Chromosome-positive Chronic Myelogenous Leukemia Research Articles

Frequency of Molecular Monitoring Correlates with Long Term Outcomes in Chronic Phase Chronic Myelogenous Leukemia Treated with First-Line Imatinib: Results of a Community Survey

AbstractAbstract 1685 Background:Molecular monitoring is recognized as an important part of evaluating treatment response in Philadelphia chromosome positive chronic myelogenous leukemia in chronic phase (Ph+ CML-CP). The latest guidelines from the National Comprehensive Cancer Network (NCCN) recommend quantitative polymerase chain reaction (QPCR) testing in the first 3 months with a goal of <10% Bcr-Abl transcripts using the international scale (IS), and then testing every 3 months to achieve at some point and maintain a 3 log reduction in transcripts (Major Molecular Response). Regular molecular monitoring provides an opportunity to detect resistance or adherence problems early. However, it remains unknown how patterns of use of molecular monitoring impact long term outcomes in non-research community settings. Methods:Community physicians who treat CML patients were invited to retrospectively submit information on Ph+ CML-CP patients in their practice who were ≥18 years old when started on first-line imatinib between 2006–2011 and who had ≥6 months of follow-up. Patients enrolled in clinical trials were excluded. Clinical characteristics at treatment initiation were collected. For each 3 month period after treatment initiation while the patient was on tyrosine kinase inhibitor (TKI) therapy, information was collected on molecular monitoring performed to assess treatment response. Information on death and progression to accelerated phase or blast crisis was collected over the entire follow-up period. Patients were grouped by the average number of QPCR tests received on TKI therapy (scaled to rate per year): the 0 tests group if they never had a QPCR test; the 1–2 tests group if they had on average more than 0 but 2 or less QPCR tests/year; and the 3–4 tests group if they had on average more than 2 but 4 or less QPCR test/year. Progression, mortality, and combined progression/mortality rates were reported for each group. In addition, Cox proportional hazards models were used to test the association between progression and progression-free survival and the average number of QPCR tests per year, controlling for the average number of cytogenetic tests per year, and for potential confounders including age, race, initial imatinib dose, Sokal score, and enlarged spleen at diagnosis. Results were reported as hazard ratios (HR) with 95% confidence intervals (CI). Results:38 hematologists and oncologists from community practices throughout the US submitted information on 402 patients initiated on first-line imatinib. Patients were followed retrospectively for a median duration of 36 months. Of these, 52 (13%) had no molecular monitoring, 164 (41%) had 1–2 tests/year, and the remaining 186 (46%) had 3–4 tests/year. The figure below shows progression, mortality, and progression/mortality by frequency of molecular testing. The progression/mortality rates tended to decrease with the number of tests received. Adjusting for cytogenetic testing frequency and potential confounders aside from the Sokal score, a higher average number of QPCR tests per year was significantly associated with a lower rate of progression and longer progression-free survival. Each additional QPCR test per year significantly decreased the risk of progression by 45% (HR=0.55; CI [0.35, 0.87], p=0.011), and progression/mortality by 48% (HR=0.52; CI [0.35, 0.79], p=0.002]. Since 48% of patients did not have a reported Sokal score at diagnosis, a separate analysis was done to also adjust for the Sokal score among those without missing data, with nearly identical results. Conclusions:Ph+ CML-CP patients who underwent QPCR testing every 3–4 months experienced decreased progression and longer progression-free survival compared to those patients monitored less frequently, with the impact of molecular monitoring being independent of the frequency of cytogenetic testing. It is possible that molecular monitoring identifies impending treatment failure earlier and enables adjustment of therapy before hematologic and cytogenetic failure occur. This analysis underscores the value of molecular monitoring every 3 months for Ph+ CML-CP patients on TKI therapy and also demonstrates that a significant number of Ph+ CML-CP patients are not undergoing QPCR at the frequencies recommended in published guidelines. Additional community based education on CML monitoring is needed to assure optimal outcomes. [Display omitted] Disclosures:Goldberg:Novartis Oncology: Research Funding, Speakers Bureau. Chen:Novartis Oncology: Employment, Own stock in Novartis Other. Ericson:Novartis Pharmaceuticals Corp: Employment, Own stock in Novartis Other. Macalalad:Analysis Group, Inc.: Consultancy, Employment, I am an employee of Analysis Group, Inc, which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding. Guerin:Analysis Group, Inc.: Consultancy, Employment, I am an employee of Analysis Group, Inc, which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding. Liu:Analysis Group, Inc.: Consultancy, Employment, I am an employee of Analysis Group, Inc, which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding. Kaminsky:Analysis Group, Inc.: Consultancy, Employment, I am an employee of Analysis Group, Inc, which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding. Wu:Analysis Group, Inc.: Consultancy, Employment, I am an employee of Analysis Group, Inc, which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding.

Immunologic Evaluation of Peptides Derived From BCR/ABL-Out-of-Frame Fusion Protein in HLA A2.1 Transgenic Mice

Philadelphia chromosome-positive chronic myelogenous leukemia and acute lymphocytic leukemia express, besides the main BCR/ABL transcripts, novel BCR/ABL transcripts derived from alternative splicing between BCR exons 1, 13, or 14 with ABL exons 4 and 5. Their translational products present at C-terminus an amino acid portion derived from out-of-frame (OOF) reading of the ABL gene. The presence of OOF-peptide-specific T cells in chronic myelogenous leukemia patients was demonstrated and a first study in in vivo model demonstrated that OOF ABL portion was immunogenic in human leukcocyte antigen (HLA)-A2.1 transgenic mice. Here we immunized HLA A2.1 mice with novel peptides designed on the ABL OOF sequence, containing epitopes with high affinity for HLA A2.1 molecule. The specific immune response, cellular and humoral, obtained ex vivo against HLA A2.1-positive human chronic myelogenous leukemia cells using peptide 22-53 and the cytotoxic activity induced by peptide 32mer confirm the possibility to use the ABL OOF portion as target to evoke a specific and multiple immune response in Philadelphia positive leukemic patients in cytogenetic remission.

Does Baseline Health-Related Quality of Life or Symptom Burden Predict Clinical Outcomes in Patients with Newly Diagnosed CML-CP Treated with Nilotinib or Imatinib?

Abstract 1025 Background:Nilotinib is a more potent and more selective inhibitor of BCR-ABL in-vitro than imatinib. A randomized Phase III study was conducted comparing these two therapies in adult patients with newly diagnosed Philadelphia Chromosome positive (Ph+) chronic myelogenous leukemia (CML) in chronic phase (CP). Aim:To evaluate whether baseline health-related quality of life (HRQL) or symptom scores were predictive of clinical outcome in this phase III trial. Methods:A total of 846 patients were randomized to receive nilotinib 300 mg BID (n=282), nilotinib 400 mg BID (n=281) or imatinib 400mg QD (n=283). For these analyses to evaluate the impact of baseline HRQL on clinical outcomes, the treatment arms were combined. HRQL was assessed using the Functional Assessment of Cancer Therapy–Leukemia (FACT-Leu). The FACT-Leu consists of four general subscales measuring physical, social/family, emotional, and functional well-being and a 17-item leukemia-specific subscale (LeuS). The FACT-G score is the sum of the four general well-being subscales. The questionnaire was administered at baseline, and at 3, 12, and 24 months. Baseline FACT-G and LeuS scores were divided into three equal-sized groups (i.e., tertiles). Patients with high, mid, and low baseline scores were compared on several clinical outcomes: best molecular response by Month 24, best cytogenetic response by Month 24, treatment discontinuation, hospitalization, dose modification of any kind (interruption, increase, or reduction), grade 3 or 4 adverse events, and missed cytogenetic tests. Chi-square tests were used to compare these dichotomous and categorical outcomes between baseline HRQL groups. The relationship between baseline HRQL scores and Sokal Risk groups was evaluated using analysis of variance. Higher scores on the FACT-G and LeuS indicate better HRQL and less symptom burden. Results:Mean baseline FACT-G scores were 97.8, 85.0, and 66.3, and mean baseline LeuS scores were 61.6, 53.8, and 42.2, for the high/mid/low tertile groups, respectively. There was no significant association between best molecular response by Month 24 or cytogenetic response by Month 24 and baseline FACT-G scores (p=0.149 and p=0.094, respectively). There was an association between best molecular response by Month 24 and baseline LeuS scores (p=0.043) but no significant association with best cytogenetic response by Month 24 (p=0.316). There were no significant associations with either dose modifications (p=0.252 for FACT-G, p=0.643 for LeuS), grade 3 or 4 adverse events (p=0.531 for FACT-G, p=0.831 for LeuS), or missed cytogenetic tests (p=0.722 for FACT-G, p=0.374 for LeuS). There was a significant association between treatment discontinuation and baseline FACT-G scores (p=0.007). Only 18% of patients with the highest baseline FACT-G scores discontinued treatment compared to 26% in the middle group and 31% in the group with the lowest baseline FACT-G scores. This relationship was not statistically significant for baseline LeuS scores (p=0.070). Fourteen percent of patients with high baseline FACT-G scores were hospitalized at some point during the study, compared to 15% of patients with mid FACT-G scores, and 22% with low baseline FACT-G (p=0.099). However, 11% of patients with high LeuS scores were hospitalized compared to 20% of patients with mid-range LeuS scores, and 21% of patients with low LeuS scores (p=0.018). The mean baseline FACT-G scores were 81.4, 83.5, and 83.4 (p=0.288), and the mean baseline LeuS scores were 51.1, 53.4, and 52.5 (p=0.042), for patients with high, intermediate, and low Sokal scores, respectively. Conclusions:In patients with newly diagnosed CML-CP, worse general HRQL at baseline was predictive for treatment discontinuation, but not predictive for best molecular response. Leukemia related symptoms at baseline were associated with a greater likelihood of subsequent hospitalization and moderately associated with molecular response. Baseline HRQL was not clearly associated with Sokal scores. These findings suggest that among patients with newly diagnosed CML-CP, examination of baseline HRQL and symptoms may allow patients and clinicians to better anticipate outcomes such as hospitalizations and continuation of therapy. Disclosures:Beaumont:Novartis: Research Funding. Nowinski:Novartis: Research Funding. Coombs:Novartis: Employment, Equity Ownership. Szczudlo:Novartis: Employment, Equity Ownership. Blakesley:Novartis: Employment, Equity Ownership. Gallagher:Novartis: Employment, Equity Ownership. Burns:Novartis: Research Funding. Cella:Novartis: Research Funding.

Upregulation of Osteoactivin Upon Exposure to Tyrosine Kinase Inhibitors Impairs the T Cell Stimulatory Capacity of Monocyte-Derived Dendritic Cells

Abstract 1112▪▪This icon denotes a clinically relevant abstractTargeted therapies using tyrosine kinase (TK) inhibitors have significantly improved the treatment of cancer patients. Imatinib (Glivec, Gleevec, STI 571) was the first TK inhibitor (TKI) established for the treatment of cancer and efficiently blocks the activity of c-ABL, a non-receptor TK which is pathologically activated in philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML). Nilotinib (Tasigna) and dasatinib (Sprycel) are second-generation TKI that have shown efficacy in the treatment of Ph+ CML resistant or intolerant to imatinib. However, molecularly detectable disease persists in the majority of patients treated with TKI, causing relapse after discontinuation of TKI treatment in many cases. Thus, multiple approaches presently aim to combine TKI treatment with immunotherapy. As TKI, besides targeting their eponymous enzyme, influence multiple other signaling pathways involved in cellular functions, analysis of potential effects of TKI on immune effector cells may be key to develop successful combinatorial strategies. Due to their unique ability to initiate powerful anti-tumor T cell responses, dendritic cells (DC) are employed in many immunotherapeutic strategies aiming to eradicate the malignant cell population. Upon activation they change their expression pattern of cell surface molecules and secreted cytokines/chemokines, a process called DC maturation. Osteoactivin, also known as transmembrane glycoprotein NMB (GPNMB) and dendritic cell-associated transmembrane protein (DC-HIL), is a type I transmembrane glycoprotein that is detected abundantly in DC but not or substantially less in monocytes. Its expression can inhibit T cell activation by binding the type 1 transmembrane proteoglycan syndecan-4 (SD-4) on T cells. Here we extend our findings that the exposure of human peripheral blood monocytes to the immunosuppressive and anti-inflammatory cytokine IL-10 or to therapeutic concentrations of TKI during differentiation into monocyte-derived DC (moDC) leads to significant upregulation of osteoactivin at the transcript and protein level in vitro (Blood 2010 116: abstract 1733). We analyzed the expression of other inhibitory receptors, such as PD-L1, PD-L2, CD80, or CD86 and observed no significant differences of the expression under TKI treatment. Furthermore, we thoroughly examined the expression of osteoactivin in the presence of relevant maturation signals such as TLR ligands, IFN-γ or TNF. LPS, Poly I:C, Pam3Cys or R848 nearly abolished osteoactivin expression compared to untreated control cells. In contrast, IFN-γ or TNF did not significantly reduce osteoactivin expression below the basal level. To evaluate the involvement of osteoactivin in TKI-triggered effects on moDC function we performed mixed lymphocyte reactions with allogenic T cells. Osteoactivin upregulation upon exposure to imatinib, dasatinib and nilotinib resulted in significantly reduced T cell stimulatory capacity of moDC. This was not due to IL-10 upregulation but rather due to direct inhibitory effects of osteoactivin on T cell proliferation which could be overcome by addition of blocking anti-osteoactivin antibody. Our data demonstrate that upregulation of osteoactivin upon exposure of immature moDC to TKI is critically involved in the inhibition of DC function. These findings indicate that inhibition of osteoactivin expression or function may serve as a novel strategy in combinatory approaches using TKI and DC-based immunotherapy and may enhance the efficacy of immunotherapeutic interventions in cancer patients. Disclosures:No relevant conflicts of interest to declare.

Pharmacodynamic Analysis of Bosutinib in Patients with Chronic Myelogenous Leukemia,

Abstract 3778 Introduction:Bosutinib (SKI-606) is an orally active, dual competitive inhibitor of the Src and Abl tyrosine kinases. In clinical studies bosutinib has demonstrated efficacy and an acceptable safety profile in patients with Philadelphia chromosome–positive chronic myelogenous leukemia (CML). The current analysis estimated the association of bosutinib pharmacokinetic (PK) exposure at steady-state with safety and efficacy. Methods:Oral bosutinib 500 mg/day was administered to patients with chronic phase (CP), accelerated phase, and blast phase CML who were resistant/intolerant to prior TKI therapy in a phase 2 trial, and to patients with newly diagnosed CP CML in a phase 3 trial. Patients with paired PK and pharmacodynamic data were included in the analysis. Bosutinib exposure metrics (area under the curve [AUC], maximal plasma concentration [Cmax], and minimum plasma concentration [Cmin]) were derived from a previously developed 2-compartment PK model with first-order absorption and an absorption lag. Evaluated safety metrics (ordinal metrics) included gastrointestinal events (diarrhea, nausea, vomiting), rash, aminotransferase elevations, and hematologic events (thrombocytopenia, neutropenia); safety data were pooled from both studies, and the maximum toxicity for each patient was assigned to a 5-point scale (0–4) based on severity (no event to grade 4 event, respectively). Response rates based on an intent-to-treat analysis were evaluated separately for each study and coded as binary variables, where 0 indicated no response and 1 indicated response. Results:A total of 749 patients were included in the pooled safety analysis: mean age was 50.2 years (range, 18–91 years); 54% were male. An exposure-response relationship (Emax model) was identified for the incidence of diarrhea (but not severity), with a predicted probability of diarrhea incidence ranging from 0.575 to 0.797 for the lowest and highest bosutinib AUC bins, respectively. There was also a weak exposure-response relationship (log-linear model) for the incidence (but not severity) of rash, with a predicted probability of rash incidence ranging from 0.216 to 0.419. However, there was no evidence to support an exposure-response relationship for the incidence or severity of nausea, vomiting, neutropenia, thrombocytopenia, or elevation of alanine and aspartate aminotransferases. In 266 patients with resistance/intolerance to prior TKI therapy, no exposure-response relationship for major cytogenetic response (MCyR) at 24 weeks was found. Although an exposure-response relationship (linear or log-linear model) was observed for cumulative complete hematologic response (CHR) in patients with prior TKI exposure, the relationship was paradoxical, with higher bosutinib exposure associated with a lower probability of cumulative CHR; the predicted probability of cumulative CHR ranged from 0.926 to 0.743 for the lowest and highest AUC bins, respectively. In 245 newly diagnosed patients with CP CML, exposure-response relationships were observed for complete cytogenetic response (CCyR), major molecular response (MMR), and CHR at 1 year. CCyR at 1 year could be related to AUC and Cmin, but not Cmax, using a sigmoid Emax model, with a predicted probability of CCyR ranging from 0.476 to 0.650. The exposure-response relationship for MMR at 1 year could be described using an Emax model for AUC and Cmax or a log-linear model for Cmin, with a predicted probability of MMR ranging from 0.238 to 0.497. The relationship of CHR at 1 year with AUC and Cmin, but not Cmax, could be described using an Emax model, with a predicted probability of CHR ranging from 0.605 to 0.763. Conclusions:An exposure-response relationship was identified for incidence of diarrhea and rash, but not for the incidence or severity of other investigated toxicities commonly observed with bosutinib treatment. Additionally, an exposure-response relationship was found for CCyR, MMR, and CHR at 1 year in newly diagnosed patients with CP CML, but the relationship between bosutinib exposure and efficacy was less clear in the pretreated population. The absence of exposure-response relationships for some safety and efficacy metrics may reflect bosutinib concentrations that exceeded the half-maximal inhibitory concentration (IC50) for these metrics and reached a plateau effect. Disclosures:Amantea:Pfizer Inc: Employment, Equity Ownership. Mould:Projections Research Inc: Employment; Pfizer Inc: Consultancy. Upton:Pfizer Inc: Consultancy. Pearce:Pfizer Inc: Employment. Hsyu:Pfizer Inc: Employment, Equity Ownership.

Impact of treatment end point definitions on perceived differences in long-term outcome with tyrosine kinase inhibitor therapy in chronic myeloid leukemia.

Different definitions of progression-free survival (PFS) and event-free survival (EFS) may result in perceived differences in outcomes with tyrosine kinase inhibitor (TKI) therapies in chronic myelogenous leukemia (CML). We analyzed the outcome of 435 patients with early chronic-phase, Philadelphia chromosome-positive CML treated with imatinib (n = 281), nilotinib (n = 78), and dasatinib (n = 76) using definitions of PFS and EFS used in the International Randomized Study of Interferon Versus STI571 (IRIS), Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients (ENEST-nd), Dasatinib Versus Imatinib Study in Treatment-Naïve CML Patients (DASISION), and MD Anderson Cancer Center (MDACC) trials. Definitions for EFS-IRIS, time without progression in ENEST-nd, PFS-DASISION, and EFS-MDACC were as previously reported. The EFS-MDACC considered an event any instance of toxicity or death from any cause on or off therapy (if not counted before death as progression/event). Of the 435 patients, 123 (28%) were taken off TKI therapy (resistance/loss of response, n = 33; blastic phase on TKI therapy, n = 6; intolerance/toxicity, n = 29; other causes, n = 55). Thirty-three patients (7.6%) have died; eight patients died on TKI therapy, two patients died within 60 days of being off TKIs, and 23 patients died after being off TKIs for more than 60 days. Of the 33 deaths, 19 deaths (eight deaths on TKI, two deaths within 60 days, and nine deaths off for resistance/relapse/transformation) would be counted as progression/events on the IRIS/ENEST-nd/DASISION studies, whereas 14 deaths would be censored at time off TKI. On the basis of the four definitions used by IRIS, ENEST-nd, DASISION, and MDACC trials, the corresponding 5-year PFS/EFS rates were 96%, 90%, 89%, and 81%. Uniform definitions of PFS and EFS are needed to compare the long-term efficacy and potential use of different TKIs in CML.

Clinical Experience to Date With Nilotinib in Gastrointestinal Stromal Tumors

Nilotinib, a novel tyrosine kinase inhibitor (TKI) that inhibits BCR-ABL, the stem cell factor receptor (KIT), and platelet-derived growth factor receptor-alpha (PDGFRα), is approved for the treatment of patients with newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukemia (CML) and those with CML that is imatinib-resistant or -intolerant. Due to its potent inhibition of KIT and PDGFRα--the two tyrosine kinases that are the central oncogenic mechanisms of gastrointestinal stromal tumors (GIST)--nilotinib also has been investigated for potential efficacy and safety in patients with GIST who have progressed on other approved treatments. Initial results have been encouraging, as nilotinib has demonstrated clinical efficacy and safety in a phase I trial as either a single agent or in combination with imatinib, as well as in heavily pretreated patients with GIST in a compassionate use program. In addition, the phase III trial of nilotinib versus best supportive care (with or without a TKI at the investigator's discretion) indicated that nilotinib may have efficacy in some third-line patients. Furthermore, the Evaluating Nilotinib Efficacy and Safety in Clinical Trials (ENEST g1 trial), a phase III randomized, open-label study comparing the safety and efficacy of imatinib versus nilotinib in the first-line treatment of patients with GIST, is currently under way. Other studies with nilotinib either have been initiated or are in development. Based on published and accruing clinical data, nilotinib shows potential as a new drug in the clinician's armamentarium for the management of GIST.

Ph陽性小児慢性骨髄性白血病に対する高用量 (340mg/m2) イマチニブ単独治療経験

Ph陽性小児慢性骨髄性白血病に対する高用量 (340mg/m2) イマチニブ単独治療経験

Proceedings of the Third Global Workshop on Chronic Myeloid Leukemia.

Tyrosine kinase inhibitor (TKI) therapy has resulted in unprecedented responses and survival rates in Philadelphia chromosome-positive chronic myelogenous leukemia (CML) that are durable for years. However, a third of patients either fail to respond or respond suboptimally to imatinib therapy, while some others are intolerant to imatinib. Increased understanding of the molecular basis of imatinib resistance has led to rational development of second-generation TKIs as effective second-line treatment options for imatinib-resistant patients. However, persistence of minimal residual disease (MRD) and development of resistance against TKI therapy are proving to be significant challenges. Treatment options are evolving for patients with CML and the promising results with several novel agents showing activity in CML, including in patients with the T315I mutation, are encouraging advancements in the field. Recently, a panel of global experts in CML deliberated on the imminent approval of second-generation TKIs in the frontline setting, ways to improve on frontline therapy, integration of new agents in current treatment algorithms, and design of future clinical trials; the proceedings of the discussion are summarized in this article.

Hospitalizations of Patients with Newly Diagnosed CML-CP Treated with Nilotinib or Imatinib: Results From a Randomized Phase III Trial

AbstractAbstract 3826Background: Imatinib is the current standard of care for chronic myelogenous leukemia (CML). Nilotinib is a highly potent and the most selective inhibitor of BCR-ABL. A Phase III multi-center, open label, randomized study (ENESTnd) was conducted comparing these two therapies in adult patients with newly diagnosed Philadelphia Chromosome positive (Ph+) CML in chronic phase. The primary endpoint analysis at 12 months demonstrated that major molecular response (MMR) was significantly improved with nilotinib 300 mg BID (44%) and nilotinib 400 mg BID (43%) compared to imatinib 400 mg QD (22%; p < 0.001). The discontinuation rate due to adverse events was lowest among the nilotinib 300mg BID treatment arm (5%) compared to 7% in the imatinib arm, and nilotinib 400 mg BID (9%). Based on the results of this clinical trial, nilotinib 300 mg BID was approved for initial use for CML-CP in the US.Aim: To evaluate the occurrence and rate of hospitalizations and time away from usual activities in this phase III trial.Methods: A total of 846 patients were randomized to receive nilotinib 300 mg BID (n=282), nilotinib 400 mg BID (n=281) or imatinib 400mg QD (n=283). Hospitalizations, defined as any visit to the hospital requiring an overnight stay, excluding pre-planned or elective surgery, were assessed throughout the study period. Overdispersed Poisson regression models were used to compare the days hospitalized per 1,000 patient-days on study. Patients were asked to report time-off, defined as average number of hours per week taken away from all usual activities due to CML and side effects of CML treatment over the past 4 weeks, at Baseline and at the end of Months 3 and 12. The Wilcoxon rank-sum test was used to compare the time off from usual activities at each assessment; and t-tests were used to evaluate the within-group changes in time off.Results: There were a total of 57 hospitalizations in the imatinib arm versus 48 hospitalizations in the nilotinib 300 mg BID arm, and 74 hospitalizations in the nilotinib 400 mg BID arm (Table). Descriptive statistics for length of stay (LOS) are presented in the Table. The hospitalization rate, expressed as hospital days per 1,000 patient days, was 47% higher in the imatinib arm compared to the nilotinib 300 mg BID arm (p=0.057) and 8% higher compared to the nilotinib 400 mg BID arm (p=0.68). Patients in the nilotinib 300mg BID arm had fewer stays and shorter LOS than the imatinib arm, whereas patients in the nilotinib 400mg BID arm had more stays than the imatinib arm but shorter LOS on average resulting in fewer total hospital days. The majority of hospitalizations (56%) in all three arms occurred within the first 9 months. Time off from usual activities, which began at an average level of 8–10 hours per week at Baseline, decreased in each arm, but the decrease did not significantly differ between arms (Table). Similar results were observed when patients reporting zero hours of time off were excluded from the analysis. There was no association between time off and age.Summary/conclusions: In patients with newly diagnosed CML-CP, nilotinib resulted in less hospital time compared to imatinib, although this difference did not reach statistical significance. Additionally, patients in all three treatment groups reported significant improvements from baseline in time off from usual activities. Disclosure:Beaumont:Novartis: Research Funding. Coombs:Novartis: Employment, Equity Ownership. Bollu:Novartis: Employment, Equity Ownership. Woodman:Novartis Oncology: Employment. Cella:Novartis: Research Funding.

Prognostic Significance of the Lost of a Major Molecular Response In Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia (Ph+CML).

AbstractAbstract 3435 Background:Albeit of well-known, dramatic improvements, there remain some questions to be solved around Ph+CML in treatment with tyrosine kinase inhibitors (TKI). Among these, the significance of the amount of minimal residual disease (MRD) measured by RT-PCR. For instance, loss of a so-called major molecular response (MMR) is claimed to be a Òsuboptimal responseÓ and following the ELN recommendations, a change in treatment should be considered in these patients. Aims:To evaluate the relevance of a loss of MMR in patients with complete cytogenetic response (CCR). Study Group and Methods:We have analized 81 patients treated with imatinib for CML in chronic phase with a median follow up of 66 months. 36 patients started imatinib after interferon failure and 45 as front line therapy. Major Molecular Response (MMR; BCR-ABL/ABL ratio<0.1% IS) at any time was achieved by 63 patients. Results:22 patients (34%) lost MMR (documented al least twice). The risk of losing MMR was higher in late MMR (>18 months) compared with those cases whose MMR came much earlier (<18 months): 70% vs 18% (p=. 000). We have found no correlation among the lost of MMR and classical prognostic factors (Sokal-Index, mutations at the TK domain or imatinib plasma levels). Of these 22 patients, 7 (32 %) recovered MMR later with no therapy changes, 8 (36%) experienced fluctuations in the BCR-ABL transcript-levels without losing CCR, 4 (19%) did not attain a MMR but remained in stable CRR, and 3 (13%) lost CCR. These regained MMR after being treated on second generation TKI. The results show how the stability of the early MMR is greater than late MMR (table1). Conclusions:In our experience, one third of the patients who lost MMR recovered it later on the same treatment. And only 13% went on to treatment failure. Perhaps some similar cases (after first losing MMR) should be closely monitored before a change in treatment. Also of note is, of course regarding only our experience, that the risk of a loss of MMR seems to be maximal in patients who achieve a late MMR.Table 1Evolution of patients after lossing MMREarly MMR (n= 9)Late MMR (n=13)Recover MMR45% (4)23% (3)Fluctuations33% (3)38% (5)Remained in Suboptimal Response11% (1)23% (3)Lost CCR11% (1)15% (2) Disclosures:No relevant conflicts of interest to declare.

Regulation of Synaptic Rac1 Activity, Long-Term Potentiation Maintenance, and Learning and Memory by BCR and ABR Rac GTPase-Activating Proteins

Rho family small GTPases are important regulators of neuronal development. Defective Rho regulation causes nervous system dysfunctions including mental retardation and Alzheimer's disease. Rac1, a member of the Rho family, regulates dendritic spines and excitatory synapses, but relatively little is known about how synaptic Rac1 is negatively regulated. Breakpoint cluster region (BCR) is a Rac GTPase-activating protein known to form a fusion protein with the c-Abl tyrosine kinase in Philadelphia chromosome-positive chronic myelogenous leukemia. Despite the fact that BCR mRNAs are abundantly expressed in the brain, the neural functions of BCR protein have remained obscure. We report here that BCR and its close relative active BCR-related (ABR) localize at excitatory synapses and directly interact with PSD-95, an abundant postsynaptic scaffolding protein. Mice deficient for BCR or ABR show enhanced basal Rac1 activity but only a small increase in spine density. Importantly, mice lacking BCR or ABR exhibit a marked decrease in the maintenance, but not induction, of long-term potentiation, and show impaired spatial and object recognition memory. These results suggest that BCR and ABR have novel roles in the regulation of synaptic Rac1 signaling, synaptic plasticity, and learning and memory, and that excessive Rac1 activity negatively affects synaptic and cognitive functions.

Phase 1 study of INNO‐406, a dual Abl/Lyn kinase inhibitor, in Philadelphia chromosome‐positive leukemias after imatinib resistance or intolerance

: INNO-406, a dual v-abl Abelson murine leukemia viral oncogene homolog (Abl)/v-yes-1 Yamaguchi sarcoma viral-related oncogene homolog (Lyn) tyrosine kinase inhibitor (TKI), has demonstrated specific Lyn kinase inhibitory activity with no or limited activity against other sarcoma (Src) family member kinases. Several breakpoint cluster region (Bcr)-Abl kinase domain mutations are sensitive to INNO-406 in vitro, including mutations that involve a phenylalanine-to-leucine or phenylalanine-to-valine substitution at codon 317 (F317L and F317V, respectively). In the current study, the authors evaluated the use of INNO-406 in patients with Philadelphia (Ph) chromosome-positive chronic myelogenous leukemia (CML) or acute lymphocytic leukemia (ALL) after imatinib resistance or intolerance. : A dose-escalation study was conducted at a starting dose of oral INNO-406 30 mg once daily. Cohorts of at least 3 patients were treated at each dose level until the maximum tolerated dose (MTD) was reached. Twice-daily dosing also was evaluated. Therapy was allowed to continue for a maximum of 24 months. : INNO-406 was administered to 56 patients with imatinib resistance (n = 40) or intolerance (n = 16). Other previous treatments included nilotinib (n = 20 patients), dasatinib (n = 26 patients), and dasatinib/nilotinib (n = 9 patients). Common mutations at the time of study entry included a tyrosine-to-histidine substitution at codon 253 (Y253H) (n = 6 patients), a glycine-to-glutamic acid substitution at codon 250 (G250E) (n = 4 patients), a threonine-to-isoleucine substitution at codon 315 (T315I) (n = 4 patients), and F317L (n = 3 patients). Of 31 patients with CML in chronic phase who received INNO-406, the major cytogenetic response rate was 19%. No responses were observed in patients who had CML in accelerated phase, CML in blastic phase, or Ph-positive ALL. The dose-limiting toxicities (DLTs) at an INNO-406 dose of 480 mg twice daily were liver function abnormalities and thrombocytopenia. : INNO-406 had anti-CML efficacy in a heavily pretreated study population. On the basis of the classic determinations of both DLT and MTD, the recommended phase 2 dose of oral INNO-406 was 240 mg twice daily. Lower doses of INNO-406 may be equally effective and should be explored.

Prognostic factors associated with complete cytogenetic response in patients with chronic myelogenous leukemia on imatinib mesylate therapy

Imatinib mesylate, a selective Bcr-Abl tyrosine kinase inhibitor, has proved to be most effective therapy of Philadelphia chromosome-positive chronic myelogenous leukemia. Imatinib induces complete haematological and cytogenetic response in high percentage of patients. The aim of this study was to identify potential prognostic factors before beginning treatment with imatinib associated with complete cytogenetic response. We analyzed 20 patients with newly diagnosed Philadelphia positive chronic myelogenous leukemia treated at our institution from June 2006 until May 2009. These patients were treated with imatinib mesylate in oral dose of 400 to 800 mg daily. Complete blood counts were performed every month, while serum chemistry evaluations and bone marrow evaluations including morphology and cytogenetics were performed every 6 months. Of the 20 patients analyzed in this study, 19 (95%) achieved complete haematologic response within three months. In all patients cytogenetic analyses were done and all have achieved absolute cytogenetic response. The best cytogenetic response rate at any time during study treatment among 20 patients was: complete cytogenetic response in 15, partial cytogenetic response in three and minor cytogenetic response in two patients. Among 11 observed base-line patients' characteristics five were independent predictors of a high rate of complete cytogenetic response; the absence of blasts and basophils in peripheral blood, the presence of less than 5 percent of bone marrow blasts, white blood cell count less than 10 x 10(9)/L and the absence of splenomegaly (p < 0.01). Our results showed that some pre-treatment characteristics of patients might be the cause of differences in treatment outcome. On the basis of this analysis, we identified several pre-treatment patients' characteristics to be independent prognostic factors for achievement of complete cytogenetic response.

Abstract B215: Ascending single-dose study of safety, tolerability, and pharmacokinetics of bosutinib (SKI-606) in healthy subjects

Abstract Introduction: Bosutinib (SKI-606), a dual inhibitor of Src and Abl tyrosine kinases, is being developed for the treatment of patients with chronic myelogenous leukemia. An oral dose of 500 mg daily shows evidence of clinical efficacy in patients with Philadelphia chromosome-positive chronic myelogenous leukemia (Cortes et al. Blood 112:1098, 2008). To support the clinical pharmacology assessment of bosutinib, a single-ascending-dose safety and pharmacokinetic (PK) evaluation was performed in healthy subjects. Methods: This was a randomized, double-blind, placebo-controlled, single-ascending dose, sequential-group study of oral bosutinib in healthy subjects. Subjects were originally to receive doses of 200, 400, 600, 800, 1000 and 1200 mg of bosutinib in the fasting state. However, subjects who received 400 mg bosutinib had multiple adverse events and then 200 mg, 400 mg, 600 mg, and 800 mg bosutinib was administered with food. Each cohort included 6 subjects who received one dose of bosutinib and 2 who received placebo. Plasma samples, collected through 96 h post-dose, were analyzed by using a liquid chromatography/tandem mass spectrometry assay for bosutinib concentrations. PK analyses were performed using a noncompartmental method and dose linearity was assessed using a power model. Results: A total of 55 subjects (41 bosutinib, 14 placebo) were enrolled (47 males, 8 females, median age [range] 28 [18–50] y, 87%White). Thirty-three (81%) subjects had adverse events (AEs) after receiving bosutinib. The most common AEs for all subjects receiving bosutinib included diarrhea (39% subjects), nausea (29%), headache (22%), postural dizziness (22%) catheter site-related reaction and fatigue (10% each). The frequency and severity of gastrointestinal AEs appeared to be dose related. Doses up to 600 (fed) were well tolerated. After administration of single ascending doses of 200–800 mg bosutinib with food, absorption of bosutinib was relatively slow with a median tmax of 6 h, and both Cmax and AUC increased with increasing dose in a linear fashion. The apparent volume of distribution (Vz/F) was large (131–214 L/kg), mean clearance (CL/F) was 2.25–3.81 L/h/kg, and mean half-life was 32–39 h. Food increased bosutinib exposure (Cmax and AUC) by ∼2-fold and 1.5-fold after administration of the 200-mg and 400-mg doses, respectively. Conclusions: Bosutinib was generally safe and well tolerated in healthy subjects after administration of single oral doses up to 600 mg (fed). The PK of bosutinib was linear when given with food, and the half-life supports a once-daily dosing regimen. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B215.

Deguelin Induces Cell Growth Arrest and Cell Death Via the Suppression of BCR-ABL and Survivin Expression in BCR-ABL-T315I Mutant Cells.

Abstract 4255Development of kinase domain mutation is a major drug-resistance mechanism for tyrosine kinase inhibitor (TKI) in cancer therapy. A particularly challenging example is found in Philadelphia chromosome-positive chronic myelogenous leukemia (CML) where TKI STI571 is ineffective against the BCR-ABL mutant, E255K or T315I. Therefore, new agents that effectively kill these cells with kinase domain mutation are absolutely necessary. Deguelin is a rotenoid from African plant Mundulea sericea, which has been recently shown to suppress the lung tumorigenesis via inhibiting the activation of PI3kinase-Akt signaling. More recently, deguelin has been shown to bind to ATP-binding pocket of heat shock protein (Hsp) 90 and inhibit functions of Hsp90 client proteins. However, the effects of deguelin on BCR-ABL mutant transformed cells are poorly understood. We investigated the effects of deguelin on the cell growth and cell death of BaF/3 pre-B-cells transformed with BCR-ABL-wild type (WT), BCR-ABL-E255K and BCR-ABL-T315I (kindly provided by Dr. Kimura, Saga University, Saga, Japan), by trypan-blue exclusion and Annexin V stain. Deguelin inhibited the proliferation of these transformed cells in a time-and a dose-dependent manner (IC50=1.0mM). In addition, flow cytometric analysis revealed a higher frequency of Annexin V(+) cells in deguelin-treated cells (mean ± SD : WT 80.1±15.3%, E255K 82.3±3.5%, T315I 94.0±0.4%, P< 0.05, respectively), compared to that in untreated cells (WT 11.5±1.6%, E255K 11.9±2.0%, T315I 15.3±4.8%, respectively). These results indicate that deguelin induces the cell-growth arrest and cell death in these cells. To better understand the mechanism of these effects, we examined the intracellular signaling and the expression of apoptosis associated proteins by immunoblot analysis. We found that deguelin suppressed BCR-ABL protein expression and prevented CrkL phosphorylation in these cells. In addition, the inhibitor of apoptosis protein, survivin expression was decreased at 24 hours after deguelin treatment. These results suggested that deguelin suppresses BCR-ABL and survivin expression, and inhibits CrkL phosphorylation in BCR-ABL mutant and WT cells. Since deguelin has been shown to inhibit the function of Hsp90 client proteins, deguelin may destabilize BCR-ABL and survivin by inhibiting Hsp90 function. Taken together, deguelin appears to induce cell growth arrest and apoptosis of BCR-ABL mutant and WT transformed cells via the suppression of BCR-ABL and survivin expression. Thus, deguelin merits further investigation as a potential therapeutic agent for CML with T315I ABL mutation. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Outcome of 125 Children with Chronic Myelogenous Leukemia Who Received Transplants from Unrelated Donors: The Japan Marrow Donor Program

Because of a small number of patients, only a few studies have addressed the outcome of bone marrow transplantation (BMT) in children with Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML), who receive graft from a volunteer-unrelated donor (VUD), especially after practical application of imatinib mesylate. The outcomes of BMT from a VUD in 125 children with Ph+ CML were retrospectively reviewed. Patients were identified through the Japan Marrow Donor Program as having undergone BMT between 1993 and 2005 and were aged 1-19 years at the time of transplant (median age, 14 years). The probabilities of 5-year overall survival (OS) and leukemia-free survival (LFS) were 59.3% and 55.5%, respectively. Multivariate analysis identified the following unfavorable survival factors: infused total nucleated cell dose<314 x 10(6) /kg (relative risk [RR]=2.43; 95% confidence interval [CI]=1.33-4.44; P=.004), advanced phase (RR=2.43; 95% CI=1.37-4.31; P=.004), and no major cytogenetic response (MCyR) at the time of BMT (RR=6.55; 95% CI=1.98-21.6; P=.002). Of the 17 patients treated with imatinib, 15 (88%) achieved MCyR at the time of BMT, and this group had an excellent 5-year OS of 81.9%. Disease phase, infused total nucleated cell dose, and cytogenetic response were independent risk factors for survival of unrelated BMT. These findings provide important information for assessing the indications for and improving outcome in unrelated BMT for the treatment of pediatric CML.

Hematopoietic stem cell origin of human fibroblasts: Cell culture studies of female recipients of gender-mismatched stem cell transplantation and patients with chronic myelogenous leukemia

Our series of studies using transplantation of single hematopoietic stem cells (HSCs) demonstrated that mouse fibroblasts/myofibroblasts are derived from HSCs. In order to determine the origin of human fibroblasts, we established a method for culturing fibroblasts from human peripheral blood (PB) mononuclear cells and studied fibroblasts from gender-mismatched HSC transplant recipients and patients with untreated Philadelphia chromosome-positive chronic myelogenous leukemia (CML). We cultured PB cells from three female subjects who showed near-complete hematopoietic reconstitution from transplantation of granulocyte-colony stimulating factor-mobilized male PB cells and examined the resulting fibroblasts using fluorescent in situ hybridization for Y chromosome. Because the mobilized PB cells may contain mesenchymal stem cells, we could not determine the HSC or mesenchymal stem cell origin of the fibroblasts seen in culture. To further document the HSC origin of human fibroblasts, we next examined fibroblasts from two patients with untreated CML, a known clonal disorder of HSCs. All cultured fibroblasts from female recipients of male cells showed the presence of Y chromosome, indicating the donor origin of fibroblasts. Cultured fibroblasts from the CML patients revealed the presence of BCR-ABL translocation. This demonstration provided strong evidence for the HSC origin of human fibroblasts because CML is a clonal disorder of the HSC. These studies strongly suggest that human fibroblasts are derived from HSCs. In addition, the results suggest that fibrosis seen in patients with CML may be a part of the clonal process.

Significance of Increasing Levels of Minimal Residual Disease in Patients With Philadelphia Chromosome–Positive Chronic Myelogenous Leukemia in Complete Cytogenetic Response

The aim of this study was to evaluate the clinical relevance of increases in quantitative polymerase chain reaction (QPCR) levels in patients with chronic myelogenous leukemia (CML) who are in complete cytogenetic response (CGCR) on therapy. Patients with Philadelphia chromosome (Ph)-positive CML receiving tyrosine kinase inhibitors (TKIs) are frequently monitored for response by QPCR studies for minimal molecular disease. The clinical significance of increasing levels of QPCR in patients in CGCR is uncertain. One hundred sixteen patients in durable CGCR, and on imatinib therapy for at least 18 months, had increases in QPCR levels (documented at least twice consecutively) as defined by literature reports. These were further analyzed by the achievement of major molecular response (MMR) defined as QPCR < or = 0.05%, as well as by the degree of increase in QPCR. Only 11 (9.5%) of 116 patients with increases in QPCR had CML progression; 10 of them were among 44 patients (23%) who either lost a MMR or never had a MMR, and had more than 1 log increase of QPCR. Most patients with increases in QPCR remain in CGCR. Patients who lose a MMR or never achieve a MMR, and have more than 1 log increase of QPCR, should be monitored more closely, and may be evaluated for mutations of BCR-ABL kinase domain and considered for investigational therapeutic interventions.

Treatment patterns of chronic myelogenous leukemia patients with suboptimal responses to imatinib

7090 Background: Imatinib is the first-line therapy for Philadelphia chromosome-positive chronic myelogenous leukemia (CML). Patients with suboptimal responses may have the dose of imatinib escalated or may be switched to an alternative kinase inhibitor such as dasatinib. The aim of this study is to examine the real-world treatment patterns of imatinib and dasatinib in CML patients. Methods: Two large U.S. administrative claims databases from January 1999 to March 2008 were combined (MarketScan and Ingenix Impact) to extract de-identified information of patients diagnosed with CML (ICD-9 code: 205.1) who were initiated on imatinib. Patients were followed from the first observed imatinib prescription to the end of data availability. Patients who increased imatinib dose to &gt;400 mg/day were defined as dose escalators, while patients who initiated on imatinib and further switched to dasatinib were considered as switchers. Rates of imatinib dose escalation and switching to dasatinib were estimated. Kaplan-Meier (KM) survival analyses were used to estimate the rate of imatinib discontinuation, defined as a lack of imatinib supply for at least 90 days. Among switchers, the rate of switching back to imatinib was also estimated using KM survival analysis. Results: Among the 5,159 CML patients initiated with imatinib, 1,144 patients either had dose escalation of imatinib (839) or were switched to dasatinib (305) during the study period. Of the 5,159 patients, 12.1% patients discontinued imatinib by the end of the first year, and 25.4% discontinued by the end of the third year. Among the 305 switchers, 115 (37.7%) had an imatinib dose increase prior to the switch, and 66 (21.6%) were escalated to 800 mg of imatinib before switching. 51 patients (16.7%) had used imatinib for &lt;6 months before switching, and 17.1% switched back to imatinib within 6 months of dasatinib treatment. Conclusions: This study showed that great variability was observed in the real world treatment pattern of CML patients. Most CML patients who initiated on imatinib did not dose increase or switch during the study period. Of those who switched to dasatinib, most did not attempt to increase the dose before switching, and a sizeable portion of patients had to switch back to imatinib. [Table: see text]