Editor's Note：Acute leukemia is a group of malignant hematological diseases that pose a serious threat to human health, making its treatment a major focus of medical research. At the 2024 American Society of Hematology (ASH) Annual Meeting, significant progress was made in the diagnosis and treatment of acute leukemia, offering new perspectives and hope for clinical practice.At the 5th Annual Meeting of Chinese Alliance for Societies of Hematology (2025 CASH), Professor Shaowei Qiu from the Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences, provided an in-depth review of research advancements in both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
Advances in AML Research
(1) Emerging Novel Combination Chemotherapy Regimens
The traditional “3+7” regimen has long been the standard for first-line induction therapy in AML, but there remains room for improvement. At this year’s ASH meeting, numerous novel combination regimens became key areas of focus.
A study conducted by Qilu Hospital of Shandong University (ASH P1521) investigated the efficacy of venetoclax (VEN) combined with idarubicin and cytarabine in newly diagnosed AML patients. The study included 32 primary AML patients aged 18–60 with an ECOG performance status of 0–2 who had not received prior treatment.
The treatment regimen consisted of:
- Idarubicin (12 mg/m², days 1–3),
- Cytarabine (100 mg/m², days 1–7),
- Oral venetoclax (100 mg on day 4, 200 mg on day 5, and 400 mg on days 6–11).
Results demonstrated that the IAV regimen exhibited significant efficacy and safety in newly diagnosed AML patients, providing a promising new option for first-line AML treatment.
Another study focusing on elderly AML patients suitable for intensive therapy (Fit AML) evaluated a treatment strategy alternating VEN+cladribine+low-dose cytarabine (LDAC) with VEN+azacitidine (AZA) (ASH Oral 56). The study included 141 newly diagnosed elderly AML patients, with key eligibility criteria being age ≥50 years (or <50 years if unfit for standard induction chemotherapy), an ECOG performance status of 0–2, and adequate liver and kidney function.
The results showed a composite complete remission (CRc) rate of 86%, with 44% of patients proceeding to CR1 transplantation. This regimen offers an effective new approach for treating elderly AML patients and highlights the critical role of molecular and genetic characteristics in guiding treatment decisions and predicting outcomes.
A Phase Ib/II study on ivosidenib (IVO) combined with VEN±AZA for the treatment of IDH1-mutated hematologic malignancies provided updated data for 2024 (ASH Oral 219). Key inclusion criteria were patients aged ≥18 years with IDH1 R132-mutated relapsed/refractory (R/R) AML, newly diagnosed high-risk myelodysplastic syndrome (MDS), and/or myeloproliferative neoplasms (MPN), an ECOG performance status ≤2, and adequate cardiac, liver, and kidney function. Patients with prior exposure to VEN or IVO were excluded.
The primary endpoints were safety and objective response rate (ORR) within five cycles. Results showed composite complete remission (CRc) rates of 100%, 94%, and 83% for patients with MDS/MPN, newly diagnosed AML (ND-AML), and R/R AML, respectively. Median overall survival (OS) for the entire cohort was not yet reached, while the median event-free survival (EFS) was 50.4 months, and the median duration of response (mDOR) was 43.4 months. The efficacy of the IVO+VEN±AZA regimen varied across different types of IDH1-mutated myeloid malignancies.
(2) Significant Advances in Targeted Therapy
In recent years, with a deeper understanding of the mechanisms underlying AML, the development and combination of targeted therapies have become a major research focus.
FLT3-ITD and FLT3-TKD mutations are relatively common in AML and have a significant impact on patient prognosis. Studies have shown that the triplet therapy of hypomethylating agents (HMA) + VEN + FLT3 inhibitors (FLT3i) can achieve durable remission and encouraging overall survival (OS) in newly diagnosed FLT3-mutated AML patients who are unfit for intensive chemotherapy (ASH Oral 220).
Among evaluable responders, 81% achieved flow cytometry-based MRD negativity (sensitivity: 10⁻⁴). Median OS for patients with FLT3-ITD mutations was 28.1 months, with a 2-year OS rate of 57%. For FLT3-TKD mutation patients, the median OS was 39.3 months, with a 2-year OS rate of 76%.
Interestingly, factors such as age, NPM1 mutation status, ELN risk stratification, or whether the patient underwent hematopoietic stem cell transplantation (SCT) did not significantly affect OS. However, mutations in the RAS pathway were associated with poorer OS, suggesting that the RAS pathway could be an important future therapeutic target to improve outcomes for patients with adverse prognoses.
These findings highlight the clinical significance of targeted therapies for FLT3 mutations in AML when combined with other agents, offering promising avenues for future research and treatment optimization.
Advances in Menin Inhibitors for R/R AML at 2024 ASH
Significant progress was made in the treatment of relapsed/refractory (R/R) AML with Menin inhibitors at the 2024 ASH Annual Meeting. Several Menin inhibitors, including Revumenib, Bleximenib, Enzomenib, Ziftomenib, and BN104, demonstrated efficacy at various stages of clinical trials.
In the Phase II AUGMENT-101 study (ASH Oral 221), Revumenib achieved an overall response rate (ORR) of 63.9% and a CR+CRh rate of 22.7% in all R/R KMT2A-rearranged acute leukemia patients, with responses observed across different types of KMT2A translocations.
In another study (ASH Oral 216), the all-oral Revumenib (SNDX-5613) regimen, combined with decitabine/cedazuridine (ASTX727) and venetoclax (SAVE regimen), showed an ORR of 82% and a CR/CRh rate of 48%. The regimen was effective across subgroups of patients with KMT2A rearrangements, NPM1 mutations, and NUP98 rearrangements, with a 65% MRD negativity rate among evaluable patients.
The Phase 1a KOMET-007 study (ASH Oral 214) evaluated Ziftomenib in combination with intensive induction therapy (7+3) in newly diagnosed NPM1-mutated or KMT2A-rearranged AML patients. Interim results showed excellent tolerability across all dose levels and strong clinical activity, with CRc rates of 100% and 83% in NPM1-mutated and KMT2A-rearranged patients, respectively. MRD negativity rates were ≥75% across dose groups, and higher doses of Ziftomenib did not adversely affect neutrophil or platelet recovery times.
These findings underscore the potential of Menin inhibitors, both as monotherapies and in combination regimens, to address the needs of specific genetic subtypes of R/R AML with promising response rates and manageable safety profiles.
These findings suggest that Menin inhibitors hold tremendous potential in the treatment of R/R AML and AML with specific genetic mutations, offering new hope for improving patient outcomes.
(3) New Breakthroughs in Transplant Strategies
Hematopoietic stem cell transplantation (HSCT) remains a critical strategy in AML treatment. The ASAP study explored whether salvage chemotherapy is necessary before transplantation in R/R AML patients (ASH Oral 776).
The study randomized 281 patients into two groups:
- Induction Remission Group (RIST): Patients received cytarabine at 3 g/m² (1 g/m² for patients >60 years old) twice daily on days 1–3, followed by mitoxantrone at 10 mg/m² on days 3–5 (HAM regimen), before sequential allo-HSCT.
- Disease Control Group (DISC): Patients underwent disease control before conditioning and allo-HSCT, with a recommendation for a watch-and-wait (w&w) approach. Low-dose cytarabine (LDAC) and a single dose of mitoxantrone were permitted for disease control when needed.
The primary endpoint was the CR rate 56 days post-transplant. Results showed no significant differences between the two groups in treatment success rate, disease-free survival (DFS), or overall survival (OS). However, the induction remission group had longer hospital stays and a higher number of adverse events.
These findings provide critical guidance for transplant strategies in R/R AML patients, indicating that deeper remission prior to transplant does not improve OS. Instead, the unique characteristics of the AML disease remain the sole determinant of outcomes in transplant patients.
Advances in ALL Research
(1) New Induction Therapy Regimens for Ph+ ALL
Philadelphia chromosome-positive (Ph+) ALL is a distinct subtype of ALL associated with poor prognosis. This year’s ASH meeting presented two novel induction therapy regimens.
One single-center, Phase II study evaluated the efficacy and safety of dasatinib combined with inotuzumab ozogamicin in newly diagnosed Ph+ ALL patients (ASH P1432). The study included 19 patients aged ≥18 years with newly diagnosed Ph+ ALL. The treatment protocol consisted of dasatinib (140 mg/day or adjusted as needed) and inotuzumab ozogamicin combined with chemotherapy, following a detailed treatment schedule and dosing plan.
Results showed that at the end of the second cycle, the complete molecular response (CMR) rate was 63%, increasing to 89.4% by the end of the third cycle. The MRD-negative rate was 68% at the end of the second cycle and improved to 89.5% by the end of the third cycle. Notably, among the seven patients in protocol 1, 100% achieved MRD negativity after the second cycle.
During the median follow-up period of 1.1 years, no relapses were observed. In terms of safety, common grade 3–4 adverse events (occurring in ≥10% of patients) included COVID-19, dyspnea, anemia, and fatigue.
The regimen demonstrated significant benefits, particularly for patients with IKZF1 abnormalities or IKZF1 plus mutations, where the CMR rate at the end of the third cycle reached 100%.
These findings highlight the significant efficacy of the dasatinib+inotuzumab ozogamicin regimen as an induction therapy for Ph+ ALL, with particularly favorable outcomes in patients with specific genetic abnormalities. Moreover, the overall safety profile was manageable.
Another single-arm, Phase II study evaluated the efficacy and safety of blinatumomab combined with dasatinib as first-line treatment for newly diagnosed Ph+ ALL patients. The study included 63 patients who received blinatumomab (28 μg/day) and dasatinib (140 mg/day) in combination. The primary endpoint was molecular response (CMR+PNQ) after two cycles of induction therapy, while secondary endpoints included MRD reduction, disease-free survival (DFS), and overall survival (OS).
Results indicated that the molecular response rate was lower in Ph+ ALL patients with IKZF1 mutations, with only 1 of 11 patients in the IKZF1 plus group achieving a molecular response (9%). This was lower than the rates observed in the IKZF1 deletion group and the group without IKZF1 abnormalities (27%, 9/33).
At a median follow-up of 18 months, the overall survival (OS) rate for IKZF1 plus patients was only 2%, significantly lower than that of patients without IKZF1 deletions (100%) and those with IKZF1 deletions (93%).
These findings suggest that the efficacy of the blinatumomab+dasatinib regimen in patients with IKZF1 abnormalities requires further optimization. This study provides valuable insights and directions for future research to improve outcomes in this subset of Ph+ ALL patients.
(2) Advances in the Treatment of Ph-Negative B-ALL
Treating elderly Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia (Ph-B-ALL) patients is challenging due to age-related factors and the characteristics of the disease. A single-center, open-label Phase I study conducted by MD Anderson Cancer Center evaluated the efficacy and safety of the Mini-hyper-CVD regimen combined with inotuzumab ozogamicin (InO) ± blinatumomab in patients aged ≥60 with Ph-B-ALL, with a follow-up spanning 10 years (ASH P1441).
Updated data revealed that among 77 patients who had not achieved complete remission (CR) at baseline, 76 (99%) eventually achieved CR or CR with incomplete recovery of blood counts (CRi). Additionally, 93% of 81 evaluable patients attained MRD negativity.
After a median follow-up of 121 months, the median progression-free survival (mPFS) was 46.6 months, and the median overall survival (mOS) was 61.6 months. The 5-year PFS rate, OS rate, and duration of remission (CRD) rate were 48.1%, 50.1%, and 79.4%, respectively. For patients treated with the stepwise addition of InO, the mPFS increased to 61.6 months, with a 3-year PFS rate of 65%, representing a significant improvement compared to the earlier protocol.
At the data cutoff, 33 patients (39.8%) were still alive.
This study demonstrates that the Mini-hyper-CVD regimen combined with InO ± blinatumomab is both effective and well-tolerated in elderly Ph-B-ALL patients, offering substantial long-term survival benefits. These findings provide a valuable treatment reference for this patient population.
Additionally, another study explored the use of lower-dose chemotherapy combined with inotuzumab ozogamicin (InO) and blinatumomab in elderly Ph-negative ALL patients (ASH P1442). The results showed a CR/CRi rate of 92% and an MRD negativity rate of 100%. The 1-year progression-free survival (PFS) rate was 55.4%, and the 1-year overall survival (OS) rate was 73.8%. The regimen demonstrated good safety, with a low incidence of grade 3 adverse events.
These findings provide more treatment options for elderly Ph-negative ALL patients, supporting the development of personalized treatment plans tailored to the specific needs of each patient.
The Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences, conducted a single-arm, Phase II study (ASH P4199) to evaluate the efficacy of inotuzumab ozogamicin (InO) in Ph-negative B-ALL patients who achieved their first complete remission (CR1) but remained MRD-positive. The study also assessed changes in MRD levels from baseline following InO treatment.
Key inclusion criteria included patients aged ≥18 years, in CR1 with Ph-B-ALL, MRD-positive or with MRD-positive relapse, ECOG scores of 0–2, normal major organ function, no active or other malignancies, and an expected survival time >12 months.
All patients received InO in Cycle 1 (0.5 mg/m² on Days 1, 8, and 15). If MRD positivity was detected via flow cytometry, patients proceeded to Cycle 2 treatment. The primary endpoint was the MRD negativity rate after the first cycle. Patients completing InO treatment per the study protocol achieved a 100% MRD negativity rate.
Additionally, 8 patients underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) following InO treatment, with no cases of hepatic veno-occlusive disease (VOD). As of July 2024, 15 patients remained in remission, while 2 experienced relapse. These results suggest that using InO as consolidation therapy early during B-ALL remission, even after a single treatment cycle, can achieve a high MRD negativity rate with good safety and no increased risk of post-transplant VOD.
(3) New Advances in R/R B-ALL Treatment
For relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), a U.S. multicenter Phase II study evaluated the efficacy of Mini-Hyper-CVD combined with inotuzumab ozogamicin (InO) ± blinatumomab (ASH P2811). The study included 133 CD22-positive R/R B-ALL patients, who were grouped into three cohorts based on different InO dosing schedules.
Results showed an overall response rate (ORR) of 86% and a CR rate of 60% across the entire population, with the D-D cohort achieving an ORR of 100%. MRD negativity rates after the first cycle and overall treatment were 53% and 85%, respectively, and 74% and 95% for the D-D cohort.
With a median follow-up of 40 months, the median overall survival (OS) for the entire population was 21 months, with a 3-year OS rate of 45%. The median relapse-free survival (RFS) was 19 months, with a 3-year RFS rate of 44%.
In terms of safety, sinusoidal obstruction syndrome (SOS) was observed in 10 patients. The study demonstrated that the Mini-Hyper-CVD regimen combined with InO ± blinatumomab can achieve deep remission and high MRD negativity rates in R/R B-ALL patients. It also significantly improved survival outcomes, while dose and schedule adjustments reduced the risk of severe adverse events such as VOD.
Conclusion
The 2024 ASH Annual Meeting showcased significant advancements in the treatment of acute leukemia.
In AML, novel combination chemotherapy regimens such as the IAV protocol and the VEN+cladribine+LDAC alternating with VEN+AZA regimen for elderly patients significantly improved response rates and survival outcomes. Targeted therapies, particularly those involving Menin inhibitors, brought new hope to patients with R/R AML and specific genetic mutations. Additionally, research on hematopoietic stem cell transplantation (HSCT) strategies provided more precise guidance for clinical decision-making.
In ALL, induction therapies like dasatinib+inotuzumab ozogamicin demonstrated remarkable efficacy for Ph+ ALL. Meanwhile, new breakthroughs in the treatment of elderly Ph-negative B-ALL and R/R B-ALL offered a wider range of effective options for patients of different types and age groups.
However, challenges remain. For instance, resistance to certain targeted therapies is an ongoing issue, and the optimal combinations and dosing strategies for novel regimens require further refinement. Additionally, the applicability of different treatment approaches to diverse populations, considering racial and individual variability, needs further investigation.
Looking ahead, deeper exploration of the mechanisms underlying leukemia, the development of novel therapies, and ongoing clinical trials hold the promise of significantly improving cure rates for acute leukemia in the future.
About Shaowei Qiu
Position: Ward Director of the Leukemia Diagnosis and Treatment Center, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences.
Education and Academic Background:
- Bachelor’s degree from Tongji Medical College, Huazhong University of Science and Technology.
- MD from Peking Union Medical College.
- Visiting scholar at the University of Alabama at Birmingham, USA.
- Master’s supervisor at Peking Union Medical College.
Achievements and Recognitions:
- Recognized as an Outstanding Young Talent in Science and Technology in Tianjin.
- Published numerous SCI papers as the first or corresponding author in leading journals, including: Blood (2023) Leukemia (2022, 2024) Cancer Research (2024) Journal of Clinical Investigation (2019) Cancer Communications (2023) Blood Cancer Journal (2024).
Research Focus: Mechanisms of acute leukemia pathogenesis, drug resistance, and immune-targeted therapy.
Professional Roles:
- Member of the Youth Committee of the Hematology Oncology Professional Committee, Chinese Anti-Cancer Association.
- Member of the Hematology Oncology Professional Committee, Chinese Anti-Cancer Association.
- Member of the Hematology Oncology Professional Committee, Tianjin Anti-Cancer Association.
Research Projects:
- Principal investigator for projects funded by the National Natural Science Foundation of China, Tianjin Natural Science Foundation, and Clinical Research Funds.
- Participant in major research initiatives, including the Ministry of Science and Technology’s Key R&D Plans and the CAMS Innovation Fund for Medical Sciences.
