Ponatinib induces a sustained deep molecular response in a chronic myeloid leukaemia patient with an early relapse with a T315I mutation following allogeneic hematopoietic stem cell transplantation: a case report
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Atypical BCR-ABL1 transcripts are detected in less than 5% of patients diagnosed with chronic myeloid leukaemia (CML), of which e19a2 is the most frequently observed, with breakpoints in the micro breakpoint cluster region (μ-BCR) and coding for the p230 BCR-ABL1 protein. p230 CML is associated with various clinical presentations and courses with variable responses to first-line imatinib.
Here we report a case of imatinib resistance due to an E255V mutation, followed by early post-transplant relapse with a T315I mutation that achieved a persistent negative deep molecular response (MR5.0) after treatment with single-agent ponatinib. Using CastPCR, we could trace back the presence of the T315I mutation to all the RNA samples up to the detection of T315 mutation by Sanger sequencing shortly after allogeneic hematopoietic stem cell transplantation (HSCT).
This case illustrates the major interest of ponatinib as a valid treatment option for e19a2 CML patients who present a T315I mutation following relapse after HSCT.
KeywordsCML T315I Relapse HSCT Ponatinib
Competitive Allele-Specific TaqMan PCR
Complete cytogenetic response
Chronic myeloid leukaemia
Donor lymphocyte infusion
Graft-versus host disease
Haematopoietic stem cell transplant
Major breakpoint cluster region
Major molecular response
Partial cytogenetic response
Tyrosine kinase inhibitor
White blood cell
Micro breakpoint cluster region
Chronic myeloid leukaemia (CML) is a myeloproliferative neoplasia caused by the fusion of the BCR and ABL1 genes, usually as the result of the reciprocal translocation t(9;22)(q34;q11.2). The exact breakpoint of the translocation and the molecular weight of the resulting fusion gene protein are variable, with most of the breakpoints on chromosome 22 falling in the major breakpoint cluster region (M-BCR), between exons 13 and 14 of the BCR gene, leading to a BCR–ABL1 mRNA with e13a2 or e14a2 junctions encoding for a p210 fusion protein . Less than 5% of patients express atypical transcript types, of which e19a2, with breakpoints in the micro breakpoint cluster region (μ-BCR) and coding for the p230 BCR-ABL1 protein, is the most frequently encountered with a frequency of 0.7–2.7% of the cases [2, 3]. p230 CML has been associated with various clinical presentations and courses with variable responses to first-line imatinib, possibly confounded due to reporting bias in favour of cases with atypical features and/or responses [4, 5, 6, 7]. The present study reports the case of a patient with p230 CML that was successfully treated with the third-generation tyrosine kinase inhibitor (TKI) ponatinib, following an early relapse with a T315I mutation after allogeneic stem cell transplantation.
Discussion and conclusions
p230 CML has been associated with various clinical presentations and courses [4, 5] with recent data suggesting that these patients have a poor response to front-line imatinib therapy, but better responses to second-line nilotinib and dasatinib [6, 7]. Point mutations in the kinase domain (KD) of the ABL1 gene represent the most common resistance mechanism to TKI therapy in CML, occurring in 30–90% of patients who develop resistance to imatinib , with more than 100 different mutations reported, although many are only rarely detected clinically . The relative in vitro sensitivity of different mutants to the various available TKI varies considerably and correlates well with the outcome after subsequent therapy with a different TKI . Similarly, mutants that are less likely to be inhibited by a given TKI are more likely to emerge clinically during therapy with such inhibitors .
Here we report a case of imatinib resistance due to an E255V mutation, followed by early post-transplant relapse with a T315I mutation that achieved a persistent negative deep molecular response (MR5.0) after treatment with single-agent ponatinib. Recently, patients with E255K/V mutations have been described as having a particularly poor prognosis, regardless of the stage of the disease at detection, with a higher risk of transformation to advanced/blast phase, and a short survival . Indeed, this mutation shows a high IC50 to all available TKIs, including third-generation ponatinb . In this case, dasatinib has been suggested as the most likely option in terms of probability of response among all available TKIs . Therefore, dasatinib treatment was initiated as a bridge to HSCT, and a CCyR was quickly achieved. However, in the following months, the patient lost CCyR and at the time of HSCT showed only a minor CyR. The best response achieved after HSCT was a PCyR, that was nevertheless quickly lost with mutation analysis revealing the presence of a T315I. Since the T315 mutation was retrospectively detected even before the detection of the E255V mutation, this suggests that at least two distinct BCR-ABL1 sub-clones were present at the start of therapy. This observation can be explained by differences in competitive advantage between mutant clones. Indeed, in vitro cell assays showed that selected mutant clones (for example, P-loop mutations Y253F, E255K) have higher transformation potency and proliferation rate compared with T315I, even in the absence of BCR-ABL1 inhibitors . Assuming that imatinib has lower activity against these mutant clones with P-loop mutations, they may expand more rapidly than clones with the T315I mutation when exposed to imatinib . On the other hand, it has been shown that dasatinib suppresses P-loop mutations to a greater extent than T315I , therefore a T315I positive clone may be able to increase its size during dasatinib treatment with relatively little competition from rapidly proliferating clones . This hypothesis is supported by the observation that dasatinib treated patients seem to more frequently show T315I mutations . This is in agreement with the model in which evolution of BCR-ABL1–positive cells is mainly shaped by TKI-selective pressure and the fitness of each ABL1 KD mutated population is the net result of the ability to survive treatment depending on the intrinsic sensitivity to the specific TKI administered and of the ability to survive the competition with all other coexisting populations .
Although our patient did not develop adverse events related to ponatinib therapy, its expected benefits must be balanced against the potential risks, including arterial hypertension, and serious arterial occlusive and venous thromboembolic events, reported in the PACE trial in 19 and 5% of patients, respectively. Published data support the observation that adverse events appear to be related to certain pre-existing cardiovascular risk factors, ponatinib dose, or both . For this reason, and since our patient was in sustained MR5.0 with no detectable disease after 27 months of ponatinib therapy, the dose was reduced to 15 mg OD. Fifteen months later, the patient maintains a sustained MR5.0 with no detectable disease. Ponatinib efficacy was previously observed in a CML e19a2 patient refractory to both imatinib and dasatinib therapy due to the presence of a T315I mutation . These results suggest that ponatinib could be an excellent therapeutic option in the treatment of e19a2 CML harbouring the T315I mutation refractory to previous therapies including HSCT, although more studies are necessary to draw a definitive conclusion.
This work was supported in part by an unrestricted grant from Incyte Corp.
Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
NC, RBF, MRT, and AC designed the study. RS was responsible for sample processing. NC and SB performed the molecular studies. CC, LT, SL and JV performed the cytogenetic analysis. RBF, FC, CPV, LL, and AC provided patient samples and clinical data. NC and RBF were responsible for the collection, analysis and interpretation of data. NC, RBF, MRT, and AC were involved in drafting the manuscript. All authors contributed to revisions, read, and approved the final version of this manuscript.
Ethics approval and consent to participate
This study is in accordance with the ethical standards of the Ethics Committee of the Portuguese Oncology Institute of Porto (approval number 38.010) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Consent for publication
Written informed consent was obtained from the patient.
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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