Treatment with dasatinib or nilotinib in chronic myeloid leukemia patients who failed to respond to two previously administered tyrosine kinase inhibitors – a single center experience

OBJECTIVE:

To evaluate hematological, cytogenetic and molecular responses as well as the overall, progression-free and event-free survivals of chronic myeloid leukemia patients treated with a third tyrosine kinase inhibitor after failing to respond to imatinib and nilotinib/dasatinib.

METHODS:

Bone marrow karyotyping and real-time quantitative polymerase chain reaction were performed at baseline and at 3, 6, 12 and 18 months after the initiation of treatment with a third tyrosine kinase inhibitor. Hematologic, cytogenetic and molecular responses were defined according to the European LeukemiaNet recommendations. BCR-ABL1 mutations were analyzed by Sanger sequencing.

RESULTS:

We evaluated 25 chronic myeloid leukemia patients who had been previously treated with imatinib and a second tyrosine kinase inhibitor. Nine patients were switched to dasatinib, and 16 patients were switched to nilotinib as a third-line therapy. Of the chronic phase patients (n=18), 89% achieved a complete hematologic response, 13% achieved a complete cytogenetic response and 24% achieved a major molecular response. The following BCR-ABL1 mutations were detected in 6/14 (43%) chronic phase patients: E255V, Y253H, M244V, F317L (2) and F359V. M351T mutation was found in one patient in the accelerated phase of the disease. The five-year overall, progression-free and event-free survivals were 86, 54 and 22% (p<0.0001), respectively, for chronic phase patients and 66%, 66% and 0% (p<0.0001), respectively, for accelerated phase patients. All blast crisis patients died within 6 months of treatment. Fifty-six percent of the chronic phase patients lost their hematologic response within a median of 23 months.

CONCLUSIONS:

Although the responses achieved by the third tyrosine kinase inhibitor were not sustainable, a third tyrosine kinase inhibitor may be an option for improving patient status until a donor becomes available for transplant. Because the long-term outcome for these patients is poor, the development of new therapies for resistant chronic myeloid leukemia patients is necessary.     

Characterization of the CDR3 structure of the Vβ21 T cell clone in patients with P210(BCR-ABL)-positive chronic myeloid leukemia and B-cell acute lymphoblastic leukemia

The clonally expanded T cells identified in most cancer patients that respond to tumor-associated antigen such as P210(BCR-ABL) protein have definite, specific antitumor cytotoxicity. T cell receptor (TCR) Vβ CDR3 repertoire diversity was analyzed in patients with chronic myeloid leukemia (CML) and BCR-ABL(+) B-cell acute lymphoblastic leukemia (B-ALL) by GeneScan. A high frequency of oligoclonal expansion of the TCR Vβ21 subfamily was observed in the peripheral blood of CML and B-ALL patients. These clonally expanded Vβ21 T cells were correlated with the pathophysiologic process of CML. A conserved amino acid motif (SLxxV) was observed within the CDR3 region in only 3 patients with CML. Preferential usage of the Jβ segments was also observed in a minority of patients. The 3-dimensional structures of the CDR3 region containing the same motif or using the same Jβ segment displayed low similarity; on the contrary, the conformation of the CDR3 region containing no conserved motif in some T cell clones was highly similar. In conclusion, our findings indicate a high frequency of TCR Vβ21 subfamily expansion in p210(BCR-ABL)-positive CML and B-ALL patients. The characterization of the CDR3 structure was complex. Regrettably, at this time it was not possible to confirm that the Vβ21 T cell clones were derived from the stimulation of p210(BCR-ABL) protein.     

Characterization of drug resistance mutations in naïve and ART-treated patients infected with HIV-1 in Yaounde, Cameroon

Currently the prevalence of HIV‐1 infection in Cameroon is 5.1%, CRF02_AG subtype is responsible for about 50% of infections. Since an HIV‐1 drug resistance test is not yet available widely, accurate data on the prevalence of resistant viral strains are missing. The objective of this study was to determine HIV‐1 genetic diversity and to characterize HIV‐1 mutations conferring drug resistance among antiretroviral therapy (ART)‐naïve and ART‐treated patients. A cohort of 239 patients infected with HIV were followed‐up between January 2007 and July 2010 in Cameroon. Two hundred and sixteen plasma samples were sequenced for phylogenetic analysis and identification of drug resistance mutations in the HIV‐1 pol region. A significant genetic diversity was found: Seven pure subtypes (A1, A3, D, F1, F2, G, H), nine circulating recombinant forms (CRFs: 01_AE, 02_AG, 06cpx, 09cpx, 11cpx, 13cpx, 16cpx, 18cpx, 37cpx) and one new unique recombinant form (URF) (G/F2). The rate of transmitted drug resistance (TDR) in naïve patients was 8.2% (4/49). Around 80% of patients failing a first‐line ART harbored a virus with at least one resistance mutation to two antiretroviral (ARV) classes, and 36% of those failing a second‐line regimen carried a virus with at least one resistant mutation to three ARV classes. The high level of drug resistance observed in the cohort is alarming because this occurred as a result of only few years of treatment. Adherence to therapy, adequate education of physicians, and the appropriate use of genotypic resistance assay are critical points of intervention for the improvement of patient care. J. Med. Virol. 84:721–727, 2012. © 2012 Wiley Periodicals, Inc.     

Prevalence of HIV-1 integrase mutations related to resistance to dolutegravir in raltegravir naïve and pretreated patients

The prevalence of HIV-1 integrase mutations related to resistance to the next-generation integrase inhibitor (INI), dolutegravir (DTG), was assessed in 440 INI-naïve subjects and in 120 patients failing a raltegravir (RTG)-containing regimen. Of the mutations selected by DTG in vitro, S153FY was not detected in any isolate while L101I and T124A were highly prevalent in both groups and significantly associated with non-B subtype. RTG-selected double and triple mutants, mostly the G140S/Q148H variant, were detected in only 32 (26.7%) RTG-treated patients. As L101I and T124A do not appear to exert any major effect in vivo and double and triple mutants resistant to DTG are infrequently selected by RTG, DTG can be effectively used in INI-naïve patients and may retain activity in many patients failing RTG.     

Is Wilms’ tumor gene 1 a useful biomarker for detecting minimal residual disease in chronic myeloid leukemia (BCR-ABL1-p210-positive) patients?

Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disorder characterized by the presence of Philadelphia (Ph) chromosome. Wilms’ tumor gene 1 (WT1) plays an important role in leukemogenesis and can be useful as a molecular marker to detect minimal residual disease (MRD). The goal of this study was to evaluate WT1 expression and compare it with BCR-ABL1 expression in peripheral blood (PB) of CML patients, in order to explore the utility of WT1 as an alternative marker for MRD detection. Eighteen newly diagnosed CML patients (BCR-ABL1-p210-positive), 16 chronic CML patients with a history of imatinib therapy, and 18 normal individuals (BCR-ABL1-p210-negative) as controls were enrolled in this study. WT1 and BCR-ABL1 expression was evaluated by quantitative real-time polymerase chain reaction (Q-RT-PCR). Analysis of RT-PCR data was performed using REST Software (2009, QIAGEN, Valencia, USA). Data were analyzed by SPSS software (v.16.0) using Spearman’s rho and Kruskal-Wallis methods. WT1 expression in all PB samples of newly diagnosed CML patients was significantly higher than that of the normal individuals (P?=?0.003). WT1 expression was not different in patients on imatinib therapy compared to normal individuals (P?=?0.6), but it was significantly lower than that of the newly diagnosed CML patients (P?=?0.001). There was no significant correlation between expression of WT1 and BCR-ABL1 and hematological findings in newly diagnosed CML patients. We confirm the oncogenic role of WT1 by WT1 upregulation in CML. Due to lack of significant correlation between BCR-ABL1 and WT1 expression, using WT1 as an additional marker for CML monitoring could not be applicable.     

Prevalence and correlates of overweight in drug-naïve patients with bipolar disorder

BACKGROUND: Patients with bipolar disorder may be at greater risk for overweight and obesity than individuals in the general population. This risk may be due to the illness itself, to mediating factors (diet, life style) and/or to medications used to treat the disorder. This investigation explores the association between body weight and bipolar illness in drug-na?ve patients. METHODS: Weight and height were retrospectively obtained from 76 clinical charts of drug-na?ve patients with bipolar disorder (DSM-IV-TR). A reference group for comparison was then selected from another psychiatric population (65 patients with obsessive-compulsive disorder) and investigated with the same methodology to estimate their BMI. A second focus was to examine the differences in baseline demographic and clinical characteristics between overweight and non-overweight bipolar patients. RESULTS: A total of 40.8% of the patients with bipolar disorder met criteria for obesity or overweight with significant difference in comparison with obsessive-compulsive patients (10.8%). The highest proportions of depression at index episode were in the overweight group (83.3%) with significant difference with the non-overweight patients (58.1%). LIMITATIONS: Retrospective study. Weight measurement not in euthymic period. CONCLUSIONS: Overweight is significantly more prevalent in drug-na?ve patients with bipolar disorder than in another drug-na?ve psychiatric patients (OCD). In agreement with previous studies, the number of patients experiencing a depressive episode was significantly higher in the overweight than in the non-overweight group. These results suggest that the prevalence of overweight in bipolar patients is also influenced by the illness itself or mediating factors such as diet and life style than by pharmacologic treatment.     

Hemochromatosis gene mutations in chronic hepatitis “C” patients

Hepatitis C virus (HCV) infection is a significant global health problem. Elevated hepatic iron concentration has often been found in patients with chronic hepatitis C, and this excess iron increases oxidative stress, which can accelerate the progression of fibrosis and may promote hepatic carcinogenesis. The current study aimed to determine the prevalence of C282Y (exchange of cysteine to tyrosine at amino acid 282) and H63D (exchange of histidine to aspartic acid at amino acid 63) in hereditary hemochromatosis gene (HFE) mutations among chronic HCV patients and to find whether elevation of serum iron indices is related to HFE gene mutations in patients with chronic hepatitis C. The study population was 80 chronic HCV patients divided into two groups: group I included 40 patients with serum iron overload, and group II included 40 patients without iron overload. HFE gene mutation was studied by PCR-restriction fragment length polymorphism (RFLP). The C282Y mutation was not found in any of the 80 patients, while the H63D mutation was present in 18.7 % of the entire study sample. Comparing the two studied groups, H63D mutation was found in 20 % of the iron overload group and 17.5 % of the non-iron overload group. Statistically, there was no significant difference between the two study groups. Regarding iron studies, results of the current study revealed no significant difference between chronic HCV patients with iron overload and those with normal iron profile regarding any of the HFE mutations. In conclusion, the current work emphasizes that the C282Y mutation is absent in our community, while H63D mutation presence does not differ greatly from other Caucasian races especially in Europe. The current study did not detect any effect of HFE mutation on increasing serum iron overload.     

Severe depression following á-interferon usage in a patient with chronic myeloid leukemia

Background

Chronic myeloid leukaemia (CML), with a median age of 40 years, is one of the commonest haematological malignancies in Nigeria. Cytoreductive agents, which were hitherto the mainstay of treatment, neither induce cytogenetic nor haematologic remission. Alphainterferon (á-IFN), an endogenous glycoprotein with cytotoxic and natural killer cell enhancer effects has been found to induce haematologic and cytogenetic remission in patients with CML, but neuro-psychiatric complications of á -interferon (á-IFN) usage were not reported in Nigeria.

Objective

To report a case of deliberate self-harm in University Lecturer as a side effect of á-IFN in the treatment of CML

Method

Clinical and laboratory follow up of a patient receiving á-IFN in the management of CML from the time of diagnosis of CML to the point of loss of contact.

Result

Severe depression is a complication that may adversely influence the clinical outcome of á-IFN usage

Conclusions/Recommendations

Although interferon related depression is uncommon, it is suggested that pre-therapy interferon assays and neuro-psychiatric assessment are carried out in prospective users of á-IFNKey words: Chronic myeloid leukaemia, interferon-á, depression     

Pre-existing YMDD mutants in treatment-naïve patients with chronic hepatitis B are not selected during lamivudine therapy

Although the rate at which mutations in the tyrosine‐methionine‐aspartate‐aspartate (YMDD) motif of hepatitis B virus polymerase form is high during prolonged lamivudine (LAM) therapy, these mutations sometimes occur naturally in treatment‐naïve patients with chronic hepatitis B. The prevalence of natural YMDD mutants differs geographically, and its clinical significance during LAM therapy is unknown. This study aimed to investigate whether pre‐existing YMDD mutants were selected during LAM therapy. It included 14 treatment‐naïve patients who were treated with LAM for at least 9 months. LAM resistance was evaluated before and at 3‐month intervals during treatment. Mutations were analyzed by direct sequencing, restriction fragment mass polymorphism (RFMP) assays, and a single‐step multiplex polymerase chain reaction (PCR) test using dual‐priming oligonucleotide (DPO) primers. DPO‐based multiplex PCR showed two YMDD mutations in two patients before LAM therapy; rtM204V and rtL180M + rtM204V/I. Further, two patients had an rtL180M mutation without an accompanying rtM204V/I mutation. No mutant was detected in any patient by direct sequencing or the RFMP assay before LAM therapy. A virological response was observed at 3 months in all patients with pre‐existing YMDD mutants. All mutations disappeared after 3 months of LAM therapy, and during the follow‐up period, no re‐emergence was detected by any of the three methods. Further, the viral load was suppressed optimally. In conclusion, pre‐existing YMDD mutants were cleared early during the course of LAM therapy, which produced a consistent virological response, and the mutants were not selected by LAM therapy. J. Med. Virol. 84:217–222, 2012. © 2011 Wiley Periodicals, Inc.     

Relationships between hippocampal shape and cognitive performances in drug-naïve patients with Alzheimer's disease

Previous studies provided hippocampal shape analysis of Alzheimer's disease (AD) patients using automated segmentation techniques. However, the relationships between the hippocampal deformations and various cognitive impairments were not clear. The aim of this study was to investigate hippocampal shape changes and their relationship to cognitive impairments.     

Antiretroviral treatment strategies and immune reconstitution in treatment-naïve HIV-infected patients with advanced disease

Treatment-na?ve advanced HIV-infected patients have a lower life expectancy than those treated early with highly active antiretroviral therapy (HAART). Early treatment allows greater immunological recovery, a reduction of AIDS progression, a reduced risk of related illnesses, and lower mortality compared with HAART initiation in advanced disease. Given the numbers with advanced disease worldwide and the high cost of care, strategies encouraging early detection may be life saving and cost effective. Factors associated with increased clinical progression include higher baseline HIV viral load and older age, emphasizing the need for early viral load suppression. HAART initiation faces many challenges; interactions between antiretroviral agents and drugs used to treat life-threatening opportunistic infections may cause subtherapeutic antiretroviral exposure and the development of resistance or supratherapeutic levels resulting in adverse effects. Immune reconstitution inflammatory syndrome can be another cause of suboptimal outcomes. The management of patients with advanced HIV infection should include rapid short-term immune reconstitution to limit the risk of disease progression plus aggressive antiviral treatment to achieve rapid virological suppression. Clear evidence on the optimal regimen and agents to use to target advanced HIV disease is lacking. Therefore, antiretroviral treatment for these patients has to be carefully tailored to the individual according to many variables.     

Comparative effectiveness of tenofovir in treatment-naïve HIV-infected patients: systematic review and meta-analysis

Introduction:

Benefits and harms of tenofovir disoproxil fumarate (TDF) in HIV-infected, antiretroviral treatment (ART)-naïve patients of any age have not been systematically reviewed since recent milestone trials were published.

Methods:

We searched MEDLINE, EMBASE, CENTRAL, SCI, LILACS, WHO GHL, and ClinicalTrials.gov for randomized controlled trials (RCTs) comparing TDF-based treatments with any other ART-regimen (last search 01/2015). Trial characteristics and results were extracted, risks of bias systematically assessed, and treatment effects synthesized in meta-analyses using random-effects models.

Results:

We included 22 RCTs (8297 patients). We found no differences between groups for mortality, AIDS, fractures, CD4 cell count, and virological failure; and inconclusive information due to inadequate reporting for cardiovascular events, renal failure, proteinuria, rash, and quality of life. Tenofovir disoproxil fumarate-based regimens significantly reduced total cholesterol (mean difference ??18.42?mg/dl; 95% confidence interval [CI] ??22.80 to ??14.0), LDL-cholesterol (???9.53?mg/dl; ??12.16 to ??6.89), HDL-cholesterol (???2.97?mg/dl; ??4.41 to ??1.53), and triglycerides (???29.77?mg/dl; ??38.61 to ??20.92), bone mineral density (BMD) (hip: ??1.41%; ??1.87 to ??0.94), and glomerular filtration rate (eGFR) (???3.47?ml/minute; ??5.89 to ??1.06) over 48?weeks of follow-up. Effects were similar in trials comparing fixed-dose TDF/FTC-based regimens with ABC/3TC-based regimens. We found no influence of baseline viral load on virological failure.

Discussion:

Moderate-quality evidence suggests similar effects of TDF-based treatment regimens and other ART on virological failure. Tenofovir disoproxil fumarate-based regimens are associated with a more favorable lipid profile, but with increased risk of reduced BMD and eGFR. Improved reporting quality is vital to allow assessment of clinical outcomes in future trials.