Blood Podcast Summary

"How I Treat" Series: 25th Anniversary of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia

Date: January 22, 2026
Host: Dr. Jason Gottlieb (Associate Editor, Blood)
Guests: Drs. Neal Shah, Simona Severini, Elisabetta Abruzzese, Yves Chalandon

Episode Overview

This special edition of the Blood Podcast celebrates the 25th anniversary of the introduction of tyrosine kinase inhibitors (TKIs) in the management of chronic myeloid leukemia (CML), a breakthrough that has dramatically changed patient outcomes and the clinical care paradigm. The episode convenes leading hematologists to discuss recent "How I Treat" articles in Blood, addressing individualized treatment approaches, resistance, pregnancy, and stem cell transplantation in CML.

Key Discussion Points and Insights

1. Evolution of Diagnosis and Initial Management

(Dr. Neal Shah: 03:00–04:02)

• Workup for Newly Diagnosed CML:

  • Incorporate patient’s goals, comorbidities, and disease phase.
  • Recommended tests: CBC with differential, metabolic panel, quantitative PCR for BCR-ABL1, FISH if PCR is negative, myeloid gene panel, risk scoring (SoCal or ELTS), hepatitis B serologies, thyroid function tests, spleen size documentation.
  • Bone marrow biopsy if considering transplantation to confirm disease phase.

• Quote:

  “It is recommended to obtain a CBC with differential, complete metabolic panel, quantitative PCR for BCR-ABL1... SoCal or ELTS risk score should be obtained.”
  — Dr. Neal Shah (03:00)

• Personalized Therapy Selection:

  • Excellent survival across TKIs, but deeper molecular responses with second-generation agents or asciminib.
  • Treatment-free remission (TFR) as a goal is increasingly possible, especially for younger or family-planning patients.
  • ASXL1 mutations may favor newer agents.
  • Cost considerations: generics can be 100x less expensive.
  • Quote:

    "There are evolving data that patients with ASXL1 mutations may preferentially benefit from these newer agents… Another factor gaining increasing attention is the cost of TKI therapy. Not only cost to the patient, but also to society."
    — Dr. Neal Shah (04:18)

2. Resistance to TKIs: Scope and Management

(Dr. Simona Severini: 05:58–10:29)

• Incidence:

  • 20–25% resistance in first-line imatinib, 10–15% in second-generation TKI.

• Defining/Monitoring Resistance:

  • ELN and NCCN provide guidelines—with ELN being more demanding.
  • PCR milestones used to track response; loss or lack of milestones indicates resistance.
  • ELN now differentiates between "unfavorable" and "warning" resistance.
  • Quote:

    “The lack or the loss of these milestones define what is resistance… the most recent ELR recommendations have mitigated the term failure into unfavorable…”
    — Dr. Simona Severini (06:19)

• Causes of Unsatisfactory Response:

  • Extrinsic: Nonadherence (most common), drug interactions, toxicity-driven interruptions.
  • Intrinsic: Acquisition of additional cytogenetic abnormalities or BCR-ABL1 mutations.
  • BCR-ABL1 mutation testing is essential when changing TKI for resistance.
  • Quote:

    “The most frequent extrinsic cause… is nonadherence. Then we should also think about drug interactions reducing TKI bioavailability, especially in elderly patients…”
    — Dr. Simona Severini (08:33)

3. Managing CML in Pregnancy

(Dr. Elisabetta Abruzzese: 10:45–14:23, 22:01–24:22, 30:12–31:51)

• Three-Tiered Considerations:

  1. CML-related: Disease biology, phase, depth of response, therapy used and timing.
  2. Pregnancy-related: Planned vs. unplanned, gestational timing, fetal exposure duration.
  3. Patient-related: Age, parity, health, emotional/social context.

• Quote:

  “There isn't a single right path or a right answer. It's a highly individualized process that require close collaboration between patient, family and physicians.”
  — Dr. Elisabetta Abruzzese (11:41)

• CML Diagnosed During Pregnancy:

  • First trimester: Avoid TKIs; consider monitoring or interferon-alpha for cytoreduction.
  • Second/third trimester: Imatinib/nilotinib can sometimes be considered after 16 weeks; dasatinib is contraindicated throughout pregnancy.

• Pregnancy During CML Treatment:

  • Ideal: Sustain TFR >1 year before pregnancy; monitor every 3 months.
  • Upon pregnancy detection: Stop TKI immediately, manage based on transcript levels.
  • Postpartum: TKI can be resumed; breastfeeding discouraged if on TKI, permitted with interferon or if in TFR.
  • Quote:

    “A woman who has been in a stable TFR for more than a year... is in the ideal position to proceed with pregnancy... so these women can be reassured and encouraged...”
    — Dr. Elisabetta Abruzzese (22:01)

• Unmet Needs:

  • Safety data for newer TKIs in pregnancy, fertility preservation, long-term child outcomes, improved multidisciplinary care pathways.
  • Quote:

    “...the goal now is to make pregnancy in CML not just possible, but predictable and safe for everyone and everywhere...”
    — Dr. Elisabetta Abruzzese (31:44)

4. Allogeneic Stem Cell Transplant in the TKI Era

(Dr. Yves Chalandon: 14:40–17:35, 24:39–26:55, 31:59–34:12)

• Current Role Diminished:

  • Now performed mostly for advanced phase CML or after multiple TKI failures.
  • Outcomes are significantly better if performed in first chronic phase.
  • Quote:

    “The most common indication for transplants nowadays are advanced phase CML... the result of transplant in advanced phase CML are much worse than in first chronic phase.”
    — Dr. Yves Chalandon (14:40)

• Timing and Risk Assessment:

  • Early referral for transplant evaluation is crucial when molecular markers indicate progression or after third-generation TKI failure—especially for young patients.
  • No perfect predictive score; ELTS risk can help guide decisions.

• Post-Transplant Management:

  • TKI maintenance used more commonly after transplant in advanced phase.
  • Molecular monitoring post-transplant is vital; TKI reintroduced upon relapse.
  • DLI (Donor Lymphocyte Infusion):
    • Less used than pre-TKI era; now sequential with TKI.
    • Timing post-engraftment depends on relapse kinetics and GVHD risk.
  • Quote:

    “Transplantation is much rarer for CML Nowadays... what is important I think is try to improve the capability of decreasing toxicity and also mortality related to the transplant setting...”
    — Dr. Yves Chalandon (31:59)

Notable Quotes & Memorable Moments

• On Individualizing Therapy:

  “We've learned that variants that lack ABL1, Exon2 are inherently resistant to asiminib, so determining the transcript type can be of importance.”
  — Dr. Neal Shah (05:24)

• On Resistance Monitoring:

  “Both the ELN recommendations and the NCCN guidelines provide us with important guidance... the gold standard for the evaluation of therapeutic efficacy is molecular response as assessed by real time quantitative RT-PCR.”
  — Dr. Simona Severini (06:19)

• On Pregnancy Management Complexity:

  “This complexity is explored through real cases showing how nuanced and hopeful this journey can be when decisions are shared and well guided.”
  — Dr. Elisabetta Abruzzese (12:16)

• On Transplant Timing:

  “The timing is truly important and not always very well considered and physician must be aware about that issue... it's important to monitor closely the CML patient...”
  — Dr. Yves Chalandon (16:11)

• On Future Research Needs:

  “There is still substantial room to improve deep molecular response rates in chronic phase CML patients... We also... need a better understanding of how to improve outcomes in patients who have coexisting ASXL1 mutations.”
  — Dr. Neal Shah (27:17)

Timestamps for Key Segments

• [03:00] New diagnosis & evaluation (Shah)
• [04:18] Individualizing initial TKI therapy (Shah)
• [05:58] Scope of resistance and guideline-based monitoring (Severini)
• [08:33] Causes of resistance and testing (Severini)
• [10:45] CML and pregnancy—three main considerations (Abruzzese)
• [12:53] Approach if CML is diagnosed during pregnancy (Abruzzese)
• [14:40] Modern indications for transplant (Chalandon)
• [16:11] Timing and risk assessment for transplant (Chalandon)
• [18:00] Dose adjustment and goals in TKI therapy (Shah)
• [19:55] Case-by-case variables for resistance management (Severini)
• [22:01] Detailed management of pregnancy during CML (Abruzzese)
• [24:39] TKIs and DLI after transplant in 2025 (Chalandon)
• [27:17] Unmet needs and research frontiers (All speakers)

Forward-Looking Insights

Unmet Needs & Exciting Research (27:17–34:12)

• Diagnosis to Predict Response: Studies to identify high-risk patients at presentation.
• Deepening Molecular Responses: Adjunct therapies to make TFR more broadly achievable.
• Better Understanding of Resistance: Broader mutation testing, including for STAMP inhibitors like asciminib, and use of NGS for genomic profiling.
• Safety in Pregnancy and Long-Term Outcomes: More data on fertility, pregnancy outcomes, and safe use of new TKIs.
• Transplantation: Innovations to further minimize toxicity and transplant-related mortality, cellular manipulation for GVHD reduction, and leveraging CML’s immunologic sensitivity.

Conclusion

This commemorative episode of Blood Podcast offers a sweeping look at 25 years of progress in CML thanks to TKIs. While most patients now have excellent prognoses, the conversation highlights the enduring need for precise, individualized care, advances for challenging cases such as resistance, and deep collaborative efforts—especially in special populations such as pregnant individuals and those facing transplantation. The future of CML research lies in better prediction of outcomes, safer therapies tailored to patient situation, and expanding the boundaries of what’s possible for quality survivorship.

For full articles and more information, visit bloodjournal.org