Introduction Of Imatinib Research Articles

Evolution of multimodality management of gastrointestinal stromal tumors of the stomach.

94 Background: Gastrointestinal stromal tumor (GIST) treatment has changed considerably with introduction of imatinib in 2001, initiation of ACOSOG adjuvant trial in 2002, and FDA adjuvant approval in 2008. However, little is known about how imatinib has been incorporated over time. Our objective was to examine the evolution of multimodality management of GISTs. Methods: Patients coded specifically as gastric GISTs were identified (n = 4,508; 443 hospitals) from the National Cancer Data Base (2001-2007). Changes over time were assessed with chi-squared test for trend. Separate multivariable regression models were developed to examine factors associated adjuvant and neoadjuvant practices. Results: Gastric GISTs reported to NCDB steadily increased: 463 in 2001 to 831 in 2007. 3,289 underwent resection: 78% partial/wedge, 6% total/near-total, and 14% multivisceral. From 2001 to 2007, use of adjuvant therapy increased from 29% to 47% (p < 0.001), although patients were less likely to get adjuvant therapy if older, tumors < 3cm, low grade, negative margins, or treated at low-volume hospitals (p < 0.01). Adjuvant systemic therapy for lesions < 3 cm also increased (17% to 25%, p = 0.001). For GISTs > 6 cm, use of adjuvant therapy increased from 41% to 49% overall, with increases of 45% to 70% at high-volume centers and of 39% to 48% at low-volume centers (all p < 0.001). Neoadjuvant therapy increased from 0% to 15% (p < 0.001) with patients more likely to receive neoadjuvant treatment if size > 6 cm, treated at high-volume centers, or treated in 2006-2007 (p < 0.001). Multivisceral resections decreased over time (19% to 12%, p < 0.001). The proportion of patients treated at high-volume centers increased slightly over time (22.2% to 26.9%, p = 0.006). Conclusions: Adjuvant systemic therapy use for GISTs was increasing and widespread prior to FDA approval of adjuvant imatinib, suggesting contemporaneous advances in advanced GIST management were being translated into the adjuvant setting more than expected. As relatively costly therapies are integrated into practice, more robust tracking systems are needed to follow and guide the incorporation of new treatments. No significant financial relationships to disclose.

Introduction of Imatinib as First-line Therapy for Chronic Myeloid Leukemia in Cuba

Chronic myeloid leukemia is the first malignant disease to be associated with a genetic lesion and is the first leukemia to provide a genotype model conducive to targeted molecular therapy. It is a chronic clonal myeloproliferative disorder, originating in a pluripotent stem cell common to all three hematopoietic lineages, characterized by overproduction of myeloid cells in all stages of maturation. Approval of the use of imatinib in the United States in 2001 and its introduction in the treatment of chronic myeloid leukemia changed the evolution and prognosis of the disease and began the era of molecular therapy for malignancies. Imatinib is highly effective and causes fewer adverse reactions than earlier treatments based on interferon and hydroxyurea. In Cuba, chronic myeloid leukemia has been treated with interferon since 1998. Starting in 2003, imatinib was gradually introduced for use in newly-diagnosed chronic myeloid leukemia patients. Evaluate the use of imatinib as first-line therapy for chronic myeloid leukemia in a group of Cuban patients, based on hematologic, cytogenetic, and molecular response; overall and event-free survival rates; and most frequency and severity of adverse reactions. During May 2003 to May 2008, 33 newly-diagnosed chronic myeloid leukemia patients (25 adults, 8 children; <6 months from diagnosis) received a single daily oral dose of imatinib 400 mg from the time of study enrollment. Variables used: (1) to evaluate treatment efficacy: hematologic, cytogenetic, and molecular response; overall and event-free survival; and (2) to evaluate safety: presence of adverse reactions leading to definitive interruption of treatment or death. Complete hematologic response occurred in 100% of patients, major cytogenetic response in 90.9%, and complete cytogenetic response in 48.5%. Molecular response occurred in 36.4% of patients. With a mean follow-up of 39 months, overall survival was 96% and estimated five-year event-free survival was 85%. No adverse reactions occurred in 39.5% of patients. Adverse reactions most frequently observed were myelosuppression (24.2%) and digestive disorders (21.2%). These were followed, in decreasing order, by edema, primarily orbital (9.1%), skin depigmentation (3%), and cardiac arrhythmias (3%). In the present study, imatinib was effective first-line therapy for patients with newly-diagnosed chronic myeloid leukemia, as determined by overall and event-free survival rates. No severe adverse reactions were observed.

Omacetaxine as an Anticancer Therapeutic: What is Old is New Again

Omacetaxine mepesuccinate was originally identified more than 35 years ago and initial studies in chronic myeloid leukemia (CML) showed promising activity. It has also been studied in other hematologic and solid tumors as both a single agent and in combination with other treatments. However, the introduction of imatinib and related tyrosine kinase inhibitors (TKIs) abated the clinical development of omacetaxine as a treatment for CML. The advent of resistance to imatinib and other TKIs in CML patients (often due to the presence of an ABL mutation at position 315) has led to a revived clinical interest in omacetaxine in CML patients who failed TKIs. Here we review omacetaxine's mechanism of action (MOA) as a protein translation inhibitor, how its MOA may translate into activity in treatment of cancers, its potential to eradicate leukemia initiating cells and other cancer stem cells and the potential significance of this activity in clinical practice.

First-line treatment of chronic myeloid leukaemia

Since the introduction of imatinib just over a decade ago, there has been a dramatic change in the treatment and prognosis of early chronic phase chronic myeloid Leukaemia (CML). This review article focuses on recent advances, culminating in the approval of nilotinib by the US Food and Drug Administration for the treatment of adult patients with newly diagnosed CML in the chronic phase.

Molecular Target Therapy in Hematological Malignancy: Front-runners and Prototypes of Small Molecule and Antibody Therapy

Molecular-targeted drugs were first introduced for the treatment of hematological malignancies. Herein, the success stories of small molecule-targeted drugs, such as imatinib for the treatment of chronic myeloid leukemia and the tumor-specific antibody rituximab for the treatment of CD20-positive lymphoma, will be introduced. The introduction of imatinib and rituximab has changed the mortality rates associated with chronic myeloid leukemia and CD20-positive lymphoma, respectively. In particular, the therapeutic outcomes of imatinib treatment have been so good that clinical trials to assess the feasibility of treatment discontinuation after remission are ongoing. Methods for developing new anti-cancer agents have changed, and structure-based chemical compounds are now screened in silico. Second- and third-generation anti-cancer agents have already been successfully identified, and resistance mechanisms have been explained based on the interaction of these chemical structures with their target molecules. In the area of antibody development, the introduction of humanized antibody has been successful, and the use of antibody carriers has resulted in the development of potent second-line antibody drugs. The discovery of new target surface markers is also being reported, and trials for both chimeric and humanized antibodies against these molecules are ongoing. Through these efforts, disease mortality rates have begun to decline. We are facing a brilliant future in which we can strive to eliminate cancer-related mortality.

Interferon Gamma (IFNγ) Interferes with the Effects of Tyrosine Kinase Inhibitors (TKI) In CML Cells.

AbstractAbstract 3393 Introduction:Chronic myeloid leukemia (CML) is a myeloproliferative disease which resolves in the constitutive activity of the BCR-ABL protein. Since the introduction of imatinib as first line therapy for CML, the overall survival of patients could be significantly extended. However, mutations of the BCR-ABL protein and environmental effects mediated by adhesion molecules, cytokines and growth factors were shown to induce resistance to TKIs. For the development of immunotherapeutic approaches that combine TKIs with vaccination strategies or donor lymphocyte infusions it is important to understand the mechanisms of possible interactions and inhibition. Therefore, we thought to determine the role of activated T cells and to analyze a possible antiapoptotic effect of released IFNγ on the CML cells. Methods:CML cell lines and primary cells from patients with CML were treated with imatinib or nilotinib and incubated with activated (PMA/ionomycin) or resting T cells in transwell experiments. Induction of apoptosis was analyzed by flow cytometry. In addition, IFNγ was used together with TKIs and apoptotic cell death and proliferation was determined. Immunoblotting was performed to analyze the involved pathways. Result:Incubation of CML cells in transwell assays with activated but not resting T lymphocytes resulted in significant inhibition of the apoptosis induction by imatinib and nilotinib. To further determine the mechanisms mediating these effects, CML cells were treated with IFNγ in addition to the TKIs. In line with the results from previous experiments, IFNγ reduced the rate of cell death and proliferation inhibition mediated by imatinib and nilotinib. Interestingly, in contrast to IFNα, IFNγ inhibited the TKIs induced downregulation of MHC-class I molecules on CML cells. In line with these results, Western blot analysis of K-562 cells incubated with imatinib or nilotinib showed an increased caspase-3 activation and PARP cleavage as well as reduced down regulation of anti-apoptotic molecules such as xIAP as compared to IFNγ treated cells. Furthermore, we observed a diminished TKI induced downregulation of Jak-2 and STAT-5 phosphorylation as well as increased nuclear expression of RUNX-1 in cells treated with IFNγ. Conclusion:Our results demonstrate that IFNγ released by activated T-cells can interfere with the action of TKIs in CML patients and might have important implications in the development of immunotherapeutic approaches. Disclosures:No relevant conflicts of interest to declare.

Distinct Impact of Imatinib on Growth In Prepubertal and Pubertal Children with Chronic Myeloid Leukemia

AbstractAbstract 2277Imatinib is now widely used for treating chronic-phase chronic myeloid leukemia (CML) in children as well as in adults, and long-term adverse effects of imatinib therapy in children are now gaining attention. One of its adverse effects is the negative impact on growth in children, suggested by 3 recently published case reports. However, the incidence or prospect of growth impairment resulting from imatinib treatment has not been fully elucidated.In this study, we retrospectively analyzed the clinical records of 48 children with chronic-phase CML who were treated with imatinib as a first-line therapy between 2001 and 2006. The median age at diagnosis was 9 years (2 to 15 years). Cumulative change in height while on imatinib was assessed using the height standard deviations score (height-SDS), the converted height data from age- and sex-adjusted Japanese norms. Our data indicated that growth impairment (decrease in height-SDS) was observed in 72.9% of the patients, with median maximum reduction in height-SDS of 0.61 during imatinib treatment. Growth impairment was noticeable in children who were prepubertal at the commencement of imatinib treatment, while only mild or no growth impairment (with no decrease of height-SDS) was observed in most patients who were pubertal at the commencement of imatinib treatment. Furthermore, in prepubertal children with growth impairment, growth velocity tended to recuperate concomitant with pubertal maturation, suggesting that imatinib has little impact on growth during puberty. To our knowledge, this is the first report to describe and compare the distinct inhibitory effect of imatinib on growth in prepubertal and pubertal children with CML.Although the introduction of imatinib was a breakthrough in CML therapy, the possibility of continuous remission after discontinuation of imatinib remains uncertain. Thus, the possibility of adverse effects of long-term exposure to imatinib has become a huge issue, especially when treating children. We consider that it is important to promote awareness of growth deceleration in children, especially in young children who started imatinib treatment before puberty and are inevitably going to be subject to prolonged exposure. Disclosures:No relevant conflicts of interest to declare.

Nilotinib for the treatment of Philadelphia-chromosome-positive chronic myeloid leukemia

Importance of the field: Although the introduction of imatinib revolutionized the management of chronic myeloid leukemia (CML), some patients exhibit resistance or intolerance to the drug. Nilotinib induces high and rapid rates of cytogenetic and molecular responses. With recent approval for newly diagnosed patients with chronic phase CML, the current algorithm for treatment will probably be transformed.Areas covered in this review: This review will describe evaluations of nilotinib in all phases of CML from 1995 to the present. Early preclinical data and Phase I, Phase II and Phase III evaluations will demonstrate the role of nilotinib in newly diagnosed CML, as well as in imatinib-resistant or imatinib-intolerant disease.What the reader will gain: Mutations in the BCR-ABL kinase domain are responsible for the majority of resistance to imatinib. In comparison with imatinib, nilotinib displays increased selectivity and potency at inhibiting proliferation of BCR-ABL expressing cells. Although several mutations, including T315I, remain resistant to nilotinib, activity in all phases of CML has been reported.Take home message: Nilotinib induces high and rapid rates of cytogenetic and molecular response, with less progression to advanced forms of disease compared with imatinib. Considering that the rapid achievement of these clinical milestones has been associated with positive long-term outcomes, nilotinib as initial therapy in patients with CML in chronic phase represents the future in CML treatment. Longer follow-up is necessary to recognize survival advantages.

Systemische Therapie von Weichgewebssarkomen

The gold standard for the treatment of primary, resectable, high-grade soft tissue sarcomas is complete surgical removal followed by radiotherapy. In cases where preservation of function is not possible, preoperative treatment options should be considered. Systemic therapy is the treatment of choice for metastatic soft tissue sarcomas. The most active single agents include the anthracyclines doxorubicin and epirubicin, as well as ifosfamide. While combination chemotherapy yields higher response rates, this is at the cost of increased toxicity with no evidence of prolonged overall survival. Current treatment strategies focus on the development of specific treatments for well defined soft tissue sarcoma subtypes. The first and highly successful targeted therapy was seen with the introduction of imatinib in the treatment of gastrointestinal stromal tumors.

Long‐term outcomes in the second‐line treatment of chronic myeloid leukemia

AbstractChronic myeloid leukemia (CML) is a progressive and often fatal myeloproliferative neoplasm. The hallmark of CML is an acquired chromosomal translocation known as the Philadelphia chromosome (Ph), which results in the synthesis of the breakpoint cluster region‐Abelson murine leukemia (BCR‐ABL) fusion oncoprotein, a constitutively active tyrosine kinase. The introduction of imatinib, a tyrosine kinase inhibitor (TKI) that is specific for BCR‐ABL, was a major breakthrough in CML therapy. Although most patients respond to first‐line imatinib therapy, some experience loss of response (resistance) or require treatment discontinuation because of toxicity (intolerance). For patients with CML, failure on standard‐dose imatinib therapy (400 mg daily), imatinib dose escalation (600‐800 mg daily) is a second‐line option. However, high‐dose imatinib is not an appropriate approach for patients who experience drug toxicity, and there remain questions over the durability of responses achieved with this strategy. Alternative second‐line options include the TKIs dasatinib and nilotinib. A substantial amount of long‐term data for these agents is available. Although both are potent and specific BCR‐ABL TKIs, dasatinib and nilotinib exhibit unique pharmacologic profiles and response patterns relative to different patient characteristics, such as disease stage and BCR‐ABL mutation status. To optimize therapeutic benefit, clinicians should select treatment based on each patient's historic response, adverse‐event tolerance, and risk factors. Cancer 2010. © 2010 American Cancer Society.

Chronic Myeloid Leukemia and Second-Generation Tyrosine Kinase Inhibitors: When, How, and Which One?

Chronic myeloid leukemia (CML) is a progressive and often fatal myeloproliferative disorder. The introduction of imatinib, a tyrosine kinase inhibitor (TKI) specific for BCR-ABL, was a major breakthrough in CML therapy. Although most patients respond to first-line imatinib therapy, some experience a loss of response (resistance) or require treatment discontinuation due to toxicity (intolerance). For patients who fail with standard-dose imatinib therapy, imatinib dose escalation is a second-line option. However, high-dose imatinib is not an appropriate approach for patients experiencing drug toxicity, and there remain questions over the durability of responses achieved with this strategy. Alternative second-line options include the newer TKIs dasatinib and nilotinib. A substantial amount of long-term data for these agents is available. Although both are potent and specific BCR-ABL TKIs, dasatinib and nilotinib exhibit unique pharmacological profiles and response patterns relative to different patient characteristics, such as disease stage and BCR-ABL mutational status. To optimize therapeutic benefit, clinicians should select treatment based on each patient's historical response, adverse-event tolerance level, and risk factors.

Age Disparity in the Dissemination of Imatinib for Treating Chronic Myeloid Leukemia

Background Imatinib is a highly effective treatment for chronic myeloid leukemia. It was approved by the Food and Drug Administration in 2001 and thereafter rapidly became front-line therapy. This study characterized the prevailing chronic myeloid leukemia therapies in the United States and assessed the impact of imatinib on chronic myeloid leukemia survival and mortality rates in the general population. Methods Investigators with the National Cancer Institute's Patterns of Care study reviewed medical records and queried physicians regarding therapy for 423 patients with chronic myeloid leukemia diagnosed in 2003 who were randomly selected from cancer registries in the Surveillance, Epidemiology, and End Results Program. Characteristics associated with the receipt of imatinib were documented, as were survival differences between those who received imatinib and those who did not. Population-based data were used to assess chronic myeloid leukemia survival and mortality rates in time periods before and after the introduction of imatinib. Results Imatinib was administered to 76% of patients in the Patterns of Care study. Imatinib use was inversely associated with age: 90%, 75%, and 46% for patients ages 20 to 59 years, 60 to 79 years, and 80 or more years, respectively. Elderly patients who received imatinib survived significantly longer than those who did not. After adjusting for age, imatinib use did not vary significantly by race/ethnicity, socioeconomic status, urban/rural residence, presence of comorbid conditions, or insurance status. Overall, chronic myeloid leukemia survival in the Surveillance, Epidemiology, and End Results population improved, and mortality in the United States declined dramatically during the period when imatinib became widely available; these improvements diminished with increasing age. Conclusion Age disparities in treatment with imatinib likely contributed to worse survival for many elderly patients with chronic myeloid leukemia.

Molecular monitoring and mutation analysis of patients with advanced phase CML and Ph+ ALL receiving dasatinib

As a result of the excellent responses achieved in chronic phase chronic myeloid leukemia since the introduction of imatinib, sensitive techniques such as reverse transcriptase real-time PCR are warranted to monitor patients receiving tyrosine kinase inhibitors (TKI). Our objective was to determine the value of molecular monitoring Ph-positive leukemias under dasatinib treatment. We used real-time PCR and ABL1 kinase domain sequencing on sequential samples from 11 patients with Philadelphia-positive leukemias who received dasatinib. We were able to detect pre-existing mutations in the kinase domain of BCR-ABL1 in four patients, particularly in patients with high BCR-ABL1 transcript levels. Most mutations disappeared with dasatinib, however, in five patients a clone with T315I appeared during dasatinib treatment. We conclude that sensitive molecular monitoring with real-time PCR for BCR-ABL1 transcripts and mutation screening of the ABL1 kinase domain of patients with Philadelphia-positive leukemias are valuable for patient management, however, mutation findings should be interpreted with caution, as mutant clones not always behave in vivo as predicted by in vitro assays.

How Much and How Long: Tyrosine Kinase Inhibitor Therapy in Chronic Myeloid Leukemia

As the first clinically successful tyrosine kinase inhibitor (TKI), imatinib pioneered a new approach to treating patients with cancer. Dramatic results from chronic myeloid leukemia (CML) clinical trials spurred the development of TKIs for other malignancies such as acute myeloid leukemia as well as kidney and lung cancer. In CML, imatinib resistance led to the rapid development of dasatinib and nilotinib, more potent second-generation ABL kinase inhibitors that can often overcome imatinib resistance. While the clinical efficacy of TKIs in CML is well established, a number of important questions remain about the optimal dose and duration of therapy. Even the best initial dose for imatinib is still under investigation. Although laboratory and clinical studies had led to the prevailing view that continual inhibition of the BCR-ABL kinase was required for optimal efficacy, recent data on dasatinib have upended this notion and have led to a change in the recommended dosing schedule. The availability of dasatinib and nilotinib also begs the question of whether they might be superior to imatinib as first-line agents. Finally, the question of whether it may be possible to stop TKI therapy at least in some patients with CML has attracted considerable attention. More than 10 years after the introduction of imatinib, optimization of TKI therapy for CML continues.

Clinical algorithms for the treatment of patients with chronic myeloid leukemia: the 2010 perspective.

Chronic myeloid leukemia (CML) is a progressive and often fatal myeloproliferative disorder. The hallmark of CML is an acquired chromosomal translocation known as the Philadelphia chromosome (Ph) that results in the synthesis of the BCR-ABL fusion protein, a constitutively active tyrosine kinase (TK). The introduction of imatinib, a TK inhibitor (TKI) specific for BCR-ABL, was a major breakthrough in CML therapy. Although most patients respond to first-line imatinib therapy, some experience a loss of response (resistance) or require treatment discontinuation because of toxicity (intolerance). In patients for whom standard-dose imatinib therapy (400 mg/day) fails, imatinib dose escalation (600-800 mg/day) is a second-line option. However, high-dose imatinib is not an appropriate approach for patients experiencing drug toxicity, and there remain questions over the durability of responses achieved with this strategy. Alternative second-line options include the newer TKIs dasatinib and nilotinib. A substantial amount of long-term data for these agents is available. Although both are potent and specific BCR-ABL TKIs, dasatinib and nilotinib exhibit unique pharmacologic profiles and response patterns relative to different patient characteristics, such as disease stage and BCR-ABL mutational status. To optimize therapeutic benefit, clinicians should select treatment based on each patient's historical response, adverse event tolerance level, and risk factors.

Abstract 4237: Foxo3a is essential for survival of leukemia-initiating cells in chronic myeloid leukemia

Abstract Chronic myelogenous leukemia (CML) is caused by a defined genetic abnormality, BCR-ABL, a constitutively active protein tyrosine kinase. Although the introduction of imatinib, a small molecule inhibitor of ABL, represented a breakthrough in the treatment of CML, major part of patients treated in chronic-phase CML are not off therapy due to resistance or intolerance. Recent studies have suggested that imatinib is a potent inhibitor of the production of differentiated leukemic cells, but does not deplete leukemia-initiating cells (LICs). To date, therapeutics that can eradicate CML LICs, however, have remained under investigation. To overcome these clinical problems, we here evaluated molecular mechanisms on survival of the CML LICs. We first generated a mouse CML model by using retroviral induction of BCR-ABL-ires-GFP gene into mouse immature hematopoietic cells, and the cells were subsequently transplanted into irradiated recipient mice. These experiments showed that CML LICs were highly enriched in c-Kit+Lin-Sca-1+ (KLS+) population in BCR-ABL+ CML cells, as previously reported. Unexpectedly, phosphorylation levels of Akt in CML LICs appeared to be lower than that in non-LICs, KLS- cells, despite it is widely believed that BCR-ABL induces activation of Akt signal. Since Forkhead O (Foxo) transcription factors, which are important downstream targets of PI3K-Akt signaling, are essential for the maintenance of self-renewal capacity of normal HSCs, we focused on analysis of Foxo3a in CML. Consistent with Akt phosphorylation status, we found that cells with nuclear localization of Foxo3a were enriched in the CML LICs, whereas non-LICs showed the cytoplasmic localization, suggesting that Foxo3a is activated via Akt inactivation in the CML LICs, but not in majority of CML cells. Serial transplantation experiments for CML LICs originated from Foxo3a-deficient mice and littermate wild-type mice indicated that Foxo3a-deficiency reduced lethality of recipient mice at 3rd transplantation. Although recipients that transplanted with wild-type LICs developed CML and acute lymphocytic leukemia (ALL) at 3rd transplantation, we did not observe development of ALL or CML in recipients of Foxo3a deficient LICs after 45 days post-3rd transplantation, suggesting that the Foxo3a deficient LICs lose their potential to generate malignancies. Furthermore, deficiency of Foxo3a led to enhanced efficiency in elimination of CML LICs in combination with imatinib treatment. These results demonstrate a critical role of Foxo pathway in survival of CML LICs, and provide a novel therapeutics approach for CML patients by suppression of FOXO signaling. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4237.

The response to imatinib and interferon- is more rapid than the response to imatinib alone: a retrospective analysis of 495 Philadelphia-positive chronic myeloid leukemia patients in early chronic phase

Before the introduction of imatinib, interferon alpha-based regimens were the gold standard for treatment of early chronic phase chronic myeloid leukemia patients. The combination of IFN-alpha with imatinib is currently being investigated in at least two large clinical trials, the German CML Study IV and the French SPIRIT trial. We reviewed the cytogenetic and molecular responses of 76 early chronic phase chronic myeloid leukemia patients who were treated with imatinib and interferon-alpha and of 419 early chronic phase chronic myeloid leukemia patients treated with imatinib alone front-line. The complete cytogenetic response rate was higher in the IM+IFN-alpha group than in the imatinib group at six months (60% vs. 42%; P=0.003), but not at 48 months (88% vs. 88%). The durability of the complete cytogenetic response was similar in the two groups with 94% and 91% of complete cytogenetic responders in continuous complete cytogenetic response at 48 months (P=0.56). The major molecular response rate was higher in the IM+IFN-alpha group at six months (58% vs. 34%; P=0.0001) and 12 months (67% vs. 47%; P=0.001) but not later on (65% vs. 57% at 48 months; P=0.25). Overall and progression free survival were comparable in the two groups; a significant trend to a better event free survival was observed in patients treated with PegIFNalpha (91% vs. 78%; P=0.02). These data suggest that the response to the combination treatment is more rapid. It is not yet known how much a rapid reduction will influence the longer-term overall and progression free survival, and the cure rate.

Summary of 615 patients of chronic myeloid leukemia in Shanghai from 2001 to 2006

BackgroundTo retrospectively review the incidence, treatment efficacy, we followed up newly diagnosed chronic myelogenous leukemia (CML) patients residing in Shanghai during 2001-2006.MethodsAll eligible cases were reviewed with the data of efficacy responses as well as overall survival (OS) and progression-free survival (PFS) time.ResultsA total of 615 cases entered the study. CML mainly afflicted those aged 40-60 years old and was slightly more frequent in males than females. More than 85% of the patients were in chronic phase (CP) when diagnosed. All patients were divided into four groups based on the main regimens - hydroxyurea, interferon alpha (IFN-α), imatinib, and hemopoietic stem cell transplantation (HSCT). With the median follow-up of 18 months, imatinib treatment induced 92.2% complete hematologic responses, and 64.3% complete cytogenetic responses among CML-CP patients. Overall the therapeutic efficacy in the imatinib group was higher than that in the hydroxyurea or IFN-α group. Meanwhile, in the imatinib group, all response rates of patients in CP were significantly greater than that in accelerated or blastic crisis phase. The patients treated with imatinib also showed the most promising results regarding OS and PFS. Patients receiving HSCT decreased markedly in number with the introduction of imatinib.ConclusionsThe number of new patients arising in Shanghai increased from 2001 to 2006. There were still patients receiving hydroxyurea and IFN-α. As the first-line regime for CML, imatinib was less administered in Shanghai before, but has received considerable development and great responses since 2003.

Optimising chronic myeloid leukaemia therapy in the face of resistance to tyrosine kinase inhibitors – A synthesis of clinical and laboratory data

The introduction of imatinib, a tyrosine kinase inhibitor (TKI) that targets the BCR-ABL protein, has revolutionised the treatment of chronic myeloid leukaemia (CML), producing high rates of response that have been durable in many patients. However, because of intrinsic or acquired mechanisms of imatinib resistance, in addition to the persistence of leukaemic stem cells that are resistant to imatinib-induced apoptosis, imatinib treatment does not appear to be curative. Cytogenetic and molecular monitoring enable the identification of patients showing signs of treatment failure and can be used to guide choices regarding subsequent therapeutic options, including imatinib dose escalation, treatment with a secondary TKI or, in selected cases, allogeneic stem cell transplant (allo-SCT). Although these alternative therapies may overcome imatinib resistance, long-term remission or cure from CML is likely to require development of novel interventions that effectively eliminate CML stem cells (Ph +HSC).

Combined Chemotherapy (daunorubicin + cytarabine) and Dasatinib as Salvage Therapy of Chronic Myeloid Leukemia (CML) in Myeloid Blast Crisis, a Pilot Study.

Abstract 2195Poster Board II-172The results of the treatment of blast crisis CML remain still disappointing with poor overall survival rates, despite the introduction of imatinib (IM) in the therapeutic arsenal of Ph+ leukemias. This compound alone provides 24% of overall initial hematologic responses in myeloid blast crisis (MBC) IM-naive patients (pts), with 7 months of median overall survival rates. Dasatinib remains disappointing with 34% of major hematological responses (MaHRs, Cortes, Blood, 2007) in IM-resistant pts. The combination of IM to daunorubicin (3 days) and cytarabine (7 days) AML schedule (“3+7”) might improve responses and survival rates with 55.5 % of complete remissions (CR) and a median overall survival of 15.9 months (B. Deau, submitted).In this preliminary pilot study, we proposed to test the combination of daunorubicin + cytarabine to dasatinib in MBC CML in order to improve outcome. Fifteen patients have been enrolled [8M, 7F, median age at diagnosis 45 (28-64) years]. Prior to enrollment, 5 pts were in chronic phase (CP), 2 in accelerated phase (AccP) on IM. Eight pts were in MBC at diagnosis, and IM-naive. Additional chromosomal abnormalities (ACA) were present at diagnosis in 5 pts [+8 (2 pts), +21 (2 pts), t(3;21) (1 pt), add(1) (1 pt), complex abnormalities (1 pt), variant Ph (2 pts)]. For CP pts Sokal index was low for 2, intermediate for 1, unknown for 2, and none had any additional chromosomal abnormality at diagnosis. One patient had an e1a2 transcript, others a M-BCR transcript. Nine pts/15 had IM prior to combined therapy [best responses to IM prior to MBC were for 5 pts in CP: 3 complete hematologic remissions (CHR), 2 major molecular responses (MMR), for 2 pts in AccP: 2 CHR, for 2 in MBC: 1 complete cytogenetic remission (CCR) and 1 hematologic response (HR)]. In these 9 pts, 1 developed IM hematologic resistance in CP, 5 cytogenetic resistance, 1 molecular progression, and 2 entered MBC. Nine were screened for BCR-ABL mutations and only one was harboring a G250E mutation. The median interval between IM start and progression to MBC was 27 (1.1-65) months. Only 2 pts were exposed to dasatinib prior to combined therapy.At MBC, 7/15 pts had ACA, 10/15 screened were unmutated, 3 mutated (G250E, and 2 unknown). The pts received a median dose of 60 mg/m2/d of daunorubicin 3 days + a median dose of 200 mg/m2/d of cytarabine for 7 days and a median dose of 140 mg/d of dasatinib starting at day 1. Eight pts/15 had G-CSF after induction chemotherapy as planned by the study, for a median of 18 (5-28) days. The induction chemotherapy was well tolerated with no pleural effusions or other particular toxicities. A median of 37 days of neutropenia (<0.5 G/l) and 27 days of thrombocytopenia (<20 G/l) since day 1 were observed, and a median of 8 (3-38) RBC transfusions and 10 (4-45) platelets transfusions were necessary. One patient remained aplastic until allogeneic transplantation. No particular infection occurred. Complete remission (CR) was obtained in 8/15 and non evidence of leukemia in 3/15 resulting in a MaHR rate of 73%. The median BCR-ABL/ABL (IS) ratio was 6 (0.04-62)% and CCR was documented in 3/15 pts. Six pts had various courses of consolidation therapy (dasatinib in all cases + anthracyclin + cytarabine in 5). Ten pts/15 could be referred for allogeneic stem cell transplantation (5 MUD, 1 haplo-identical, 3 cord blood, 1 related, 6 conventional, 4 reduced intensity). The median delay between day 1 combined therapy and transplant was 5 (2.9-5.4) months. In evaluable pts, acute GVHD did not occur in 4 pts (1 grade 2, 4 unknown). At 3 months post-transplant 4/8 evaluable pts were in CHR, 3 in complete molecular remission, 2 in CCR. With a median follow-up since combined chemotherapy of 8 (1-20.9) months, 6/15 (40%) pts are alive (4 in CMR, 2 in MMR). The median overall survival (OS) since MBC onset was 12.3 months as shown in figure 1 (dashed lines are 95% CI), but did not significantly differ between transplanted and untransplanted patients (12.3 vs 4.8 months respectively, p=0.604) in this small series of pts heterogeneously transplanted. In addition the OS was not different between pts previously submitted to IM or not (p=0.87). [Display omitted] This strategy provides encouraging initial results compared to TKIs alone, without specific toxicity, however, it does not translate into survival improvement, but might still represent a suitable preparative regimen for allogeneic transplant whenever it is possible. Disclosures:No relevant conflicts of interest to declare.