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1.  Defining the Course and Prognosis of Adults With Acute Lymphocytic Leukemia in First Salvage After Induction Failure or Short First Remission Duration 
Cancer  2010;116(24):5568-5574.
BACKGROUND
Results from salvage therapy in adult patients with acute lymphocytic leukemia (ALL) are wide-ranging and depend on several disease and patient characteristics. The objectives of this study were to define the prognosis for adult patients with ALL after first salvage through multivariate analyses of patient and disease characteristics.
METHODS
Adults with ALL who had primary resistance to frontline therapy or who had a disease recurrence after a first complete response (CR) duration <1 year were analyzed. Multivariate analyses for subsequent CR and survival were conducted.
RESULTS
Seventy-five of 245 patients (31%) achieved CR. The median CR duration was 5 months, the median survival was 4.7 months. In multivariate analysis, independent poor prognostic factors for not achieving CR were age >55 years, bone marrow blasts ≥20%, and platelet count <75 × 109/L Variables that were associated independently with shorter survival were age >55 years, bone marrow blasts ≥20%, platelet count <75 × 109/L, albumin level <3 g/L, and lactic dehydrogenase level ≥1000 IU/L. Patients who had ≥3 of the 5 adverse factors (45%) had a median survival of 2 to 3 months and CR rates of 8% to 15%. Achieving CR was associated independently with improved survival in a landmark multivariate analysis (P<.0001; hazard ratio, 0.40; 95% confidence interval, 0.03–0.72).
CONCLUSIONS
The current analyses identified a subset of adults patients ALL in first salvage for whom standard therapies were associated with an extremely poor outcome. The results also confirmed the importance of achieving CR to attain improved survival.
doi:10.1002/cncr.25354
PMCID: PMC4332768  PMID: 20737576
acute lymphocytic leukemia; salvage therapy; prognosis; survival; complete response
2.  Current Event-Free Survival After Sequential Tyrosine Kinase Inhibitor Therapy for Chronic Myeloid Leukemia 
Cancer  2010;117(2):327-335.
BACKGROUND
Imatinib is an effective tyrosine kinase inhibitor (TKI) for patients with chronic myeloid leukemia (CML) in chronic phase (CP). Although some patients may fail on therapy with imatinib, effective salvage therapy is available with second-generation TKIs. Current measurement of efficacy for each therapy is judged by its individual impact on overall survival and event-free survival (EFS).
METHODS
In total, 586 patients with CML in CP who received imatinib were included in this analysis in 2 cohorts: imatinib as front-line therapy (n =281) or after failure on interferon-α (IFN-α) (n =305). By accounting for successful salvage treatment (ie, regain of complete cytogenetic response), the current EFS (CEFS) rate was calculated to obtain a more accurate impression of the outcome of patients with CML who received treatment with sequential TKIs.
RESULTS
For patients who received imatinib after failing on IFN-α, the 7-year EFS rate was 61%, whereas the CEFS rate was 69%. The 7-year EFS rate for patients who received imatinib as initial therapy was 81% compared with a 7-year CEFS rate of 88%.
CONCLUSIONS
CEFS provided a more accurate representation of the outcome of patients with CML in CP. These patients may frequently be treated successfully with subsequent TKIs after experiencing failure on the first TKI.
doi:10.1002/cncr.25604
PMCID: PMC4327987  PMID: 20845478
event-free survival; chronic myeloid leukemia; tyrosine kinase inhibitor; current event-free survival; interferon-α; failure
3.  Long-Term Prognostic Impact of the Use of Erythropoietic-Stimulating Agents in Patients With Chronic Myeloid Leukemia in Chronic Phase Treated With Imatinib 
Cancer  2010;117(5):982-991.
BACKGROUND
Anemia is a frequent side effect of imatinib in patients with chronic myeloid leukemia (CML). Erythropoietic-stimulating agents have been used for treatment of imatinib-induced anemia. There are no data on long-term safety of erythropoietic-stimulating agents in CML patients.
METHODS
The records of chronic phase CML patients who received treatment with imatinib were reviewed for use of erythropoietic-stimulating agents and occurrence of thrombotic events. Data on cytogenetic response and survival were analyzed by use of erythropoietic-stimulating agent.
RESULTS
A total of 608 patients were included, and 217 patients received erythropoietic-stimulating agents. There were 30 thrombotic episodes. Patients who received erythropoietic-stimulating agents had a higher rate of thrombosis (8.5% vs 2.6%, P = .0025). There was no difference in cytogenetic response rate and survival by use of erythropoietic-stimulating agent. Development of grade 3–4 anemia occurred in 62 (10%) patients and was associated with significantly worse response and survival in patients in late chronic phase. By multivariate analysis, use of erythropoietic-stimulating agents was not a risk factor for event-free survival.
CONCLUSIONS
In our cohort of chronic phase CML patients, use of erythropoietic-stimulating agents did not impact survival or cytogenetic response rate, but was associated with a higher thrombosis rate. Severe anemia is associated with worse survival and response.
doi:10.1002/cncr.25533
PMCID: PMC4324729  PMID: 20960502
chronic myeloid leukemia; imatinib; anemia; erythropoiesis-stimulating agents; tyrosine kinase inhibitors
4.  Prognostic Impact of Deletions of Derivative Chromosome 9 in Patients With Chronic Myelogenous Leukemia Treated With Nilotinib or Dasatinib 
Cancer  2011;117(22):5085-5093.
BACKGROUND
Deletions of derivative chromosome 9 are a poor prognostic factor in patients with chronic myeloid leukemia (CML) treated with hydroxyurea, interferon, or stem cell transplantation. Imatinib may overcome the adverse prognostic impact of deletions of derivative chromosome 9.
METHODS
A study was undertaken to investigate the prognostic impact of deletions of derivative chromosome 9 in 353 patients with CML receiving the second generation tyrosine kinase inhibitors (TKIs) nilotinib (n = 161) or dasatinib (n = 192).
RESULTS
Deletion of derivative chromosome 9 status was determined in 245 (69%). Twenty-eight (11%) patients, 22 in chronic phase, 4 in accelerated phase, and 2 in blast phase, carried deletions of derivative chromosome 9, including 17 receiving nilotinib and 11 receiving dasatinib (P = .47). Overall survival (OS) at 24 months was similar between patients with or without deletions of derivative chromosome 9 (70% vs 71%, P = .76). For patients in chronic phase, no significant differences in overall major cytogenetic response (77% vs 82%, P = .57) or complete cytogenetic response (77% vs 81%, P = .71) rates were observed between patients with or without deletions of derivative chromosome 9. At 24 months, patients with CML in chronic phase without deletions of derivative chromosome 9 had improved event-free survival (EFS) (88% vs 66%, P = .07) and OS (96% vs 82%; P = .08) compared with those carrying deletions of derivative chromosome 9. However, multivariate analysis established second-line versus frontline second generation TKI therapy as the only adverse prognostic factor for EFS and increased bone marrow blast burden and older age as independent adverse prognostic factors for OS.
CONCLUSIONS
Deletions of derivative chromosome 9 do not appear to be an in dependent risk factor for survival among patients with CML in chronic phase receiving second generation TKIs.
doi:10.1002/cncr.26147
PMCID: PMC4324753  PMID: 21523765
BCR-ABL1; nilotinib; dasatinib; deletion; derivative chromosome 9
5.  FLT3 Inhibitors in the Treatment of Acute Myeloid Leukemia 
Cancer  2011;117(15):3293-3304.
Despite recent modest improvements in the chemotherapy regimens used to treat acute myeloid leukemia (AML), many patients diagnosed with AML ultimately die of the disease. Commonly occurring genetic alterations have been identified that strongly affect the prognosis for patients with AML. These alterations represent possible targets for investigational therapies that could act to specifically halt the aberrant growth of AML cells while limiting damage to normal cells. One such gene is the Fms-like tyrosine kinase 3 (FLT3) gene, which is mutated in approximately 30% of adult patients with AML and has a significant impact on prognosis. In particular, internal tandem duplications in FLT3 confer a poor prognosis to this large subgroup of patients with AML. Agents that target FLT3 are in development for the treatment of patients who have AML and offer a potential paradigm change in the current standard treatment of AML. For this report, the authors reviewed the prognostic significance of genetic alterations observed in AML with a focus on the therapeutic implications of targeting FLT3. The introduction of such agents may be the next major step toward the era of personalized therapy in AML.
doi:10.1002/cncr.25908
PMCID: PMC4316826  PMID: 21319142
acute myeloid leukemia; cytogenetics; FLT3 protein; molecular abnormalities
6.  Imatinib Front-Line Therapy Is Safe and Effective in Patients With Chronic Myelogenous Leukemia With Pre-Existing Liver and/or Renal Dysfunction 
Cancer  2010;116(13):3152-3159.
BACKGROUND
Imatinib 400 mg daily is the standard treatment for patients with chronic myelogenous leukemia (CML). The safety and efficacy of imatinib in CML patients with pre-existing liver and/or renal dysfunction has not been analyzed.
METHODS
The authors analyzed the outcome of 259 patients with early chronic phase CML treated with imatinib (starting dose 400 mg in 50, 800 mg in 209). Pre-existing liver and/or renal dysfunction was seen in 38 (15%) and 11 (4%) patients, respectively.
RESULTS
Dose reductions were required in 91 (43%) of 210 patients with normal organ function, compared with 8 (73%) of 11 (P =.065) with renal dysfunction, and 19 (50%) of 38 (P =.271) with liver dysfunction. Grade 3-4 hematologic toxicities including anemia (29%, 10%, and 7% of patients with renal dysfunction, liver dysfunction, and normal organ function, respectively), neutropenia (57%, 30%, and 30%), and thrombocytopenia (43%, 30%, and 26%) were more frequent in patients with pre-existing renal dysfunction treated with high-dose imatinib. Grade 3-4 nonhematologic toxicities were observed at similar frequencies. Complete cytogenetic response rates, event-free survival, and overall survival were similar in all groups.
CONCLUSIONS
Although patients with pre-existing liver and/or renal dysfunction might have a higher rate of hematologic toxicity and require more frequent dose reductions, most patients can be adequately managed, resulting in response rates and survival similar to those without pre-existing organ dysfunction.
doi:10.1002/cncr.25071
PMCID: PMC4314210  PMID: 20564631
imatinib; chronic myelogenous leukemia; liver and/or renal dysfunction; dose reduction; survival
7.  Immune Modulation of Minimal Residual Disease in Early Chronic Phase Chronic Myelogenous Leukemia 
Cancer  2010;117(3):572-580.
BACKGROUND
Most patients with chronic myelogenous leukemia (CML) harbor residual disease, as evidenced by molecular techniques even after treatment with high-dose imatinib (ie, 800 mg/d). Interferon alpha (IFN α) is efficacious in CML likely due to its immunomodulatory properties, and is synergistic in vitro with imatinib and granulocyte macrophage-colony stimulating factor (GM-CSF).
METHODS
A study was undertaken to determine whether adding pegylated (PEG) IFN α-2b and GM-CSF to high-dose imatinib may improve the complete molecular response rate in patients with CML in chronic phase. Ninety-four patients were treated with imatinib 800 mg/d for the first 6 months, then randomly assigned to continue high-dose imatinib alone (n = 49) or in combination with PEG IFN α-2b 0.5 µg/kg/wk and GM-CSF 125 mg/m2 3× weekly (n = 45).
RESULTS
The median follow-up for all patients was 54 months (range, 7–70 months). There were no differences in the rates of complete cytogenetic response (87% vs 90%; P = 1.0), or of major (77% vs 77%; P = 1.0) or complete (11% vs 13%; P = 1.0) molecular response (on the international scale) at 12 months between the 2 arms, or at any time during the study. Adverse events led to PEG IFN α-2b discontinuation in all patients.
CONCLUSIONS
The addition of PEG IFN α-2b and GM-CSF to high-dose imatinib therapy does not improve significantly the cytogenetic or molecular response rates compared with high-dose imatinib alone. The high dropout rate in the PEG IFN α-2b arm may have compromised its potential immunomodulatory benefit.
doi:10.1002/cncr.25438
PMCID: PMC4312759  PMID: 20886606
chronic myeloid leukemia; granulocyte-macrophage colony-stimulating factor; imatinib; immune modulation; interferon alpha-2b
8.  Phase II, Open Label, Randomized Comparative Trial of Ondansetron Alone versus the Combination of Ondansetron and Aprepitant for the Prevention of Nausea and Vomiting in Patients with Hematologic Malignancies Receiving Regimens Containing High-Dose Cytarabine 
BioMed Research International  2015;2015:497597.
Background. Aprepitant is a P/neurokinin-1 receptor antagonist approved for the prevention of CINV in moderate emetic risk chemotherapy. We explored its effectiveness in patients with leukemia receiving cytarabine-based chemotherapy. Methods. Patients were randomized to ondansetron (OND) 8 mg IV 30 minutes before cytarabine followed by 24 mg IV continuous infusion daily until 6–12 hours after the last dose of chemotherapy alone or with aprepitant (APREP) oral 125 mg 6–12 hrs before chemotherapy and 80 mg daily until 1 day after the last dose of chemotherapy. Results. Forty-nine patients were enrolled in each arm; 42 in OND and 41 in OND + APREP arm were evaluable for efficacy. The ORR with OND + APREP was 80% compared to 67% with OND alone (P = 0.11). On days 6 and 7, higher proportion of patients treated with OND + APREP were free from nausea (74%, 74% versus 68%, 67%; P = 0.27 and 0.18, resp.). Requirement of rescue medications on days 2 and 3 was fewer in OND + APREP arm 7% and 5% compared to 21% and 16% in the OND arm, respectively (P = 0.06 and P = 0.07). Conclusions. There was a trend for overall improvement in emesis with ondansetron plus aprepitant. The potential benefit of this approach with specific chemotherapy combinations remains to be determined.
doi:10.1155/2015/497597
PMCID: PMC4310492  PMID: 25654108
9.  Outcome of Therapy-Related Acute Promyelocytic Leukemia With or Without Arsenic Trioxide as a Component of Frontline Therapy 
Cancer  2010;117(1):110-115.
BACKGROUND
Patients with therapy-related acute promyelocytic leukemia (t-APL) have been commonly exposed to topoisomerase inhibitors and may potentially benefit from induction regimens omitting anthracyclines.
METHODS
Retrospective analysis of the outcomes of 29 patients with t-APL who were either treated with arsenic trioxide (ATO) and all-trans-retinoic acid (ATRA) or with standard ATRA plus anthracycline-based chemotherapy was performed.
RESULTS
Prior therapy included chemotherapy alone, radiation alone, or a combination of the 2 in 19%, 33%, and 47% of patients, respectively. The combination of ATO and ATRA (n = 19) for induction resulted in a similar remission rate compared with ATRA plus chemotherapy (n = 10) (89% vs 70%; P = .35). The median overall survival for the patients treated with ATRA plus ATO was not reached compared with that for patients treated with ATRA plus chemotherapy (161 weeks; P =.79).
CONCLUSIONS
In this cohort of t-APL patients, outcomes with ATO and ATRA appeared to be comparable to anthracycline-containing induction regimens. This combination may be preferable in t-APL patients to avoid any risk of anthracycline-induced toxicities.
doi:10.1002/cncr.25585
PMCID: PMC4287232  PMID: 20803607
therapy-related acute promyelocytic leukemia; arsenic trioxide; outcome; all-trans-retinoic acid
10.  Post hoc analysis of the relationship between baseline white blood cell count and survival outcome in a randomized Phase III trial of decitabine in older patients with newly diagnosed acute myeloid leukemia 
Background
In a Phase III trial, 485 patients (≥65 years) with newly diagnosed acute myeloid leukemia received decitabine 20 mg/m2 intravenously for 5 days every 4 weeks or a treatment choice (supportive care or cytarabine 20 mg/m2 subcutaneously for 10 days every 4 weeks).
Materials and methods
We summarized overall and progression-free survival by baseline white blood cell count using two analyses: <1, 1–5, >5×109/L; ≤10 or >10×109/L.
Results
There were 446 deaths (treatment choice, n=227; decitabine, n=219). Median overall survival was 5.0 (treatment choice) versus 7.7 months (decitabine; nominal P=0.037). Overall survival differences between white blood cell groups were not significant; hazard ratios (HRs) favored decitabine. Significant progression-free survival differences favored decitabine for groups 1–5×109/L (P=0.005, HR =0.67), greater than 5×109/L (P=0.027, HR =0.71), and up to 10×109/L (P=0.003, HR =0.72).
Conclusion
There was a trend toward improved outcome with decitabine, regardless of baseline white blood cell count.
doi:10.2147/JBM.S64067
PMCID: PMC4295530
decitabine; acute myeloid leukemia; prognosis; leukemia; adult
12.  A retrospective study of venous thromboembolism in acute leukemia patients treated at the University of Texas MD Anderson Cancer Center 
Cancer Medicine  2014;4(1):27-35.
The purpose was to determine the incidence and prevalence of venous thromboembolism (VTE) in acute leukemia patients from our institution. We conducted a retrospective study on newly diagnosed acute leukemia patients who presented at our institution from November 1999 to May 2005. Descriptive statistics and cross-tabulation were used to describe patient characteristics. Measures of morbidity were used to address VTE risk. Chi-square testing, Fisher's exact testing, Mann–Whitney analyses, or median testing were used to determine between-group differences. Data analyses were conducted using Stata version 11 (Stata Corp., College Station, TX). Two hundred and ninety-nine patients with acute lymphoblastic leukemia (ALL) and 996 patients with acute myeloid leukemia (AML) were included. After excluding patients diagnosed with VTE prior to or at the time of leukemia diagnosis, during the mean time follow-up period of 2.5 years (range: 0.0025–10.3 years), the overall incidence rate of VTE was 3.7 per 100 person-years: 4.2 per 100 person-years for ALL and 3.4 per 100 person-years for AML. Among all patients, the majority (80.6%) developed VTE within 12 months after diagnosis and during thrombocytopenia. The most common VTE was central venous catheter (CVC)-associated upper-extremity deep venous thrombosis. Pulmonary embolism occurred in 15% of ALL patients and 8% of AML patients. VTE recurred in 20.7% of ALL patients and 18.6% of AML patients. VTE occurs frequently in patients with acute leukemia. Studies are needed to identify risk factors for the development and recurrence of VTE among patients with acute leukemia and to establish more effective methods for preventing and treating VTEs in leukemia patients who have thrombocytopenia and/or CVC.
doi:10.1002/cam4.332
PMCID: PMC4312115  PMID: 25487644
Acute leukemia; anticoagulation; cancer; thrombosis; venous thromboembolism
13.  Kit inhibitor APcK110 extends survival in an AML xenograft mouse model 
Investigational new drugs  2010;29(5):1094-1097.
Summary
Background
Constitutive activation of kit contributes to pathogenesis of acute myeloid leukemia (AML) and targeting Kit may be of therapeutic benefit. APcK110, a novel inhibitor of Kit, has potent proapoptotic and antiproliferative activity in AML cell lines and primary AML samples. Here we extend our studies to the activity of APcK110 in a xenograft mouse model.
Methods
After sub-lethal whole body radiation, OCI/AML3 cells were injected intravenously in NOD-SCID mice. Ten days later, either APcK110 or phosphate buffered saline (PBS) was injected intraperitoneally every other day. Kaplan-Meier estimates were used to calculate survival.
Results
We show that 1) all mice injected with OCI/AML3 cells developed a clinical and histological picture consistent with myelomonocytic AML; and 2) survival of APcK110-treated mice was significantly longer compared with mice injected with PBS (p=.02).
Conclusions
APcK110 is a novel kit kinase inhibitor with anti-AML activity in vitro and in vivo. Further evaluation in toxicology and clinical studies is warranted.
doi:10.1007/s10637-010-9459-6
PMCID: PMC4251765  PMID: 20517635
APcK110; Acute myeloid leukemia; Kit inhibitor
14.  Similar outcome of patients with chronic myeloid leukemia treated with imatinib on or off clinical trials 
Clinical lymphoma, myeloma & leukemia  2013;13(6):10.1016/j.clml.2013.05.011.
Introduction
Outcomes of CML-CP patients treated in clinical trials are frequently perceived to not be representative of those treated outside of clinical trials.
Materials and Methods
We investigated the outcomes of patients receiving imatinib outside of a clinical trial (off protocol) or on a clinical trial (on protocol) for CML-CP.
Results
We identified 65 patients treated with imatinib off protocol and 71 patients treated on protocol with standard-dose imatinib. The overall complete cytogenetic response (CCyR) rates were 83% and 83% for patients treated on and off protocol, respectively. CCyR rates 12 months after initiation of imatinib were not different (61% vs 66%, respectively; p=.15). Patients treated off protocol had similar rates of overall major molecular response (72% vs 73%) compared to the patients treated on protocol. The 5-year event free survival rates were 84% and 86% for off and on protocol patients, respectively. There was also no significant difference in 5-year transformation free survival (94% vs 96%) and overall survival (96% vs 90%).
Conclusion
These results suggest that patients with CML treated outside of a clinical trial may have the same excellent outcome as those treated on a clinical trial provided they are followed with the same rigor.
doi:10.1016/j.clml.2013.05.011
PMCID: PMC3835390  PMID: 24060289
15.  Significance of Deeper Molecular Responses in Patients with Chronic Myeloid Leukemia in Early Chronic Phase Treated with Tyrosine Kinase Inhibitors 
American journal of hematology  2013;88(12):10.1002/ajh.23560.
Most patients with chronic myeloid leukemia (CML) in chronic phase (CP) treated with tyrosine kinase inhibitors (TKI) achieve complete cytogenetic response (CCyR). An increasing number of patients also achieve deep molecular responses (MR). We determined the frequency and significance of deep MR after TKI therapy for CML in CP. MR included: major molecular response (MMR), MR4, MR4.5, and undetectable transcripts (UND), ie BCR-ABL/ABL of ≤0.1%, ≤0.01%, ≤0.0032%, and undetectable transcripts, respectively. 483 patients received imatinib 400mg/day (IM400, 71, July 2000-April 2001), imatinib 800mg/day (IM800, 204, June 2001-July 2005), nilotinib (NILO, 106, July 2005 to date), or dasatinib (DASA, 102, November 2005 to date). UND rates at 36 months were 18.1%, 30.6%, 29.2%, and 28.6%, respectively. Patients achieving UND have superior transformation-free survival (TFS) and overall survival (OS) versus those obtaining ≤MMR, but not other MR levels. At the 18- and 24-month landmark analysis patients achieving UND have no advantage in TFS and OS compared to those achieving a lesser degree of MR. Among patients achieving MR4.5, those who maintain it for ≥2 years (susMR4·5) have no additional benefit in TFS or OS. Most patients with early CP CML receiving TKI achieve MMR. BCR-ABL transcripts become undetectable in a significant fraction of them. Deeper MR at 18 or 24 months are not associated with a benefit in TFS or OS. Furthermore, achieving susMR4·5 does not appear to further reduce the risk of transformation or death.
doi:10.1002/ajh.23560
PMCID: PMC3849405  PMID: 23913852
chronic myeloid leukemia; tyrosine kinase inhibitors; BCR-ABL; molecular response
16.  Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents 
Leukemia  2013;28(6):1280-1288.
Blockade of immune checkpoints is emerging as new form of anticancer therapy. We studied the expression of PD-L1, PD-L2, PD-1 and CTLA4 mRNA expression in CD34+ cells from MDS, CMML and AML patients (N=124). Aberrant up-regulation (≥2 fold) was observed in 34%, 14%, 15% and 8% of the patients respectively. Increased expression of these 4 genes was also observed in PBMNC (N=61). The relative expression of PD-L1 from PBMNC was significantly higher in MDS (p=0.018) and CMML (p=0.0128) compared to AML. By immunohistochemical (IHC) analysis, PD-L1 protein expression was observed in MDS CD34+ cells, whereas stroma/non-blast cellular compartment was positive for PD-1. In a cohort of patients treated with epigenetic therapy, PD-L1, PD-L2, PD-1 and CTLA4 expression was upregulated. Patients resistant to therapy had relative higher increments in gene expression compared to patients that achieved response. Treatment of leukemia cells with decitabine resulted in a dose dependent up-regulation of above genes. Exposure to decitabine resulted in partial demethylation of PD-1 in leukemia cell lines and human samples. This study suggests PD-1 signaling may be involved in MDS pathogenesis and resistance mechanisms to HMAs. Blockade of this pathway can be a potential therapy in MDS and AML.
doi:10.1038/leu.2013.355
PMCID: PMC4032802  PMID: 24270737
programmed death-1; myelodysplastic syndromes; DNA methylation
18.  Tyrosine kinase inhibition: A therapeutic target for the management of chronic-phase chronic myeloid leukemia 
Expert review of anticancer therapy  2013;13(12):1433-1452.
Chronic myeloid leukemia (CML) is a hematologic neoplasm with a progressive, ultimately terminal, disease course. In most cases, CML arises owing to the aberrant formation of a chimeric gene for a constitutively active tyrosine kinase. Inhibition of the signaling activity of this kinase has proved to be a highly successful treatment target transforming the prognosis of patients with CML. New tyrosine kinase inhibitors (TKIs) continue to improve the management of CML, offering alternative options for those resistant to or intolerant of standard TKIs. Here we review the pathobiology of CML and explore emerging strategies to optimize the management of chronic-phase CML, particularly first-line treatment.
doi:10.1586/14737140.2013.859074
PMCID: PMC4181370  PMID: 24236822
tyrosine kinase inhibition; chronic myeloid leukemia; molecular response; suboptimal response
19.  CXCR4 Expression, CXCR4 Activation, and Wild Type NPM1 Are Independently Associated with Unfavorable Prognosis in Patients with Acute Myeloid Leukemia 
BACKGROUND
CXC chemokine receptor 4 (CXCR4) is activated by phosphorylation and is essential for migration of hematopoietic precursors to bone marrow. CXCR4 overexpression predicts unfavorable prognosis in patients with acute myeloid leukemia (AML). Nucleophosmin (NPM1) mutation is the most frequent genetic abnormality in AML patients and predicts a favorable prognosis. In vitro studies have suggested that mutant NPM decreases CXCR4-mediated chemotaxis by downregulating CXCR4, thereby linking the NPM and CXCR4 pathways.
PATIENTS AND METHODS
In a group of 117 untreated adults with AML we used immunohistochemistry to assess bone marrow specimens for CXCR4 and phosphorylated (p) CXCR4 (pCXCR4) expression. All cases were also analyzed for NPM1 mutations using PCR-based methods.
RESULTS
CXCR4 expression was detected in 75 (64%) and pCXCR4 expression was detected in 31 (26%) patients. NPM1 mutations were detected in 63 (54%) patients. NPM1 mutations did not correlate with CXCR4 (p = 0.212) or pCXCR4 (p = 0.355) expression. The median 5-year overall survival was 27% (95% CI: 19-36%), with a median follow-up of 8 months (95%CI: 6-15). In a multivariate Cox proportional hazards model, reduced overall and progression-free survival rates were associated with a history of antecedent hematological disorder, failure to achieve complete remission, thrombocytopenia, unfavorable cytogenetics, CXCR4 expression, and wild type NPM1. pCXCR4 expression was independently associated with shorter progression-free survival.
CONCLUSION
There is no correlation between NPM1 mutations and CXCR4 or phosphorylated CXCR4 expression suggesting that the CXCR4 and NPM pathways act independently in adult AML.
doi:10.1016/j.clml.2013.05.013
PMCID: PMC4206258  PMID: 24035716
Acute myeloid leukemia; AML; CXCR4; CXCR4 phosphorylation; CXCR4 activation; NPM1; prognosis
20.  Modest Activity of Pomalidomide in Patients with Myelofibrosis and Significant Anemia 
Leukemia research  2013;37(11):1440-1444.
We evaluated single agent pomalidomide for myelofibrosis-associated anemia. First, 21 patients received pomalidomide 3.0mg/day on 21-day-on/7-day-off schedule. Due to poor tolerance the study was quickly suspended. Second, 29 patients received pomalidomide 0.5mg/day continuously. Three patients (10%) experienced clinical improvement in hemoglobin per International-Working-Group criteria (median time to response 1.6 months; median response duration 6.7 months). Ten patients were RBC-transfusion-dependent per Delphi criteria; 2 (20%) achieved RBC-transfusion-independence (time to response 0.9 months in both; response duration of 8.3 and 15 months). One grade 3/4 toxicity (neutropenia) occurred. Pomalidomide at low dose is well tolerated but has modest clinical activity in myelofibrosis.
doi:10.1016/j.leukres.2013.07.007
PMCID: PMC4232180  PMID: 23890523
pomalidomide; myelofibrosis; anemia
21.  A phase 2 study of ruxolitinib, an oral JAK1 and JAK2 inhibitor, in patients with advanced polycythemia vera who are refractory or intolerant to hydroxyurea 
Cancer  2013;120(4):513-520.
BACKGROUND
Polycythemia vera (PV) is a myeloproliferative neoplasm associated with somatic gain-of-function mutations of Janus kinase-2 (JAK2). Therapeutic options are limited in patients with advanced disease. Ruxolitinib, an oral JAK1/JAK2 inhibitor, is active in preclinical models of PV. The long-term efficacy and safety of ruxolitinib in patients with advanced PV who are refractory or intolerant to hydroxyurea were studied in a phase 2 trial.
METHODS
Response was assessed using modified European LeukemiaNet criteria, which included a reduction in hematocrit to < 45% without phlebotomy, resolution of palpable splenomegaly, normalization of white blood cell and platelet counts, and reduction in PV-associated symptoms.
RESULTS
Thirty-four patients received ruxolitinib for a median of 152 weeks (range, 31 weeks-177 weeks) or 35.0 months (range, 7.1 months-40.7 months). Hematocrit < 45% without phlebotomy was achieved in 97% of patients by week 24. Only 1 patient required a phlebotomy after week 4. Among patients with palpable splenomegaly at baseline, 44% and 63%, respectively, achieved nonpalpable spleen measurements at weeks 24 and 144. Clinically meaningful improvements in pruritus, night sweats, and bone pain were observed within 4 weeks of the initiation of therapy and maintained with continued treatment. Ruxolitinib treatment also reduced elevated levels of inflammatory cytokines and granulocyte activation. Thrombocytopenia and anemia were the most common adverse events. Thrombocytopenia of ≥ grade 3 or anemia of ≥ grade 3 (according to National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0) occurred in 3 patients each (9%) (1 patient had both) and were managed with dose modification.
CONCLUSIONS
Ruxolitinib was generally well tolerated and provided rapid and durable clinical benefits in patients with advanced PV who were refractory or intolerant to hydroxyurea. Cancer 2014;120:513–20. © 2013 The Authors published by Wiley Periodicals, Inc. on behalf of American Cancer Society.
In the current study, patients with polycythemia vera who were refractory or intolerant to hydroxyurea achieved clinically meaningful and durable benefit from treatment with ruxolitinib with respect to reductions in hematocrit, platelet and white blood cell counts, splenomegaly, and symptoms. Given the limited therapeutic options for patients with advanced polycythemia vera, these results suggest that ruxolitinib has the potential to address an important unmet medical need in this patient population.
doi:10.1002/cncr.28441
PMCID: PMC4231215  PMID: 24258498
polycythemia vera; myeloproliferative neoplasm; ruxolitinib; Janus kinase (JAK) inhibitor; phase 2
22.  The synthetic heat shock protein 90 (Hsp90) inhibitor EC141 induces degradation of Bcr-Abl p190 protein and apoptosis of Ph-positive acute lymphoblastic leukemia cells 
Investigational new drugs  2010;29(6):1206-1212.
Summary
The prognosis of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) is poor. Chemotherapy is rarely curative and tyrosine kinase inhibitors (TKIs) induce only transient responses. Heat shock protein 90 (Hsp90) is a chaperone protein that is important in signal transduction, cell cycle control, and transcription regulation in both normal and leukemia cells. In the current study, we tested the growth inhibitory and apoptotic effects of a novel Hsp90 inhibitor, EC141 on the Ph+ ALL lines Z-119, Z-181, and Z-33, as well as primary bone marrow-derived blasts from patients with newly diagnosed Ph+ ALL. We found that EC141 inhibited the growth of Ph+ ALL cells in a concentration-dependent manner with IC50 ranged from 1 to 10 nM. EC141 also inhibited the proliferation of primary bone marrow-derived blasts using the ALL blast colony assay. EC141 down-regulated Hsp90 and up-regulated Hsp70 protein levels, inhibited CrkL phosphorylation, and induced degradation of Bcr-Abl p190 protein through ubiquitin-dependent proteasomal pathway. Furthermore, exposure of Ph+ ALL cells to EC141 resulted in activation of caspase-3, cleavage of poly (ADP-ribose) polymerase (PARP), and induction of apoptosis. In conclusion, our data suggest that EC141 is a potent Hsp90 inhibitor with activity against Ph+ ALL. Further studies to investigate the anticancer effect of EC141 either as a single agent, or in combination in Ph+ ALL and other hematological malignancies are warranted.
doi:10.1007/s10637-010-9465-8
PMCID: PMC4230707  PMID: 20533075
Leukemia; Hsp90 inhibitor; EC141; Apoptosis; Ph+ ALL
23.  Kit Inhibitor APcK110 Induces Apoptosis and Inhibits Proliferation of Acute Myeloid Leukemia Cells 
Cancer research  2009;69(9):3910-3917.
Kit is a membrane-bound tyrosine kinase and receptor for stem cell factor (SCF) with a crucial role in hematopoiesis. Mutations of KIT occur in almost half of patients with core-binding factor leukemias where they have been associated with worse outcome. Development of new compounds targeting Kit may therefore hold promise for therapy. We investigated the activity and mechanism of action of APcK110, a novel Kit inhibitor, in the mastocytosis cell line HMC1.2 (KITV560G and KITD816V), AML lines OCIM2 and OCI/AML3 (both wild-type) and primary samples from patients with AML. We demonstrate that: (1) APcK110 inhibits proliferation of the mastocytosis cell line HMC1.2 and the SCF-responsive cell line OCI/AML3 in a dose dependent manner; (2) APcK110 is a more potent inhibitor of OCI/AML3 proliferation than the clinically used Kit inhibitors imatinib and dasatinib and at least as potent as cytarabine; (3) APcK110 inhibits the phosphorylation of Kit, Stat 3, Stat5, and Akt, in a dose-dependent fashion demonstrating activity of APcK110 on Kit and its downstream signaling pathways; (4) APcK110 induces apoptosis by cleavage of caspase 3 and PARP; (5) APcK110 inhibits proliferation of primary AML blasts in a clonogenic assay, but does not affect proliferation of normal colony-forming cells. Although APcK110 activity may partly depend on cytokine responsiveness (e.g. SCF) and not exclusively KIT mutation status, it remains a potent inhibitor of AML and mastocytosis cell lines and primary AML samples. APcK110 and similar compounds should be evaluated in clinical trials of patients with AML.
doi:10.1158/0008-5472.CAN-08-0034
PMCID: PMC4220548  PMID: 19383925
Acute myeloid leukemia; c-Kit; targeted therapy; APcK110
24.  Characteristics of translocation (16;16)(p13;q22) acute myeloid leukemia 
American journal of hematology  2012;87(3):317-318.
A subgroup of patients with core binding factor acute myeloid leuke-mias (AML) is characterized by the presence of the fusion gene CBFb-Myh11. At the cytogenetic level, most of these patients are identified by the presence of an inversion of chromosome 16 [inv(16)(p13q22)] and rarely by a translocation t(16;16)(p13;q22). The aim of this study is to describe the natural history of patients with t(16;16) [N = 6] treated at MD Anderson Cancer Center and compared them with a cohort of patients with inv(16)(p13q22) [n = 5 61]. In patients with t(16;16) the complete remission rate (CR) was 100% when treated with a combination of fludarabine and high-dose cytarabine. Median overall survival (OS) had not been achieved. There was no difference in response or OS or progression free survival between both groups. Presence of additional chromosomal abnormalities and molecular aberrations had no effect on prognosis. In conclusion, and consistent with previous reports, the natural history of patients with t(16:16)(p13;q22) is similar to that of classic patients with inv16 AML and therefore should be treated similarly.
doi:10.1002/ajh.22258
PMCID: PMC4221258  PMID: 22228403
25.  Survival Outcomes for Clonal Evolution in Chronic Myeloid Leukemia Patients on Second Generation Tyrosine Kinase Inhibitor Therapy 
Cancer  2010;116(11):2673-2681.
BACKGROUND
Clonal evolution is frequently detected in patients developing resistance to imatinib. The outcome of patients with clonal evolution treated with second generation tyrosine kinase inhibitors is not known.
METHODS
The authors analyzed the outcome of 177 CML patients after second tyrosine kinase inhibitor therapy.
RESULTS
Ninety-five patients were in chronic phase, 30 had clonal evolution, 28 were in accelerated phase (AP), and 24 were in AP plus clonal evolution. Major cytogenetic response rates were 58%, 54%, 28%, and 13%; 2-year overall survival (OS) rates were 86%, 73%, 68%, and 33%; and 2-year event-free survival (EFS) rates were 69%, 67%, 31%, and 8%, respectively. The hematologic and cytogenetic response rates, OS, and EFS were no different between patients in chronic phase with clonal evolution and patients with chronic phase and no clonal evolution. However, clonal evolution had a significant adverse impact when associated with other features of AP. On multivariate analysis, clonal evolution had no independently significant effect on achieving major cytogenetic response on the second generation tyrosine kinase inhibitors. The factors predicting increasing major cytogenetic response to second generation tyrosine kinase inhibitors were prior achievement of major cytogenetic response with imatinib, higher hemoglobin levels, no splenomegaly, lower percentage of Philadelphia chromosome-positive metaphases, and no prior chemotherapy.
CONCLUSIONS
Clonal evolution constitutes a heterogeneous entity with variable outcome with second generation tyrosine kinase inhibitors, with trisomy 8, chromosome 17, and complex abnormalities having the worst outcome, regardless of the number of metaphases involved. The molecular events behind these abnormalities and potential therapeutic approaches directed at them need to be defined.
doi:10.1002/cncr.25015
PMCID: PMC4216809  PMID: 20499401
clonal expression; clonal evolution; chronic myeloid leukemia; dasatinib; nilotinib

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