CML paper summary - November 2025

How I manage chronic myeloid leukemia during pregnancy

Abruzzese E et al. Blood, August 2025

Link to full paper: https://ashpublications.org/blood/article-abstract/doi/10.1182/blood.2024026513/546477/How-I-Manage-Chronic-Myeloid-Leukemia-During?redirectedFrom=fulltext

Summary

This comprehensive review provides practical, scenario-based guidance for managing chronic myeloid leukemia (CML) during pregnancy. As tyrosine kinase inhibitors (TKIs) are teratogenic – particularly during organogenesis – they must be discontinued immediately when pregnancy is confirmed. Interferon-α (IFN-α) is the safest cytoreductive option throughout pregnancy, while imatinib or nilotinib may be cautiously considered after 16 weeks in selected situations due to limited placental transfer. Management decisions depend on disease phase, depth of molecular response at conception, gestational age, molecular kinetics, and patient values. Seven real-world cases illustrate best practices, emphasising shared decision-making, frequent molecular monitoring, and individualised treatment strategies. When carefully managed, maternal and fetal outcomes can be favourable.

Key points for clinicians 

• TKIs should be stopped at the first positive pregnancy test to avoid teratogenic exposure during weeks 5–10.
• IFN-α is the preferred therapy at any gestational age; hydroxyurea may be used only briefly for uncontrolled hyperleukocytosis if leukapheresis is unavailable.
• Imatinib and nilotinib can be considered after 16 weeks; dasatinib must be avoided due to high placental crossing and fetal toxicity.
• Treatment strategy depends heavily on initial response status: women in stable deep molecular response (DMR) have the best chance of remaining untreated during pregnancy.
• Rapid rises in BCR::ABL1 transcripts (>1–10%) or loss of complete hematologic remission (CHR) warrant reinitiating therapy.
• Breastfeeding is not recommended with TKIs; could be considered if on IFN. 

Introduction

The advent of TKIs has transformed CML into a chronic, manageable disease, expanding expectations around fertility and family planning. As many women of childbearing age now live long-term with CML, oncologists increasingly face the challenge of managing pregnancy safely. TKIs are highly effective but largely contraindicated in early pregnancy due to teratogenicity; thus, pregnancy requires a balance between maternal disease control and fetal protection.

Two major clinical situations arise:

1. CML newly diagnosed during pregnancy, often requiring urgent cytoreduction without TKIs.
2. Pregnancy occurring during TKI therapy, where treatment interruption, monitoring, and sometimes re-initiation are critical.

This article provides detailed therapeutic guidance - including drug safety profiles, monitoring recommendations, and case-based insights - to support hematologists in optimising outcomes for both mother and child. 

Methods

This is a narrative, expert-driven “How I manage” review using:

• Seven real clinical cases illustrating typical and complex CML and pregnancy scenarios.
• Extensive review of literature, registry data, pharmacokinetic studies, and embryology to guide safety assessments and therapeutic decisions.
• Summaries of drug mechanisms and placental transfer data, including Hydroxyurea, IFN-α, and all approved TKIs.
• A management algorithm (see table) for first, second, and third trimesters depending on BCR::ABL1 IS levels, remission status, gestational age, and cytopenias.

The review’s strength lies in translating guidelines, clinical evidence, and pharmacologic principles into practical recommendations across diverse clinical circumstances. 

This research was originally published in Blood. Abruzzese E et al. How I manage chronic myeloid leukemia during pregnancy.
Blood 2025 Aug 4:blood.2024026513. doi: 10.1182/blood.2024026513. © by the American Society of Hematology.

Key findings

Drug safety profiles during pregnancy

• Interferon-α (IFN-α) – safest agent
• Does not cross the placenta; long safety record.
• Effective for complete hematologic response (CHR) and modest molecular control.
• Preferred first-line option in all trimesters.
• Tyrosine kinase inhibitors (TKIs)
• First trimester (weeks 5–10): all TKIs contraindicated due to teratogenicity.
• Second–third trimester: Imatinib or nilotinib may be considered if BCR::ABL1 rises or CHR is lost.
• Dasatinib: must be avoided – freely crosses placenta; linked to fetal hydrops, malformations, IUFD.
• Bosutinib: limited data but theoretically high placental transfer; discontinue during pregnancy.
• Ponatinib and asciminib: insufficient safety data; avoid.

Maternal disease management principles

• Immediate steps when pregnancy is confirmed:
• Stop TKIs at the first positive pregnancy test (typically week 3–4) - exposure before this period is unlikely to cause anomalies.
• Begin intensified molecular and hematologic monitoring.
• Monitoring frequency:
• Monthly BCR::ABL1 until week 16, then every 6–8 weeks depending on kinetics.
• CBC every 6–8 weeks or more if cytoses rise.
• When to initiate or reinitiate therapy:
• Initiate IFN-α if:
  • No CHR
  • Rapid kinetics in newly diagnosed CML
  • Rising BCR::ABL1 (e.g., >1–10%)
• Restart imatinib/nilotinib (after 16 weeks) if:
  • Rapid transcript rise
  • CHR threatened or lost
  • IFN-α insufficient

Fetal considerations

• Critical teratogenic window: weeks 5–10 (organogenesis).
• After week 16, placental barrier reduces drug transfer; malformation risk is lower.
• Limited data but reassuring long-term developmental outcomes for children exposed to chemotherapy/TKIs in utero (mostly late exposure).

Breastfeeding

• Not recommended with any TKI (drug transferred into breast milk).
• Allowed with IFN-α or off-therapy.
• Breastfeeding must be weighed against need for rapid TKI resumption postpartum.

Case-based practical insights

The seven cases cover:

• Case #1: Newly diagnosed CML in early pregnancy:
  • IFN-α safely controlled hyperleukocytosis 
  • Demonstrates feasibility of avoiding TKIs entirely until delivery if CHR is achieved.
• Case #2: Newly diagnosed in second trimester:
  • Hematologic control may improve spontaneously due to plasma volume expansion; treatment may be deferred.
• Case #3: Early pregnancy during TKI therapy (not yet TFR candidate):
  • Loss of MR3 or rapid BCR::ABL1 increase requires restarting imatinib.
• Case #4: Pregnancy in patient with prior resistance requiring ponatinib:
  • Achieving DMR with ponatinib + IFN combination enabled safe TKI cessation at conception.
• Case #5: Planned pregnancy with stable MMR but not TFR candidate:
  • Nilotinib restarted in late second trimester after molecular relapse; no placental transfer detected in cord blood.
• Cases #6 and #7: TFR candidates with rising transcripts during pregnancy:
  • IFN-α can bridge pregnancy until postpartum even when BCR::ABL1 rises, avoiding TKIs during organogenesis.

Conclusions

Managing CML during pregnancy requires a multidisciplinary, individualised plan that prioritises fetal safety while ensuring maternal disease control. Early discontinuation of TKIs, frequent molecular monitoring, and timely initiation of IFN-α are central strategies. Imatinib or nilotinib may be reintroduced after 16 weeks when clinically justified, but dasatinib and newer agents (bosutinib, ponatinib, asciminib) should be avoided.

Although no single approach fits all cases, successful outcomes are achievable with shared decision-making, education, careful assessment of disease kinetics, and flexible treatment adjustments. Real-world cases highlight that – even in challenging scenarios - healthy pregnancies and long-term maternal remission are realistic goals when evidence-based principles are applied.

CML paper summary - August 2025

Favourable rates of cardiovascular events with stringent cardiovascular monitoring and a lowered dose of ponatinib as second-line treatment in chronic phase chronic myeloid leukemia patients failing or intolerant to first-line second-generation tyrosine kinase inhibitor treatment: Results of the prospective PONS Trial

Le Coutre P. et al. Acta Haematol, May 2025

Link to full paper: https://karger.com/aha/article-abstract/doi/10.1159/000545826/926666/Favorable-Rates-of-Cardiovascular-Events-with?redirectedFrom=fulltext

Summary

This prospective phase 2 study evaluated ponatinib at a lowered starting dose (30 mg daily) as a second-line treatment in chronic phase chronic myeloid leukemia (CP-CML) patients who were resistant or intolerant to a first-line second-generation TKI. With stringent cardiovascular (CV) monitoring and patient selection based on low CV risk, ponatinib was found to be both effective and safe. At 12 months, 55.6% of patients achieved major molecular response (MMR), and no grade ≥3 cardiovascular events occurred. These results suggest that careful monitoring enables the use of ponatinib earlier in therapy with manageable toxicity and promising efficacy.

Introduction

While first-line treatment with imatinib, nilotinib, dasatinib, or bosutinib in patients with CML provides high survival rates, a subset of patients experiences treatment failure and/or intolerance. Ponatinib, a third-generation TKI, has broad activity including against the resistant T315I mutation, but earlier trials reported substantial rates of cardiovascular adverse events (CAEs), limiting its use to later lines. The PONS trial (NCT03807479) was designed to evaluate ponatinib as a second-line option at a reduced dose of 30 mg daily with stringent CV monitoring, aiming to improve safety while maintaining efficacy.

Study methods

• Design: Non-randomised, single-arm, prospective phase 2 trial.
• Eligibility: Adults with CP-CML resistant or intolerant to first-line TKI, ECOG 0–2, adequate organ function, and low baseline CV risk. Patients with significant CV history or pancreatitis were excluded.
• Intervention: Ponatinib 30 mg daily (with dose reduction to 15 mg upon achieving MMR, or escalation to 45 mg if needed).
• Monitoring: Rigorous CV surveillance including blood pressure, ankle-brachial index, duplex ultrasonography, ECG, echocardiography, oral glucose tolerance, and fundoscopy every 3 months.
• Endpoints:
  • Primary endpoint: Proportion achieving MMR at 12 months.
  • Secondary endpoints: Complete hematologic remission (CHR), cytogenetic and molecular responses (MR4), safety (especially CV toxicity).
• Recruitment: 22 patients screened, 18 enrolled across 6 German sites 
  (11 with TKI failure, 7 with intolerance).

Key findings

• Efficacy:
  • At 12 months: 72.2% CHR, 55.6% MMR (primary endpoint), 27.8% MR4.
  • Responses occurred in both resistant and intolerant groups.
• Safety:
  • No grade ≥3 CAEs observed.
  • Only mild CV findings (grade 1 carotid artery stenosis, grade 1 hypertension, and one grade 2 coronary artery disease).
  • Hematologic grade 3 toxicity was rare (e.g., thrombocytopenia in 1 patient).
  • Non-hematologic grade 3 events included isolated cases of pancreatitis, diarrhea, hepatotoxicity, glucose elevation, erectile dysfunction, and rash.
• Treatment exposure: 
  • Median treatment duration 17.7 months. 
  • Dose modifications occurred in ~28% of patients.
• Comparisons: Outcomes appeared more favourable than in the OPTIC trial’s 30 mg cohort, likely due to earlier-line use, strict patient selection, and intensive monitoring.

Conclusions

The PONS trial demonstrates that ponatinib at 30 mg daily can be safely used as a second-line therapy in CP-CML patients with low CV risk when combined with intensive CV risk-monitoring. This approach yielded favourable efficacy with no serious CV events. While recruitment was limited, the findings support the feasibility of earlier ponatinib use in selected patients. Implementation outside of clinical trials may be challenging given the intensive monitoring requirements, but the study provides a framework for safer ponatinib integration in clinical practice.

This summary is provided solely for informational purposes. Ponatinib is not generally approved for second-line use in chronic phase CML, except in patients with the T315I mutation. The results of the PONS trial are presented to highlight how careful patient selection and cardiovascular risk monitoring may influence outcomes. The iCMLf does not endorse or recommend any specific drug or treatment approach. Clinical decisions should always follow local regulatory approvals, clinical guidelines, and individual patient considerations.

CML paper summary - April 2025

High-throughput drug screening identifies SMAC mimetics as enhancers of NK cell cytotoxicity in chronic myeloid leukemia

Nygren P. et al. Blood, January 2025

Link to full paper: https://doi.org/10.1182/blood.2024025286

Summary

This study explored how natural killer (NK) cells, a type of immune cell known for targeting cancer cells, could be more effective against chronic myeloid leukemia (CML) when supported by specific drugs. Using a high-throughput drug screening of over 500 small-molecule compounds, the researchers evaluated the impact of oncological drugs on NK cell-mediated cytotoxicity against CML cells.

Introduction

CML is a myeloproliferative disorder driven by the BCR::ABL1 fusion gene. Although tyrosine kinase inhibitors (TKIs) have revolutionized treatment, many patients fail to achieve long-term treatment-free remission, often due to the persistence of leukemic stem cells. NK cells have the potential to control residual disease and achieve remission. However, the efficacy of NK cell-based immunotherapy in CML has not been demonstrated. This study was conducted to identify drugs that enhance NK cell cytotoxicity and better understand the molecular mechanisms behind NK cell-mediated anti-leukemia activity.

Study methods

The researchers employed a high-throughput drug screening approach using a library of 527 oncological compounds. The screening involved co-culturing NK cells with K562 leukemia cells, with target cell viability assessed via a luciferase-based assay. Differential drug sensitivity scores (dDSS) were calculated to quantify the effects of each drug on NK cell-mediated killing.

Subsequent experiments validated top hits using flow cytometry and colony-forming assays on both cell lines and primary CML patient samples. The researchers also utilized single-cell RNA sequencing to profile drug-induced transcriptomic changes in NK and target CML cells, identifying shifts in activation states and gene expression pathways.

Key findings

• SMAC mimetics identified as enhancers: SMAC mimetics birinapant and NVP-LCL161 significantly increased NK cell cytotoxicity in both cell lines and patient-derived CML samples.

• Negative impact of certain drugs: Glucocorticoids (e.g., dexamethasone) and some TKIs (e.g., dasatinib) suppressed NK cell activity and IFN-γ production.

• Single-cell insights: Drug-induced changes in NK and CML cell transcriptomes revealed enhanced NF-κB signalling with SMAC mimetics and inhibition of activation markers with suppressive drugs.

• Clinical implications: The findings support the potential of SMAC mimetics in combination NK cell immunotherapy, especially for advanced-phase CML or TKI-resistant cases.

Conclusions

This research presents a promising strategy for enhancing NK cell-based immunotherapy in CML. The identification of SMAC mimetics as potent enhancers of NK cell cytotoxicity offers a foundation for clinical studies and suggests broader applications in other malignancies. Further preclinical and clinical studies are needed to assess safety, efficacy, and optimal treatment combinations.

Further commentary:

SMAC mimetics in action in chronic myeloid leukemia
Ali G. Turhan. Blood, April 2025
https://doi.org/10.1182/blood.2024027994