Publications by authors named "Jane F Apperley"

159 Publications

Validation of CIP2A as a Biomarker of Subsequent Disease Progression and Treatment Failure in Chronic Myeloid Leukaemia.

Cancers (Basel) 2021 Apr 29;13(9). Epub 2021 Apr 29.

Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool L69 3GA, UK.

Background: It would be clinically useful to prospectively identify the risk of disease progression in chronic myeloid leukaemia (CML). Overexpression of cancerous inhibitor of protein phosphatase 2A (PP2A) (CIP2A) protein is an adverse prognostic indicator in many cancers.

Methods: We examined CIP2A protein levels in diagnostic samples from the SPIRIT2 trial in 172 unselected patients, of whom 90 received imatinib and 82 dasatinib as first-line treatment.

Results: High CIP2A levels correlated with inferior progression-free survival ( = 0.04) and with worse freedom from progression ( = 0.03), and these effects were confined to dasatinib recipients. High CIP2A levels were associated with a six-fold higher five-year treatment failure rate than low CIP2A levels (41% vs. 7.5%; = 0.0002), in both imatinib (45% vs. 11%; = 0.02) and dasatinib recipients (36% vs. 4%; = 0.007). Imatinib recipients with low CIP2A levels had a greater risk of treatment failure ( = 0.0008). CIP2A levels were independent of Sokal, Hasford, EUTOS (EUropean Treatment and Outcome Study), or EUTOS long-term survival scores (ELTS) or the presence of major route cytogenetic abnormalities. No association was seen between CIP2A levels and time to molecular response or the levels of the CIP2A-related proteins PP2A, SET, SET binding protein 1 (SETBP1), or AKT.

Conclusions: These data confirm that high diagnostic CIP2A levels correlate with subsequent disease progression and treatment failure. CIP2A is a simple diagnostic biomarker that may be useful in planning treatment strategies.
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http://dx.doi.org/10.3390/cancers13092155DOI Listing
April 2021

Additional chromosomal abnormalities at chronic myeloid leukemia diagnosis predict an increased risk of progression.

Blood Adv 2021 Feb;5(4):1102-1109

Liverpool Clinical Trials Centre, University of Liverpool, Liverpool, United Kingdom.

At diagnosis of chronic-phase chronic myeloid leukemia (CML), there are conflicting data as to whether additional cytogenetic abnormalities (ACAs) beyond a standard Philadelphia (Ph) translocation confer a higher risk of subsequent disease progression. In the United Kingdom SPIRIT2 trial comparing imatinib 400 mg daily with dasatinib 100 mg daily, diagnostic karyotypes were available in 763 of the 814 patients recruited. Of these, 27 had ACAs in either/both the original 4 major route group (trisomy 8 or 19, iso17q or a second Ph) or the 5 additional lesions recently described (trisomy 21, 3q26.2, monosomy 7/7q-, 11q23, and complex karyotypes), and their progression rate was significantly higher (22.2%) than in patients without one of these ACAs (2.2%; P < .001). Patients with ACAs had worse progression-free survival (PFS; hazard ratio [HR], 5.21; 95% confidence interval [CI], 2.59-10.50; P < .001) and freedom from progression (FFP; HR, 12.66; 95% CI, 4.95-32.37; P < .001) compared with patients without ACAs. No association was seen between the Sokal or European Treatment and Outcome Study long-term survival (ELTS) scores and the presence of ACAs. Univariate analysis showed that higher Sokal and ELTS scores and the presence of ACAs were associated with poorer PFS, though only ACAs and high-risk ELTS scores were associated with poorer FFP. Multivariable models identified both the Sokal/ELTS score and ACAs as significant independent factors for PFS but only ELTS score and ACAs as significant independent factors for FFP. The data support the view that certain ACAs are predictive of disease progression independently of Sokal or ELTS scores.
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http://dx.doi.org/10.1182/bloodadvances.2020003570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903225PMC
February 2021

Prognostic impact of early-versus-late responses to different induction regimens in patients with myeloma undergoing autologous hematopoietic cell transplantation: Results from the CALM study by the CMWP of the EBMT.

Eur J Haematol 2021 May 27;106(5):708-715. Epub 2021 Feb 27.

University Hospital of Lille, Inserm, CHU Lille, INSERM, Infinite, Lille, France.

Background: In autologous stem cell transplant (ASCT)-eligible myeloma patients, prolonged induction does not necessarily improve the depth of response.

Method: We analyzed 1222 ASCT patients who were classified based on (a) the interval between induction and stem cell collection, (b) the type of induction regimen: BID (Bortezomib, IMiDs, and Dexamethasone), Bortezomib-based, or CTD (Cyclophosphamide, Thalidomide, and Dexamethasone), and (c) the time to best response (Early ie, best response within 4 or 5 months, depending on the regimen vs Late; Good ie, VGPR or better vs Poor).

Results: The length of induction treatment required to achieve a Good response did not affect PFS (P = .65) or OS (P = .61) post-ASCT. The three types of regimen resulted in similar outcomes: median PFS 31, 27.7 and 30.8 months (P = .31), and median OS 81.7, 92.7, and 77.4 months, respectively (P = .83). On multivariate analysis, neither the type nor the duration of the induction regimen affected OS and PFS, except for Early Good Responders who had a better PFS compared to Early Poor Responders (HR = 1.21, P-value = .02). However, achieving a Good response at induction was associated with a better response (≥VGPR) post-transplant.

Conclusion: The kinetics of response did not affect outcomes.
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http://dx.doi.org/10.1111/ejh.13602DOI Listing
May 2021

TKI dose reduction can effectively maintain major molecular remission in patients with chronic myeloid leukaemia.

Br J Haematol 2021 Apr 24;193(2):346-355. Epub 2020 Dec 24.

Department of Haematology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK.

Targeted therapy for chronic myeloid leukaemia (CML) has allowed for a near-normal patient life-expectancy; however, quality of life and aggravation of existing co-morbidities have posed new treatment challenges. In clinical practice, TKI dose reduction occurs frequently, often on multiple occasions, because of intolerance. We conducted a retrospective 'real-world practice' review of 246 patients receiving lower than standard dose (LD) TKI after the achievement of major molecular response (MR3), because of intolerable adverse events. In 274 of 298 cases of dose reduction (91·9%), MR3 was maintained at median follow-up of 27·3 months. One patient progressed to blast crisis while on LD TKI. Two patients developed two new ABL kinase domain mutations (T315I and V299L), of whom one had achieved deep molecular response on an alternative LD TKI at last follow-up. Seventy-six patients eventually discontinued LD TKI and the two-year treatment-free remission (TFR) rate in these patients was 74·1%. The majority of patients with CML in at least MR3 appear to be safely managed with LD TKI, although three of 246 patients had new events (progression and new mutation), indicating that this approach requires vigilance. TKI LD does not prevent the achievement of TFR in this patient population.
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http://dx.doi.org/10.1111/bjh.17286DOI Listing
April 2021

Identification of genetic targets in acute myeloid leukaemia for designing targeted therapy.

Br J Haematol 2021 01 6;192(1):137-145. Epub 2020 Oct 6.

Imperial College London, London, UK.

Few effective therapies exist for acute myeloid leukaemia (AML), in part due to the molecular heterogeneity of this disease. We sought to identify genes crucial to deregulated AML signal transduction pathways which, if inhibited, could effectively eradicate leukaemia stem cells. Due to difficulties in screening primary cells, most previous studies have performed next-generation sequencing (NGS) library knockdown screens in cell lines. Using carefully considered methods including evaluation at multiple timepoints to ensure equitable gene knockdown, we employed a large NGS short hairpin RNA (shRNA) knockdown screen of nearly 5 000 genes in primary AML cells from six patients to identify genes that are crucial for leukaemic survival. Across various levels of stringency, genome-wide bioinformatic analysis identified a gene in the NOX family, NOX1, to have the most consistent knockdown effectiveness in primary cells (P = 5∙39 × 10 , Bonferroni-adjusted), impacting leukaemia cell survival as the top-ranked gene for two of the six AML patients and also showing high effectiveness in three of the other four patients. Further investigation of this pathway highlighted NOX2 as the member of the NOX family with clear knockdown efficacy. We conclude that genes in the NOX family are enticing candidates for therapeutic development in AML.
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http://dx.doi.org/10.1111/bjh.17129DOI Listing
January 2021

Persistence of Drug-Resistant Leukemic Stem Cells and Impaired NK Cell Immunity in CML Patients Depend on Antiproliferative and PP2A-Activating Functions.

Blood Cancer Discov 2020 Jul;1(1):48-67

Department of Haematology, Hammersmith Hospital, Imperial College London, London, United Kingdom.

Persistence of drug-resistant quiescent leukemic stem cells (LSC) and impaired natural killer (NK) cell immune response account for relapse of chronic myelogenous leukemia (CML). Inactivation of protein phosphatase 2A (PP2A) is essential for CML-quiescent LSC survival and NK cell antitumor activity. Here we show that has antiproliferative and PP2A-activating functions that are dose dependently differentially induced by CCND2/CDK6 and SET inhibition, respectively. is upregulated in CML LSCs and NK cells by bone marrow microenvironment (BMM) signals to induce quiescence and impair immune response, respectively. Conversely, BCR-ABL1 downregulates in CML progenitors to prevent growth arrest and PP2A-mediated apoptosis. Quiescent LSCs escape apoptosis by upregulating long noncoding RNA that uncouples and limits function to cytostasis. Genetic and pharmacologic modulation and/or PP2A-activating drug treatment restore NK cell activity, inhibit BMM-induced growth arrest, and selectively trigger LSC apoptosis and in patient-derived xenografts; hence, the importance of and PP2A activity for CML development and therapy.
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http://dx.doi.org/10.1158/0008-5472.BCD-19-0039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510943PMC
July 2020

Acute myeloid leukemia with a severe coagulopathy and t(8;16)(p11;p13).

Am J Hematol 2021 01 28;96(1):163-164. Epub 2020 Jul 28.

Centre for Haematology, St Mary's Hospital Campus, Imperial College London, St Mary's Hospital, Praed Street, London, UK.

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http://dx.doi.org/10.1002/ajh.25903DOI Listing
January 2021

An ex vivo investigation of interactions between primary acute myeloid leukaemia and mesenchymal stromal cells yields novel therapeutic targets.

Br J Haematol 2020 08 10;190(4):e236-e239. Epub 2020 Jun 10.

Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, UK.

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http://dx.doi.org/10.1111/bjh.16810DOI Listing
August 2020

Prolonged treatment-free remission in chronic myeloid leukemia patients with previous kinase domain mutations.

Haematologica 2020 05 19;105(5):e225-e227. Epub 2019 Sep 19.

Department of Haematology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London.

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http://dx.doi.org/10.3324/haematol.2019.234179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193492PMC
May 2020

Laying the foundation for genomically-based risk assessment in chronic myeloid leukemia.

Leukemia 2019 08 17;33(8):1835-1850. Epub 2019 Jun 17.

School of Medicine, University of Adelaide, Adelaide, Australia.

Outcomes for patients with chronic myeloid leukemia (CML) have substantially improved due to advances in drug development and rational treatment intervention strategies. Despite these significant advances there are still unanswered questions on patient management regarding how to more reliably predict treatment failure at the time of diagnosis and how to select frontline tyrosine kinase inhibitor (TKI) therapy for optimal outcome. The BCR-ABL1 transcript level at diagnosis has no established prognostic impact and cannot guide frontline TKI selection. BCR-ABL1 mutations are detected in ~50% of TKI resistant patients but are rarely responsible for primary resistance. Other resistance mechanisms are largely uncharacterized and there are no other routine molecular testing strategies to facilitate the evaluation and further stratification of TKI resistance. Advances in next-generation sequencing technology has aided the management of a growing number of other malignancies, enabling the incorporation of somatic mutation profiles in diagnosis, classification, and prognostication. A largely unexplored area in CML research is whether expanded genomic analysis at diagnosis, resistance, and disease transformation can enhance patient management decisions, as has occurred for other cancers. The aim of this article is to review publications that reported mutated cancer-associated genes in CML patients at various disease phases. We discuss the frequency and type of such variants at initial diagnosis and at the time of treatment failure and transformation. Current limitations in the evaluation of mutants and recommendations for future reporting are outlined. The collective evaluation of mutational studies over more than a decade suggests a limited set of cancer-associated genes are indeed recurrently mutated in CML and some at a relatively high frequency. Genomic studies have the potential to lay the foundation for improved diagnostic risk classification according to clinical and genomic risk, and to enable more precise early identification of TKI resistance.
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http://dx.doi.org/10.1038/s41375-019-0512-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893870PMC
August 2019

De-escalation of tyrosine kinase inhibitor therapy before complete treatment discontinuation in patients with chronic myeloid leukaemia (DESTINY): a non-randomised, phase 2 trial.

Lancet Haematol 2019 Jul 12;6(7):e375-e383. Epub 2019 Jun 12.

Paul O'Gorman Leukaemia Research Centre, University of Glasgow, Glasgow, UK.

Background: All studies of treatment-free remission (TFR) in patients with chronic myeloid leukaemia have discontinued tyrosine kinase inhibitor (TKI) treatment abruptly and have focussed on patients with stable MR4 (BCR-ABL to ABL ratio ≤0·01%). We aimed to examine the effects of gradual treatment withdrawal and whether TFR is feasible for patients with less deep but stable remission.

Methods: The De-Escalation and Stopping Treatment with Imatinib, Nilotinib, or sprYcel (DESTINY) study is a non-randomised, phase 2 trial undertaken at 20 UK hospitals. We recruited patients (aged ≥18 years) with chronic myeloid leukaemia in first chronic phase, who had received TKI therapy for 3 years or more, with three or more BCR-ABL quantitative PCR transcript measurements (BCR-ABL to ABL1 ratio) less than 0·1% (major molecular response [MMR]) in the 12 months before entry. Patients with all PCR measurements less than 0·01% were assigned to the MR4 group. Patients with results between 0·1% and 0·01% were allocated to the MMR group. TKI treatment was de-escalated to half the standard dose for 12 months, then stopped for a further 24 months, with frequent PCR monitoring. Recurrence was defined as the first of two consecutive samples with PCR measurement greater than 0·1%, which required treatment recommencement at full dose. The primary endpoint was the proportion of patients who could first de-escalate their treatment for 12 months, and then stop treatment completely for a further 2 years, without losing MMR. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01804985.

Findings: Treatment at entry was imatinib (n=148), nilotinib (n=16), or dasatinib (n=10), for a median of 6·9 years (IQR 4·8-10·2). Between Dec 16, 2013, and May 6, 2015, we enrolled 49 patients into the MMR group and 125 into the MR4 group. In the MR4 group, 84 (67%) patients reached the 36-month trial completion point and recurrence-free survival was 72% (95% CI 64-80). In the MMR group, 16 (33%) entrants completed the study and recurrence-free survival was 36% (25-53). No disease progression was seen and two deaths occurred due to unrelated causes. All recurrences regained MMR within 5 months of treatment resumption.

Interpretation: Initial de-escalation before discontinuation might improve the success of TFR protocols, although the mechanism of its benefit is not yet clear. The findings also suggest that TFR merits further study in patients with stable MMR.

Funding: Newcastle University and Bloodwise.
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http://dx.doi.org/10.1016/S2352-3026(19)30094-8DOI Listing
July 2019

Preclinical toxicology and safety pharmacology of the first-in-class GADD45β/MKK7 inhibitor and clinical candidate, DTP3.

Toxicol Rep 2019 19;6:369-379. Epub 2019 Apr 19.

CCSI, Department of Medicine, Imperial College London, London, UK.

Aberrant NF-κB activity drives oncogenesis and cell survival in multiple myeloma (MM) and many other cancers. However, despite an aggressive effort by the pharmaceutical industry over the past 30 years, no specific IκBα kinase (IKK)β/NF-κB inhibitor has been clinically approved, due to the multiple dose-limiting toxicities of conventional NF-κB-targeting drugs. To overcome this barrier to therapeutic NF-κB inhibition, we developed the first-in-class growth arrest and DNA-damage-inducible (GADD45)β/mitogen-activated protein kinase kinase (MKK)7 inhibitor, DTP3, which targets an essential, cancer-selective cell-survival module downstream of the NF-κB pathway. As a result, DTP3 specifically kills MM cells, and , ablating MM xenografts in mice, with no apparent adverse effects, nor evident toxicity to healthy cells. Here, we report the results from the preclinical regulatory pharmacodynamic (PD), safety pharmacology, pharmacokinetic (PK), and toxicology programmes of DTP3, leading to the approval for clinical trials in oncology. These results demonstrate that DTP3 combines on-target-selective pharmacology, therapeutic anticancer efficacy, favourable drug-like properties, long plasma half-life and good bioavailability, with no target-organs of toxicity and no adverse effects preclusive of its clinical development in oncology, upon daily repeat-dose administration in both rodent and non-rodent species. Our study underscores the clinical potential of DTP3 as a conceptually novel candidate therapeutic selectively blocking NF-κB survival signalling in MM and potentially other NF-κB-driven cancers.
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http://dx.doi.org/10.1016/j.toxrep.2019.04.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6502747PMC
April 2019

Somatic variants in epigenetic modifiers can predict failure of response to imatinib but not to second-generation tyrosine kinase inhibitors.

Haematologica 2019 12 9;104(12):2400-2409. Epub 2019 May 9.

Centre for Haematology, Department of Medicine, Imperial College, London, UK.

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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http://dx.doi.org/10.3324/haematol.2018.200220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959189PMC
December 2019

MR4 sustained for 12 months is associated with stable deep molecular responses in chronic myeloid leukemia.

Haematologica 2019 11 28;104(11):2206-2214. Epub 2019 Mar 28.

Department of Haematology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK.

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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http://dx.doi.org/10.3324/haematol.2018.214809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821602PMC
November 2019

Mesenchymal stromal cells for acute graft-versus-host disease: response at 1 week predicts probability of survival.

Br J Haematol 2019 04 13;185(1):89-92. Epub 2019 Jan 13.

King's College London, London, UK.

Mesenchymal stromal cells (MSCs) have been successfully used for the treatment of steroid-resistant graft-versus-host-disease (GvHD). However, the lack of early predictors of clinical responses impacts on the time at which to add further treatment and consequently the design of informative clinical trials. Here, we present the UK experience of one of the largest cohorts of GvHD patients undergoing MSC infusions so far reported. We show that clinical responses assessed as early as 1 week after MSC infusion predict patients' overall survival. In our cohort, cell dose, patients' age and type of organ involvement are crucial factors associated with clinical responses.
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http://dx.doi.org/10.1111/bjh.15749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916615PMC
April 2019

Management of adverse events associated with bosutinib treatment of chronic-phase chronic myeloid leukemia: expert panel review.

J Hematol Oncol 2018 12 27;11(1):143. Epub 2018 Dec 27.

University of Milano-Bicocca, Milan, Italy.

Bosutinib, a BCR-ABL1 tyrosine kinase inhibitor (TKI), has been available for several years as a treatment for chronic-, accelerated-, and blast-phase chronic myeloid leukemia (CML), for patients with resistance or intolerance to prior therapy. In 2017, the BFORE trial demonstrated efficacy of bosutinib as first-line treatment in adult patients with newly diagnosed chronic-phase chronic myeloid leukemia (CP-CML). The most common adverse events (AEs) of any grade in bosutinib-treated patients in BFORE were diarrhea, nausea, thrombocytopenia, increased alanine aminotransferase, and increased aspartate aminotransferase, consistent with the most commonly reported AEs in earlier studies. To balance the efficacy and tolerability of treatment to optimize patient adherence with medications, treating physicians commonly use various strategies such as initiating treatment at a lower dose, dose reduction, or dose interruption, depending on the type and severity of the AEs and the clinical setting. In light of the recent data from first-line treatment, an expert panel of hematologists reviewed management strategies for the use of bosutinib in treatment of CP-CML and made the recommendations reported here. Although the panel focused on first-line treatment, the principles can be for the most part extended to bosutinib use in later lines of treatment. Recommendations include advice regarding prophylaxis and management for diarrhea. The panel also considered optimum timing for referral to a specialist for specific AEs. Across the commonly occurring AEs, the panel highlighted the importance of education and communication with patients about anticipated AEs.
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http://dx.doi.org/10.1186/s13045-018-0685-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6307238PMC
December 2018

The argument for using imatinib in CML.

Hematology Am Soc Hematol Educ Program 2018 11;2018(1):161-167

Department of Clinical Haematology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom; and.

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.
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http://dx.doi.org/10.1182/asheducation-2018.1.161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6246007PMC
November 2018

Back to the future: Treatment-free remission and pregnancy in chronic myeloid leukemia.

Eur J Haematol 2019 Feb 29;102(2):197-199. Epub 2018 Nov 29.

Memorial Sloan Kettering Cancer Center, New York City, New York.

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http://dx.doi.org/10.1111/ejh.13192DOI Listing
February 2019

Impact of route and adequacy of nutritional intake on outcomes of allogeneic haematopoietic cell transplantation for haematologic malignancies.

Clin Nutr 2019 04 28;38(2):738-744. Epub 2018 Mar 28.

Centre for Haematology, Imperial College London at Hammersmith Hospital, London, UK.

Background: Allogeneic haematopoietic cell transplantation (HCT) is often associated with poor oral intake due to painful mucositis and gastrointestinal sequalae that occur following a preparative regimen of intensive chemotherapy and/or total body radiation. Although attractive to assume that optimal nutrition improves HCT outcomes, there are limited data to support this. It is also unclear whether artificial nutrition support should be provided as enteral tube feeding or parenteral nutrition (PN).

Methods: We analysed day-100 non-relapse mortality (NRM), incidence of acute graft-versus-host disease (GvHD), acute gastrointestinal GvHD, 5-year survival and GvHD-free/relapse-free survival (GRFS) according to both route and adequacy of nutritional intake prior to neutrophil engraftment, together with other known prognostic factors, in a retrospective cohort of 484 patients who underwent allogeneic HCT for haematologic malignancy between 2000 and 2014.

Results: Multivariate analyses showed increased NRM with inadequate nutrition (hazard ratio (HR) 4.1; 95% confidence interval (CI) 2.2-7.2) and adequate PN (HR 2.9; 95% CI 1.6-5.4) compared to adequate enteral nutrition (EN) both P < .001. There were increased incidences of gastrointestinal GvHD of any stage and all GvHD ≥ grade 2 in patients who received PN (odds ratio (OR) 2.0; 95% CI 1.2-3.3; P = .006, and OR 1.8; 95% CI 1.1-3.0; P = .018, respectively), compared to adequate EN. Patients who received adequate PN and inadequate nutrition also had reduced probabilities of survival and GRFS at 5 years.

Conclusion: Adequate EN during the early transplantation course is associated with reduced NRM, improved survival and GRFS at 5 years. Furthermore, adequate EN is associated with lower incidence of overall and gut acute GvHD than PN, perhaps because of its ability to maintain mucosal integrity, modulate the immune response to intensive chemo/radiotherapy and support the gastrointestinal tract environment, including gut microflora.
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http://dx.doi.org/10.1016/j.clnu.2018.03.008DOI Listing
April 2019

Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: final 5-year results of the phase 2 PACE trial.

Blood 2018 07 22;132(4):393-404. Epub 2018 Mar 22.

The University of Texas MD Anderson Cancer Center, Houston, TX.

Ponatinib has potent activity against native and mutant BCR-ABL1, including BCR-ABL1 The pivotal phase 2 Ponatinib Ph ALL and CML Evaluation (PACE) trial evaluated efficacy and safety of ponatinib at a starting dose of 45 mg once daily in 449 patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) resistant/intolerant to dasatinib or nilotinib, or with BCR-ABL1 This analysis focuses on chronic-phase CML (CP-CML) patients (n = 270) with 56.8-month median follow-up. Among 267 evaluable patients, 60%, 40%, and 24% achieved major cytogenetic response (MCyR), major molecular response (MMR), and 4.5-log molecular response, respectively. The probability of maintaining MCyR for 5 years was 82% among responders. Dose reductions were implemented in October 2013 to decrease the risk of arterial occlusive events (AOEs); ≥90% of CP-CML patients who had achieved MCyR or MMR maintained response 40 months after elective dose reductions. Estimated 5-year overall survival was 73%. In CP-CML patients, the most common treatment-emergent adverse events were rash (47%), abdominal pain (46%), thrombocytopenia (46%), headache (43%), dry skin (42%), and constipation (41%). The cumulative incidence of AOEs in CP-CML patients increased over time to 31%, while the exposure-adjusted incidence of new AOEs (15.8 and 4.9 per 100 patient-years in years 1 and 5, respectively) did not increase over time. These final PACE results demonstrate ponatinib provides durable and clinically meaningful responses, irrespective of dose reductions, in this population of heavily pretreated CP-CML patients. This trial was registered at www.clinicaltrials.gov as #NCT01207440.
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http://dx.doi.org/10.1182/blood-2016-09-739086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071555PMC
July 2018

Protease nexin-1 prevents growth of human B cell lymphoma via inhibition of sonic hedgehog signaling.

Blood Cancer J 2018 02 26;8(2):24. Epub 2018 Feb 26.

Department of Haematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China.

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http://dx.doi.org/10.1038/s41408-018-0063-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5827524PMC
February 2018

Evidence for B Cell Exhaustion in Chronic Graft-versus-Host Disease.

Front Immunol 2017 12;8:1937. Epub 2018 Jan 12.

Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, United States.

Chronic graft-versus-host disease (cGvHD) remains a major complication of allogeneic hematopoietic stem cell transplantation (HSCT). A number of studies support a role for B cells in the pathogenesis of cGvHD. In this study, we report the presence of an expanded population of CD19+CD21- B cells with features of exhaustion in the peripheral blood of patients with cGvHD. CD21- B cells were significantly increased in patients with active cGvHD compared to patients without cGvHD and healthy controls (median 12.2 versus 2.12 versus 3%, respectively;  < 0.01). Compared with naïve (CD27-CD21+) and classical memory (CD27+CD21+) B cells, CD19+CD21- B cells in cGvHD were CD10 negative, CD27 negative and CD20hi, and exhibited features of exhaustion, including increased expression of multiple inhibitory receptors such as FCRL4, CD22, CD85J, and altered expression of chemokine and adhesion molecules such as CD11c, CXCR3, CCR7, and CD62L. Moreover, CD21- B cells in cGvHD patients were functionally exhausted and displayed poor proliferative response and calcium mobilization in response to B-cell receptor triggering and CD40 ligation. Finally, the frequencies of circulating CD21- B cells correlated with cGvHD severity in patients after HSCT. Our study further characterizes B cells in chronic cGVHD and supports the use of CD21-CD27-CD10- B cell frequencies as a biomarker of disease severity.
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http://dx.doi.org/10.3389/fimmu.2017.01937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5770573PMC
January 2018

Melphalan 140 mg/m or 200 mg/m for autologous transplantation in myeloma: results from the Collaboration to Collect Autologous Transplant Outcomes in Lymphoma and Myeloma (CALM) study. A report by the EBMT Chronic Malignancies Working Party.

Haematologica 2018 03 7;103(3):514-521. Epub 2017 Dec 7.

University Hospital Hamburg-Eppendorf, Hamburg, Germany.

Melphalan at a dose of 200 mg/m is standard conditioning prior to autologous hematopoietic stem cell transplantation for multiple myeloma, but a dose of 140 mg/m is often used in clinical practice in patients perceived to be at risk of excess toxicity. To determine whether melphalan 200 mg/m and melphalan 140 mg/m are equally effective and tolerable in clinically relevant patient subgroups we analyzed 1964 first single autologous transplantation episodes using a series of Cox proportional-hazards models. Overall survival, progression-free survival, cumulative incidence of relapse, non-relapse mortality, hematopoietic recovery and second primary malignancy rates were not significantly different between the melphalan 140 mg/m (n=245) and melphalan 200 mg/m (n=1719) groups. Multivariable subgroup analysis showed that disease status at transplantation interacted with overall survival, progression-free survival, and cumulative incidence of relapse, with a significant advantage associated with melphalan 200 mg/m in patients transplanted in less than partial response (adjusted hazard ratios for melphalan 200 mg/m melphalan 140 mg/m: 0.5, 0.54, and 0.56). In contrast, transplantation in very good partial or complete response significantly favored melphalan 140 mg/m for overall survival (adjusted hazard ratio: 2.02). Age, renal function, prior proteasome inhibitor treatment, gender, or Karnofsky score did not interact with overall/progression-free survival or relapse rate in the melphalan dose groups. There were no significant survival or relapse rate differences between melphalan 200 mg/m and melphalan 140 mg/m patients with high-risk or standard-risk chromosomal abnormalities. In conclusion, remission status at the time of transplantation may favor the use of melphalan 200 mg/m or melphalan 140 mg/m for key transplant outcomes (NCT01362972).
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http://dx.doi.org/10.3324/haematol.2017.181339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830386PMC
March 2018

Cost and quality issues in establishing hematopoietic cell transplant program in developing countries.

Hematol Oncol Stem Cell Ther 2017 Dec 14;10(4):167-172. Epub 2017 Jul 14.

Oncology Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

The hematopoietic cell transplant (HCT) activity has grown significantly over the past two decades in both developing and developed countries. Many challenges arise in establishing new HCT programs in developing countries, due to scarcity of resources and manpower in expertise in HCT. While cost issues can potentially hinder establishment of new HCT programs in certain regions, the focus on quality and value should be included in the general vision of leadership before establishing an HCT program. The main challenge in most developing countries is the lack of trained/qualified personnel, enormous start-up costs for a tertiary care center, and quality maintenance. Herein, we discuss the main challenges from a cost and quality perspective which occur at initiation of a new HCT program. We give real world examples of two developing countries that have recently started new HCT programs despite significant financial constraints. We also portray recommendations from the Worldwide Network of Blood and Marrow Transplantation for levels of requirements for a new HCT program. We hope that this review will serve as a general guide for new transplant program leadership with respect to the concerns of balancing high quality with concurrently lowering costs.
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http://dx.doi.org/10.1016/j.hemonc.2017.05.017DOI Listing
December 2017

De-escalation of tyrosine kinase inhibitor dose in patients with chronic myeloid leukaemia with stable major molecular response (DESTINY): an interim analysis of a non-randomised, phase 2 trial.

Lancet Haematol 2017 Jul 26;4(7):e310-e316. Epub 2017 May 26.

Paul O'Gorman Leukaemia Research Centre, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.

Background: Discontinuation of tyrosine kinase inhibitor (TKI) therapy is feasible for some patients with chronic myeloid leukaemia with deep molecular responses; however, patients with stable major molecular response (MMR), but not MR4, have not been studied, nor has the effect of treatment de-escalation rather than outright cessation. We aimed to examine the effects of treatment de-escalation as a prelude to complete cessation, not only in patients with MR4 or greater, but also in those with MMR but not MR4.

Methods: We did this interim analysis of a non-randomised, phase 2 trial at 20 hospitals in the UK. We recruited patients (aged ≥18 years) with chronic myeloid leukaemia in first chronic phase who had received TKI for 3 years or more and were either in stable MR4 (BCR-ABL1:ABL1 ratio <0·01%; MR4 cohort) or in stable MMR (BCR-ABL1:ABL1 ratio consistently <0·1%) but not MR4 (MMR cohort) for 12 months or longer. Participants received half their standard TKI dose (imatinib 200 mg daily, dasatinib 50 mg daily, or nilotinib 200 mg twice daily) for 12 months. Molecular recurrence was defined as loss of MMR (BCR-ABL1:ABL1 ratio >0·1%) on two consecutive samples. The primary endpoint of this interim analysis was the proportion of patients who lost MMR on de-escalation and regained MMR on TKI resumption. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01804985.

Findings: Between Dec 16, 2013 and April 10, 2015, we enrolled 174 patients into the MMR cohort (n=49) or the MR4 cohort (n=125). During the 12 months of half-dose therapy, 12 patients (7%) had molecular recurrence, all of whom regained MMR within 4 months of full-dose TKI resumption (median time to recovery 77 days). Recurrence was significantly lower in the MR4 cohort (three [2%; 90% CI 0·2-4·8] of 121 evaluable patients) than in the MMR cohort (nine [19%; 90% CI 9·5-28·0] of 48 evaluable patients; hazard ratio 0·12, 90% CI 0·04-0·37; p=0·0007), but was unrelated to previous TKI or TKI therapy duration. Adverse events (eg, lethargy, diarrhoea, rash, and nausea) improved during the first 3 months of de-escalation, though not thereafter. 16 serious adverse events were reported, including one fatality due to worsening pre-existing peripheral arterial occlusive disease in a patient who had received only imatinib.

Interpretation: TKI de-escalation is safe for most patients with excellent responses to TKI therapy, and is associated with improvement in symptoms. These findings show that lower TKI doses might maintain responses in these patients, implying that such patients could be unnecessarily overtreated. Studies of more ambitious de-escalation are warranted.

Funding: Newcastle University and Bloodwise.
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http://dx.doi.org/10.1016/S2352-3026(17)30066-2DOI Listing
July 2017