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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.  The Pim-1 Protein Kinase Is an Important Regulator of MET Receptor Tyrosine Kinase Levels and Signaling 
Molecular and Cellular Biology  2014;34(13):2517-2532.
MET, the receptor for hepatocyte growth factor (HGF), plays an important role in signaling normal and tumor cell migration and invasion. Here, we describe a previously unrecognized mechanism that promotes MET expression in multiple tumor cell types. The levels of the Pim-1 protein kinase show a positive correlation with the levels of MET protein in human tumor cell lines and patient-derived tumor materials. Using small interfering RNA (siRNA), Pim knockout mice, small-molecule inhibitors, and overexpression of Pim-1, we confirmed this correlation and found that Pim-1 kinase activity regulates HGF-induced tumor cell migration, invasion, and cell scattering. The novel biochemical mechanism for these effects involves the ability of Pim-1 to control the translation of MET by regulating the phosphorylation of eukaryotic initiation factor 4B (eIF4B) on S406. This targeted phosphorylation is required for the binding of eIF4B to the eIF3 translation initiation complex. Importantly, Pim-1 action was validated by the evaluation of patient blood and bone marrow from a phase I clinical trial of a Pim kinase inhibitor, AZD1208. These results suggest that Pim inhibitors may have an important role in the treatment of patients where MET is driving tumor biology.
doi:10.1128/MCB.00147-14
PMCID: PMC4054323  PMID: 24777602
11.  REDUCED INTENSITY HEMATOPOIETIC CELL TRANSPLANTATION FOR PATIENTS WITH PRIMARY MYELOFIBROSIS: A COHORT ANALYSIS FROM THE CENTER FOR INTERNATIONAL BLOOD AND MARROW TRANSPLANT RESEARCH 
We evaluated the outcomes and associated prognostic factors in 233 patients undergoing allogeneic hematopoietic cell transplantation (HCT) for primary myelofibrosis (MF) using reduced intensity conditioning (RIC). Median age at HCT was 55 years. Donors were: matched sibling donor (MSD), 34%; HLA-well-matched unrelated donors (URD), 45%; and partially/mismatched URD, 21%. Risk stratification according to Dynamic International Prognostic Scoring System (DIPSS): low, 12%; intermediate-1, 49%; intermediate-2, 37%; and high, 1%. The probability of survival at 5-years was 47% (95% CI 40–53). In a multivariate analysis, donor type was the only independent factor associated with survival. Adjusted probabilities of survival at 5-years for MSD, well matched URD and partially matched/mismatched URD were 56% (95% CI 44–67), 48% (95% CI 37–58), and 34% (95% CI 21–47), respectively (p=0.002). Relative risks (RR) for NRM for well-matched URD and partially matched/mismatched URD were 3.92 (p=0.006) and 9.37 (p<0.0001), respectively. A trend towards increased NRM (RR 1.7, p=0.07) and inferior survival (RR 1.37, p=0.10) was observed in DIPSS-intermediate-2/high-risk patients compared to DIPSS-low/intermediate-1 risk patients.
RIC HCT is a potentially curative option for patients with MF, and donor type is the most important factor influencing survival in these patients.
doi:10.1016/j.bbmt.2013.10.018
PMCID: PMC3886623  PMID: 24161923
Myelofibrosis; allogeneic transplantation; reduced intensity; prognosis
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.  DETECTION OF DORMANT CHRONIC MYELOID LEUKEMIA CLONES IN THE BONE MARROW OF PATIENTS IN COMPLETE MOLECULAR REMISSION 
In an attempt to detect minimal residual disease (MRD) in patients with chronic myeloid leukemia (CML) in complete molecular remission (CMR) on tyrosine kinase inhibitor (TKI) therapy, we performed clonogenic assays on mononuclear bone marrow cells from 14 patients. Of the 10 assessable samples, 6 were from patients in CMR and 4 from patients in complete cytogenetic remission (CCyR) but detectable MRD by PCR (positive controls). At least 10 colonies per sample were microaspirated and individual colonies were subjected to PCR analysis. Of the 6 patients in CMR, 5 harbored BCR-ABL1 negative colonies but in 1 sample 1 of the 10 colonies analyzed was positive for BCR-ABL1. Of the 4 patients with evidence of MRD in peripheral blood, 2 had negative and 2 had positive BCR-ABL1 colonies. In conclusion, MRD is still detectable by clonogenic assays in some patients with CML after achieving CMR on TKI therapy, which is likely responsible for relapse upon TKI discontinuation. Because of the large number of single colonies that need to be analyzed, the use of clonogenic assays in clinical practice to determine the feasibility of TKI discontinuation is not recommended.
doi:10.1016/j.clml.2013.07.010
PMCID: PMC4162086  PMID: 24060288
Chronic myeloid leukemia; BCR-ABL1; tyrosine kinase inhibitor; clonogenic assay; minimal residual disease
19.  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
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.  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
22.  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
23.  Phase II Study of Rabbit Anti-Thymocyte Globulin, Cyclosporine, and Granulocyte Colony Stimulating Factor in Patients with Aplastic Anemia and Myelodysplastic Syndrome 
Leukemia  2009;23(7):1297-1302.
Background
Severe aplastic anemia (AA) is treated with equine anti-thymocyte globulin (hATG) and cyclosporine with response rates up to 65%. Rabbit anti-thymocyte globulin (rATG, Thymoglobulin®) has been used successfully in relapsed and refractory patients. Immunosuppressive therapy is also effective in some subsets of patients with Myelodysplastic syndrome (MDS).
Methods
In this single-arm, phase II study, we investigated the efficacy (primary endpoint) and safety (secondary endpoint) of combined rATG, cyclosporine and G-CSF as first-line therapy for patients with AA and low/intermediate-1 or hypoplastic MDS. Thymoglobulin 3.5 mg/kg (or 2.5 mg/kg/day for patients with MDS and ≥55 years) was given for 5 days. Methylprednisolone (1 mg/kg/day) was given for 5 days followed by a tapering dose of oral prednisone. Cyclosporine (5 mg/kg), and GCSF (5 μg/kg) were given daily and continued for up to 6 months or longer at the discretion of the treating physician. All patients received prophylactic broadspectrum antimicrobials. Responses were assessed about 3 and 6 months after initiating therapy.
Results
Thirty-six patients have been enrolled on study with 3 patients choosing alternative therapies and 1 patient dying before initiation of therapy. Among the 32 patients treated, 25 were evaluable for a response (13 with AA, 12 with MDS); the rest are too early in the treatment course. The median age was 62 years (20-83) for patients with AA and 63 (42-80) for patients with MDS. Twelve of 13 (92%) patients with AA responded (5 CR, 7 PR), while four of 12 (33%) patients with MDS responded (1 CR, 3 PR). For patients with AA, the median time to response (TTR) was 93 days (79-623), while in the MDS group the median TTR was 111 days (77-139). Grade 3/4 toxicities were mainly cytopenias and neutropenic fever.
Conclusion
The combination of rabbit thymoglobulin (rATG), cyclosporine and G-CSF is safe and effective as first-line treatment of AA and has significant activity in low-risk MDS.
doi:10.1038/leu.2009.28
PMCID: PMC4217203  PMID: 19242494
Rabbit ATG; Cyclosporine; aplastic anemia; MDS
24.  Adult Acute Erythroleukemia: An Analysis of 108 patients treated at a single institution 
Leukemia  2009;23(12):2275-2280.
Acute erythroleukemia (AML-M6) is an uncommon subtype of acute myeloid leukemia (AML); it is considered to have a poor prognosis. From January 1st, 1980 to May 21st, 2008, 108 patients with newly diagnosed AML-M6 were seen at the University of Texas – M.D. Anderson Cancer Center (UT-MDACC). Half (50%) had a history of myelodysplatic syndrome (MDS), compared to 41% in our control group (patients with other AML subtypes) (p=0.05). Poor risk cytogenetics was more common in patients with AML-M6 (69% versus 46%, p<0.001). Complete remission rates were 63% for patients with AML-M6, comparing to 58% for the control group (p = 0.285). Median disease free survival (DFS) for patients with AML-M6 was 31 weeks, versus 49 weeks for the control group (p = 0.004). Median overall survival (OS) of patients with AML-M6 was 33 weeks, compared to 42 weeks for the control group (p = 0.13). On multivariate analysis for DFS and OS, AML-M6 was not an independent risk factor. Acute erythroleukemia is commonly associated with a previous diagnosis of MDS and poor risk karyotype. The diagnosis of AML-M6 does not impart by itself a worse prognosis, and treatment decisions on this disease should be guided by well know AML prognostic factors.
doi:10.1038/leu.2009.181
PMCID: PMC4217206  PMID: 19741728
Acute erythroleukemia; adults; clinical features; prognosis
25.  Patients with Polycythemia Vera and Essential Thrombocythemia with Prior Malignancy Do Not Have Significantly Worse Outcome 
Leukemia research  2013;37(11):10.1016/j.leukres.2013.08.002.
The clinical relevance of prior malignancy (PM) in patients with essential thrombocythemia (ET) and polycythemia vera (PV) is largely unknown. We retrospectively evaluated 437 patients (ET, n=263; PV, n=174) treated at MD Anderson between 1960 and 2010. Forty-four patients had PM (ET, 10%; PV, 11%), with median time to diagnosis of 66 months. PM was not associated with abnormal cytogenetics, JAK2-mutation frequency, blood-cell counts or progression to acute leukemia or myelofibrosis. In multivariate analysis, only older age and high LDH levels were associated with worse OS. In conclusion, PM does not predict worse outcomes for patients with ET and PV.
doi:10.1016/j.leukres.2013.08.002
PMCID: PMC3818458  PMID: 23993426
myeloproliferative disorders; polycythemia vera; essential thrombocythemia; prior malignancy; transformation to acute leukemia; transformation to myelofibrosis

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