Changes in Common Blood Parameters After Discontinuation of Tyrosine Kinase Inhibitors for Chronic Myeloid Leukaemia

Abstract

Tyrosine Kinase inhibitors (TKI) have transformed the management of chronic myeloid leukaemia (CML), and whilst previously the primary aim was prevention of disease progression, a more recent goal is treatment-free remission (TFR) [1]. Patient-reported outcomes have shown improvements in quality of life for those who are able to stop TKIs indefinitely [2, 3]. In part, this may be related to restoration of normal blood cell parameters, with cessation of any possible myelosuppression and/or electrolyte imbalance.

Reversible dose-dependent haematological toxicity is commonly seen on TKI therapy [4]. Cytopaenias might represent a reduced bone marrow reserve of Philadelphia-negative haemopoiesis, rather than direct toxicity of TKI [5, 6], a concept that is reinforced by the low rate of haematological toxicity when TKIs are used for non-haematological diseases [7]. However, off-target signalling of pathways implicated in normal haemopoiesis, such as C-KIT, SRC and PDGFR, all play a role in myelosuppression and have the potential to disrupt normal haemopoiesis [8]. Dasatinib is associated with higher rates of myelosuppression than imatinib and nilotinib, which is attributed to its more potent kinase inhibition [7]. To investigate the reversibility of these effects, we sought to describe alterations in common blood parameters occurring after TKI discontinuation.

We retrospectively reviewed data from 177 patients, treated at Imperial College Healthcare NHS Trust, who discontinued TKI therapy between 7 April 2011 and 19 June 2023. Of these, 104 patients met the eligibility criteria, which included patients in chronic phase treated with any TKI, who met the ELN-defined criteria for treatment discontinuation [1], remained off TKI for a minimum of 6 months and who had locally available regular blood testing. Predefined exclusion criteria included prior transplant, patients who restarted their TKI within 6 months of stopping and patients with incomplete datasets. Blood parameters, as listed in Table 1, were assessed. C-reactive protein (CRP), lactate dehydrogenase (LDH) and urate levels were excluded due to insufficient data. The median baseline was recorded for each parameter using annual readings over 3 years prior to stopping TKI therapy. The median change from baseline was calculated annually for all parameters. Data for analysis were collected only from patients off TKI therapy. Ethics approval for this analysis was attained by Imperial College Healthcare NHS Trust, as part of a service evaluation.

The median age of our patients was 46 (15–86) years at diagnosis, and 51 (49%) were male.

EUTOS long-term survival (ELTS) scores at diagnosis classified patients as low (n = 63, 61%), intermediate (n = 21, 20%) and high risk (n = 9, 9%). The median age at TKI discontinuation was 58.5 years (25–91) and the median duration of TFR was 57 (7–149) months. Sixty-one (59%), 23 (22%) and 20 (19%) patients discontinued first, second- or third-line therapy, respectively. No patient received more than 3 lines of TKI therapy prior to TFR. At the time of discontinuation, 49 (47%), 25 (24%), 20 (19%), 7 (7%), 2 (2%) and 1 (1%) were on imatinib, nilotinib, dasatinib, bosutinib, ponatinib and asciminib, respectively.

The following full blood count parameters (white cell count, red blood cell count, haemoglobin, haematocrit, platelets, neutrophils) all had statistically significant median changes from baseline annually until at least 4 years post TFR, and documented as far out as year 7; WCC (p = 0.0039), RBC (p = 0.0010), Hb (p = 0.0125), HCT (p = 0.0078), platelets (p = 0.0216) and neutrophils (p = 0.0024), (Table 1). Whilst statistically significant, in real terms the changes do not result in any clinically meaningful alterations—the maximum annual median change in WCC is +0.7 × 10⁹/L and similarly, the median change annually from a baseline haemoglobin of 132 g/L was a maximum rise of +4 g/L. Of note, 8 patients had mild thrombocytopaenia (>100 × 10⁹/L), and all normalised their platelet count post TKI discontinuation. No clinically or statistically significant changes were seen in lymphocyte counts.

Sixteen patients (9%) had elevations in their haemoglobin and haematocrit above the normal reference range (Hb > 165 g/L and HCT > 0.45L/L) following TFR. This cohort was exclusively male with a median age of 62.5 (41–88) years at discontinuation. No JAK2 mutations were detected, nor did any patient have any thrombotic complications. One patient received intermittent venesection (3 times over 4 years), suggesting post-TFR erythrocytosis phenotype was different to that of primary polycythaemia, and thus requires further investigation. Our data show that 6 years post TKI discontinuation, blood parameters reach a steady state with no statistically significant annual changes, suggesting this phenomenon is unlikely to occur after this time point.

Liver and bone profile parameters (alanine transaminase [ALT], alkaline phosphatase [ALP], adjusted calcium and inorganic phosphate) were assessed. There were no statistically significant changes in either ALT or adjusted calcium. Ninety-four patients (90%) experienced statistically significant median changes of ALP from their baseline of +15.5unit/L (p < 0.0001) from years 1 to 8 post TKI discontinuation. Inorganic phosphate levels rose by +0.085 mmol/L at Year 1 post TKI discontinuation (p < 0.0001) and showed a statistically significant rise from median baseline annually up to 4 years post TFR (p = 0.0442). Despite the increase in absolute values, both ALP and inorganic phosphate remained in the normal range. There is increasing awareness of renal adverse events on long-term TKI therapy, with improvement in eGFR on cessation [9, 10]. However, in our cohort, there was no statistically significant difference in either creatinine or eGFR. (Figure 1)

Inhibition of bone reabsorption is a TKI class effect resulting from their impact on haemopoiesis and mesenchymal stem cells [11] (MSCs). In clinical practice, in the early years, imatinib was often associated with hypophosphatemia with increased urinary phosphorus excretion [9, 12]. Secondary hyperparathyroidism and hypophosphatemia are commonly seen in TKI therapy [10]. Cessation of off-target signalling results in increased osteoclastogenesis, of which ALP elevation is an early sign. As a result, the minimal increases, however clinically insignificant, in inorganic phosphate and ALP levels following TKI discontinuation are expected. Our data suggest that for biochemical parameters to reach a steady state require a median of 4–8 years following TKI discontinuation.

The International-Berlin-Frankfurt-Münster (I-BFM) group recommend routine bone densitometry in paediatric CML-CP patients on TKI therapy, but there are few data on bone health in children or adults after TKI discontinuation, and this requires further consideration. Whilst we identified statistically significant changes in some blood parameters, the median changes from baseline over 9 years of observation were all clinically insignificant and remained within the normal range. Our study has some limitations; not only is it a retrospective single-centre data collection, but the number of patients evaluable diminished over the years post-discontinuation. Nevertheless, our data suggest that TKI therapy is associated with minimal myelosuppression and that there is an inconsequential impact of discontinuation of TKI therapy on blood parameters.

FF, CW and JFA wrote the manuscript. JFA, DM, SC, AJI and FF were responsible for the clinical care of the patients. All authors reviewed and edited the manuscript and figures. All authors approved the final manuscript version.

Ethics approval for this analysis was attained by Imperial College Healthcare NHS Trust, as part of a service evaluation.

The authors have confirmed patient consent statement is not needed for this submission.

FF: speakers bureau (Novartis), research funding (Pfizer). JFA: Honoraria, research funding, and speakers bureau (incyte, Pfizer); honoraria and speakers bureau (Bristol Myers Squibb, Novartis). DM: Honoraria (Incyte, Novartis, Pfizer, Ascentage Pharma), Research funding (Incyte and Pfizer). AJI: Speakers bureau (Incyte), speakers bureau and advisory board (Novartis). All other authors report no conflict of interest.