Diagnosing chronic myeloid leukaemia (CML) during pregnancy is rare. Tyrosine kinase inhibitors (TKIs) have traditionally been contraindicated owing to their teratogenicity. Management decisions ...should consider the risks to mother and foetus of uncontrolled disease and teratogenic medications. Further cases are required to build upon the paucity of current literature. We report 22 cases of CML diagnosed during pregnancy from 2002 to date. Twenty-one pregnancies resulted in healthy babies and one patient miscarried. Some patients remained untreated throughout pregnancy but the majority received one or both of interferon-α and leucapheresis. One patient was started on imatinib at Week 26, and one on hydroxycarbamide in the third trimester. We report haematological parameters during pregnancy to provide clinicians with realistic expectations of management. There were no fetal abnormalities related to treatment during pregnancy. Seventeen patients achieved at least major molecular response on first-line TKI. A diagnosis of CML during pregnancy can be managed without significant consequences for mother or child. Leucapheresis and interferon-α are generally safe throughout pregnancy. Despite having been avoided previously, there is growing evidence that certain TKIs may be used in particular circumstances during the later stages of pregnancy. Future work should aim to further elucidate this safety profile.
Background:
In recent years, the use of second‐generation TKIs has increased in both first and second‐line settings in CML. Extended follow‐up of the phase III study of first‐line nilotinib (NIL) ...(ENESTnd) saw an unexpected increase in cardiovascular events (CVE) in the NIL arms, particularly in patients (pts) with higher Framingham risk scores. However, ‘real‐life’ data on the risk of CVE in Nil treated pts are still limited.
Aims:
We aimed to determine the probabilities of all CVE and ischaemic arterial events (IAE) at any time from NIL start, in a ‘real‐life’ setting.
Methods:
We retrospectively analysed 193 CML pts (75 male, 49.2%) given NIL in our centre. Univariate analysis was performed by Kaplan‐Meier and multivariate analysis by Cox proportional hazard model. For both univariate and multivariate analysis, the impact of cardiovascular risk factors (CVRF) was analysed independently of age.
Results:
The median ages at diagnosis and start of NIL were 46 (18–89) and 51 (20–89), respectively. The overall follow‐up from diagnosis was 110 mths (12–286) and from start of NIL 37 mths (0.1–139). Baseline CVRF were known for 143/193 pts (74%). At least 1 CVRF was present in 94/143 pts (65.7%) and were more common in pts > 60 (p < 0.001). A total of 70 CVE occurred in 50/193 pts (25.9) (Figure 1a). The median duration of NIL therapy in those with CVE was 35.3 months vs 38.5 months in unaffected pts. The median times to occurrence of any CVE or IAE were 19.6 months (0.1–88) and 28.6 months (0.17–85), respectively. The 3 and 5 probabilities of any CVE were 18.1% (95%CI: 17.5–18.7) and 27.9% (95%CI: 27.2–28.6), respectively, while for IAE these were 10% (95%CI: 9.6–10.5) and 13.7% (95%CI: 13.1–14.3), respectively. The duration of NIL doses of 600–800 mg in pts experiencing IAE was 25.8 months (0.17–85), compared to 14.7 months (0.2–124) in unaffected pts (p = 0.86); for CVE, these periods were 24.1 months (0.1–88) and 12.4 months (0.2–124), respectively (p = 0.45). In univariate analysis, age ≥51, presence of any CVRF and male sex were significantly associated with a higher probability of CVE (p = 0.001, p = 0.025, p = 0.005, respectively), while only age ≥51 was significant for the occurrence of IAE (p = 0.0001). ROC analysis of age and occurrence of IAE identified 59 years as the cut‐off with highest sensitivity and specificity (AUC 0.738, p < 0.001). Using this information, the 5 year probability of any CVE was 47.5% (95%CI: 46.1–48.9) for pts ≥59 years and 17.7% (95%CI: 16.9–18.5) for pts <59 years (p = 0.000058), while for IAE this was 27.5% (95%CI: 26.3–28.8) vs 6.4% (95%CI: 5.9–6.9), respectively (p = 0.000028)(Figure 1b). In multivariate analysis, age ≥ 59 and male sex remained significantly associated with occurrence of CVE (HR = 2.295%CI: 1.4–4.8, p = 0.001 and HR 1.8 95%CI: 0.9–3.2, p = 0.047, respectively); age ≥ 59 was again the only variable significantly associated with IAE (HR = 5.2395%CI: 2.2–12.7, p = 0.0001). At last follow‐up 182 pts (94.3%) are still alive, of whom 82 (47%) remain on NIL, 2 (1%) on imatinib, 33 (18%) on dasatinib, 24 (13%) on bosutinib, 9 (5%) on ponatinib, 1 on ABL001, 31 off‐TKI (20 in TFR and 11 post‐allogeneic transplant). Eleven patients (5.7%) have died, due to CML‐progression (6), secondary malignancy (1), cardiovascular disease (1) and unknown causes after loss to follow‐up (3).
Summary/Conclusion:
Although requiring validation by larger studies, our data confirm the significant association of NIL with long‐term CVE and identifies age as the most critical factor for their occurrence.
Background:
Ruxolitinib, like other clinically tested JAK2 inhibitors, is effective in reducing spleen size and symptom burden in patients with myelofibrosis (MF), but in most patients does not ...significantly reduce the mutant clone or bone marrow fibrosis. Additionally most patients develop resistance after an initial response or require dose reductions due to toxicity. Lastly, given compelling evidence that the microenvironment plays a crucial role in the development of myeloproliferative neoplasms (MPN), targeting the MPN cell clone in isolation may have limited efficacy.
Aims:
Therefore, we aimed to identify the signalling pathways promoting the survival of MPN cells in the presence of Ruxolitinib and the microenvironment.
Methods:
We applied a pooled shRNA library screen of ∼5000 genes (Cellecta, Inc.) to HEL cells, a JAK2 V617F‐mutated MPN cell line model, and we used conditioned medium (CM) from human‐derived stromal cells (HS‐5) to recapitulate in vitro the microenvironment component. Two culture conditions were tested, each run in duplicate: CM + ruxolitinib and RPMI + ruxolitinib. We also performed shRNA library screen for CD34+ cells derived from peripheral blood from a patient with primary MF treated with JAK2‐inhibitor. Primary cells were cultured in CM and the identified candidate shRNAs were compared with those resulting from the cell line screen. Chemical validation of the top‐depleted shRNAs was carried out in vitro in both the HEL cell line and primary CD34+ cells from MF patients using proliferation (MTS) and Trypan‐blue viability assays following culture with the inhibitors.
Results:
shRNAs were considered significant for the cell survival if their depletion was ≥ 2‐fold compared to baseline sample and was observed in at least 2 shRNAs targeting the same gene.
Our screening of the ruxolitinib‐treated HEL cells cultured in CM identified 13 candidate genes with high fold depletion only in presence of the microenvironment, which will be part of future analysis. We decided in first instance to focus our attention on those genes whose depletion was maintained in the presence of the microenvironment. Among these, nucleocytoplasmic transport (confirming the recently published evidence: D Yan et al., 2018) and ubiquitin‐proteasome pathway genes were the most depleted in both settings (with and without CM). Interestingly, some of the proteasome machinery genes were highly depleted also in the primary cell shRNA screen.
The in vitro proliferation and viability assays showed that proteasomal inhibition reduces the viability of both HEL cells and MF CD34+ cells and that the combination of carfilzomib with ruxolitinib is additive or synergistic.
Summary/Conclusion:
The proteasome is crucial to cell response to oxidative stress, which may be induced by JAK/STAT pathway. The latter represents the main pathogenic driver of MPNs. Furthermore, proteasome inhibitors are known to negatively affect the NF‐Kb pathway, which has been shown to be hyperactive in MPN, especially in MF. In view of the above evidence, it is possible to speculate that proteasome inhibition may have a significant role in the lethality of MPN cells, although potential alternative mechanisms responsible for the efficacy of carfilzomib cannot be ruled out.
Although our findings still require a mechanistic explanation, they show for the first time that the combination of JAK2 and proteasome inhibitors increases the lethality of MPN cells and deserves further investigation as a potential therapeutic strategy for MPN patients.
There are no validated molecular biomarkers to identify newly-diagnosed individuals with chronic-phase chronic myeloid leukemia likely to respond poorly to imatinib and who might benefit from ...first-line treatment with a more potent second-generation tyrosine kinase inhibitor. Our inability to predict these 'high-risk' individuals reflects the poorly understood heterogeneity of the disease. To investigate the potential of genetic variants in epigenetic modifiers as biomarkers at diagnosis, we used Ion Torrent next-generation sequencing of 71 candidate genes for predicting response to tyrosine kinase inhibitors and probability of disease progression. A total of 124 subjects with newly-diagnosed chronic-phase chronic myeloid leukemia began with imatinib (n=62) or second-generation tyrosine kinase inhibitors (n=62) and were classified as responders or non-responders based on the
transcript levels within the first year and the European LeukemiaNet criteria for failure. Somatic variants affecting 21 genes (e.g.
) were detected in 30% of subjects, most of whom were non-responders (41% non-responders, 18% responders to imatinib, 38% non-responders, 25% responders to second-generation tyrosine kinase inhibitors). The presence of variants predicted the rate of achieving a major molecular response, event-free survival, progression-free survival and chronic myeloid leukemia-related survival in the imatinib but not the second-generation tyrosine kinase inhibitors cohort. Rare germline variants had no prognostic significance irrespective of treatment while some pre-leukemia variants suggest a multi-step development of chronic myeloid leukemia. Our data suggest that identification of somatic variants at diagnosis facilitates stratification into imatinib responders/non-responders, thereby allowing earlier use of second-generation tyrosine kinase inhibitors, which, in turn, may overcome the negative impact of such variants on disease progression.
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