Evaluation of Serum Posaconazole Concentrations in Patients with Hematological Malignancies Receiving Posaconazole Suspension Compared to the Delayed-Release Tablet Formulation

Posaconazole (PCZ) is frequently used for prophylaxis against invasive fungal infections (IFI) in patients undergoing induction chemotherapy for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Posaconazole is commercially available as an oral suspension (PCZ-susp) and as a delayed-release tablet (PCZ-tab). Differences in absorption and bioavailability between these formulations may result in variability in serum posaconazole concentrations. The primary objective of this retrospective analysis was to compare attainment of goal serum posaconazole steady state concentrations (Css) ≥ 700 ng/ml in patients with AML/MDS undergoing induction chemotherapy receiving PCZ-susp 600–800 mg per day (N=118) versus PCZ-Tablet 300 mg twice daily for one day, followed by 300 mg daily (N=64). Sixty-two patients (97%) in the PCZ-tab group compared to 20 patients (17%) in the PCZ-susp group achieved goal Css (P<0.0001). Median posaconazole serum Css was 1,665 ng/ml (522–3,830 mg/ml) in the PCZ-tab group versus 390 ng/ml (51–1,870 ng/ml) in the PCZ-susp group (P<0.0001). There was no difference in hepatotoxicity, QTc prolongation, or breakthrough IFI. Patients receiving PCZ-tab were significantly more likely to achieve goal Css and demonstrated higher Css versus patients receiving PCZ-susp. Prospective studies are needed to assess the potential correlation of serum concentrations with efficacy and toxicity.

Human T-Cell Lymphotropic Virus Types 1 and 2 Seropositivity among Blood Donors at Mbarara Regional Blood Bank, South Western Uganda

Background. The human T-cell lymphotropic virus types 1 and 2 (HTLV 1/2) are retroviruses associated with different pathologies. HTLV-1 causes adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP); HTLV-2 is not clearly associated with a known clinical disease. Both viruses may be transmitted by whole blood transfusion, from mother to child predominantly through breastfeeding, and by sexual contact. Presently, none of the regional blood banks in Uganda perform routine pretransfusion screening for HTLV. The aim of this study was to determine the prevalence of anti-human T-cell lymphotropic virus types 1/2 (HTLV-1/2) antibodies among blood donors at Mbarara Regional Blood Bank in South Western Uganda. A cross-sectional study was conducted between June 2014 and September 2014. Methodology. Consecutive blood samples of 368 blood donors were screened for anti-HTLV-1/2 antibodies using an enzyme linked immunosorbent assay (ELISA). Samples reactive on a first HTLV-1/2 ELISA were further retested in duplicate using the same ELISA. Of the three hundred and sixty-eight blood donors (229 (62.2%) males and 139 (37.8%) females), only two male donors aged 20 and 21 years were HTLV-1/2 seropositive, representing a prevalence of 0.54%. Conclusion. HTLV-1/2 prevalence is low among blood donors at Mbarara Regional Blood Bank. Studies among other categories of people at risk for HTLV 1/2 infection should be carried out.

Effectiveness and Cost-Effectiveness of Sequential Treatment of Patients with Chronic Myeloid Leukemia in the United States: A Decision Analysis

Currently several tyrosine kinase inhibitors (TKIs) are approved for treatment of chronic myeloid leukemia (CML). Our goal was to identify the optimal sequential treatment strategy in terms of effectiveness and cost-effectiveness for CML patients within the US health care context. We evaluated 18 treatment strategies regarding survival, quality-adjusted survival, and costs. For model parameters, the literature data, expert surveys, registry data, and economic databases were used. Evaluated strategies included imatinib, dasatinib, nilotinib, bosutinib, ponatinib, stem-cell transplantation (SCT), and chemotherapy. We developed a Markov state-transition model, which was analyzed as a cohort simulation over a lifelong time horizon with a third-party payer perspective and discount rate of 3%. Remaining life expectancies ranged from 5.4 years (3.9 quality-adjusted life years (QALYs)) for chemotherapy treatment without TKI to 14.4 years (11.1 QALYs) for nilotinib→dasatinib→chemotherapy/SCT. In the economic evaluation, imatinib→chemotherapy/SCT resulted in an incremental cost-utility ratio (ICUR) of $171,700/QALY compared to chemotherapy without TKI. Imatinib→nilotinib→chemotherapy/SCT yielded an ICUR of $253,500/QALY compared to imatinib→chemotherapy/SCT. Nilotinib→dasatinib→chemotherapy/SCT yielded an ICUR of $445,100/QALY compared to imatinib→nilotinib→chemotherapy/SCT. All remaining strategies were excluded due to dominance of the clinically superior strategies. Based on our analysis and current treatment guidelines, imatinib→nilotinib→chemotherapy/SCT and nilotinib→dasatinib→chemotherapy/SCT can be considered cost-effective for patients with CML, depending on willingness-to-pay.

Hsp90 Inhibitors for the Treatment of Chronic Myeloid Leukemia

Chronic myeloid leukemia (CML) is a hematological malignancy that arises due to reciprocal translocation of 3′ sequences from c-Abelson (ABL) protooncogene of chromosome 9 with 5′ sequence of truncated break point cluster region (BCR) on chromosome 22. BCR-ABL is a functional oncoprotein p210 that exhibits constitutively activated tyrosine kinase causing genomic alteration of hematopoietic stem cells. BCR-ABL specific tyrosine kinase inhibitors (TKIs) successfully block CML progression. However, drug resistance owing to BCR-ABL mutations and overexpression is still an issue. Heat-shock proteins (Hsps) function as molecular chaperones facilitating proper folding of nascent polypeptides. Their increased expression under stressful conditions protects cells by stabilizing unfolded or misfolded peptides. Hsp90 is the major mammalian protein and is required by BCR-ABL for stabilization and maturation. Hsp90 inhibitors destabilize the binding of BCR-ABL protein thus leading to the formation of heteroprotein complex that is eventually degraded by the ubiquitin-proteasome pathway. Results of many novel Hsp90 inhibitors that have entered into various clinical trials are encouraging. The present review targets the current development in the CML treatment by availing Hsp90 specific inhibitors.

Isochromosome 17q in Chronic Lymphocytic Leukemia

In chronic lymphocytic leukemia (CLL), presence of acquired cytogenetic abnormalities may help to estimate prognosis. However, deletion of TP53 gene, which is associated with an aggressive course of the disease and poor prognosis along with a lack of response to treatment, is one of the alterations which may escape cytogenetic diagnoses in CLL. Thus, other techniques have emerged such as interphase fluorescence in situ hybridization (iFISH). Deletion of TP53 may but must not go together with the formation of an isochromosome i(17q); surprisingly this subgroup of patients was not in the focus of CLL studies yet. This study was about if presence of i(17q) could be indicative for a new subgroup in CLL with more adverse prognosis. As a result, TP53 deletion was detected in 18 out of 150 (12%) here studied CLL cases. Six of those cases (~33%) had the TP53 deletion accompanied by an i(17q). Interestingly, the cases with i(17q) showed a tendency towards more associated chromosomal aberrations. These findings may be the bases for follow-up studies in CLL patients with TP53 deletion with and without i(17q); it may be suggested that the i(17q) presents an even more adverse prognostic marker than TP53 deletion alone.

Metformin Induces Cell Cycle Arrest and Apoptosis in Drug-Resistant Leukemia Cells

Recent epidemiological studies indicate that the antidiabetic drug metformin has chemosensitizing and chemopreventive effects against carcinogenesis. Here, we demonstrate that metformin exerts varying degrees of antitumor activity against human leukemia cells, as reflected by differences in growth inhibition, apoptosis, and alterations to metabolic enzymes. In metformin-sensitive cells, autophagy was not induced but rather it blocked proliferation by means of arresting cells in the S and G2/M phases which was associated with the downregulation of cyclin A, cyclin B1, and cdc2, but not that of cyclin E. In 10E1-CEM cells that overexpress Bcl-2 and are drug-resistant, the effect of metformin on proliferation was more pronounced, also inducing the activation of the caspases 3/7 and hence apoptosis. In all sensitive cells, metformin decreased the Δψm and it modified the expression of enzymes involved in energy metabolism: PKCε (PKCepsilon) and PKCδ (PKCdelta). In sensitive cells, metformin altered PKCε and PKCδ expression leading to a predominance of PKCε over PKCδ which implies a more glycolytic state. The opposite occurs in the nonresponsive cells. In conclusion, we provide new insights into the activity of metformin as an antitumoral agent in leukemia cells that could be related to its capability to modulate energy metabolism.

Characteristics of Adult T-Cell Leukemia/Lymphoma Patients with Long Survival: Prognostic Significance of Skin Lesions and Possible Beneficial Role of Valproic Acid

We describe the clinical and biological features of ten patients with a survival superior to ten years (long survival), out of 175 patients diagnosed with Adult T-cell Leukemia/Lymphoma (ATL) in Martinique (1983–2013). There were 5 lymphoma and 5 chronic subtypes. Five of them (3 chronic, 2 lymphoma) had been treated with valproic acid (VA) for neurological disorders developed before or after ATL diagnosis, suggesting a beneficial role for VA as a histone deacetylase inhibitor (HDI) in ATL treatment. Total duration of uninterrupted VA treatment ranged from 8 to 37 years. Overall, the 175 incident ATL cases presented with a median survival of 5.43 months. The five VA-treated (VA+) patients presented with longer survival compared to VA treatment-free patients (VA−). For chronic subtypes, survival periods were of 213 months for 3 VA+ patients and of 33 months for 11 VA− patients (p=0.023). For lymphoma subtypes, survival periods were of 144 months for 2 VA+ patients versus 6 months for 49 VA− patients (p=0.0046). ATL cases with skin lesions, particularly lymphoma subtypes, had a longer survival (13.96 months) compared to those without skin lesions (6.06 months, p=0.002). Eight out of the 10 patients presenting with long survival had skin lesions.

A Novel Cryptic Three-Way Translocation t(2;9;18)(p23.2;p21.3;q21.33) with Deletion of Tumor Suppressor Genes in 9p21.3 and 13q14 in a T-Cell Acute Lymphoblastic Leukemia

Acute leukemia often presents with pure chromosomal resolution; thus, aberrations may not be detected by banding cytogenetics. Here, a case of 26-year-old male diagnosed with T-cell acute lymphoblastic leukemia (T-ALL) and a normal karyotype after standard GTG-banding was studied retrospectively in detail by molecular cytogenetic and molecular approaches. Besides fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA) and high resolution array-comparative genomic hybridization (aCGH) were applied. Thus, cryptic chromosomal aberrations not observed before were detected: three chromosomes were involved in a cytogenetically balanced occurring translocation t(2;9;18)(p23.2;p21.3;q21.33). Besides a translocation t(10;14)(q24;q11) was identified, an aberration known to be common in T-ALL. Due to the three-way translocation deletion of tumor suppressor genes CDKN2A/INK4A/p16, CDKN2B/INK4B/p15, and MTAP/ARF/p14 in 9p21.3 took place. Additionally RB1 in 13q14 was deleted. This patient, considered to have a normal karyotype after low resolution banding cytogenetics, was treated according to general protocol of anticancer therapy (ALL-BFM 95).

Postinduction Supportive Care of Pediatric Acute Myelocytic Leukemia: Should Patients be Kept in the Hospital?

Children with AML become profoundly neutropenic while they undergo remission induction chemotherapy. It is unknown whether these children should be kept in the hospital while they are severely neutropenic to prevent life-threatening complications associated with neutropenia and reduce fatality. We at our institution routinely discharge patients after completing remission induction chemotherapy in the presence of profound neutropenia, unless it is clinically contraindicated. We reviewed all AML patients who were consecutively treated at our hospital from 1989 to 2011. Thirteen patients were electively discharged after completion of induction I chemotherapy. Of the 13, 4 died due to relapse or complications of stem cell transplants (not due to neutropenia related complications). Another eight are long term survivors. In this very small series, discharge from the hospital even though patients were severely neutropenic did not adversely affect the survival.

Molecularly Targeted Therapies in Multiple Myeloma

Multiple myeloma (MM) is a hematological malignancy that remains incurable because most patients will eventually relapse or become refractory to the treatments. Although the treatments have improved, the major problem in MM is the resistance to therapy. Novel agents are currently in development for the treatment of relapsed/refractory MM, including immunomodulatory drugs, proteasome inhibitors, monoclonal antibodies, cell signaling targeted therapies, and strategies targeting the tumor microenvironment. We have previously reviewed in detail the contemporary immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies therapies for MM. Therefore, in this review, we focused on the role of molecular targeted therapies in the treatment of relapsed/refractory multiple myeloma, including cell signaling targeted therapies (HDAC, PI3K/AKT/mTOR, p38 MAPK, Hsp90, Wnt, Notch, Hedgehog, and cell cycle) and strategies targeting the tumor microenvironment (hypoxia, angiogenesis, integrins, CD44, CXCR4, and selectins). Although these novel agents have improved the therapeutic outcomes for MM patients, further development of new therapeutic agents is warranted.