In patients with CML treated with imatinib for some years, poor adherence may be the predominant reason for inability to obtain adequate molecular responses.

Imatinib is highly effective in most patients with CML-CP; patients who respond are likely to live substantially longer than those treated with earlier therapies. Achieving CCyR correlated with PFS and overall survival, but achieving MMR had no further predictive value. However, approximately one third of patients still need better therapy.

A single measurement of BCR-ABL1 transcripts performed at 3 months is the best way to identify patients destined to fare poorly, thereby allowing early clinical intervention.

No abstract

The majority of patients with chronic myeloid leukemia in chronic phase gain substantial benefit from imatinib but some fail to respond or lose their initial response. In 2006, the European LeukemiaNet published recommendations designed to help identify patients responding poorly to imatinib. Patients were evaluated at 3, 6, 12, and 18 months and some were classified as "failure" or "suboptimal responders." We analyzed outcomes for 224 patients with chronic myeloid leukemia in chronic phase treated in a single institution to validate these recommendations. Patients were followed for a median of 46.1 months. At each time point, patients classified as "failure" showed significantly worse survival, progression-free survival, and cytogenetic response than other patients; for example, based on the assessment at 12 months, the 5-year survival was 87.1% versus 95.1% (P ‫؍‬ .02), progression-free survival 76.% versus 90% (P ‫؍‬ .002), and complete cytogenetic response rate 26.7% versus 94.1% (P < .001). Similarly, the criteria for "suboptimal response" at 6 and 12 months identified patients destined to fare badly, although criteria at 18 months were less useful. The predictive value of some other individual criteria varied. In general, the LeukemiaNet criteria have useful predictive value, but a case could now be made for combining the categories "failure" and "suboptimal response." (Blood. 2008;112:4437-4444)

Chronic myeloid leukemia (CML) is characterized by formation of the BCR-ABL fusion gene, usually as a consequence of the Philadelphia (Ph) translocation between chromosomes 9 and 22. Large deletions on the derivative chromosome 9 have recently been reported, but it was unclear whether deletions arose during disease progression or at the time of the Ph translocation. Fluorescence in situ hybridization (FISH) analysis was used to assess the deletion status of 253 patients with CML. The strength of deletion status as a prognostic indicator was then compared to the Sokal and Hasford scoring systems. The frequency of deletions was similar at diagnosis and after disease progression but was significantly increased in patients with variant Ph translocations. In patients with a deletion, all Ph ؉ metaphases carried the deletion. The median survival of patients with and without deletions was 38 months and 88 months, respectively (P ‫؍‬ .0001). By contrast the survival difference between Sokal or Hasford high-risk and non-high-risk patients was of only borderline significance (P ‫؍‬ .057 and P ‫؍‬ .034). The results indicate that deletions occur at the time of the Ph translocation. An apparently simple reciprocal translocation may therefore result in considerable genetic heterogeneity ab initio, a concept that is likely to apply to other malignancies associated with translocations. Deletion status is also a powerful and independent prognostic factor for patients with CML. IntroductionChronic myeloid leukemia (CML) is a clonal hematologic malignancy that results from transformation of a multipotent hemopoietic stem cell. [1][2][3] The molecular hallmark of CML is the formation of a BCR-ABL fusion gene, usually formed as a consequence of the Philadelphia (Ph) translocation involving chromosomes 9 and 22. 4-6 BCR-ABL plays a pivotal role in the pathogenesis of CML and its formation is likely to represent the initiating event. In support of this concept transgenic and retroviral transduction studies have demonstrated that expression of BCR-ABL in murine bone marrow cells resulted in leukemia, with some cases closely resembling CML. [7][8][9][10][11][12][13] In one recent transgenic model the leukemia could be reversed by down-regulating BCR-ABL. 14 Chronic myeloid leukemia is a biphasic disease with an initial chronic phase that is readily controlled. However, this is followed by an ill-defined accelerated phase, and then a terminal blastic phase that resembles an acute leukemia, which is usually refractory to therapy. Transformation to blast crisis is accompanied by secondary cytogenetic changes in about 85% of cases, 15 but the molecular basis for this transformation is poorly understood. A number of molecular changes have been identified in a minority of cases of blast crisis, including mutations or deletions of p53, p16 INKA , and the retinoblastoma protein, and mutation or overexpression of Ras and EVI-1. 1,2 However, none provide a method for prospectively distinguishing those patients who will progress rapidly to blast...

We studied the relation between adherence to imatinib measured with microelectronic monitoring systems and the probabilities of losing a complete cytogenetic response (CCyR) and of imatinib failure in 87 CCyR chronic myeloid leukemia patients receiving long-term therapy. We included in our analysis the most relevant prognostic factors described to date. On multivariate analysis, the adherence rate and having failed to achieve a major molecular response were the only independent predictors for loss of CCyR and discontinuation of imatinib therapy. The 23 patients with an adherence rate less than or equal to 85% had a higher probability of losing their CCyR at 2 years (26.8% vs 1.5%, P ‫؍‬ .0002) and a lower probability of remaining on imatinib (64.5% vs 90.6%, P ‫؍‬ .006) than the 64 patients with an adherence rate more than 85%. In summary, we have shown that poor adherence is the principal factor contributing to the loss of cytogenetic responses and treatment failure in patients on long-term therapy. (Blood. 2011; 117(14):3733-3736)

IntroductionMultiple myeloma (MM) is an incurable plasma cell (PC) malignancy of the bone marrow (BM). Although acquired genetic events and the tumor microenvironment are well-established regulators of myeloma cell survival and proliferation pathways, the identity and functional properties of the myeloma-propagating cells have been a matter of controversy. 1,2 The terminal differentiation of normal mature B lymphocytes to immunoglobulin (Ig)-secreting PCs entails conversion of antigennaive to antigen-experienced B cells in the germinal center of secondary lymphoid organs and their subsequent differentiation to either memory B cells or PCs. 3,4 Each stage of B-cell differentiation can be defined by surface markers with naive and memory B cells expressing CD19 and terminally differentiated normal and malignant PCs, but not B cells, expressing CD138 (Syndecan-1). 5,6 Given this linear B-cell lineage developmental process, it was suggested that myeloma cell growth is sustained by a minority of cells more immature than the PC. This hypothesis is supported by the presence of CD19 ϩ CD138 Ϫ clonotypic B cells (ie, cells sharing the same Ig heavy chain [IgH] complementarity region 3 [CDR3] sequence with the myeloma PCs) in peripheral blood (PB) and BM of patients with MM. 7-10 Indeed, because CD138 Ϫ but not CD138 ϩ PCs were found to lead to myeloma engraftment in NOD/SCID mice, it was proposed that CD138 Ϫ cells were the principal myeloma-propagating or "myeloma stem" cells [11][12][13][14] Earlier studies, For personal use only. on May 9, 2018. by guest www.bloodjournal.org From though, using a huSCID mouse model, had concluded that mature PCs (defined as CD38 hi CD45 Ϫ ), and not the CD19 ϩ B-cell fraction, contained the entire myeloma-propagating activity, 15 whereas more recently, CD19 Ϫ CD138 Ϫ as well as CD138 ϩ cells engrafted SCID-rab mice with myeloma. 16 Furthermore, whereas earlier studies reported that the myeloma side population is enriched in clonogenic activity and identifies with CD138 Ϫ but not CD138 ϩ myeloma cells, 13 recent evidence shows that both CD138 ϩ and CD138 Ϫ cells are included in the highly clonogenic myeloma side population. 17 Whether these discrepancies result from different animal models and phenotypic definitions of PC is not clear. Here, through a detailed phenotypic and genetic analysis of primary human myeloma cells and a prospective, dynamic ex vivo and in vivo study of the constituents of the myeloma cellular architecture, we show that a phenotypic and functional interconvertible state between CD138 ϩ and CD138 Ϫ cells underpins myelomapropagating activity and clinical drug resistance. Methods Patient and normal donor BM and PB samplesPatient BM and PB samples were obtained after written informed consent and appropriate institutional ethics committee approval. Patient characteristics are shown in supplemental Table 1 (available on the Blood Web site; see the Supplemental Materials link at the top of the online article). Diagnosis, remission, and relapse of MM were defined accordi...