J M Goldman’s research while affiliated with Imperial College London and other places

Patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKIs) often have constant minor side-effects which have a significant impact on their daily lives and on their adherence to prescribed medication. One possible strategy to minimize these side effects is to take advantage of low cross intolerance between different TKIs and to “proactively” change therapy. However it is not clear whether such a change can adversely affect response, induce resistance or indeed eliminate a given side effect. In this work we describe outcomes in 57 patients who after attaining complete cytogenetic response changed from imatinib to a second generation TKI solely due to persistent minor side effects. After one or more changes of therapy 46 of the 57 patients were entirely free of side effects and an additional 11 patients had nearly complete resolution of side effects resulting in total or almost complete absence of minor persistent side effects in all cases. Furthermore all patients improved their levels of molecular response and BCR-ABL1 kinase mutations were not detected in any patient after change of therapy. Proactively changing therapy on account of persistent minor side effects seems to be an effective and safe therapeutic option for CML patients.

Background Ponatinib is a potent oral tyrosine kinase inhibitor of unmutated and mutated BCR-ABL, including BCR-ABL with the tyrosine kinase inhibitor-refractory threonine-to-isoleucine mutation at position 315 (T315I). We conducted a phase 2 trial of ponatinib in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL). Methods We enrolled 449 heavily pretreated patients who had CML or Ph-positive ALL with resistance to or unacceptable side effects from dasatinib or nilotinib or who had the BCR-ABL T315I mutation. Ponatinib was administered at an initial dose of 45 mg once daily. The median follow-up was 15 months. ResultsAmong 267 patients with chronic-phase CML, 56% had a major cytogenetic response (51% of patients with resistance to or unacceptable side effects from dasatinib or nilotinib and 70% of patients with the T315I mutation), 46% had a complete cytogenetic response (40% and 66% in the two subgroups, respectively), and 34% had a major molecular response (27% and 56% in the two subgroups, respectively). Responses were observed regardless of the baseline BCR-ABL kinase domain mutation status and were durable; the estimated rate of a sustained major cytogenetic response of at least 12 months was 91%. No single BCR-ABL mutation conferring resistance to ponatinib was detected. Among 83 patients with accelerated-phase CML, 55% had a major hematologic response and 39% had a major cytogenetic response. Among 62 patients with blast-phase CML, 31% had a major hematologic response and 23% had a major cytogenetic response. Among 32 patients with Ph-positive ALL, 41% had a major hematologic response and 47% had a major cytogenetic response. Common adverse events were thrombocytopenia (in 37% of patients), rash (in 34%), dry skin (in 32%), and abdominal pain (in 22%). Serious arterial thrombotic events were observed in 9% of patients; these events were considered to be treatment-related in 3%. A total of 12% of patients discontinued treatment because of an adverse event. Conclusions Ponatinib had significant antileukemic activity across categories of disease stage and mutation status. (Funded by Ariad Pharmaceuticals and others; PACE ClinicalTrials.gov number, NCT01207440.)

The original recognition of leukemia in the nineteenth century and the story of our progressive understanding of the biology and the development of treatment of chronic myeloid leukemia (CML) have been well reviewed in recent years [1, 2]. Today the diagnosis of CML usually presents few problems. In contrast, planning a therapeutic strategy for a patient who presents in chronic phase and monitoring a patient who starts treatment with a tyrosine kinase inhibitor (TKI) present a number of challenges. The same is true for a patient in chronic phase whose disease proves resistant to initial treatment with a TKI. Even more difficult may be the issue of how best to treat a patient presenting in or progressing to an advanced phase of CML. In this chapter, we will review some of the essentials of diagnosis of CML, which will be mostly self-evident to practicing hematologists, but the main focus will be on available treatment options, the results to date of using these various options, and guidance on therapeutic strategy.

Whilst chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL) may be grouped together for some purposes, they differ in many ways. CML is a disease with well-defined progressive stages (chronic phase, acceleration, transformation, blast crisis) accruing in middle life; CLL is a relatively indolent disease involving mainly the elderly. Whereas CML has well-characterized molecular features, which can reasonably be assumed to be related to its pathogenesis, the cause of CLL is less well characterized. The observations which have led to our current state of knowledge and ability to treat patients are the subject of this chapter. Reviews of the history of CML have also been provided by Piller in 1997 [1] and Geary in 2000 [2]. © 2013 Springer Science+Business Media New York. All rights reserved.

Neoplastic Diseases of the Blood integrates the history, epidemiology, pathology, pathophysiology, and therapeutics of modern neoplastic hematopathology. The book is divided into five major sections, with the first four covering the spectrum of hematologic neoplasia Chronic Leukemias and Related Disorders , Acute Leukemias, Myeloma and Related Disorders, and Lymphomas. The fifth section covers a variety of topics in supportive care. Now in its fifth edition, this classic and invaluable text brings together a team of internationally renowned experts and offers in-depth coverage of the complex interface between diagnosis and therapy. Chapters feature an accessible and easy-to-read layout and provide updates on the tremendous progress made in the last decade in the understanding of the nature of hematologic malignancies and their treatment. An authoritative and indispensable resource for students, trainees, and clinicians, this fifth edition is sure to distinguish itself as the definitive reference on this topic. © 2013 Springer Science+Business Media New York. All rights reserved.

Key Points TKIs impair B-cell immune responses in CML through off-target inhibition of kinases important for B-cell signaling. Our results call for close monitoring of patients on TKI to assess the long-term impact of impaired B-cell function.

The BCR-ABL T315I mutation confers resistance to currently licensed tyrosine kinase inhibitors in chronic myelogenous leukemia. However, the impact on survival at early stages of disease, in chronic phase, has never been detailed. Using matched pair analysis, a cohort of 64 chronic phase patients harboring a T315I mutation and resistant to imatinib mesylate, was compared to a similar cohort of 53 chronic phase patients resistant to imatinib, but with no detectable T315I mutation, in the pre-ponatinib era. These patients were matched according to age at diagnosis, interval between disease diagnosis and imatinib, imatinib duration. Kaplan-Meier survival analyses demonstrate the significant negative impact of the presence of the T315I mutation on overall (since imatinib-resistance T315I+ 48.4 months versus not reached for T315I-, p=0.006) and failure-free survival (since imatinib-resistance: T315I+ 34.7 months versus not reached for T315I-, p=0.003). In addition, Cox proportional hazard models adjusted on overall survival demonstrate the negative influence of the T315I mutation (p=0.02, HR=2.54). These results confirm early assumptions concerning the poor prognosis of chronic phase chronic myelogenous leukemia patients with the T315I mutation who are not eligible for allogeneic transplant, and demonstrate the need for more therapeutic options.