June 2018 was the 20th anniversary of the clinical use of the first tyrosine kinase inhibitor (TKI), imatinib, for chronic myeloid leukemia. Since then, the change in prognosis for patients with this ...disease is one of the major success stories of modern cancer medicine. The dilemmas that face physicians and patients are no longer only those concerned with delaying inevitable progression to the terminal blastic phase or selecting the individuals most likely to benefit from allogeneic stem-cell transplantation; rather, they are now focused also on the choice of TKI, the management of comorbidities and adverse effects, strategies to improve quality of life, and the appropriateness of a trial of therapy discontinuation. Interestingly, with 4 TKIs approved for frontline use, the choice of initial therapy continues to cause controversy, a situation made more complicated by the tantalizing prospect of treatment-free remission. In this manuscript, we will explore the factors influencing this decision and try to provide a pragmatic and clinically applicable solution.
SARS-CoV-2 infection, and resulting disease, COVID-19, has a high mortality amongst patients with haematological malignancies. Global vaccine rollouts have reduced hospitalisations and deaths, but ...vaccine efficacy in patients with haematological malignancies is known to be reduced. The UK-strategy offered a third, mRNA-based, vaccine as an extension to the primary course in these patients. The MARCH database is a retrospective observational study of serological responses in patients with blood disorders. Here we present data on 381 patients with haematological malignancies. By comparison with healthy controls, we report suboptimal responses following two primary vaccines, with significantly enhanced responses following the third primary dose. These responses however are heterogeneous and determined by haematological malignancy sub-type and therapy. We identify a group of patients with continued suboptimal vaccine responses who may benefit from additional doses, prophylactic extended half-life neutralising monoclonal therapies (nMAB) or prompt nMAB treatment in the event of SARS-CoV-2 infection.
Second-generation tyrosine kinase inhibitors (2GTKI) are more effective in inducing rapid molecular responses than imatinib when used first-line in patients with chronic myeloid leukemia in chronic ...phase (CML-CP). However, failure of first line-2GTKI (1L-2GTKI) still occurs and there is no consensus regarding subsequent management. We retrospectively analyzed the outcome of 106 CML-CP patients treated with 1L-2GTKI and with a median follow-up of 91 months. 45 patients (42.4%) switched to an alternative TKI, 28 for intolerance (26.4%) and 17 (16%) for resistance. Most patients who remained on 1L-2GTKI achieved deep molecular responses (DMR) and 15 (14.1%) are in treatment-free remission (TFR). Intolerant patients also obtained DMR, although most required multiple TKI changes and were slower to respond, particularly if treated with 2L-imatinib. Inferior outcomes were observed in resistant patients, who failed alternative 2L-2GTKI and required 3/4GTKI and/or allogeneic hematopoietic stem cell transplant (alloSCT). 7yr-OS was significantly lower for these individuals (66.1%) than for intolerant patients and those who remained on 1L-2GTKI (100% and 97.9%, respectively; p = 0.001). It is apparent that failure of 1L-2GTKI is a challenging problem in modern CML therapy. Intolerance can be effectively managed by switching to an alternative 2GTKI, but resistance requires early consideration of 3/4GTKI.
Most cases of autosomal-dominant hereditary spastic paraplegia are linked to mutations in
SPG4 encoding spastin, a protein involved in microtubule dynamics and membrane trafficking. In pyramidal ...neurons of the motor cortex and in immortalized motor neurons, spastin is localized to the synaptic terminals and growth cones. However, in other neurons and in proliferating cells spastin is prevalently nuclear. The mechanisms that determine targeting of spastin to the nucleus or the cytoplasm are unknown. We show here that the
SPG4 mRNA is able to direct synthesis of two spastin isoforms, 68 and 60 kDa, respectively, through usage of two different translational start sites. Both isoforms are imported into the nucleus, but the 68-kDa isoform contains two nuclear export signals that efficiently drive export to the cytoplasm. Nuclear export is leptomycin-B sensitive. The cytoplasmic 68-kDa spastin isoform is more abundant in the brain and the spinal cord than in other tissues. Our data indicate that spastin function is modulated through usage of alternative translational start sites and active nuclear import and export, and open new perspectives for the pathogenesis of hereditary spastic paraplegia.
Background: Hepatotoxicity is a well-recognised side effect of tyrosine kinase inhibitors (TKI) and in some patients it can be a challenge to find a well-tolerated and effective drug. Isolated ...hyperbilirubinemia is common but, particularly in the case of nilotinib, is generally attributed to concomitant Gilbert's syndrome, characterized by the reduced expression of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). We have previously reported hyperbilirubinemia in association with the homozygous Gilbert genotype in patients treated with imatinib, dasatinib and nilotinib and have now extended our studies to more recent TKI. In addition we have analysed the incidence of TKI-associated transaminitis and attempted to identify safer alternative TKI. Methods: From our database of >900 patients presenting with CML CP1 from 2000-2022 and treated with a TKI, we identified 467 individuals who had received only TKI (prior interferon, combination experimental therapy, auto- and allografted patients all excluded), had normal liver function tests (LFT) at TKI start and for whom serial consecutive LFT were available. Variations in dinucleotide repeats in the UGT1A1 promoter region were analyzed by PCR with genotypes: 6/6 (homozygous for (TA) 6 allele; wild-type), 7/7 (homozygous for (TA) 7 allele) and 6/7 (heterozygous). Because individual patients could receive more than one TKI, we defined the period on treatment with each TKI as an ‘episode’ so as to attribute abnormal LFT to a specific drug. Abnormal LFT were graded according to the CTCAE version 4.0 and any occurrence of abnormalities was cross-checked to exclude a confounding reason (e.g. antibiotics, cholecystitis). Patients were censored at last LFT. Results: 229 females and 238 males (median age at diagnosis 47 yrs (range 11-90) had 955 separate TKI episodes: imatinib 406, dasatinib 222, nilotinib 189, bosutinib 87, ponatinib 28 and asciminib 23. The median number of LFT per patient was 47 (range 3-264). 7 UGT1A1 genotypes were identified, of which 45%, 41% and 13% were wild type 6/6, heterozygous 6/7 and homozygous 7/7 respectively (6 patients with other genotypes excluded). With the exception of asciminib, hyperbilirubinemia was more frequent in homozygous patients for all TKI. It was also common in all patients treated with nilotinib but in wild type and heterozygous patients, was frequently associated with concomitant transaminitis. A close temporal relationship between start of TKI and raised bilirubin suggests causality (Fig 1a-d). The incidences of transaminitis of any grade were 44%, 47%, 65%, 66%, 43% and 39%, and of >grade 1 were 7%, 8%, 17%, 32%, 18% and 13% for imatinib, dasatinib, nilotinib, bosutinib, ponatinib and asciminib respectively. Of 202 patients with a transaminitis on first line TKI, 94 were subsequently switched to a 2 nd line TKI, and 27 of those to a 3 rd line TKI. Irrespective of the TKI used, recurrent transaminitis of any grade was common occurring in 60/94 (64%) on 2 nd line and 19/27 (71%) on 3 rd line, although abnormalities >grade 2 were unusual (<1% on 2 nd line, <5% on 3 rd line). 179 patients developed transaminitis on imatinib, 46 and 29 switched (rarely for transaminitis) to dasatinib and nilotinib respectively. 28 (61%) on dasatinib and 23 (79%) on nilotinib had a second transaminitis (dasatinib - 14% >grade 1, nilotinib - 22% >grade 1)). Of 227 patients without transaminitis on imatinib, 63 and 67 switched to dasatinib or nilotinib. 28 (44%) on dasatinib and 38 (57%) on nilotinib developed further transaminitis (dasatinib - 0% >grade 1, nilotinib 19% >grade1). With respect to identifying a ‘safer’ drug we studied in detail 15 patients with grades 3-4 transaminitis on 1 st line therapy; imatininb-10, dasatinib-1, nilotinib-3, bosutinib -1. Four settled on dose reduction, and of the remaining 11, 7 returned to normal or maximum grade 1 on dasatinib. Conclusion: With the exception of asciminib the previous association of TKI, homozygous Gilbert and hyperbilirubinemia was confirmed. Grade 1 transaminitis is common on all TKIs, with higher grades of severity most frequent on bosutinib. Patients experiencing abnormal transaminases on 1 st line TKI are likely to have similar problems on 2 nd and 3 rd line agents, with a trend to higher incidence/severity on nilotinib compared to dasatinib.
Enzyme replacement therapy (ERT) has become the standard of care for several lysosomal storage disorders (LSDs). Despite ERT's undisputed efficacy, the requirement for multiple and costly ...administrations as well as ERT's limited improvement of some LSD manifestations prompts the search for better therapies. Using a mouse model of mucopolysaccharidosis VI, we compared the efficacy of a single intravascular administration of an adeno-associated viral vector targeting liver to weekly infusions of human recombinant enzyme at the same doses used in mucopolysaccharidosis VI patients. While gene therapy results in increased and stable levels of circulating enzyme up to 1 year after vector administration, ERT has typical peak-and-drop serum kinetics. Both therapies similarly reduced glycosaminoglycan levels in urine and tissues including heart valves and myocardium, with gene therapy improving skeletal skull abnormalities slightly better, although not significantly, than ERT. Both therapies seem to similarly improve animal motor performance, with gene therapy possibly associated with less animal distress. Thus, a single vector administration that converts liver into a factory organ for systemic secretion of therapeutic proteins is at least as effective as ERT in a mouse model of LSD, potentially eliminating problems with compliance and costs. Only testing in humans will prove whether this holds true in a clinical setting.
The majority of patients with newly diagnosed chronic myeloid leukemia (CML) will enjoy a life expectancy equivalent to that of unaffected individuals, but will remain on life-long treatment with a ...concomitant requirement for on-going hospital interactions for molecular monitoring and drug dispensing. In order to determine more accurately the frequency of monitoring required, we performed a 'real-life' retrospective single-center cohort study of 450 patients with CML in at least major molecular remission (MR3) to analyze the risk of loss of MR3 defined as at least 2 consecutive real-time quantitative polymerase chain reaction (RT-qPCR) results >0.1% International Scale (IS). Patients who achieved sustained MR4 (sMR4, BCR-ABL1 RT-qPCR <0.01% IS for 12 months) had a probability of loss of MR3 at 1 and 5 years of 0 and 2.6% (95%CI: 1.2-5.4) respectively, compared to 4.4% (95%CI: 1.9-9.8) and 25.4% (95%CI: 16.7-36.7) respectively, in those who achieved sustained MR3 (sMR3) but not sMR4 (
<0.001). No patient who improved their response to a deep molecular level (at least MR4) lost MR3 if they were considered compliant, had no history of resistance and remained on standard dose tyrosine kinase inhibitor (TKI). MR4 maintained for at least one year represents a secure response threshold for patients with CML, after which no MR3 loss occurs if certain conditions are satisfied (standard TKI dose, full compliance, and lack of previous TKI resistance). This finding may justify reduction of the frequency of hospital interaction, with an associated positive impact on quality of life, survivorship, and economic burden to both patients and healthcare providers.
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