From December 7 to 10, 2024, the 66th American Society of Hematology (ASH) Annual Meeting convened in San Diego, bringing together global hematology experts to discuss the latest advancements in CML research and treatment. To provide an in-depth analysis of these developments, Hematology Frontier invited Dr. Huanling Zhu from West China Hospital, Sichuan University, to offer her perspective on six major breakthroughs in CML presented at the conference.Six Key Advances in CML Research
First-Line Asciminib Shows Long-Term Efficacy
One of the most significant updates at ASH 2024 was the 96-week data on asciminib as a first-line therapy, following up on last year’s 48-week results. The updated findings confirmed that asciminib outperformed investigator-chosen TKIs, including imatinib and dasatinib. While the 48-week data showed a modest efficacy advantage of only 2% over second-generation TKIs, by 96 weeks, this gap had widened significantly to 15%, reinforcing asciminib’s superior long-term efficacy and tolerability. Notably, asciminib has now been submitted for regulatory approval in China, making its future clinical impact highly anticipated.
Asciminib as a Second-Line Therapy in TKI-Resistant Patients
Another study examined asciminib as a second-line therapy in patients with an inadequate response or resistance to first-line TKIs. The initial dose was set at 80 mg once daily, with dose escalation to 200 mg once daily or 200 mg twice daily if no optimal response was achieved within six months. The results confirmed asciminib’s effectiveness in improving outcomes for patients who had previously failed TKI therapy.
ASCEND Study: Combination Therapy with Asciminib
The ASCEND study explored whether combining asciminib with another TKI could enhance response rates in patients with suboptimal outcomes on asciminib monotherapy. While most patients demonstrated adequate response to asciminib alone, three cases required combination therapy. The study also performed genetic analysis on patients with inadequate response, revealing mutation profiles that differed from those traditionally associated with TKI resistance, such as the A337T mutation. Despite these challenges, switching to alternative TKIs still led to effective disease control, highlighting the importance of individualized treatment strategies.
TGRX-678-1001: A Novel TKI for Resistant CML
Beyond asciminib, other emerging therapeutic approaches were also highlighted. Professor Jiang Qian led a phase Ia/Ib study evaluating TGRX-678-1001 in patients resistant or intolerant to imatinib, dasatinib, and nilotinib. Two-thirds of the participants were in chronic phase (CP) and one-third in accelerated phase (AP). The trial aimed to determine the maximum tolerated dose (MTD) while assessing safety and preliminary efficacy. The initial results were promising, and phase II trials are expected to yield even more robust data.
Real-World Study on Olverembatinib in Second-Line Therapy
A study presented by Professor Li Weiming focused on olverembatinib, which is currently approved in China only for patients with the T315I mutation. This study examined its potential use as a second-line therapy, and although only 42 patients were enrolled, the study demonstrated a positive therapeutic trend, reinforcing the drug’s potential beyond its currently approved indications.
Ponatinib Sequential Therapy to Reduce Cardiovascular Risks
A final study investigated ponatinib, a third-generation TKI with high potency but significant cardiovascular risks. Researchers explored a sequential treatment approach, using ponatinib as an initial induction therapy to rapidly reduce tumor burden within six months, followed by imatinib for maintenance therapy. This strategy successfully maintained disease control while significantly reducing cardiovascular adverse events, offering a novel approach for safer ponatinib use in clinical practice.
Looking Ahead: Innovations in CML Treatment and TFR Biomarker Exploration
These studies highlight the continuous advancements in CML treatment, particularly in optimizing TKI therapy and developing novel targeted agents. The increasing role of asciminib in both first-line and second-line settings underscores its potential to reshape the treatment landscape, while research on olverembatinib, ponatinib sequencing, and new-generation TKIs signals further progress in personalized therapy.
In addition to new drug developments, biomarker exploration for treatment-free remission (TFR) remains a key area of research. Identifying predictive markers for sustained remission after TKI discontinuation could help tailor treatment approaches and improve long-term patient outcomes. As scientific research progresses, the future of CML management is moving toward greater precision, improved safety, and more durable responses, offering new hope for patients striving for long-term remission and enhanced quality of life.
Unlocking New Biomarkers for Treatment-Free Remission (TFR) in Chronic Myeloid Leukemia (CML)
Dr. Huanling Zhu emphasized that research on treatment-free remission (TFR) has accumulated significant academic progress, and achieving TFR has become an essential therapeutic goal in CML treatment. At this year’s ASH conference, Shaun D. Patterson and colleagues presented new insights into predictive biomarkers for TFR, based on data from the DESTINY trial (O994).
Key Findings from the DESTINY Trial
The study enrolled CML patients in chronic phase (CP-CML) who had achieved MR4/MR3 while on tyrosine kinase inhibitor (TKI) therapy. These patients underwent a 12-month dose reduction phase and, if they maintained MR3, discontinued TKIs and were followed for an additional 24 months. Some patients experienced molecular relapse, while others successfully maintained TFR.
Biomarker Analysis and Immune Cell Differentiation
Analysis of bone marrow samples revealed that patients who experienced relapse had a decrease in common lymphoid progenitors (CLP) and downregulation of mTORC1 pathway target genes. Further in vitro studies using OP9/OP9-DL1 co-culture models showed that CD34+ mononuclear cells (MNCs) from relapsed patients had a higher tendency to differentiate into T cells (CD3+CD19-), but no significant differences in differentiation into NK cells (CD3-CD56+) or B cells (CD3-CD19+).
Additionally, naïve B cells (CD3-CD19+IgD+CD27-CD38low) were reduced in patients who later relapsed, while switched memory B cells (CD3-CD19+IgD-CD27+CD38lowIgMlow) increased, compared to those who successfully maintained TFR.
Identification of Four Predictive Biomarkers for TFR
- Decreased CLP levels in the bone marrow.
- Downregulation of mTORC1 pathway target genes in CLPs.
- Increased differentiation of hematopoietic stem cells into T cells.
- Reduction in naïve B cell populations.
These findings provide new potential biomarkers for predicting TFR success in CML patients. Future studies will further validate these markers to refine CML treatment strategies, ensuring more precise, individualized patient management and enhanced therapeutic outcomes.
Study Overview: Common Lymphoid Progenitors and B Cell Subpopulations Predict Treatment-Free Remission in CML (O994)
The DESTINY clinical trial (NCT01804985) enrolled 174 CP-CML patients in MR4/MR3 who were on imatinib, nilotinib, or dasatinib, attempting TFR. The study included a 12-month TKI dose reduction phase, followed by full TKI discontinuation for those maintaining MR3. At 36 months, the TFR rate was 72% in the MR4 group and 36% in the MR3 group.
Objective and Methods
To identify predictive biomarkers for TFR success, researchers analyzed bone marrow mononuclear cells (BM-MNCs) using flow cytometry, measuring various stem/progenitor cells and immune cell subtypes. Logistic regression models were used to determine statistically significant predictive markers, with additional RNA sequencing and in vitro differentiation assays to explore molecular mechanisms.
Key Results
Compared to TFR patients, those who relapsed had a significantly lower percentage of CLPs (Lin-CD34+CD10+), but no significant differences in granulocyte-macrophage progenitors (GMPs), common myeloid progenitors (CMPs), or megakaryocyte-erythroid progenitors (MEPs). RNA sequencing of isolated CLPs from relapsed patients showed downregulation of mTORC1 pathway genes, suggesting a possible role in TFR failure.
Further co-culture studies demonstrated that CD34+ MNCs from relapsed patients preferentially differentiated into T cells, but not into NK or B cells. However, there were no overall differences in total differentiated T cells, NK cells, or B cells between the TFR and relapse groups.
Predictive Model for TFR Success
A logistic regression model incorporating CLP levels and naïve B cell populations showed strong predictive value, with an area under the ROC curve (AUC) of 0.826 (P=0.008). These findings indicate that higher CLP levels and increased naïve B cells correlate with a higher likelihood of successful TFR.
Conclusion and Future Directions
The data suggest that bone marrow CLP and naïve B cell levels at the time of TKI discontinuation can serve as predictors of successful TFR in CML patients. Downregulation of mTORC1 signaling in CLPs is associated with molecular relapse, further elucidating the biological mechanisms underlying TFR maintenance.
Future studies will focus on functional and transcriptomic analyses to develop a clinically applicable biomarker panel, helping to identify patients most likely to achieve long-term TFR.
Dr. Huanling Zhu
Affiliation: Department of Hematology, West China Hospital, Sichuan University Title: Chief Physician, Professor, Master’s Supervisor
Professor Zhu has been with West China Hospital since 1985 and was a visiting scholar at Vancouver General Hospital, University of British Columbia, Canada, specializing in clinical flow cytometry diagnostics.
She is a Standing Member of the Clinical Flow Cytometry Society of the Chinese Society for Immunology and has served on various hematology research committees, including:
- Chinese Society of Bioengineering Cell Analysis Committee
- Chinese Anti-Cancer Association Hematology Clinical Flow Cytometry Alliance
- Seventh to Ninth Chinese Hematology Society Red Blood Cell Group
- Tenth Chinese Hematology Society Experimental Hematology Group
- Standing Member of the Sichuan Hematology Physicians Association
- Deputy Director of the Sichuan Blood Medical Quality Control Center
- Committee Member of Sichuan Medical Association Rare Disease Division
- Vice Chairman of the Chengdu Hematology Society
She also serves as an editorial board member for:
- Chinese Journal of Hematology
- Chinese Journal of Medical Genetics
- Chinese Medical Journal
- Journal of Sichuan University (Medical Edition)
- International Journal of Blood Transfusion and Hematology
Professor Zhu is a member of the Chinese Food and Drug Administration (CFDA) Expert Panel and a medical malpractice assessment expert in Sichuan Province and Chengdu.
