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CML paper summary: The e13a3 (b2a3) and e14a3 (b3a3) BCR::ABL1 isoforms are resistant to asciminib (Leske IB and Hantschel O. Leukemia, Sept 2024)

CML paper summary - January 2025

The e13a3 (b2a3) and e14a3 (b3a3) BCR::ABL1 isoforms are resistant to asciminib

Leske IB and Hantschel O. Leukemia, September 2024

Leukemia 2024 Sep;38(9):2041-2045: https://www.nature.com/articles/s41375-024-02314-7

Introduction:

Asciminib, a first-in-class allosteric BCR::ABL1 inhibitor, has shown significant efficacy in patients with Philadelphia chromosome-positive chronic myeloid leukemia (CML) who have been previously treated with other tyrosine kinase inhibitors (TKIs). This study by Leske and Hantschel investigates the potential resistance of specific BCR::ABL1 isoforms to asciminib, particularly focusing on the e13a3 (b2a3) and e14a3 (b3a3) isoforms. These isoforms, which lack exon 2 of ABL1 and are present in less than 1% of CML patients, hypothesised to be resistant to asciminib due to the absence of a functional SH3 domain crucial for the drug's mechanism of action.

Leske Hantschel Fig 1a

 

 

 

Fig 1: Overview of BCR::ABL1 exon organisation of the common e13a2, e14a2 transcript variants, as well as e13a3 and e14a3 that lack ABL1 exon 2.

Study design:

  • Objective: To evaluate the resistance of BCR::ABL1 e13a3 and e14a3 isoforms to asciminib treatment.
  • Methodology: The study involved generating cDNAs for the e13a3 and e14a3 isoforms and testing their response to asciminib in BaF3 cells. The effect of asciminib on BCR::ABL1-dependent cell proliferation and survival was measured using a range of asciminib concentrations.
  • Comparison: The results for e13a3 and e14a3 were compared to the more common e14a2 isoform, which is known to be sensitive to asciminib.

Study results:

  • Asciminib sensitivity:
    • The e13a3 and e14a3 isoforms demonstrated significant resistance (~10,000-fold) to asciminib, with no inhibition observed at concentrations below 50 µM. In contrast, the e14a2 isoform showed a half-maximal growth inhibition (GC50) of approximately 1 nM.
    • Both e13a3 and e14a3 isoforms were highly sensitive to dasatinib, an ATP-competitive inhibitor.
  • Mechanism of resistance:
    • The resistance observed for the e13a3 and e14a3 isoforms was attributed to the absence of a functional SH3 domain, which is required for asciminib's allosteric inhibition of BCR::ABL1. Structural modelling and binding studies confirmed that the lack of exon 2 disrupts the SH3 domain, preventing the necessary conformational changes for asciminib-mediated inhibition.
    • Immunoblotting revealed that STAT5A/B phosphorylation, critical for leukemogenesis, remained unaffected by asciminib in e13a3 and e14a3 cells.

Leske Hantschel Fig 2a

 

 

 

 

 

 

Fig 2: BCR::ABL1 e14a2 and e14a3 are asciminib resistant, but sensitive to dasatinib. Normalised viability of Ba/F3 cells expressing BCR::ABL1 e14a2, e14a3 and e13a3 fusion transcripts was measured in the presence of the indicated concentrations of asciminib (a)
or dasatinib (b) after 48 h.

Conclusion
This study provides evidence of a primary resistance mechanism to asciminib in CML patients with the e13a3 and e14a3 BCR::ABL1 isoforms. These findings are crucial for personalising treatment strategies in CML and suggest that ATP-competitive BCR::ABL1 inhibitors, such as dasatinib, should be preferred for patients with these isoforms. Genetic screening for BCR::ABL1 isoforms is crucial before initiating therapy to ensure optimal treatment selection for CML patients.

iCMLf Forum 2024 - Meeting Summary

Topic: Advancing Treatment-Free Remission (TFR) in CML Worldwide
Date: December 6, 2024 | Location: San Diego (USA)

Meeting chair: Dr Katia Pagnano, HEMOCENTRO / UNICAMP – Brazil)

The 2024 iCMLf Forum focused on advancing Treatment-Free Remission (TFR) for CML globally. Expert speakers shared progress in research, diagnostics, and strategies for enhancing TFR access, particularly in low- and middle-income countries (LMICs).

Folie1Session 1: The iCMLf – Planning for the future

Speaker: Nicola Evans, Chief Executive, iCMLf

Nicola Evans provided an overview of iCMLf’s mission, vision and future direction, emphasising the continued support for equal access to treatment, diagnostics, and care for all CML patients.

The iCMLf leadership is finalising the strategies and projects for the next 10 years.
This will focus on:

  • Expanding CML education globally with a dedicated focus on LMICs
  • Increasing access to diagnostics
  • Providing overarching global patient support and information
  • Continuing to research optimal treatment pathways

More details to follow in early 2025…

Session 2: Understanding the Optimal Pathway to Successful TFR

Folie2Presentation: Biological Barriers to Cure

Speaker: Professor Brian J. Druker, OHSU Knight Cancer Institute, USA

Professor Druker discussed intrinsic and extrinsic barriers preventing TFR and proposed research strategies to overcome them.

Key Points:

  • Barriers to achieving TFR:
    • Cell-intrinsic factors: Kinase-independent survival pathways, epigenetic reprogramming, and metabolic adaptations allow residual leukemia cells to persist.
    • Cell-extrinsic factors: Immune system interactions, inflammatory responses, and the bone marrow niche play critical roles in maintaining minimal residual disease (MRD).
  • Long-term patient management:
    • Achieving deep molecular response remains a priority, with current therapies enabling TFR in only 10-20% of patients.
    • Shared decision-making is vital for managing treatment cessation, balancing benefits (e.g., reduced toxicity) with potential relapse.
  • Strategic goals for future therapies:
    • Targeting residual leukemic stem cells through safe, precise therapies.
    • Utilising global sample repositories to identify novel therapeutic targets and biomarkers for TFR success


Presentation: Innovative Biomarkers for TFR

Folie3Speaker: Professor Ong Sin Tiong, Duke-NUS Medical School, Singapore

Professor Ong presented data on biomarkers predicting TFR success and relapse, using single-cell technologies to identify stem cell differences.


Key Points:

  • Role of leukemic stem cells (LSCs):
    • Pre-treatment biology at the LSC level determines TFR outcomes, with specific biomarkers predicting relapse or sustained remission.
    • Patients with high LSC burden or certain genetic signatures exhibit higher risk of relapse post-TKI cessation.
  • Predictive biomarkers:
    • Rapid BCR::ABL1 decline at three months is linked to long-term TFR success, suggesting favourable pre-existing stem cell biology.
    • Identification of cell surface protein biomarkers (e.g., in CD34+ cells) at diagnosis may enable patient stratification for TFR attempts.
  • Single-cell technologies:
    • Leveraging single-cell RNA sequencing to map stem cell states, highlighting proliferative pathways (e.g., IL-2/STAT5 signalling) in relapsed patients.
    • Epigenetic gene sets in relapsed LSCs provide potential therapeutic targets for future interventions.


Session 3: Successful TFR Globally

Folie5Presentation: TFR in Low-and-Middle-Income Countries

Professor Akhil Ranjon Biswas, Dhaka Medical College, Bangladesh (presented by Dr Shanmuganathan)

Insights on TFR in LMICs, including how this can be achieved, patient perceptions and the challenges of limited access to TKIs, testing, and monitoring infrastructure.


Key Points:

  • Access barriers in LMICs:
    • Limited availability of TKIs due to lack of insurance and reliance on out-of-pocket expenses.
    • Variable access to molecular testing with concerns over sensitivity, reliability, and high costs.
  • Practical monitoring solutions:
    • Use of FISH cytogenetics and qualitative PCR as cost-effective alternatives to quantitative BCR-ABL testing.
    • Reducing test frequency while maintaining safety, e.g., bimonthly testing in the first six months.
  • Improving patient compliance:
    • Health literacy programs to educate patients on the importance of adherence and timely molecular monitoring.
    • Strengthening government support for free TKIs and subsidised diagnostics.

Folie4Presentation: Optimal TFR Monitoring

Speaker: Dr Naranie Shanmuganathan, Royal Adelaide Hospital, Australia

Dr Shanmunagathan presented optimised TFR monitoring strategies and practical approaches to improve global accessibility.

Key Points:

  • Optimised monitoring protocols:
    • Modelling reduced testing regimes (e.g., monthly for six months, then bi-monthly) showed significant cost reductions while maintaining safety.
    • Real-world implementation of updated NCCN and ELN guidelines would reduce testing burden.
  • Global disparities:
    • Successful TFR programs rely on reliable, timely, and affordable BCR::ABL1 testing infrastructure.
    • Regional and national efforts must address gaps in testing capabilities for widespread adoption of TFR strategies.

Folie6Presentation: Expanding Diagnostics for CML

Speaker: Professor Jerry Radich, Fred Hutchinson Cancer Center, USA

Professor Radich highlighted novel diagnostic solutions, including portable PCR devices, lateral flow assays, and nanopore sequencing for LMICs.

Key Points:

  • InnovativeV diagnostic tools:
    • Development of electricity-free PCR and lateral flow assays as affordable, portable options for LMICs.
    • Digital PCR offers superior sensitivity compared to conventional RT-PCR for detecting MRD and predicting relapse.
  • Advances in sequencing technologies:
    • Portable nanopore sequencing provides real-time results, enabling genetic analysis without reliance on centralised facilities.
    • Integration of sequencing data into mobile applications allows for rapid diagnostics and results sharing in remote areas.
  • Future directions:
    • Use of dried blood spot technology for multiplexed testing, including resistance mutations and whole-genome panels.
    • Expanding programs like “Spot on CML” to support large-scale diagnostics globally.

Panel Discussion

Moderator: Giora Sharf, CML Advocates Network
Panellists shared insights on the challenges and future of TFR, emphasising practical, affordable solutations for LMICs. 

Key Topics:

  • Balancing monitoring rigor and accessibility:
    • Flexible protocols (e.g., reduced testing frequency) are necessary for resource-limited settings without compromising safety.
  • Long-term monitoring beyond five years:
    • Shared decision-making with patients is critical, with proposals for six-monthly or annual testing based on individual risk.
  • Practical TFR implementation in LMICs:
    • Strategies to increase government-funded TKIs and diagnostics, alongside education programs to improve compliance and patient outcomes.

Conclusion

The 2024 iCMLf Forum delivered actionable insights to advance TFR worldwide. Experts emphasised collaboration, innovation, and equity in addressing barriers to care, particularly in LMICs, with a shared vision of achieving a cure for CML. 

iCMLf publication notice - September

 

As part of our monthly news service we would like to make you aware of the CML publications of the month. From the many papers published every month Professor Timothy Hughes has selected topical, interesting papers for your perusal that also include an interesting pediatric papers and publications from the LMICs.

Hughes.Tim Precision Medicine 3 PURERead Professor Hughes' CML publications of the month: September 2024

Clinical CML papers

Scientific CML papers

Pediatric papers

LMIC Papers

CML paper summary: Point-of-care BCR::ABL1 transcript monitoring using capillary dried blood in CML patients (Sala-Torra O et al. Leukemia, June 2024)

CML paper summary - October 2024

Point-of-care BCR::ABL1 transcript monitoring using capillary dried blood in CML patients

Sala-Torra O et al. Leukemia, June 2024
Leukemia (2024) 38:1822–1824  https://doi.org/10.1038/s41375-024-02285-9

Introduction:

This study explores a novel method for monitoring BCR::ABL1 transcripts in CML patients using a point-of-care dried capillary blood (DCB) collection system. With CML requiring lifelong treatment and frequent monitoring, the method aims to address the challenges faced by patients in remote locations or with limited access to healthcare facilities.

Study design:

  • 01 Figure 1AThe researchers developed and evaluated a capillary dried blood collection method using the Tasso-M20 device.
  • Twenty patients enrolled at Fred Hutchinson Cancer Center were monitored using DCB samples, which were compared with standard venous blood monitoring via quantitative reverse-transcription polymerase chain reaction (RT-PCR).
  • The samples were tested for BCR::ABL1 transcripts using the Xpert® BCR-ABL Ultra assay (Cepheid).

Study endpoints:

  • The primary goal was to assess the correlation between BCR::ABL1 transcript levels in DCB and standard venous blood samples.
  • Key outcomes included major molecular response (MMR) rates and overall sensitivity of the DCB method compared to venous blood.

Study results:

  • DCB collection using the Tasso-M20 device was well-tolerated, with patients reporting minimal pain (mean pain score <1.5).
  • Strong correlations (r=0.96) between BCR::ABL1 levels in DCB and venous samples were observed.
  • Fifteen patients achieved MMR by DCB measurements, of which 12 were concordant with venous blood results.
  • Patients with BCR::ABL1 transcripts <0.09% in venous blood were not reliably detected by the DCB method.

Discussion:

The study demonstrates the feasibility of patient-directed DCB collection for CML monitoring, providing a low-cost, stable, and convenient alternative to traditional venous blood testing. While the method is effective for detecting MMR and loss of response, its sensitivity for deeper molecular responses may be limited due to the smaller blood volume.
Future improvements, including larger sample collections, could enhance detection sensitivity.

Conclusion:

Capillary dried blood sampling offers a promising point-of-care tool for CML monitoring, especially in resource-limited settings. However, further developments are required to expand its use in treatment-free remission assessments.

CML paper summary: Asciminib in newly diagnosed CML (Hochhaus A et al. NEJM, May 2024)

CML paper summary - July 2024

Asciminib in Newly Diagnosed Chronic Myeloid Leukemia

Hochhaus A et al. NEJM, May 2024
ClinicalTrials.gov no. NCT04971226

Introduction

The study investigated the efficacy and safety of asciminib, a novel BCR::ABL1 inhibitor targeting the ABL myristoyl pocket, in patients newly diagnosed with chronic myeloid leukemia (CML). The objective was to determine if asciminib offered superior efficacy and safety compared to current first-line ATP-competitive tyrosine kinase inhibitors (TKIs), including imatinib and second-generation TKIs.

Trial Design

The trial enrolled a total of 405 patients, who were randomly assigned in a 1:1 ratio to receive either asciminib (80 mg once daily) or the investigator-selected TKI - one of the approved frontline TKIs, which included imatinib, nilotinib, dasatinib, or bosutinib.

Patients were stratified by European Treatment and Outcome Study long-term survival risk categories (low, intermediate, or high) and the TKI selected prior to randomization (imatinib or a second generation TKI).

Study endpoints

The primary endpoints were the major molecular response (MMR) at week 48, both for asciminib versus all TKIs collectively and specifically against imatinib.

Results
Patient Demographics and Follow-up:

  • 201 patients received asciminib, and 204 received a TKI.
  • Median follow-up was 16.3 months for asciminib and 15.7 months for TKIs.

Efficacy:

  • At week 48, 67.7% of patients in the asciminib group achieved MMR, compared to 49.0% in the Investigator-selected TKI group (difference: 18.9 percentage points; 95% CI, 9.6 to 28.2; P<0.001).
  • In the imatinib stratum (comparing only the patients where the investigator selected imatinib prior to randomization), 69.3% of asciminib-treated patients achieved MMR versus 40.2% in the imatinib group (difference: 29.6 percentage points; 95% CI, 16.9 to 42.2; P<0.001).
  • In the second-generation TKI stratum, MMR was 66.0% with asciminib and 57.8% with second-generation TKIs (difference: 8.2 percentage points; 95% CI, −5.1 to 21.5).

Safety:

  • Asciminib had a markedly favorable safety and tolerability profile, with fewer grade ≥3 AEs and AEs leading to treatment discontinuation vs all IS-TKIs

Discussion

The study demonstrated that asciminib significantly improved MMR rates compared to the investigator-selected TKI and to imatinib, in newly diagnosed CML patients. The safety profile of asciminib was also favourable, with a low rate of discontinuations due to side effects.

These results suggest that asciminib could become a preferred frontline therapy for CML,

Long-term follow-up is necessary to confirm the durability of these responses and the potential for treatment-free remission.

Abstract iCMLf Prize 2023: Hematology service for CML patients in Ukraine: challenges and successes

Collage 2023 iCMLf Prize winnersProfessor Irina Dyagil (Kyiv, Ukraine)
Head of the Department of Radiation Oncohematology
National Scientific Center for Radiation Medicine of the National Academy of Medical Sciences of Ukraine
Kyiv (Ukraine)

Dr Kostyantyn Kotlyarchuk (Lviv, Ukraine)
Head of the Hematology Department
SI ‘Institute of Blood Pathology and Transfusion Medicine NAMS’,
Lviv (Ukraine)

Management of chronic myeloid leukemia (CML) improved dramatically over the last two decades. Introduction of imatinib and later other tyrosine kinase inhibitors (TKIs) changed prognostic expectations for these patients from quite poor to those approaching general population. However, availability of both therapeutic and diagnostic tools to achieve these results were and still are not the same in different countries around the world. Ukraine is one of the biggest countries in Europe with a total population of an estimated 40 million at the beginning of 2022. Already back then in relatively peaceful times, access to appropriate diagnostics and treatment for CML was quite challenging for Ukrainian patients and physicians. Now after almost two years of open war, this is a story of many struggles and losses and yet of many wins and successes.

01 1In Ukraine, CML accounts for approximately 3500 patients according to the most recent analyses and the average age at diagnosis is 48 – younger than one would expect in the majority of other countries. Up to the year 2000, most of these patients would be treated either with interferon or hydroxyurea or in some occasional cases with busulfan. Bone marrow transplantation could be performed in even more rare situations. Diagnostic possibilities were limited to peripheral blood hematology test, bone marrow cytology and karyotyping. At the beginning of the TKI era, thanks to the enthusiasm of patients and physicians, first attempts to use imatinib were made already in 2003 - 2004 - sooner than in some countries with higher economical standards. This initiative evolved into even broader access to the medication within clinical trials and starting from 2008 – within a dedicated national program “Right to Live” with the ultimate goal to create ongoing access to life-saving therapy for CML patients and to implement International diagnostics and treatment of CML in Ukraine.

These efforts led to a gradual improvement of all aspects of medical service for this cohort of patients. Currently, in most of the cases CML diagnostic process in Ukraine - apart from the basic evaluations - includes also karyotyping and both quantitative and qualitative PCR-investigation. Patients can be treated with imatinib as well as the 2nd generation TKIs including nilotinib, dasatinib and bosutinib according to the indication. Thanks to these possibilities, 10-year overall survival for CML patients in Ukraine is estimated at 78%.

However, there are many issues yet to be solved. From the diagnostic perspective it is critical to improve access to PCR-monitoring of CML, which is currently limited to very few dedicated institutions. Conduction of conventional or next generation sequencing for resistant patients requiring detection of BCR-ABL1 mutations is still impossible in Ukraine. Regarding the spectrum of treatment options patients are lacking access to later generation TKIs capable of overcoming the resistant mutant clones including T315I mutation. Possibility to utilize allogeneic hematopoietic stem cell transplantation as potentially curative option for refractory patients is also limited to very few procedures per year. With the beginning of an open military intervention, in addition to the issues described above, the Ukrainian hematological community had to also face situations, in which even basic medical service could be unavailable for patients located in areas most affected by the war.

02 2Taking into account all the obstacles, challenges and unfavorable circumstances, one would hardly expect medical service for CML in Ukraine to improve significantly. Nevertheless, certain solutions are found and some successes have been achieved. Progress is seen regarding improved availability of PCR monitoring for CML, which is probably the most important tool to understand the course of the disease. In addition to one centre in Kyiv, a dedicated institution in Lviv and later some private institutions started monitoring CML patients with this method. Apart from local efforts, the development of PCR monitoring in Lviv was possible thanks to the support from the iCMLf within its “ICMLf Diagnosis and Testing Program”. International cooperation in these turbulent times is one of the most powerful solutions also for other issues like for example assessment of BCR-ABL1 mutations. Samples of these patients are investigated with support of MLL Münchner Leukämielabor in Germany. Patients requiring 3rd generation TKIs or treatments currently unavailable in Ukraine are either referred to hospitals in other countries or apply for medications within compassionate use program and other support programs including those by The Max Foundation.

Several years ago, transplantation activity in adult Ukrainian patients was limited only to autologous procedures. Despite obvious challenges, allogeneic transplantations for this cohort of patients were recently initiated.  The number of procedures performed in 2022 increased 7-fold as compared to 2021. These first steps are very promising and include not only the rising access to this critical treatment method but also the creation of the Ukrainian Association of Bone Marrow Transplantation and an active International cooperation within the Help for Ukrainian Hematology Patients (HUP) initiative in particular. Careful but visible restoration of clinical trial activity is also detected, which is a very important option not only in CML but in other malignant blood disorders as well.

04 4Progress in providing better service for CML patients means not only achievements in diagnostics and treatment – there are many other aspects that are important. Patient organizations are becoming more and more active and influential in Ukraine initiating educational and social events, participating in governmental boards responsible for medical decisions on the national level, integrating in international patient organizations and activities etc. There are ongoing research projects dealing with pregnancy in CML, TKI toxicity, disease course prognosis, treatment-free remission and many other issues.

One of the main priorities for the development of hematology in Ukrainian and the management of CML in particular, is International cooperation. Ukrainian researchers are participating in cooperative groups and networks including European LeukemiaNet, are taking part in joint projects and publications, which lift the standards of care for CML patients in the country to higher levels.

In conclusion, despite many challenges every effort is made by the hematological community in Ukraine (patients, physicians, researchers etc.) to bring medical service for CML in accordance with modern standards. International cooperation has been and continues to be crucial to keep CML treatment and diagnostics on an acceptable level during troubled times and to prepare for a fast development in more peaceful time once a normal life has been restored.

Contact:

Professor Irina Dyagil
Head of the Department of Radiation Oncohematology
National Scientific Center for Radiation Medicine of the National Academy of Medical Sciences of Ukraine, Kyiv
leuk@ukr.net

Dr Kostyantyn Kotlyarchuk
Head of the Hematology Department
SI ‘Institute of Blood Pathology and Transfusion Medicine NAMS’, Lviv
hematology_k@yahoo.com