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Clinical Case of the Month – Maintenance TKI after alloHSCT for CML in blast crisis – when, which and why?

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Clinical Case of the Month

Title: Maintenance TKI after alloHSCT for CML in blast crisis – when, which and why?

Submitted by: Dr Sarah Kelliher, Specialist Registrar, St. James’ Hospital, Dublin, Ireland

Physician expert perspective: Dr Chris Armstrong, Consultant Haematologist, St. James’ Hospital, Dublin, Ireland

Clinical Case Summary

A 37 year old man was diagnosed with chronic phase CML in 2022 with hyperleukocytosis (129 x 109/L) and splenomegaly of 25cm. A standard p210 BCR::ABL1 transcript type was identified and there was an additional chromosomal abnormality in the form of i(17q). The ELTS risk group was intermediate. He was commenced on imatinib 400mg daily and failed to achieve a response within the first 6 months of treatment. Overt leucocytosis was present at 6 months post-diagnosis, and a repeat bone marrow aspirate and trephine identified ongoing chronic phase disease and ABL1 kinase domain mutation analysis showed a E355G mutation. In addition to the ABL1 resistance mutation, erratic medication compliance was identified as a cause of treatment failure. 

The patient was switched to dasatinib 100mg at this timepoint and in the subsequent year failed to achieve cytogenetic or molecular response, with a nadir BCR::ABL1 transcript ratio of 4.4% (IS) by 17 months post-diagnosis. He was subsequently referred to his local transplant centre for an opinion and at that time was in overt chronic phase disease with a BCR::ABL1 ratio of 54.6% (IS) and a white cell count of 67 x 109/L. Medication compliance was identified as the primary driver of the lack of response. Shortly after the patient had a repeat bone marrow aspirate and trephine with a concern for myeloid blastic transformation and was commenced on FLAG-IDA with ponatinib. He received 2 courses of treatment and achieved a return to CP2 but with persistent high level BCR::ABL1 transcripts. At the time of transformation the E355G mutation persisted and a somatic mutation in ASXL1 was identified. 

A myeloablative conditioned allo-HSCT was performed with a 10/10 HLA matched unrelated donor using fludarabine, busulfan and post-transplant cyclophosphamide with tacrolimus and mycophenolate mofetil. Immediately prior to transplant the BCR::ABL1 ratio was 18.9% (IS). Neutrophil engraftment occurred on day 18, and platelets on day 20. At 1 month post-transplant the BCR-ABL1 ratio was 0.008% (IS) and tacrolimus was weaned from D+60 in the absence of acute graft versus host disease. At 2 months post-transplant the BCR::ABL1 ratio was 0.002% (IS) and donor chimerism was complete (whole blood and CD3+ compartment).

Question

At 3 months post-transplant the BCR::ABL1 transcripts were not detected (test sensitivity MR5), which course of action would you take?

  1. Prophylactic DLI at a dose of 0.1 x 107/kg CD3+ cells
  2. Screen for ABL1 kinase domain mutation and ASXL1 persistence
  3. Start prophylactic imatinib 400mg once daily
  4. Start prophylactic second generation TKI
  5. Start a prophylactic allosteric TKI (asciminib) or potent orthosteric TKI (ponatinib)

Expert Review 

This case describes a man with classical chronic phase CML (CP-CML) at the time of diagnosis. The latest iteration of the WHO classification of haematological malignancies saw significant nomenclature change in CML classification, with a move from a triphasic classification to a binary one1. Within the now widened group of CP-CML, sub-categorisation is important to identify adverse risk features, and in this case the additional chromosomal abnormality and the emergence of resistance mutations on treatment firmly places him into the “High-risk chronic phase” category. While not an indication for upfront allo-HSCT, knowing donor options and considering transplant suitability early can be helpful in this group of patients2. Interestingly, despite the advances in molecular characterisation and risk stratification of most myeloid malignancies, its role in CP-CML prognostication is not yet standardised, primarily as mutations do not predict response to specific TKIs, however there is growing evidence to suggest their prognostic role more generally. The most widely used prognostic tool, the ELTS, requires only simple clinical characteristics. In this case, the intermediate risk disease stratification and the i(17q) both raised some early warning signs for a potential adverse outcome. Ultimately adverse disease biology, coupled with partial TKI compliance, which exerts selective pressure leading to ABL1 kinase domain mutagenesis, led to disease progression and the need for a consolidative allograft in this case.

Many ABL1 kinase domain mutations have been described in CML, and their implications for drug-resistance patterns are well categorised, particularly for traditional first, second and third generation TKIs. In this case the E355G mutation is associated with resistance to imatinib and nilotinib (due to c lobe location) but is typically sensitive to dasatinib3. However, in vitro antiproliferative activity of TKIs is not always replicated in vivo and except for the most accurately correlated mutations, such as E255K, V299L and T315I (amongst others), careful interpretation in the clinic context is required4. Poor medication compliance remains a challenge in some patients with CML, and despite expected disease sensitivity to dasatinib in this case, sporadic drug exposure allowed for ongoing clonal proliferation, the selection of a clone with drug-resistance mechanisms, and ultimately disease transformation.

The role of allo-HSCT remains important for a small group of patients with CML, particularly those with adverse risk features, after treatment failure and in those who progress to blast crisis at any point. What is clear from registry studies is that patients transplanted before blast transformation and those who achieve a return to chronic phase have better long-term disease-free survival. The evidence to guide remission induction and bridging to transplant in blast phase CML (BP-CML) is limited by disease rarity, but the MATCHPOINT trial provides useful objective data, albeit in a small number of patients, to support the use of FLAG-IDA backbone chemotherapy alongside the third generation TKI ponatinib5. This treatment offers both lineage agnostic coverage and accounts for most ABL1 KD mutation resistance mechanisms. 

Outcomes following BP-CML are highly dependent on successful allo-HSCT, and in suitable patients, early transplant following a return to CP2 is recommended6. In this case a return to CP2 was achieved following FLAG-IDA + ponatinib, but interestingly, and despite no new ABL1 KD mutations arising, the BCR::ABL1 transcripts remained essentially unchanged prior to transplantation. Myeloablative conditioning is the preferred intensity in those who are fit enough, and modern T-cell depleting strategies such as PTCy are demonstrably efficacious in CML, which was the rationale for the conditioning chosen for this patient7. The sensitivity of CML to allo-HSCT is here clearly demonstrated by the achievement of deep MMR within a month of stem cell infusion. Nevertheless, long term survival in BP-CML is globally suboptimal, mediated particularly by disease relapse, and therefore strategies to identify and modulate this risk are necessary. 

De Lavallade and colleagues from the EBMT, ELN and wider CML community have recently devised consensus guidance on when and how to intervene post-transplant in CML, and this document will shortly be published. Currently the two main therapeutic options in the post-allograft setting are DLI and TKI. CML is demonstrably sensitive to a GVL effect, and therefore DLI in those with mixed chimerism or relapsing disease is long known to be effective, particularly in those unable to receive an appropriate TKI. However, its use in a prophylactic manner (i.e. full donor chimerism, in molecular remission) is not well supported and is currently not recommended. In patients with BP-CML, many of whom have not yet exhausted all available TKIs prior to transplant, the option of post-transplant maintenance is attractive. However, objective data to support this is lacking, and indeed the 2019 CIBMTR study (n=89, registry-based study from 2007-2014) could not demonstrate a leukemia-free survival advantage8. 

TKIs may also be difficult to administer post-transplant, particularly in those with major toxicities and weaker graft function. In this case engraftment was robust and there was no spontaneous aGVHD. We therefore elected to start prophylactic TKI at 3 months post-transplant. In choosing a TKI several considerations were necessary. Firstly, the previous E355G mutation, which would suggest avoidance of imatinib and nilotinib. While in theory dasatinib should have efficacy, the history of disease progression while partially compliant with this drug is noteworthy. Ponatinib is often used post-transplant due to its wide coverage of resistance mechanisms, however it can be difficult to maintain due to cytopenia and longer term it has an unfavourable cardiovascular risk profile, which is relevant for long-term survivors post-allo-HSCT. Furthermore, in this case, despite 3 months of ponatinib exposure in the pre-transplant period, no meaningful reduction in BCR::ABL1 transcripts was achieved. The second consideration is the ASXL1 somatic mutation identified at blast transformation, for which there is increasing evidence to suggest adverse responses to all currently available TKIs (at least in CP-CML), including asciminib9. Ultimately, due to the suboptimal molecular response to ponatinib, we elected to switch to asciminib for maintenance therapy in this case, which to date has been well tolerated with ongoing MRD negative remission. Emerging data to support its tolerability and efficacy post-transplant is encouraging10,11. Consensus on the optimal duration of treatment suggests at least 2 years with deep molecular response, with consideration for extension depending on response kinetics and tolerance. 

It must be noted that licensing and access to TKI in the post-transplant setting is highly variable geographically, and therefore it would not be unreasonable to consider a second generation TKI (other than nilotinib), or ponatinib in this case. In the absence of access to any prophylactic TKI, comprehensive monitoring of both MRD and chimerism in peripheral blood, at least 3 monthly for the first 2 years, would be recommended with early intervention with DLI, TKI or both for mixed chimerism/molecular relapse. Low level fluctuant molecular positivity is not necessarily predictive of relapse in CP-CML, but in BP-CML, the implications of rising MRD are significant, as re-emergence of overt disease carries a dismal prognosis. The thresholds for defining molecular relapse to guide intervention are suggested by De Lavallade et al, and they draw particular attention to the kinetics of response, regular monitoring early post-transplant, and the importance of swift confirmatory testing with a sensitive assay.

Correct Answer  –  4, 5

References

  1. Khoury, J.D., Solary, E., Abla, O. et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia 36, 1703–1719 (2022)
  2. Apperley, J.F., Milojkovic, D., Cross, N.C.P. et al. 2025 European LeukemiaNet recommendations for the management of chronic myeloid leukemia. Leukemia 39, 1797–1813 (2025). 
  3. Reddy EP, Aggarwal AK. The ins and outs of bcr-abl inhibition. Genes Cancer. 2012 May;3(5-6):447-54.
  4. Soverini S. Resistance mutations in CML and how we approach them. Hematology Am Soc Hematol Educ Program. 2023 Dec 8;2023(1):469-475.
  5. Copland M, Slade D, McIlroy G, Horne G, Byrne JL, Rothwell K, Brock K, De Lavallade H, Craddock C, Clark RE, Smith ML, Fletcher R, Bishop R, Milojkovic D, Yap C. Ponatinib with fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor chemotherapy for patients with blast-phase chronic myeloid leukaemia (MATCHPOINT): a single-arm, multicentre, phase 1/2 trial. Lancet Haematol. 2022 Feb;9(2):e121-e132. 
  6. Chalandon Y, Sbianchi G, Gras L, Koster L, Apperley J, Byrne J, Salmenniemi U, Sengeloev H, Aljurf M, Helbig G, Kinsella F, Choi G, Reményi P, Snowden JA, Robin M, Lenhoff S, Mielke S, Passweg J, Broers AEC, Kröger N, Yegin ZA, Tan SM, Hayden PJ, McLornan DP, Yakoub-Agha I; Chronic Malignancies Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Allogeneic hematopoietic cell transplantation in patients with chronic phase chronic myeloid leukemia in the era of third generation tyrosine kinase inhibitors: A retrospective study by the chronic malignancies working party of the EBMT. Am J Hematol. 2023 Jan;98(1):112-121.
  7. Ortí G, Gras L, Koster L, Kulagin A, Byrne J, Apperley JF, Halaburda K, Blau IW, Clark A, Kröger N, Griskevicius L, Carlson K, Collin M, Bloor A, Raiola AM, Blaise D, Aljurf M, López-Corral L, Sakellari I, Beguin Y, Wrobel T, de Rosa L, de Lavallade H, Hayden PJ, McLornan D, Chalandon Y, Yakoub-Agha I. Graft-versus-Host Disease Prophylaxis with Post- Transplantation Cyclophosphamide in Chronic Myeloid Leukemia Patients Undergoing Allogeneic Hematopoietic Cell Transplantation from an Unrelated or Mismatched Related Donor: A Comparative Study from the Chronic Malignancies Working Party of the EBMT (CMWP-EBMT). Transplant Cell Ther. 2024 Jan;30(1):93.e1-93.e12. 
  8. DeFilipp Z, Ancheta R, Liu Y, Hu ZH, Gale RP, Snyder D, Schouten HC, Kalaycio M, Hildebrandt GC, Ustun C, Daly A, Ganguly S, Inamoto Y, Litzow M, Szer J, Savoie ML, Hossain N, Kharfan-Dabaja MA, Hamadani M, Reshef R, Bajel A, Schultz KR, Gadalla S, Gerds A, Liesveld J, Juckett MB, Kamble R, Hashmi S, Abdel-Azim H, Solh M, Bacher U, Lazarus H, Olsson R, Cahn JY, Grunwald MR, Savani BN, Yared J, Rowe JM, Cerny J, Chaudhri NA, Aljurf M, Beitinjaneh A, Seo S, Nishihori T, Hsu JW, Ramanathan M, Alyea E, Popat U, Sobecks R, Saber W. Maintenance Tyrosine Kinase Inhibitors Following Allogeneic Hematopoietic Stem Cell Transplantation for Chronic Myelogenous Leukemia: A Center for International Blood and Marrow Transplant Research Study. Biol Blood Marrow Transplant. 2020 Mar;26(3):472-479.
  9. Shanmuganathan N, Wadham C, Yeung DT. Strong association between cancer gene variants at diagnosis, especially ASXL1, and emergence of kinase domain mutation driven resistance in CML patients despite frontline treatment with more potent BCR::ABL1 inhibitors. Blood. 2024; 144(Supplement 1):991.
  10. Fernando F, Innes AJ, Claudiani S, Pryce A, Hayden C, Byrne J, et al. The outcome of post-transplant asciminib in patients with chronic myeloid leukaemia. Bone Marrow Transplant. 2023;58(7):826–8.
  11. Mohamed Isam Sharif YV, Daniel Wolff,  Kathrin Reuthner,  Francesca Bonifazi,  Ahmet Emre Eşkazan,  Osman Sahin, mehmet sezgin pepeler,  Leylagul Kaynar,  Mohsen Alzahrani,  Mohamed Abu Haleeqa,  Acy Quixada, Ivan Moiseev,  Elena Morozova,  Dennis Kim. Post-transplant Asciminib Treatment as Maintenance, Pre-emptive or Relapse therapy in Philadelphia-Positive Advanced Leukemias: Multicenter Real-World Data Analysis.  European Haematology Association; Stockholm 2026.

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