Since its approval in 2001 for frontline management of chronic myelogenous leukemia (CML), imatinib has proven to be very effective in achieving high remission rates and improving prognosis. However, up to 33% of patients will not achieve optimal response. This has led researchers to develop new second- and third-generation tyrosine kinase inhibitors. In this article, we review the mechanisms of resistance, recommendations for monitoring, assessment of milestones, and management options for patients with CML who are resistant to imatinib therapy. We further explain the potential pitfalls that can lead to unnecessary discontinuation, the prognosis of patients whose condition fails to respond to treatment, and the upcoming therapies.

We hypothesized that the dynamic acquisition of cytogenetic abnormalities (ACA) during the follow up of myelodysplastic syndromes (MDS) could be associated with poor prognosis. We conducted a retrospective analysis of 365 patients with IPSS low or intermediate-1 risk MDS who had at least two consecutive cytogenetic analyses during the follow up. Acquisition of cytogenetic abnormalities was detected in 107 patients (29%). The most frequent alteration involved chromosome 7 in 21% of ACA cases. Median transformation-free and overall survival for patients with and without ACA were 13 vs. 52 months (P =0.01) and 17 vs. 62 months (P =0.01), respectively. By fitting ACA as a time-dependent covariate, multivariate Cox regression analysis showed that patients with ACA had increased risk of transformation (HR=1.40; P = 0.03) or death (HR=1.45; P = 0.02). Notably, female patients with therapy-related MDS (t-MDS) had an increased risk of developing ACA (OR= 5.26; P<0.0001), although subgroup analysis showed that prognostic impact of ACA was not evident in t-MDS. In conclusion, ACA occurs in close to one third of patients with IPSS defined lower risk MDS, more common among patients with t-MDS, but has a significant prognostic impact on de novo MDS.

Dramatically improved survival associated with tyrosine kinase inhibitor (TKI) therapy has transformed the disease model for chronic myeloid leukemia (CML) to one of long-term management, but treatment success is challenged with poor medication adherence. Many risk factors associated with poor adherence can be ameliorated by close monitoring, dose modification, and supportive care. Controlling risk factors for poor adherence in combination with patient education that includes direct communication between the health care team and the patient are essential components for maximizing the benefits of TKI therapy. Am. J. Hematol. 87:687-691, 2012. V V C 2012 Wiley Periodicals, Inc. IntroductionThe last three decades have witnessed extraordinary advances in the treatment of chronic diseases, among which tyrosine kinase inhibitor (TKI) therapy for chronic myeloid leukemia (CML) is perhaps one of the most outstanding examples. Between 1975 and 1977, the 5-year relative survival rate of patients with CML was only 24% [1]. Allogeneic stem cell transplantation offered a potential cure for a small subset of patients; however, the risk of serious infection, graft-versus-host disease, relapse, and mortality presented substantial limitations [2,3]. The introduction of imatinib (Gleevec 1 , Novartis Pharmaceuticals Corporation, East Hanover, NJ) in 2001 replaced interferon-a as the standard of care for CML patients, with a result of remarkable improvement in patient survival. For example, the 8-year follow-up analysis of imatinib treatment in 553 CML patients participating in the International Randomized Study of Interferon versus STI571 demonstrated an overall survival (OS) rate of 85%; OS was 93% when only CMLrelated deaths and those before stem cell transplantation are considered [4]. With this prolonged survival and the recent approval of the more potent agents nilotinib (Tasigna 1 , Novartis Pharmaceuticals Corporation, East Hanover, NJ) and dasatinib (Sprycel 1 , Bristol-Myers Squibb Company, Princeton, NJ), which may be able to provide additional survival benefit, CML more closely resembles a chronic rather than a fatal disease. A new challenge has arisen, however, stemming directly from the success of TKI therapy. Poor medication adherence has come into focus as a major impediment to successful treatment of patients with CML: New evidence has shown that inadequate adherence to imatinib and suboptimal outcomes are inextricably linked [5][6][7].Difficulty in maintaining high medication adherence is not limited to TKI therapy or patients with CML, however. Indeed, the problem is pervasive across chronic conditions. For example, a 2003 report from the World Health Organization found the average rate of long-term adherence for diseases such as asthma, diabetes, hypertension, and tuberculosis was only about 50% in developed countries, and assumed to be even lower in developing countries where health resources are fewer and access to care is unpredictable [8]. The report identified five key areas that affect adherence, includin...

Purpose Outcomes of patients with acute myeloid leukemia (AML) who are refractory to high-dose Cytarabine (HiDAC)-based induction are dismal. Allogeneic hematopoietic stem cell transplantation (AHSCT) as initial salvage may be effective and potentially superior to conventional salvage chemotherapy. Methods Eighteen percent (285 of 1597) of AML patients were primary refractory to HiDAC-based regimens at the MD Anderson Cancer Center between 1995 and 2009. AHSCT was the initial salvage in 28 cases. These patients were compared against 149 patients who received salvage chemotherapy, but never received AHSCT. Results Patients receiving salvage chemotherapy were older, had higher bone marrow blasts percentage, and higher incidence of unfavorable cytogenetics (P<0.001). Median time from induction to AHSCT was 76 days. Objective response was achieved in 23 of 28 patients (82%) undergoing AHSCT. The incidence of grade III/IV acute and chronic graft versus-host-disease was 11% and 29%, respectively. Median follow up for living patients is 80 months. Median overall survival (OS) was 15.7 months and 2.9 months for AHSCT and chemotherapy, respectively (P<0.001); the 3-year OS rates were 39% and 2%, respectively. ASHCT as initial salvage therapy was identified as an independent prognostic factor for survival in multivariate analysis (HR = 3.03; P < 0.001). Conclusion Initial salvage therapy with AHSCT in patients with primary HiDAC refractory AML is feasible and may yield superior outcomes to salvage chemotherapy.

Outpatient auto-HCT can be safely performed for selected patients with MM. Differences in outcomes are likely related to baseline clinical characteristics rather than choice of treatment setting.