Publications by authors named "David M Ross"

67 Publications

How much imatinib is enough?

Authors:
David M Ross

Br J Haematol 2021 Apr 19. Epub 2021 Apr 19.

Department of Haematology and Bone Marrow Transplantation, Royal Adelaide Hospital, Adelaide, Australia.

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http://dx.doi.org/10.1111/bjh.17444DOI Listing
April 2021

Treatment-free remission following frontline nilotinib in patients with chronic phase chronic myeloid leukemia: 5-year update of the ENESTfreedom trial.

Leukemia 2021 Mar 11. Epub 2021 Mar 11.

University of Turin, Orbassano, Italy.

The ENESTfreedom trial assessed the feasibility of treatment-free remission (TFR) in patients with chronic myeloid leukemia in chronic phase (CML-CP) following frontline nilotinib treatment. Results for long-term outcomes after a 5-year follow-up are presented herein. Patients who had received ≥2 years of frontline nilotinib therapy and achieved MR underwent a 1-year nilotinib treatment consolidation phase before attempting TFR. At the 5-year data cut-off, 81/190 patients entering the TFR phase (42.6%) were still in TFR, with 76 (40.0%) in MR. Patients who lost major molecular response (MMR) entered a treatment re-initiation phase; 90/91 patients entering this phase (98.9%) regained MMR and 84/91 patients (92.3%) regained MR. The Kaplan-Meier estimated treatment-free survival rate at 5 years was 48.2%. No disease progression or CML-related deaths were reported. Whereas the incidence of adverse events (AEs) declined from 96 weeks following the start of TFR, an increase in AE frequency was observed for patients in the treatment re-initiation phase. Low Sokal risk score, BCR-ABL1 levels at 48 weeks of TFR and stable MR response for the first year of TFR were associated with higher TFR rates. Overall, these results support the efficacy and safety of attempting TFR following upfront nilotinib therapy of >3 years in patients with CML-CP.
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http://dx.doi.org/10.1038/s41375-021-01205-5DOI Listing
March 2021

Myeloid somatic mutation panel testing in myeloproliferative neoplasms.

Pathology 2021 Apr 3;53(3):339-348. Epub 2021 Mar 3.

Myeloproliferative Neoplasms Working Party, Australasian Leukaemia and Lymphoma Group, Melbourne, Vic, Australia; Department of Clinical Haematology, Royal Melbourne Hospital, Peter MacCallum Cancer Centre, Department of Medicine, The University of Melbourne, Melbourne, Vic, Australia.

Myeloproliferative neoplasms are characterised by somatic mutations in pathways that regulate cell proliferation, epigenetic modifications, RNA splicing or DNA repair. Assessment of the mutational profile assists diagnosis and classification, but also aids assessment of prognosis, and may guide the use of emerging targeted therapies. The most practical way to provide information on numerous genetic variants is by using massively parallel sequencing, commonly in the form of disease specific next generation sequencing (NGS) panels. This review summarises the diagnostic and prognostic value of somatic mutation testing in Philadelphia-negative myeloproliferative neoplasms: polycythaemia vera, essential thrombocythaemia, primary myelofibrosis, chronic neutrophilic leukaemia, systemic mastocytosis, and chronic eosinophilic leukaemia. NGS panel testing is increasing in routine practice and promises to improve the accuracy and efficiency of pathological diagnosis and prognosis.
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http://dx.doi.org/10.1016/j.pathol.2021.01.003DOI Listing
April 2021

Predicting chemotherapy-induced menopause using baseline and post-chemotherapy anti-Müllerian hormone levels: Results of a pilot study.

Cancer Rep (Hoboken) 2021 Mar 3:e11342. Epub 2021 Mar 3.

Flinders University, Adelaide, Australia.

Background: Chemotherapy can cause premature menopause which may result in adverse effects such as fertility loss, osteoporosis, cardiovascular disease and menopausal symptoms. It is thus very important that women are provided with accurate information regarding their risk of premature menopause as a consequence of proposed chemotherapy. Unfortunately, at present there are no reliable tools which can be applied in clinical practice to estimate the risk of premature menopause in women undergoing chemotherapy, beyond age of the patient and form of chemotherapy utilized.

Aim: This was a pilot study to determine whether AMH levels pre and during chemotherapy are able to predict for chemotherapy induced menopause, and to assess quality of life and menopausal symptoms.

Methods And Results: Premenopausal women between 18 to 45 who were planned to undergo gonadotoxic chemotherapy with curative intent for either breast cancer or haematologic malignancy were recruited from a single centre. AMH, FSH, LH and oestradiol levels were recorded prior to commencement of therapy, during and following completion of chemotherapy. Menstrual status, menopausal symptoms and quality of life data were collected at baseline and during follow-up. Twenty two women were recruited. The baseline AMH was higher in women who regained menses post-chemotherapy (median 23.1 vs 9.9 pM (P = .06). Menopausal symptoms were significantly higher at 1 year post diagnosis than at baseline however quality of life was similar.

Conclusion: AMH may be useful for predicting chemotherapy induced menopause. Further research is still required to determine the place of such testing for patient counselling and management.
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http://dx.doi.org/10.1002/cnr2.1342DOI Listing
March 2021

Persistence of myelofibrosis treated with ruxolitinib: biology and clinical implications.

Haematologica 2021 May 1;106(5):1244-1253. Epub 2021 May 1.

Precision Medicine Theme, South Australian Health and Medical Research Institute, and Adelaide Medical School, University of Adelaide.

Activation of JAK-STAT signaling is one of the hallmarks of myelofibrosis, a myeloproliferative neoplasm that leads to inflammation, progressive bone marrow failure, and a risk of leukemic transformation. Around 90% of patients with myelofibrosis have a mutation in JAK2, MPL, or CALR: so-called 'driver' mutations that lead to activation of JAK2. Ruxolitinib, and other JAK2 inhibitors in clinical use, provide clinical benefit but do not have a major impact on the abnormal hematopoietic clone. This phenomenon is termed 'persistence', in contrast to usual patterns of resistance. Multiple groups have shown that type 1 inhibitors of JAK2, which bind the active conformation of the enzyme, lead to JAK2 becoming resistant to degradation with consequent accumulation of phospho-JAK2. In turn, this can lead to exacerbation of inflammatory manifestations when the JAK inhibitor is discontinued, and it may also contribute to disease persistence. The ways in which JAK2 V617F and CALR mutations lead to activation of JAK-STAT signaling are incompletely understood. We summarize what is known about pathological JAK-STAT activation in myelofibrosis and how this might lead to future novel therapies for myelofibrosis with greater disease-modifying potential.
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http://dx.doi.org/10.3324/haematol.2020.262691DOI Listing
May 2021

Changing of the guard: Leukemia Research 2021.

Leuk Res 2021 01 13;100:106510. Epub 2021 Jan 13.

Flinders Medical Centre, P.O. Box 2100, Bedford Park, SA, 5001, Australia. Electronic address:

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http://dx.doi.org/10.1016/j.leukres.2021.106510DOI Listing
January 2021

Sudden onset vision loss: an atypical presentation of giant cell arteritis and myeloproliferative neoplasm.

Med J Aust 2021 01 8;214(1):14-15.e1. Epub 2020 Dec 8.

Royal Adelaide Hospital, Adelaide, SA.

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http://dx.doi.org/10.5694/mja2.50888DOI Listing
January 2021

Counterpoint: There is a best duration of deep molecular response for treatment-free remission, but it is patient-specific, and that is the challenge.

Br J Haematol 2021 01 10;192(1):24-27. Epub 2020 Nov 10.

Precision Medicine Theme, South Australian Health & Medical Research Institute, Adelaide, Australia.

There is considerable clinical and scientific interest in identifying reliable predictors of treatment-free remission in chronic myeloid leukaemia. Most predictors have been identified from non-randomized clinical trials or retrospective cohorts that could be subject to bias. The validity of predictive factors, such as duration of treatment or of deep molecular response, has been questioned. We briefly review the relevant data and the potential for bias, arguing that the risk of bias may be overstated, and that accumulating data strongly suggest that depth and duration of molecular response are critical factors to enable us to predict the probability of treatment-free remission.
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http://dx.doi.org/10.1111/bjh.17111DOI Listing
January 2021

Early BCR-ABL1 kinetics are predictive of subsequent achievement of treatment-free remission in chronic myeloid leukemia.

Blood 2021 Mar;137(9):1196-1207

Department of Haematology, Royal Adelaide Hospital and SA Pathology, Adelaide, Australia.

With treatment-free remission (TFR) rapidly becoming the ultimate goal of therapy in chronic myeloid leukemia (CML), there is a need to develop strategies to maximize sustained TFR by improving our understanding of its key determinants. Chronic-phase CML patients attempting TFR were evaluated to identify the impact of multiple variables on the probability of sustained TFR. Early molecular response dynamics were included as a predictive variable, assessed by calculating the patient-specific halving time of BCR-ABL1 after commencing tyrosine kinase inhibitor (TKI) therapy. Overall, 115 patients attempted TFR and had ≥12 months of follow-up. The probability of sustained TFR, defined as remaining in major molecular response off TKI therapy for 12 months, was 55%. The time taken for the BCR-ABL1 value to halve was the strongest independent predictor of sustained TFR: 80% in patients with a halving time of <9.35 days (first quartile) compared with only 4% if the halving time was >21.85 days (last quartile) (P < .001). The e14a2 BCR-ABL1 transcript type and duration of TKI exposure before attempting TFR were also independent predictors of sustained TFR. However, the BCR-ABL1 value measured at 3 months of TKI was not an independent predictor of sustained TFR. A more rapid initial BCR-ABL1 decline after commencing TKI also correlated with an increased likelihood of achieving TFR eligibility. The association between sustained TFR and the time taken for BCR-ABL1 to halve after commencing TKI was validated using an independent dataset. These data support the critical importance of the initial kinetics of BCR-ABL1 decline for long-term outcomes.
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http://dx.doi.org/10.1182/blood.2020005514DOI Listing
March 2021

Meta-Analysis of Memory-Focused Training and Multidomain Interventions in Mild Cognitive Impairment.

J Alzheimers Dis 2020 ;76(1):399-421

Department of Physical Medicine & Rehabilitation, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Background: Meta-analysis examining the efficacy of cognitive interventions on neuropsychological outcomes have suggested interventions that focus on memory may actually provide greater benefit against the cognitive declines associated with mild cognitive impairment (MCI). However, it remains unclear if memory-based training would be more effective at addressing the cognitive deficits associated with MCI than multidomain forms of intervention.

Objective: A meta-analytic review and subgroup analysis was conducted to examine the effects of cognitive training in individuals diagnosed with MCI and to compare the efficacy of memory-based training with multidomain interventions.

Methods: A total of 32 randomized controlled trials met inclusion criteria for the meta-analysis, which included 9 studies on memory-focused training and 17 studies on multidomain interventions.

Results: We found significant, large effects for memory-focused training (Hedges' g observed = 0.947; 95% CI [-1.668, 3.562]; Z = 2.517; p = 0.012) and significant, moderate effects for multidomain interventions (Hedges' g observed = 0.420; 95% CI [-0.4491, 1.2891]; Z = 3.525; p < 0.001). A subgroup analysis found significant point estimates for memory-based forms of training and multidomain interventions, with memory-based forms of content yielding significantly greater summary effects than multidomain interventions (SMD Z = 2.162; p = 0.031, two-tailed; all outcomes). There was no difference between effect sizes when comparing outcomes limited to its respective domain.

Conclusion: Overall, these findings suggest that, while both interventions were beneficial, treatment interventions that were strictly memory-based were more effective at improving cognition in individuals diagnosed with MCI than interventions that targeted multiple cognitive domains.
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http://dx.doi.org/10.3233/JAD-200261DOI Listing
January 2020

Clinical utility of genomic DNA Q-PCR for the monitoring of a patient with atypical e19a2 transcripts in chronic myeloid leukemia.

Leuk Lymphoma 2020 10 6;61(10):2527-2529. Epub 2020 Jun 6.

Cancer Program, Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, Australia.

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http://dx.doi.org/10.1080/10428194.2020.1772476DOI Listing
October 2020

Treatment-free remission in patients with chronic myeloid leukaemia.

Nat Rev Clin Oncol 2020 08 6;17(8):493-503. Epub 2020 May 6.

Leukaemia Laboratory, Precision Medicine Theme, South Australian Health and Medical Research Institute, University of Adelaide, Adelaide, Australia.

In the past few years, international treatment guidelines for chronic myeloid leukaemia have incorporated recommendations for attempting discontinuation of treatment with tyrosine-kinase inhibitors (TKIs) outside of the setting of a clinical trial with the aim of a treatment-free remission (TFR). Physicians involved in the treatment of chronic myeloid leukaemia need to be sufficiently well informed to guide patients through decision-making about the discontinuation of treatment with TKIs targeting BCR-ABL1 by providing a balanced assessment of the potential risks and benefits of stopping or continuing therapy. These guidelines also seek to ensure that the risks associated with being off treatment are kept to a minimum. In this Review, we summarize the clinical studies of TFR and how their results can guide routine clinical practice with a focus on specific aspects such as molecular monitoring and the pregnancy-specific risks associated with a TFR attempt in female patients. We also address the development of predictors of outcome after TKI discontinuation and present strategies that warrant further consideration to enable more patients to enter TFR.
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http://dx.doi.org/10.1038/s41571-020-0367-1DOI Listing
August 2020

Successful treatment-free remission in chronic myeloid leukaemia and its association with reduced immune suppressors and increased natural killer cells.

Br J Haematol 2020 11 30;191(3):433-441. Epub 2020 Apr 30.

Precision Medicine Theme, South Australia Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia.

There is currently no biomarker that reliably predicts treatment-free remission (TFR) in chronic myeloid leukaemia (CML). We characterised effector and suppressor immune responses at the time of tyrosine kinase inhibitor (TKI) cessation in patients from the CML8 and CML10 clinical studies. Natural killer (NK) cells with increased expression of activating NK receptors were higher in patients who achieved TFR. There was no difference in the proportion of CD4 or CD8 T cells. Furthermore, we found that FoxP3 regulatory T cells (T reg) and monocytic myeloid-derived suppressor cells (Mo-MDSCs) were concomitantly decreased in TFR patients, suggesting that the effector and suppressor arms of the immune system work in concert to mediate TFR. A discovery cohort (CML10) was used to generate a predictive model, using logistic regression. Patients classified into the high-risk group were more likely to relapse when compared with the low-risk group (HR 7·4, 95% CI 2·9-19·1). The model was successfully validated on the independent CML8 cohort (HR 8·3, 95% CI 2·2-31·3). Effective prediction of TFR success may be obtained with an effector-suppressor score, calculated using absolute NK cell, T reg, and Mo-MDSC counts, at TKI cessation, reflecting the contribution of both immune suppressors and effectors in the immunobiology underlying successful TFR.
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http://dx.doi.org/10.1111/bjh.16718DOI Listing
November 2020

Use of romiplostim in pregnancy for refractory idiopathic thrombocytopenic purpura: Two case reports with maternal and fetal outcomes and literature review.

Obstet Med 2020 Mar 29;13(1):45-50. Epub 2018 May 29.

Lyell McEwin Hospital, Elizabeth Vale, Australia.

Idiopathic thrombocytopenic purpura is a relatively rare complication occurring in pregnancy, with the potential for serious maternal and fetal outcomes. Rarely, the poor response to established first-line therapies results in consideration of second-line therapies, which may have poorly understood risks to the fetus. We report two women with severe idiopathic thrombocytopenic purpura during pregnancy unresponsive to corticosteroids and intravenous immunoglobulin who were treated with romiplostim, a thrombopoietin receptor agonist. One woman with chronic idiopathic thrombocytopenic purpura had a partial response to romiplostim and suffered a post-partum haemorrhage related to uterine atony. The second woman developed severe idiopathic thrombocytopenic purpura in pregnancy and initially responded well to romiplostim. However, a lower segment Caesarean section was performed at 37 weeks for pre-eclampsia. The newborn suffered from severe idiopathic thrombocytopenic purpura and a grade 1 cerebral haemorrhage requiring intravenous immunoglobulin and platelet transfusions. Romiplostim might be a useful therapy for severe idiopathic thrombocytopenic purpura in pregnancy but requires further study.
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http://dx.doi.org/10.1177/1753495X18773960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7133099PMC
March 2020

Asciminib in Chronic Myeloid Leukemia after ABL Kinase Inhibitor Failure.

N Engl J Med 2019 12;381(24):2315-2326

From the South Australian Health and Medical Research Institute and the University of Adelaide, Adelaide, SA, Australia (T.P.H., D.Y., D.M.R.); Memorial Sloan Kettering Cancer Center, New York (M.J.M., M.S.T., J.H.P.); University of Texas M.D. Anderson Cancer Center, Houston (J.E.C.); Kobe University Graduate School of Medicine, Kobe (H.M.), and the National Cancer Center Hospital East, Chiba (Y.M.) - both in Japan; Hôpital Saint-Louis, Paris (D.R.), and the University of Bordeaux, Bordeaux (F.-X.M.) - both in France; Dana-Farber Cancer Institute, Boston (D.J.D.); Sapienza University, Rome (M.B.); Singapore General Hospital, Singapore (Y.-T.G.); University of Michigan Comprehensive Cancer Center, Ann Arbor (M.T.); Universitätsklinikum Jena, Jena (A.H.), Charité Hospital, Berlin (P.C.), and the Department for Hematology-Oncology, Goethe University Hospital, Frankfurt am Main (F.L.) - all in Germany; University of Cardiff, Cardiff, United Kingdom (O.O.); Veterans Affairs Portland Health Care System (M.C.H.) and Oregon Health and Science University Knight Cancer Institute (M.C.H., B.J.D.), Portland; Hospital de la Princesa and Instituto de Investigación Sanitaria Princesa, Madrid (J.L.S.); Huntsman Cancer Institute, University of Utah, Salt Lake City (M.W.N.D.); Amsterdam University Medical Centers, VU University Medical Center, Amsterdam (J.J.W.M.J.); Novartis Pharma, Basel, Switzerland (D.H., Y.D., C.M., F.H.-P., K.G.V.); and Seoul St. Mary's Hematology Hospital, Catholic University of Korea, Seoul, South Korea (D.-W.K.).

Background: Asciminib is an allosteric inhibitor that binds a myristoyl site of the BCR-ABL1 protein, locking BCR-ABL1 into an inactive conformation through a mechanism distinct from those for all other ABL kinase inhibitors. Asciminib targets both native and mutated BCR-ABL1, including the gatekeeper T315I mutant. The safety and antileukemic activity of asciminib in patients with Philadelphia chromosome-positive leukemia are unknown.

Methods: In this phase 1, dose-escalation study, we enrolled 141 patients with chronic-phase and 9 with accelerated-phase chronic myeloid leukemia (CML) who had resistance to or unacceptable side effects from at least two previous ATP-competitive tyrosine kinase inhibitors (TKIs). The primary objective was to determine the maximum tolerated dose or the recommended dose (or both) of asciminib. Asciminib was administered once or twice daily (at doses of 10 to 200 mg). The median follow-up was 14 months.

Results: Patients were heavily pretreated; 70% (105 of 150 patients) had received at least three TKIs. The maximum tolerated dose of asciminib was not reached. Among patients with chronic-phase CML, 34 (92%) with a hematologic relapse had a complete hematologic response; 31 (54%) without a complete cytogenetic response at baseline had a complete cytogenetic response. A major molecular response was achieved or maintained by 12 months in 48% of patients who could be evaluated, including 8 of 14 (57%) deemed to have resistance to or unacceptable side effects from ponatinib. A major molecular response was achieved or maintained by 12 months in 5 patients (28%) with a T315I mutation at baseline. Clinical responses were durable; a major molecular response was maintained in 40 of 44 patients. Dose-limiting toxic effects included asymptomatic elevations in the lipase level and clinical pancreatitis. Common adverse events included fatigue, headache, arthralgia, hypertension, and thrombocytopenia.

Conclusions: Asciminib was active in heavily pretreated patients with CML who had resistance to or unacceptable side effects from TKIs, including patients in whom ponatinib had failed and those with a T315I mutation. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02081378.).
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http://dx.doi.org/10.1056/NEJMoa1902328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724923PMC
December 2019

Lineage of measurable residual disease in patients with chronic myeloid leukemia in treatment-free remission.

Leukemia 2020 04 25;34(4):1052-1061. Epub 2019 Nov 25.

Cancer Program, Precision Medicine Theme, South Australian Health & Medical Research Institute, Adelaide, SA, Australia.

Approximately half of patients with chronic myeloid leukemia (CML) in sustained deep molecular response who discontinue tyrosine kinase inhibitors (TKIs) remain in treatment-free remission (TFR). Some of these patients have measurable residual disease (MRD) by BCR-ABL1 mRNA testing, and most have detectable BCR-ABL1 DNA by highly sensitive methods. We used fluorescence-activated cell sorting and BCR-ABL1 DNA PCR to investigate the lineage of residual CML cells in TFR. Twenty patients in TFR for >1 year provided blood for sorting into granulocytes, monocytes, B cells, T cells, and NK cells. MRD was identified predominantly in the lymphoid compartment and never in granulocytes. B cells were more often BCR-ABL1 positive than T cells (18 vs 11/20 patients) and at higher levels (median 10 vs 10; P = 0.014). In 13 CML patients studied at diagnosis lymphocytes expressing BCR-ABL1 mRNA comprised a small proportion of total leukocytes. These data improve our understanding of TFR biology, since it is now clear that MRD in the blood of TFR patients need not imply the persistence of multipotent CML cells. Lineage-specific assessment of MRD could be explored as a means to improve the prediction of TFR.
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http://dx.doi.org/10.1038/s41375-019-0647-xDOI Listing
April 2020

Cardiac and hepatic siderosis in myelodysplastic syndrome, thalassemia and diverse causes of transfusion-dependent anemia: the TIMES study.

Hemasphere 2019 Jun 4;3(3):e224. Epub 2019 Jun 4.

Monash Medical Centre, Melbourne, Australia.

The significant morbidity and mortality associated with iron overload can be reduced by effective iron chelation. Magnetic resonance imaging (MRI) provides accurate and reproducible iron load assessment. The aim of this epidemiological study was to assess the prevalence and severity of cardiac and hepatic siderosis by MRI and to evaluate the impact of MRI on clinical management in patients with transfusion-dependent anemia and non-transfusion-dependent thalassemia (NTDT). We enrolled 243 patients with myelodysplastic syndromes (MDS), thalassemia major (TM), NTDT or other chronic anemia. Overall, 10% and 48% had cardiac and hepatic siderosis, respectively. Mean liver iron concentration (LIC) was above target range in all groups; mean myocardial T2 was normal. Hepatic siderosis was more prevalent than myocardial siderosis in patients with MDS, occurring in 54.4% and 4.4% of patients, respectively. As also observed in patients with NTDT or other anemia, hepatic siderosis was present in a large proportion of MDS patients who were chelation naïve (57.7%), as well as in patients receiving iron chelation therapy (ICT) (52.4%), despite a lower transfusion load compared with TM. Correlation between LIC and serum ferritin was observed across diseases; however, not all patients requiring ICT could be identified with serum ferritin alone, as serum ferritin underestimated LIC in 4.4% and overestimated LIC in 7.5% of patients. Exploratory analyses showed serum ferritin thresholds for liver siderosis detected by MRI at approximately 300 ng/mL higher in MDS than in TM. Most patients reported low-medium adherence to ICT; MRI assessment led to change in ICT in 46% of evaluable patients, including 52% of MDS patients. Accurate organ iron monitoring by MRI facilitated appropriate initiation of chelation, dose optimization and clinical decision making. ClinicalTrials.gov: NCT01736540.
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http://dx.doi.org/10.1097/HS9.0000000000000224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746020PMC
June 2019

Changing incidence of myeloproliferative neoplasms in Australia, 2003-2014.

Am J Hematol 2019 04 12;94(4):E107-E109. Epub 2019 Feb 12.

School of Public Health, Curtin University, Perth, Western Australia, Australia.

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http://dx.doi.org/10.1002/ajh.25407DOI Listing
April 2019

The effect of tyrosine kinase inhibitor interruption and interferon use on pregnancy outcomes and long-term disease control in chronic myeloid leukemia.

Leuk Lymphoma 2019 07 11;60(7):1796-1802. Epub 2019 Jan 11.

a Department of Clinical Hematology , Austin Hospital , Heidelberg , Australia.

The management of CML in pregnancy is challenging with the need to balance disease control against potential teratogenic effects of TKI therapy. In this multi-center case-cohort study of 16 women in chronic phase, CML ceased TKI treatment pre- or post-conception during their first pregnancy. Thirteen patients were on imatinib; 9 ceased their TKI prior to conception and 7 ceased at pregnancy confirmation. Twelve patients had achieved either MMR or better at time of TKI cessation. Eleven women lost MMR during pregnancy and two patients lost CHR. Fourteen women reestablished MMR on TKI recommenced. The depth molecular response prior to conception appeared to correlate well with restoration of disease control on TKI recommencement though duration of MMR did not appear to be as important. While interruption of TKI treatment for pregnancy usually leads to loss of molecular response, loss of hematological response is uncommon and disease control is reestablished with resumption of therapy in the majority of women.
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http://dx.doi.org/10.1080/10428194.2018.1551533DOI Listing
July 2019

Accumulation of JAK activation loop phosphorylation is linked to type I JAK inhibitor withdrawal syndrome in myelofibrosis.

Sci Adv 2018 11 28;4(11):eaat3834. Epub 2018 Nov 28.

Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, South Australia, Australia.

Treatment of patients with myelofibrosis with the type I JAK (Janus kinase) inhibitor ruxolitinib paradoxically induces JAK2 activation loop phosphorylation and is associated with a life-threatening cytokine-rebound syndrome if rapidly withdrawn. We developed a time-dependent assay to mimic ruxolitinib withdrawal in primary JAK2 and CALR mutant myelofibrosis patient samples and observed notable activation of spontaneous STAT signaling in JAK2 samples after drug washout. Accumulation of ruxolitinib-induced JAK2 phosphorylation was dose dependent and correlated with rebound signaling and the presence of a JAK2 mutation. Ruxolitinib prevented dephosphorylation of a cryptic site involving Tyr in JAK2 blocking ubiquitination and degradation. In contrast, a type II JAK inhibitor, CHZ868, did not induce JAK2 phosphorylation, was not associated with withdrawal signaling, and was superior in the eradication of flow-purified JAK2 mutant CD34 progenitors after drug washout. Type I inhibitor-induced loop phosphorylation may act as a pathogenic signaling node released upon drug withdrawal, especially in JAK2 patients.
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http://dx.doi.org/10.1126/sciadv.aat3834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6261652PMC
November 2018

Recommendations for the use of pegylated interferon-α in the treatment of classical myeloproliferative neoplasms.

Intern Med J 2019 08;49(8):948-954

Department of Haematology, Royal Adelaide Hospital and Flinders Medical Centre, and Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, South Australia, Australia.

The classical myeloproliferative neoplasms (MPN) are uncommon clonal haemopoietic malignancies characterised by excessive production of mature blood cells. Clinically, they are associated with thrombosis, haemorrhage, varying degrees of constitutional disturbance and a risk of progression to myelofibrosis or acute myeloid leukaemia. Many of the disease manifestations may be ameliorated by treatment with interferon-α (IFN), but its use in Australian MPN patients has been limited due to the inconvenience of frequent injections and side-effects. The pegylated form of IFN is a long-acting preparation, which is better tolerated, and its Pharmaceutical Benefits Scheme listing is likely to lead to increased usage. We review the literature on risks and benefits of IFN treatment for MPN, suggest criteria for patient selection in each of these diseases and discuss strategies to manage the side-effects of pegylated IFN.
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http://dx.doi.org/10.1111/imj.14154DOI Listing
August 2019

Long-term treatment-free remission of chronic myeloid leukemia with falling levels of residual leukemic cells.

Leukemia 2018 12 12;32(12):2572-2579. Epub 2018 Oct 12.

Cancer Theme, South Australian Health & Medical Research Institute, Adelaide, Australia.

Following the achievement of deep molecular response on tyrosine kinase inhibitors (TKIs), approximately half of patients with chronic myeloid leukemia (CML) can discontinue TKI and remain in treatment-free remission (TFR). The ALLG CML8 study enrolled 40 imatinib-treated patients with undetectable BCR-ABL1 mRNA (approximately MR). Molecular relapse was defined as detectable BCR-ABL1 on two consecutive tests or any single value >0.1%. With a median follow-up of 8.6 years (range 5.7-11.2 years), 18 patients remain in continuous TFR (45.0%; 95% confidence interval 31.9-63.4%). The latest relapse detected was 27 months after stopping imatinib. No patient progressed to advanced phase. Twenty-two patients met criteria for imatinib re-treatment and all regained undetectable molecular response. Nine patients in long-term TFR were monitored by highly sensitive individualized BCR-ABL1 DNA PCR in a sufficient number of samples to enable more precise quantification of residual leukemia. BCR-ABL1 DNA decreased from a median of MR in the first year of TFR to MR in the sixth year of TFR. Our results support the long-term safety and remarkable stability of response after imatinib discontinuation in appropriately selected CML patients. Serial high sensitivity testing provides a new and unexpected finding of gradually reducing CML cells in patients in long-term TFR.
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http://dx.doi.org/10.1038/s41375-018-0264-0DOI Listing
December 2018

genomic DNA PCR response kinetics during first-line imatinib treatment of chronic myeloid leukemia.

Haematologica 2018 12 5;103(12):2026-2032. Epub 2018 Jul 5.

Cancer Theme, South Australian Health & Medical Research Institute, Adelaide, Australia

Accurate quantification of minimal residual disease (MRD) during treatment of chronic myeloid leukemia (CML) guides clinical decisions. The conventional MRD method, RQ-PCR for mRNA, reflects a composite of the number of circulating leukemic cells and the transcripts per cell. genomic DNA only reflects leukemic cell number. We used both methods in parallel to determine the relative contribution of the leukemic cell number to molecular response. DNA PCR and RQ-PCR were monitored up to 24 months in 516 paired samples from 59 newly-diagnosed patients treated with first-line imatinib in the TIDEL-II study. In the first three months of treatment, mRNA values declined more rapidly than DNA. By six months, the two measures aligned closely. The expression of mRNA was normalized to cell number to generate an expression ratio. The expression of e13a2 was lower than that of e14a2 transcripts at multiple time points during treatment. DNA was quantifiable in 48% of samples with undetectable mRNA, resulting in MRD being quantifiable for an additional 5-18 months (median 12 months). These parallel studies show for the first time that the rapid decline in mRNA over the first three months of treatment is due to a reduction in both cell number and transcript level per cell, whereas beyond three months, falling levels of mRNA are proportional to the depletion of leukemic cells.
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http://dx.doi.org/10.3324/haematol.2018.189787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269287PMC
December 2018

Integrative genomic analysis reveals cancer-associated mutations at diagnosis of CML in patients with high-risk disease.

Blood 2018 08 2;132(9):948-961. Epub 2018 Jul 2.

School of Medicine, Faculty of Health and Medical Sciences, and.

Genomic events associated with poor outcome in chronic myeloid leukemia (CML) are poorly understood. We performed whole-exome sequencing, copy-number variation, and/or RNA sequencing for 65 patients to discover mutations at diagnosis and blast crisis (BC). Forty-six patients with chronic-phase disease with the extremes of outcome were studied at diagnosis. Cancer gene variants were detected in 15 (56%) of 27 patients with subsequent BC or poor outcome and in 3 (16%) of 19 optimal responders ( = .007). Frequently mutated genes at diagnosis were , , and The methyltransferase was a novel recurrently mutated gene. A novel class of variant associated with the Philadelphia (Ph) translocation was detected at diagnosis in 11 (24%) of 46 patients comprising fusions and/or rearrangement of genes on the translocated chromosomes, with evidence of fragmentation, inversion, and imperfect sequence reassembly. These were more frequent at diagnosis in patients with poor outcome: 9 (33%) of 27 vs 2 (11%) of 19 optimal responders ( = .07). Thirty-nine patients were tested at BC, and all had cancer gene variants, including kinase domain mutations in 58%. However, mutations cooccurred with other mutated cancer genes in 89% of cases, and these predated mutations in 62% of evaluable patients. Gene fusions not associated with the Ph translocation occurred in 42% of patients at BC and commonly involved fusion partners that were known cancer genes (78%). Genomic analysis revealed numerous relevant variants at diagnosis in patients with poor outcome and all patients at BC. Future refined biomarker testing of specific variants will likely provide prognostic information to facilitate a risk-adapted therapeutic approach.
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http://dx.doi.org/10.1182/blood-2018-02-832253DOI Listing
August 2018

Management of Pregnancy in Women With Chronic Myeloid Leukemia.

J Clin Oncol 2018 09 31;36(25):2657-2658. Epub 2018 May 31.

David M. Ross, Royal Adelaide Hospital, South Australian Health and Medical Research Institute, and Flinders University and Medical Centre, Adelaide, South Australia, Australia; Kate L. Burbury, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, and University of Melbourne, Melbourne, Victoria, Australia; Andrew P. Grigg, Austin Hospital, Melbourne, Victoria, Australia; Timothy P. Hughes, Royal Adelaide Hospital and South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia; and John F. Seymour, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, and University of Melbourne, Melbourne, Victoria, Australia.

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http://dx.doi.org/10.1200/JCO.2018.78.6137DOI Listing
September 2018

Chronic myeloid leukaemia: going off piste.

Authors:
David M Ross

Lancet Oncol 2018 06 4;19(6):717-718. Epub 2018 May 4.

Department of Haematology, Royal Adelaide Hospital, Adelaide, SA 5000, Australia; Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia; Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia; Department of Haematology and Molecular Medicine, Flinders University and Medical Centre, Adelaide, SA, Australia. Electronic address:

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http://dx.doi.org/10.1016/S1470-2045(18)30206-7DOI Listing
June 2018

Durable treatment-free remission in patients with chronic myeloid leukemia in chronic phase following frontline nilotinib: 96-week update of the ENESTfreedom study.

J Cancer Res Clin Oncol 2018 May 22;144(5):945-954. Epub 2018 Feb 22.

Abteilung Hämatologie/Onkologie, Universitätsklinikum Jena, Jena, Germany.

Purpose: ENESTfreedom is evaluating treatment-free remission (TFR) following frontline nilotinib in patients with chronic myeloid leukemia (CML) in chronic phase. Following our primary analysis at 48 weeks, we here provide an updated 96-week analysis.

Methods: Attempting TFR required ≥ 3 years of nilotinib, a molecular response of MR [BCR-ABL1 ≤ 0.0032% on the International Scale (BCR-ABL1)], and sustained deep molecular response (DMR) during a 1-year consolidation phase. Patients restarted nilotinib following loss of major molecular response (MMR; BCR-ABL1 ≤ 0.1%).

Results: Ninety-six weeks after stopping treatment (3.6-year median prior nilotinib duration), 93 of 190 patients (48.9%) remained in TFR. Of 88 patients who restarted nilotinib following loss of MMR, 87 regained MMR and 81 regained MR by the data cut-off. Ninety-six-week TFR rates were 61.3, 50.0, and 28.6% in patients with low, intermediate, and high Sokal risk scores at diagnosis, respectively. Patients consistently in MR during consolidation had higher TFR rates (50.6%) than patients with ≥ 1 assessment without MR during consolidation (35.0%). In a landmark analysis, 96-week TFR rates for patients with MR, MR (BCR-ABL1 ≤ 0.01%) but not MR, and MMR but not MR at TFR week 12 were 82.6, 23.1, and 0%, respectively. There were no reports of disease progression or death due to CML; overall adverse event frequency decreased following TFR. Within the follow-up period, TFR did not adversely affect disease outcomes.

Conclusions: These results demonstrate the feasibility and durability of TFR following frontline nilotinib and emphasize the importance of sustained DMR for TFR.
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http://dx.doi.org/10.1007/s00432-018-2604-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5916993PMC
May 2018

Chronic myeloid leukaemia and tyrosine kinase inhibitor therapy: assessment and management of cardiovascular risk factors.

Intern Med J 2018 02;48 Suppl 2:5-13

Department of Cardiology, Mater Hospital and University of Queensland, Brisbane, Queensland, Australia.

Several BCR-ABL1 tyrosine kinase inhibitors (TKIs) are approved for the first-line treatment of chronic phase chronic myeloid leukaemia (CML). Disease control is achieved in the vast majority of patients and disease-specific survival is excellent. Consequently, there is now emphasis on managing comorbidities and minimising treatment-related toxicity. Second-generation TKIs have cardiovascular risks that are greater than with imatinib treatment, but these risks must be balanced against the superior CML responses encountered with more potent TKIs. Cardiovascular risk should be assessed at baseline using a locally validated model based on the Framingham risk equation. Clinicians involved in the care of CML patients should be aware of the vascular complications of TKIs and manage cardiovascular risk factors early to mitigate treatment-related risks. Reversible risk factors, such as dyslipidaemia, smoking, diabetes and hypertension, should be addressed. We summarise the available data on cardiovascular complications in CML patients treated with TKIs. Using the latest evidence and collective expert opinion, we provide practical advice for clinicians to assess, stratify and manage cardiovascular risk in people with CML receiving TKI therapy.
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http://dx.doi.org/10.1111/imj.13716DOI Listing
February 2018