The SOCS-1 gene methylation in chronic myeloid leukemia patients

SOCS-1, an important protein in the JAK/STAT pathway, has a role in the down stream of BCR-ABL protein kinase. We investigated 56 CML patients and 16 controls for the methylation status of SOCS-1 gene promoter and Exon 2 regions. Exon 2 was found to be methylated in 58.9% of the patients and 93.8% of the controls [P = 0.020, OR = 0.121(0.015-0.957)%95CI]. The promoter region was found unmethylated in all patient samples and controls. Although previous studies revealed a relation between SOCS1 gene Exon-2 hypermethylation and CML development or progression, the results of this study showed no such correlation. On the contrary, our results might be indicating hypomethylation in CML patients, this hypothesis need to be studied in larger study population.     

Recent developments in drug resistance mechanism in chronic myeloid leukemia: a review

A revolution in medical science was marked with the advent of imatinib, a site-specific drug for the management of patients with chronic myeloid leukemia (CML). Imatinib mesylate (also known as Glivec, Gleevec, STI-571, CGP57148), an orally administered 2-phenylaminopyrimidine derivative approved by FDA in 2001 for the treatment for CML, is highly effective in treating the early stages of CML, but remission induced in advanced phase was observed to be relatively short-lived. The primary cause of resistance in patients with CML is the mutations in the BCR-ABL kinase domain. This review discusses the different mechanisms leading to imatinib resistance and various treatment options to over-ride imatinib resistance.     

Iron-sorbital complex as a possible factor in the development of a blastic crisis in chronic myeloid leukemia

Summary A case of chronic myeloid leukemia who developed a blastic crisis following injections of iron sorbitol complex is presented. When the blastic crisis occurred the patient was in myleran induced remission. The caudal relationship between the development of blastic crisis and parenteral administration of iron sorbitol complex is discussed.

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Zusammenfassung Es wird über einen Patienten mit chronischer mycloischer Leukämie berichter, bei demsich nach Injektionen eines Eisen-Sorbit-Komplexes eine blastische Krise entwickelte. Zum Zeitpunkt des Eintritts dieser blastischen Krise befand sich der Patient im Stadium einer Remission nach Behandlung mit Myleran. Die möglichen ursächlichen Zusammenhänge zwischen der Entstehung der blastischen Krise und der parenteralen Verabfolgung des Eisen-Sorbit-Komplexes werden diskutiert.

     

Overexpression of cyclooxygenase-2 correlates with advanced stages of colorectal cancer

OBJECTIVE: We aimed to investigate the associations of cyclooxygenase-2 (COX-2) with pathological features and survival in patients with colorectal cancer. METHODS: The expression of COX-2 was examined by immunohistochemistry in 112 primary colorectal cancers, with 64 samples from the corresponding normal mucosa and 16 metastases in the regional lymph nodes of patients with colorectal cancer. The associations of COX-2 expression with clinicopathological features, including survival, were analyzed. RESULTS: The frequency and intensity of COX-2 staining were remarkably increased from the normal samples (17%) to the primary tumors (72%) and to the metastases (100%). Expressions of COX-2 were 25%, 74%, 78%, and 67% in Dukes' A, B, C, and D tumors, respectively (p = 0.005), and positively related to proliferative activity (p = 0.003). COX-2 expressions were 80% in colonic tumors and 60% in rectal tumors (p = 0.03). The expression of COX-2 was positively related to the better differentiated tumors in the colon (p = 0.04). We were unable to find any relationship of COX-2 with patient age, sex, tumor growth pattern, apoptosis, and patient survival (p > 0.05). CONCLUSION: We found that the expression of COX-2 was upregulated from normal cells to primary tumors and to metastases, and related to proliferative activity, tumor location, Dukes' stage, and differentiation. These results further support the evidence that COX-2 may be involved in tumorigenesis and development of colorectal cancer.     

Pure red cell aplasia as possible early manifestation of chronic myeloid leukemia

Cytogenetic studies as well as erythroid and myeloid progenitor cell assays were performed in a 29-yr-old epileptic man with pure red cell aplasia (PRCA) who had been treated with primidone for several years. Despite clinical evidence of preleukemia, our studies indicated an underlying atypical Philadelphia chromosome-positive myeloproliferative disorder. These laboratory findings were confirmed by the subsequent development of chronic myeloid leukemia (CML) which terminated in a CALLA-positive lymphoblastic crisis 32 months later. The rare concurrent occurrence of PRCA and CML and the possible inducing role of the preceding antiepileptic treatment are discussed.     

Monocytic crisis in chronic myeloid leukemia: a case report

We report a 17-year-old female with chronic myeloid leukemia (CML) who developed monocytic crisis. She was diagnosed as chronic phase of Ph1-chromosome positive CML at 14 years old. Three years after the diagnosis of the disease, she was admitted to the hospital because of low grade fever, lethargy and marked splenomegaly. Small dose of Ara-C relieved her symptoms and splenomegaly. Six months later, however, a marked leukocytosis over 70,000/microliters were observed, and the peripheral blood smear disclosed that about 80% of the leukocytes were relatively mature monocytoid cells. Chromosomal analysis revealed additional abnormalities (double Ph1, +8, +9, +19). Lysozyme levels in serum and urine were high and NAP score was elevated. These monocytoid cells expressed receptors for IgG-Fc and C3, phagocytic activity, and monocytoid antigens which were determined by monoclonal antibodies (MY4, Mo2, OKM5). Cytochemically, almost all of monocytoid cells were positive for peroxidase and naphthol-ASD-chloroacetate esterase (CAE), but the monocytoid cells positive for non-specific esterase were limited. These data suggested that this case was monocytic crisis in CML with proliferation of CAE positive monocytoid cells. Among several types of blast crisis, monocytic crisis is extremely rare condition. The definite monocytic crisis demonstrated by this case may support the hypothesis that target cells of CML are pluripotent hematopoietic precursors.     

Networking for advanced molecular diagnosis in acute myeloid leukemia patients is possible: the PETHEMA NGS-AML project

Next-generation sequencing (NGS) has recently been introduced to efficiently and simultaneously detect genetic variations in acute myeloid leukemia (AML). However, its implementation in the clinical routine raises new challenges focused on the diversity of assays and variant reporting criteria. In order to overcome this challenge, the PETHEMA group established a nationwide network of reference laboratories aimed to deliver molecular results in the clinics. We report the technical cross-validation results for NGS panel genes during the standardization process and the clinical validation in 823 samples of 751 patients with newly diagnosed or refractory/relapse AML. Two cross-validation rounds were performed in seven nationwide reference laboratories in order to reach a consensus regarding quality metrics criteria and variant reporting. In the pre-standardization cross-validation round, an overall concordance of 60.98% was obtained with a great variability in selected genes and conditions across laboratories. After consensus of relevant genes and optimization of quality parameters the overall concordance rose to 85.57% in the second cross-validation round. We show that a diagnostic network with harmonized NGS analysis and reporting in seven experienced laboratories is feasible in the context of a scientific group. This cooperative nationwide strategy provides advanced molecular diagnostic for AML patients of the PETHEMA group (clinicaltrials gov. Identifier: {"type":"clinical-trial","attrs":{"text":"NCT03311815","term_id":"NCT03311815"}}NCT03311815).     

Autologous hematopoietic stem cell transplantation in chronic myeloid leukemia with different clinical stages.

Seven patients with Philadelphia (Ph) chromosome-positive chronic myeloid leukemia (CML) were treated with an ICE-based regimen plus G-CSF with the aim of mobilizing and collecting Ph-negative peripheral stem cells in the setting of an autologous transplant program. Five patients had CML in the first chronic phase and 2 in the accelerated phase. All patients had been previously treated with interferon-alpha. Median value and ranges for harvested mononuclear cells, CD34+ cells and CFU-GM, respectively: 5.65 x 10(8)/kg (2.61-11.38); 1.48 x 10(6)/kg (0.216-3.5), and 3.43 x 10(4)/kg (0.243-11.6). FISH was the only useful method for detection of minimal residual disease on apheresis product showing <5% t(9;22) positive cells in 2 cases and <10% positive cells in 4 other cases. Four of seven autologous grafts have been transplanted to date. Busulfan conditioning was used in 1 case and TBI/Cy conditioning in 3 other cases. All patients are alive and well following transplantation and are on interferon-alpha therapy.     

Prognostic factors in chronic myeloid leukemia: allografting

Risk assessment for allografting differs from that for conventional therapy mainly because the transplant intervenes far from initial diagnosis and generates a new source of morbidity and mortality, graft-versus-host disease (GvHD). Major well-defined pre-, peri- and post-transplant risk factors influence two endpoints: transplant-related mortality (TRM) and relapse incidence (RI), which in turn determine the principal outcomes-leukemia-free survival (LFS) and survival. Some factors have concordant effects on both endpoints, like disease stage. Other risk factors have divergent effects: histocompatibility, intensity of conditioning, or GvHD prevention. The impact of risk factors with divergent effects differs in various time periods post-transplant. The main pretransplant factors are disease stage, patient age and sex, donor-recipient sex combination, histocompatibility, and time from diagnosis to transplant. The primary peritransplant factors are the intensity of conditioning and of GvHD prevention. The main post-transplant factor is severity of acute and chronic GvHD. Determination of the risk profile for an individual patient is reliable and should form an integral part of pretransplant counseling. The management strategies for patients with high-risk disease and low TRM risk profiles and for patients with low-risk disease and high TRM risk profiles should be different.     

Nilotinib-induced hypothyroidism in a patient with chronic myeloid leukemia

Peripheral edema often occurs in patients with chronic myeloid leukemia (CML) treated with kinase inhibitors (TKIs). However, there are few reports indicating that the edema is caused by TKIs-induced hypothyroidism. We present the case of a 76-year-old man with chronic-phase CML who suffered from severe systemic edema after introduction of nilotinib. Laboratory tests revealed hypothyroidism; the patient was euthyroid prior to introduction of nilotinib. After further examination, we attributed this hypothyroidism to nilotinib. His edema regressed dramatically after thyroid hormone replacement therapy, with continued treatment with nilotinib. Laboratory examination of thyroid function also improved markedly. Although sunitinib, a multi-targeted TKI, is associated with a high incidence of hypothyroidism, TKIs targeting Bcr-Abl have rarely been reported to cause hypothyroidism. We report nilotinib-induced hypothyroidism, and suggest that hypothyroidism should be considered as a possible etiology when patients receivingTKIs suffer from edema.     

IL-2 in the treatment of chronic myeloid leukemia after lymphoid blast crisis: a pilot study

Five patients with lymphoid blastic transformation of chronic myeloid leukemia have been treated with IL2 associated with Vincristine (VCR) plus Prednisone (PDN). Our study indicates that IL2 may be employed in the management of this disease without excessive toxicity at the higher doses in hospitalized patients and at the lower doses as outpatients. Concerning the therapeutic efficacy, our preliminary results indicate that IL2 might be useful in enhancing the chemosensitivity of the leukemic blasts. It remains to be seen if this will result in a rapid return to the CP and in a prolongation of survival.