hematologic Diseases

Deputy Editor-in-Chief, Journal of Hematology & Oncology (IF11.059)

Editor-in-Chief, Chinese Journal of Hematology (2012-2016)

Chairman, Hematologic Oncology Committee, Chinese Anti-Cancer Association (2012-2015)

Recipient of the “National Distinguished Youth Scholar,” “New Century Talents Project” National Candidate, Expert of Outstanding Contribution to Health Ministry, Expert with Special Government Allowance from the State Council

Lead Developer of CD19 and CD33 CAR-T therapies

A leading figure in leukemia treatment, known for prognostic stratification, intensive induction, and comprehensive management, significantly improving the efficacy of acute leukemia treatment

Led the formulation of multiple guidelines for the diagnosis and treatment of “Acute Myeloid Leukemia,” “Acute Lymphoblastic Leukemia,” and “Chronic Myeloid Leukemia”

Recipient of the NIH Outstanding Postdoctoral Research Award, 10th “Wu Jieping Medical Research Award – Paul Janssen Pharmaceutical Research Award” First Prize, First Prize for Scientific and Technological Progress in Tianjin (as the first author)