Mark W. Drummond

Early prediction of success or failure of treatment with second-generation tyrosine kinase inhibitors in patients with chronic myeloid leukemia

Background Second-generation tyrosine kinase inhibitors induce cytogenetic responses in approximately 50% of patients with chronic myeloid leukemia in chronic phase in whom imatinib treatment has failed. However, it has not yet been established which of the patients in whom imatinib treatment fails are likely to benefit from therapy with second-generation tyrosine kinase inhibitors. Design and Methods We analyzed a cohort of 80 patients with chronic myeloid leukemia who were resistant to imatinib and who were treated with dasatinib or nilotinib while still in first chronic phase. We devised a scoring system to predict the probability of these patients achieving complete cytogenetic response when treated with second-generation tyrosine kinase inhibitors. Results The system was based on three factors: cytogenetic response to imatinib, Sokal score and recurrent neutropenia during imatinib treatment. We validated the score in an independent group of 28 Scottish patients. We also studied the relationship between cytogenetic responses at 3, 6 and 12 months and subsequent outcome. We classified the 80 patients into three categories, those with good risk (n=24), intermediate risk (n=27) and poor risk (n=29) with 2.5-year cumulative incidences of complete cytogenetic response of 100%, 52.2% and 13.8%, respectively (P<0.0001). Moreover, patients who had less than 95% Philadelphia chromosome-positive metaphases at 3 months, those with 35% or less Philadelphia chromosome-positive metaphases at 6 months and patients in complete cytogenetic response at 12 months all had significantly better outcomes than patients with lesser degrees of cytogenetic response. Conclusions Factors measurable before starting treatment can accurately predict response to second-generation tyrosine kinase inhibitors. Cytogenetic responses at 3, 6 and 12 months may influence the decision to continue treatment with second-generation tyrosine kinase inhibitors.

Safety and Efficacy of Fedratinib in Patients With Primary or Secondary Myelofibrosis: A Randomized Clinical Trial

IMPORTANCE Myelofibrosis (MF) is a BCR-ABL-negative myeloproliferative neoplasm characterized by anemia, splenomegaly, debilitating constitutional symptoms, and shortened survival. Fedratinib, a JAK2-selective inhibitor, previously demonstrated clinically beneficial activity in patients with MF in early-phase trials. OBJECTIVE To evaluate the efficacy and safety of fedratinib therapy in patients with primary or secondary (post-polycythemia vera or post-essential thrombocythemia) MF. DESIGN, SETTING, AND PARTICIPANTS Double-blind, randomized, placebo-controlled phase 3 study in 94 sites in 24 countries in which 289 adult patients (≥18 years of age) with intermediate-2 or high-risk primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF were randomly assigned between December 2011 and September 2012 to once-daily oral fedratinib, at a dose of 400 mg or 500 mg, or placebo, for at least 6 consecutive 4-week cycles. MAIN OUTCOMES AND MEASURES The primary end point was spleen response (≥35% reduction in spleen volume from baseline as determined by magnetic resonance imaging or computed tomography) at week 24 and confirmed 4 weeks later. The main secondary end point was symptom response (≥50% reduction in total symptom score, assessed using the modified Myelofibrosis Symptom Assessment Form). RESULTS The primary end point was achieved by 35 of 96 (36% [95% CI, 27%-46%]) and 39 of 97 (40% [95% CI, 30%-50%]) patients in the fedratinib 400-mg and 500-mg groups, vs 1 of 96 (1% [95% CI, 0%-3%]) in the placebo group (P < .001). Symptom response rates at week 24 were 33 of 91 (36% [95% CI, 26%-46%]), 31 of 91 (34% [95% CI, 24%-44%]), and 6 of 85 (7% [95% CI, 2%-13%]) in the fedratinib 400-mg, 500-mg, and placebo groups, respectively (P < .001). Common adverse events with fedratinib treatment were anemia, gastrointestinal symptoms, and increased levels of liver transaminases, serum creatinine, and pancreatic enzymes. Encephalopathy was reported in 4 women who received fedratinib 500 mg/d. A diagnosis of Wernicke encephalopathy was supported by magnetic resonance imaging in 3 cases and suspected clinically in 1 case. CONCLUSIONS AND RELEVANCE Fedratinib therapy significantly reduced splenomegaly and symptom burden in patients with MF. These benefits were accompanied by toxic effects in some patients, the most important being encephalopathy of unknown mechanism. Clinical development of fedratinib was subsequently discontinued. TRIAL REGISTRATION clinicaltrials.gov identifier: NCT01437787.

Results of the Phase I Trial of RG7112, a Small-Molecule MDM2 Antagonist in Leukemia.

Purpose: RG7112 is a small-molecule MDM2 antagonist. MDM2 is a negative regulator of the tumor suppressor p53 and frequently overexpressed in leukemias. Thus, a phase I study of RG7112 in patients with hematologic malignancies was conducted. Experimental Design: Primary study objectives included determination of the dose and safety profile of RG7112. Secondary objectives included evaluation of pharmacokinetics; pharmacodynamics, such as TP53-mutation status and MDM2 expression; and preliminary clinical activity. Patients were divided into two cohorts: Stratum A [relapsed/refractory acute myeloid leukemia (AML; except acute promyelocytic leukemia), acute lymphoblastic leukemia, and chronic myelogenous leukemia] and Stratum B (relapsed/refractory chronic lymphocytic leukemia/small cell lymphocytic leukemia; CLL/sCLL). Some Stratum A patients were treated at the MTD to assess clinical activity. Results: RG7112 was administered to 116 patients (96 patients in Stratum A and 20 patients in Stratum B). All patients experienced at least 1 adverse event, and 3 dose-limiting toxicities were reported. Pharmacokinetic analysis indicated that twice-daily dosing enhanced daily exposure. Antileukemia activity was observed in the 30 patients with AML assessed at the MTD, including 5 patients who met International Working Group (IWG) criteria for response. Exploratory analysis revealed TP53 mutations in 14% of Stratum A patients and in 40% of Stratum B patients. Two patients with TP53 mutations exhibited clinical activity. p53 target genes were induced only in TP53 wild-type leukemic cells. Baseline expression levels of MDM2 correlated positively with clinical response. Conclusions: RG7112 demonstrated clinical activity against relapsed/refractory AML and CLL/sCLL. MDM2 inhibition resulted in p53 stabilization and transcriptional activation of p53-target genes. We provide proof-of-concept that MDM2 inhibition restores p53 function and generates clinical responses in hematologic malignancies. Clin Cancer Res; 22(4); 868–76. ©2015 AACR.

Eradication of Chronic Myeloid Leukemia Stem Cells: A Novel Mathematical Model Predicts No Therapeutic Benefit of Adding G-CSF to Imatinib

Imatinib mesylate induces complete cytogenetic responses in patients with chronic myeloid leukemia (CML), yet many patients have detectable BCR-ABL transcripts in peripheral blood even after prolonged therapy. Bone marrow studies have shown that this residual disease resides within the stem cell compartment. Quiescence of leukemic stem cells has been suggested as a mechanism conferring insensitivity to imatinib, and exposure to the Granulocyte-Colony Stimulating Factor (G-CSF), together with imatinib, has led to a significant reduction in leukemic stem cells in vitro. In this paper, we design a novel mathematical model of stem cell quiescence to investigate the treatment response to imatinib and G-CSF. We find that the addition of G-CSF to an imatinib treatment protocol leads to observable effects only if the majority of leukemic stem cells are quiescent; otherwise it does not modulate the leukemic cell burden. The latter scenario is in agreement with clinical findings in a pilot study administering imatinib continuously or intermittently, with or without G-CSF (GIMI trial). Furthermore, our model predicts that the addition of G-CSF leads to a higher risk of resistance since it increases the production of cycling leukemic stem cells. Although the pilot study did not include enough patients to draw any conclusion with statistical significance, there were more cases of progression in the experimental arms as compared to continuous imatinib. Our results suggest that the additional use of G-CSF may be detrimental to patients in the clinic.

Telomere shortening correlates with prognostic score at diagnosis and proceeds rapidly during progression of chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is associated increased stem cell turnover. We have previously shown that short telomeres in chronic phase (CP) predict for early progression to blast phase (BP). Poor prognostic score patients may therefore exhibit increased telomere loss at diagnosis and/or a greater than normal rate of loss during the disease course. We prospectively studied newly diagnosed CML patients for degree of telomere loss; measured telomere length in CML patients at all stages of disease; and performed follow-up sampling according to cytogenetic response to imatinib mesylate. Using flow-FISH, telomere length in peripheral blood leucocytes (PBL) from 32 consecutive newly diagnosed patients was measured (with ex-vivo expanded T-cells as an internal BCR-ABL negative control), in addition to 65 samples from all CML stages and 7 paired CP/BP samples. Fifty-five normal individuals served as a control population. Patients who attained either a complete cytogenetic response (CCR, 0% Ph+, n = 10) or no CR (100% Ph+, n = 11) underwent follow-up measurement. All statistical tests were two sided. Telomeres in accelerated phase (AP) and BP patients were significantly shorter than in CP, and mean telomere shortening was significantly greater in high-risk score than low-risk patients (P < 0.05) at diagnosis. The rate of shortening during disease progression was 10-20 times the rate observed in normal granulocytes. BP samples had undergone at least 30-60 additional divisions from baseline Ph- telomere length. Our findings show that telomere shortening in CML is greatest in high-risk score patients at diagnosis, and occurs rapidly during disease progression.

A pilot study of continuous imatinib vs pulsed imatinib with or without G-CSF in CML patients who have achieved a complete cytogenetic response

A pilot study of continuous imatinib vs pulsed imatinib with or without G-CSF in CML patients who have achieved a complete cytogenetic response

Guidelines for the diagnosis and management of adult myelodysplastic syndromes.

Sally B. Killick, Chris Carter, Dominic Culligan, Christopher Dalley, Emma Das-Gupta, Mark Drummond, Helen Enright, Gail L. Jones, Jonathan Kell, Juliet Mills, Ghulam Mufti, Jane Parker, Kavita Raj, Alexander Sternberg, Paresh Vyas, David Bowen and British Committee for Standards in Haematology The Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust, Bournemouth, Hull and East Yorkshire Hospitals NHS Trust, Hull, Aberdeen Royal Infirmary, Aberdeen, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, Nottingham University Hospitals NHS Trust, Nottingham, Beatson West of Scotland Cancer Centre, Glasgow, UK, Tallaght Hospital Dublin, Trinity College Medical School, Dublin, Ireland, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, University Hospital of Wales, Cardiff, Worcestershire Acute Hospitals NHS Trust and Birmingham NHS Foundation Trust, Birmingham, Kings College Hospital NHS Foundation Trust, London, Northampton General Hospital NHS Trust, Northampton, Guys and St Thomas’ and Kings College Hospitals NHS Foundation Trusts, London, Great Western Hospitals NHS Foundation Trust, Swindon, Oxford University and Oxford University Hospitals NHS Trust, Oxford, and St. James’s Institute of Oncology, Leeds Teaching Hospitals, Leeds, UK

Identification of high oxygen affinity hemoglobin variants in the investigation of patients with erythrocytosis

Erythrocytosis is a disorder of red cell production that can arise from several different causes. Familial cases have been classified into four groups (ECYT1-4) by Online Mendelian Inheritance in Man (OMIM) as listed at the website: . Erythrocytosis

Mobilization of Ph chromosome-negative peripheral blood stem cells in chronic myeloid leukaemia patients with imatinib mesylate-induced complete cytogenetic remission

Summary. Imatinib mesylate (IM, STI 571, Glivec®) can induce a high rate of complete cytogenetic response (CCR) in chronic myeloid leukaemia (CML) patients, although to date the majority of patients continue to have detectable disease by sensitive reverse transcription polymerase chain reaction (RT‐PCR). It is therefore possible that these patients may ultimately relapse and require treatment such as autologous peripheral blood stem cell transplant (APBSCT). We attempted mobilization of haemopoietic progenitor cells from 58 patients in CCR using recombinant human granulocyte colony‐stimulating factor [rHu‐G‐CSF; 10 µg/kg/d subcutaneously (s.c.) for at least 4 d] alone, while continuing IM treatment. The median d 5 (peak) CD34+ count was 11·5/µl (range 0–108/µl), and 43/58 (74%) patients underwent a median of two (range 1–3) apheresis procedures. A median dose of 2·1 × 106/kg CD34+ cells (range 0·1–6·5 × 106/kg) was collected. Some 84% of 31 collections analysed were negative for the Philadelphia (Ph) chromosome or breakpoint cluster region and Abelson murine leukaemia viral oncogene homologue (BCR‐ABL) translocation by cytogenetics or fluorescent in situ hybridization respectively. No toxicity was reported with the regimen. Overall, the target CD34+ dose (2 × 106/kg CD34+) was attained in 23/58 (40%) patients who entered the study. In summary, we have demonstrated that successful mobilization of Ph– CD34+ cells from IM‐treated patients in CCR is possible using rHu‐G‐CSF alone.

Modification of British Committee for Standards in Haematology diagnostic criteria for essential thrombocythaemia

The diagnosis of the myeloproliferative neoplasms (MPN)‒ essential thrombocythaemia (ET) and primary myelofibrosis (PMF) ‒ in patients lacking a molecular marker is challenging. Recently, mutations in exon 9 of the calreticulin gene (CALR) have been described in around one-third of ET and MF patients (Klampfl et al, 2013a; Nangalia et al, 2013). Notably, these mutations are almost always seen in JAK2 V617F-negative and MPL-non-mutated patients and account for the majority of these cases. Such is the prevalence of these mutations we suggest that they are added to the British Committee for Standards in Haematology criteria for the diagnosis of ET and also PMF (Harrison et al, 2010; Reilly et al, 2012) (evidence grade 1A). The modified diagnostic criteria and algorithms are shown in