Clinical Case Discussion Forum
To share and enhance best practice management of CML, experts and interested clinicians can discuss difficult or interesting CML cases here. Physicians submit a brief history of the patient and the case for discussion using this forum.
CML with small size TP53/17p deletion
Male, 55 y. Clinical diagnosis: Chronic myeloid leukemia (CML), chronic phase, Philadelphia chromosome-positive (Ph+). Deep molecular response (MR5) achieved in 2023. Loss of molecular response (resistance to first-generation tyrosine kinase inhibitor).
Medical history: CML was diagnosed in 2006. The patient continuously received treatment with a first-generation tyrosine kinase inhibitor (Gleevec/imatinib) at a dose of 400 mg daily. In 2017, the dose was increased to 600 mg daily because of an insufficient treatment response. Since 2021, the patient has been followed remotely. The medication was taken regularly, however, the dose was occasionally reduced due to insufficient drug supply. Loss of treatment response was documented in 2026.
Laboratory data:
Molecular biological test dated 20-Feb-2017: Expression of the BCR::ABL (p210) gene was detected in peripheral blood leukocytes and amounted to 2.5% relative to the normal ABL gene.
Molecular biological test dated 11-Jun-2018: Expression of the BCR::ABL (p210) gene was detected in peripheral blood leukocytes and amounted to 2.3% relative to the normal ABL gene.
Molecular biological test dated 28-Jun-2019: Expression of the BCR::ABL (p210) gene was detected in peripheral blood leukocytes and amounted to 0.73% relative to the normal ABL gene.
Molecular biological test dated 09-Mar-2020: Expression of the BCR::ABL (p210) gene was detected and amounted to 0.03% relative to the normal ABL gene.
Molecular biological test dated 14-Sep-2023: BCR::ABL transcript level ≤0.001% relative to the normal ABL gene.
Molecular biological test dated 12-Mar-2026: BCR::ABL transcript level 2.28% relative to the normal ABL gene.
Molecular biological test dated 09-Jun-2026: BCR::ABL transcript level 1.69% relative to the normal ABL gene.
Bone marrow report 08.07.2026 The peripheral blood is normocellular and shows an approximately normal distribution of cells. No left shift, no blasts, no basophilia, no thrombocytosis. The particle-free, highly cellular bone marrow aspirate shows a relatively increased granulopoiesis. The blast proportion is 2%. The erythropoiesis is underestimated due to the sample quality. Immature myeloid cells are present (1%). These findings provide no evidence of an increased blast count.
Molecular genetics report Using nested PCR, a BCR::ABL1 fusion transcript of type M-BCR (e13a2 corresponding to p210) was detected. The requested analysis for BCR::ABL1 resistance mutations could not be performed successfully due to the low BCR::ABL1 expression. Report of chromosome and FISH analyses Detected aberrations (with prognostic and/or therapeutic relevance, if applicable): - t(9;22)(q34;q11): BCR::ABL1 rearrangement with additional BCR::ABL1 fusion signal - derivative chromosome 17, TP53/17p deletion Karyotype (according to ISCN): 46,XY,t(9;22)(q34;q11)[1]/ 46,XY,t(9;22)(q34;q11),der(17)t(17;22)(p11;q11)t(9;22)(q34;q11)[3]/ 46,XY[19] FISH on interphase nuclei: Detection of a BCR::ABL1 rearrangement and detection of a BCR::ABL1 rearrangement with an additional BCR::ABL1 fusion signal No detection of a MECOM rearrangement No detection of a TP53/17p deletion No detection of a KMT2A rearrangement Chromosome banding analysis showed a clone with a TP53 deletion. However, this clone is of such small size, that it was not detected by FISH on interphase nuclei but identified in chromosome banding analysis due to proliferation advantage.
In your opinion, what treatment plan will be optimal for the patient? Thank you in advance
This is a 55 year old man, diagnosed before 2017 with CP-CML and commenced on imatinib. Inadequate response to imatinib 400mg and dose increased to 600mg in 2017. Thereafter, slowly reducing BCR::ABL1 level, achieving MR2 in 2019, MR3 in 2020 and DMR in 2023. A gap in results, then in 2026 loss of MR2 in 2 samples, but still <10% BCR::ABL1. Bone marrow test in July showed loss of CCyR with a small clone 3/22 cells with t(9;22) and possible TP53 deletion although results below are contradictory.
Additional cytogenetic abnormalities suggest clonal evolution – it is unclear if karyotype is the same as at diagnosis.
Mutation screen failed.
Regarding treatment:
I would discuss compliance with the patient as this is often poor with imatinib 600mg.
In terms of next line of therapy, any of nilotinib, dasatinib, bosutinib. I would repeat bone marrow and cytogenetics after 3-6 months to ensure resolution of additional cytogenetic abnormality and re-attainment of CCyR.
In view of possible clonal evolution, I would also discuss possibility of alloSCT and perform tissue typing.
If failed 2G TKI, then I would switch to ponatinib and work up for alloSCT.
I suggest to screen mutation by NGS because of loss of CCyR and failure by Sanger sequencing. In the absence of T315I and comorbidity, switching dasatinib may be considered. If CCyR can not be achieved after 3 or 6 months and still in the chronic phase, I prefer to switch 3G- or 4G-TKI. If none of these work, TKI based combination therapy or transplant may be considered.
This is a very concerning case. Loss of response along with clonal progression, even at a low level, suggests disease worsening. This is what was once called early acceleration. Although a new TKI may give temporary control, this patient appears to be heading to a blast crisis. I would recommend allogeneic stem cell transplant before it gets that far, if at all possible. If not, consider ponatinib or asciminib if the former not available. Waiting is not an option.