The dramatic decline in mortality rates in chronic myelogenous leukemia (CML) is a direct result of the advent of tyrosine kinase inhibitors (TKIs) and the dawning of the targeted era. Although many patients experience long-term benefits from imatinib or related agents, problems with resistance and tolerance dampen the outcomes for many others. During his presentation at the NCCN 19th Annual Conference, Dr. Jerald Radich reviewed the ever-expanding menu of TKIs for CML and shared his thoughts on resolving the clinical questions regarding when to start which drugs, how to sequence the drugs, and how best to decide when to change the therapeutic tack.
Jerald P. Radich
The success of various generations of tyrosine kinase inhibitors in chronic myelogenous leukemia (CML) is well-known, with many patients experiencing long-term benefits from treatment. However, not every patient with CML can tolerate this therapy, shows response to initial treatment, or avoids disease progression or drug resistance. During his presentation at the NCCN 20th Annual Conference, Jerald Radich, MD, shared his thoughts and some supportive data on the critical role of monitoring response at 3 months, the often-neglected yet key issue of patient adherence to therapy, the recommended timing for mutational analysis, and the pressing need to prevent patients from going from chronic-phase disease into accelerated phase/blast crisis.
Jerald P. Radich
Chronic myelogenous leukemia represents the poster child of successful precision medicine in cancer, with amazing survival results achieved with targeted tyrosine kinase inhibitors (TKIs) in many patients with chronic-phase disease. Unfortunately, however, this good news has not extended to patients in blast crisis, for whom survival has not clearly been improved with TKIs. During his presentation at the NCCN 21st Annual Conference, Jerald P. Radich, MD, briefly explored the biology behind advanced-stage disease and several of the molecular findings in disease progression. He also reviewed some of the therapeutic options in advanced disease, emphasizing that transplantation, although fraught with some difficulties, offers the best long-term prognosis for patients in blast crisis.
Jerald P. Radich
Unlike in other leukemias, survival rates have climbed dramatically in early-phase chronic myelogenous leukemia (CML). This improvement in long-term prognosis is primarily the result of the tyrosine kinase inhibitor (TKI) imatinib and its second-generation cousins nilotinib and dasatinib. In his presentation at the NCCN 18th Annual Conference, Dr. Jerald P. Radich reviewed the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) recommendations for monitoring response to treatment with the TKIs, which center on complete cytogenetic response, and the role of mutational analysis for guiding treatment decisions in the setting of imatinib resistance. He also offered a brief mention of 2 new agents recently approved for resistant CML—ponatinib and bosutinib.
Jerald P. Radich and Vivian Oehler
Tyrosine kinase inhibitors (TKIs) are now standard up-front therapy for chronic myeloid leukemia (CML). Patients with newly diagnosed chronic-phase CML treated with the TKI imatinib mesylate typically experience a complete cytogenetic remission. Outcomes for patients with advanced-phase disease are distinctly worse. Unfortunately, a small proportion of chronic-phase patients experience relapse during this therapy, and most with advanced-phase disease develop resistance to imatinib mesylate after months of therapy. Hematopoietic cell transplantation remains the only curative approach for CML and can salvage patients with advanced-phase disease. Therefore, physicians must carefully monitor patients with chronic-phase CML treated with TKIs so that they can undergo hematopoietic cell transplant (or treatment with another TKI or experimental therapy) before frank progression occurs. Fortunately, monitoring CML using cytogenetic and molecular methods (i.e., quantitative polymerase chain reaction) effectively defines end points that correlate highly with outcome.
Merav Bar and Jerald Radich
Because of their outstanding efficacy and low toxicity, tyrosine kinase inhibitors (TKIs) have replaced allogeneic hematopoietic cell transplant (HCT) as the standard frontline therapy for patients with newly diagnosed chronic myeloid leukemia (CML). Until a decade ago, HCT was the preferred treatment for CML, with 5-year overall survival rates of approximately 80%, 40%, and 20% for patients in chronic, accelerated, and blast crisis phases, respectively. Relapse after transplant is a problem for patients who undergo transplant in advanced phase disease and those undergoing a T-depleted transplant. Until the introduction of TKIs, therapy for relapsed CML after transplant relied on interferon and/or donor leukocyte infusion (DLI). Although effective in inducing remission, DLI is associated with clinically significant graft-versus-host disease or myelosuppression, with an accompanying treatment-related mortality of 5% to 20%. TKIs have emerged as an attractive alternative therapy for persistent or relapsing CML after HCT. Similar to DLI, the effectiveness of TKI posttransplant is largely determined by the phase of disease at relapse, showing very good response in patients experiencing relapse in the chronic phase, with high rates (>60%) of hematologic and cytogenetic remissions, but less favorable outcomes in patients with advanced disease, with only a minority experiencing durable cytogenetic or molecular remissions. Molecular monitoring of the BCR-ABL chimeric mRNA posttransplant is important for early detection of patients at high risk of relapse.
Hema Sundar and Jerald Radich
Chronic myelogenous leukemia (CML) is characterized by the presence of the Philadelphia chromosome arising from a reciprocal translocation between chromosomes 9 and 22 [t(9;22)]. This translocation results in the formation of the BCR-ABL fusion gene. The product of this fusion gene, p210, a protein with deregulated tyrosine kinase activity, plays a central role in the pathogenesis of CML. Tyrosine kinase inhibitor (TKI) therapy with small molecule inhibitors of BCR-ABL tyrosine kinase has significantly reduced the annual mortality rate among patients with CML. Although most of these patients respond to first-line TKI therapy, the use of TKIs is complicated by the development of resistance or intolerance in some patients, resulting in a loss of response or discontinuation of treatment. Inadequate response to TKI therapy is associated with poor long-term outcome, and the cases of patients with resistance or intolerance should be carefully evaluated for alternative treatment options. This report discusses the challenges associated with the management of newly diagnosed chronic phase CML in a patient with intolerance to multiple TKI therapies.
Jean McDougall, Scott D. Ramsey and Jerald Radich
Cecilia Yeung, Bret Helton and Jerald Radich
Susan O'Brien, Ellin Berman, Joseph O. Moore, Javier Pinilla-Ibarz, Jerald P. Radich, Paul J. Shami, B. Douglas Smith, David S. Snyder, Hema M. Sundar, Moshe Talpaz and Meir Wetzler
The advent of imatinib has dramatically improved outcomes in patients with chronic myelogenous leukemia (CML). It has become the standard of care for all patients with newly diagnosed chronic-phase CML based on its successful induction of durable responses in most patients. However, its use is complicated by the development of resistance in some patients. Dose escalation might overcome this resistance if detected early. The second-generation tyrosine kinase inhibitors (TKIs) dasatinib and nilotinib provide effective therapeutic options for managing patients resistant or intolerant to imatinib. Recent studies have shown that dasatinib and nilotinib provide quicker and potentially better responses than standard-dose imatinib when used as a first-line treatment. The goal of therapy for patients with CML is the achievement of a complete cytogenetic response, and eventually a major molecular response, to prevent disease progression to accelerated or blast phase. Selecting the appropriate TKI depends on many factors, including disease phase, primary or secondary resistance to TKI, the agent's side effect profile and its relative effectiveness against BCR-ABL mutations, and the patient's tolerance to therapy. In October 2010, NCCN organized a task force consisting of a panel of experts from NCCN Member Institutions with expertise in the management of patients with CML to discuss these issues. This report provides recommendations regarding the selection of TKI therapy for the management of patients with CML based on the evaluation of available published clinical data and expert opinion among the task force members.