Diagnostic Tools of Waldenströms Macroglobulinemia - Best Possibilities for Non-invasive and Long-term Disease Monitoring.

Waldenströms macroglobulinemia (WM) is a B-cell malignancy characterized by high level of monoclonal immunoglobulin M (IgM) paraprotein in blood serum and associated with the bone marrow infiltration by malignant cells with lymphoplasmacytic differentiation. WM remains incurable advances in therapy. Most of WM cases are associated with a somatic point mutation L265P in MYD88. Significantly higher risk of progression from the IgM monoclonal gammopathy of undetermined significance (IgM MGUS) to WM for patients with mutated MYD88 gene suggests that this mutation is an early oncogenic event and plays a central role in development of malignant clones. The second, most prevalent mutation in WM is found in the CXCR4 gene and is often associated with drug resistance and aggressive disease presentation. Therefore, detection of these mutations (MYD88L265P and CXCR4S338X) could be useful diagnostic and prognostic tool for the patients with WM. While detection of these mutations in bone marrow sample is common, the aim of our study was to compare sensitivity of detection of mutation from different cell fraction from peripheral blood and bone marrow. The results show possibility to describe MYD88 and CXCR4 mutation status even from peripheral blood sample (sensitivity for MYD88L265P was 100%, for CXCR4S338X 91%), which significantly facilitate material collection. Moreover, comparable detection sensitivity of these mutations in bone marrow and peripheral blood samples examined before and during the therapy offers a promising tool for more routine diagnostic and monitoring of disease progression.Key words: Waldenström macroglobulinemia - hematology - neoplasms - lymphoma - mutation - MYD88 - CXCR4.

Graft-versus-host disease management.

Graft-versus-host disease (GVHD) remains a major problem of allogeneic hematopoietic-stem cell transplantation (HSCT) and an obstacle for successful outcome. Clinically significant acute GVHD (grade II or higher) developed in 20 to 65 percent of the patients. Death due to this complication accounts for approximately 50 percent of the deaths that are not due to a relapse of the neoplasm. Up to 70 % of patients who survive beyond day 100 develop chronic GVHD and it is the leading cause of nonrelapse mortality more than 2 years after allogeneic HSCT. In addition, chronic GVHD is associated with decreased quality of life, impaired functional status, and ongoing need for immunosuppressive medications. The incidence of chronic GVHD is increasing because of expansion of the donor population beyond HLA-identical siblings, older recipient age, use of peripheral blood cells as the graft source, and infusion of donor lymphocytes for treatment of recurrent malignancy after HSCT. With the current rush in new findings related to GVHD, we see a significant advancement in its management. Given these various new options and challenges, it is important to identify the minimal requirements for diagnosis and treatment of GVHD, as access to the most sophisticated advances may vary depending on local circumstances (Tab. 4, Fig. 1, Ref. 51).

[Pomalidomide in the treatment of relapsed and refractory multiple myeloma]. / Pomalidomid v liecbe relabujúceho a refraktérneho mnohopocetného myelómu.

Despite improvements in multiple myeloma therapy, the vast majority of patients continue to suffer relapses. Unfortunately, many patients event. develop disease that is refractory to lenalidomide and bortezomib and have few treatment options. Pomalidomide is a potent second-generation immunomodulatory agent with direct antiproliferative, pro-apoptotic, and antiangiogenic effects, as well as modulatory effects on bone resorption and on the immune system. Pomalidomide exhibited more potent anti-myeloma activity compared with thalidomide and lenalidomide. The optimal starting dose of pomalidomide is 4 mg given orally on days 1-21 of each 28-day cycle and combination with dexamethasone produces synergistic effects. In clinical trials, pomalidomide plus low-dose dexamethasone has shown better responses, progression-free and overall survival than high-dose dexamethasone or pomalidomide alone. Pomalidomide has limited cross-resistance with lenalidomide, and the overall response rates of pomalidomide in lenalidomide/bortezomib dual-refractory patients ranged from 26 to 31%. The most common grade 3 or 4 adverse events are hematologic, consisting of neutropenia, thrombocytopenia and anemia. Pomalidomide was approved by the FDA and the EMA in patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on their last therapy. We review pomalidomide mechanism of action, clinical trials in relapsed and refractory patients, and novel pomalidomide-based combinations.

[Role of cardiac bio-markers in monitoring of cardiotoxicity after hematopoietic stem cell transplantation]. / Úloha kardiálnych bio-markerov v monitorovaní kardiotoxicity po transplantácii kmenových krvotvorných buniek.

Advances in hematopoietic stem cell transplantation (HSCT) have increased survival in hematologic diseases. However, HSCT survivors are at risk of developing acute and longterm complications. Cardiac events, such as heart failure, myocardial ischemia and arrhythmias may represent potentially life  threatening conditions. Acute cardiotoxicity can occur during the first 100 days after HSCT. Conditioning regimens, including total body irradiation and high dose chemotherapy, previous chemoradiotherapy, including anthracyclines and chest irradiation, are known to be associated with an increased risk of cardiac complications after HSCT. Infectious complications resulting in sepsis due to posttransplant granulocytopenia may also impair myocardial function. Therefore the main strategy for minimizing cardiotoxicity is early detection of high risk patients and prompt prophylactic treatment. Measurement of cardio specific bio-markers can be a valid diagnostic tool for early identification, assessment, and monitoring of cardiotoxicity. In the present article, we review the usefulness of cardiac troponins and natriuretic peptides, the most commonly used bio-markers of myocardial ischemia and ventricular dysfunction, to detect and to predict the development of cardiotoxicity after HSCT.

[Lenalidomide maintenance therapy in patients with multiple myeloma]. / Udrziavacia liecba lenalidomidom u pacientov s mnohopocetným myelómom.

Maintenance therapy was recently defined as any treatment administered after the completion of induction therapy in patients whose disease is either responsive or nonprogressive at the time, with the goal of prolonging survival. Several studies have evaluated the use of novel agents as part of posttransplantation maintenance to improve progression free survival and overall survival. As shown by recent clinical trials, thalidomide and bortezomib are more indicated as consolidation agents, increasing the response rates. In contrast, lenalidomide showed a low toxicity profile and a benefit from prolonged treatment, making the drug one of the best choices for maintenance treatment. The role of lenalidomide in the maintenance therapy was evaluated in three randomized clinical trials. Lenalidomide was associated with a significantly increased progression free survival and in one study with a significant survival benefit. An unexpected finding from these trials was a modest increase in the incidence of secondary cancers. Whether lenalidomide maintenance should be routinely offered to patients is controversial among experts. For now, lenalidomide maintenance should be considered standard for patients not achieving a complete remission after stem cell transplantation, and for highrisk patients. For patients with low risk disease, the risk/ benefits of lenalidomide maintenance versus watchful waiting should be discussed until we have more data regarding survival benefits. Further analysis of lenalidomide maintenance therapy to determine the longterm risk of secondary malignancies and longer followup to assess the impact on overall survival is required.

The feasibility of an early hospital discharge following chemotherapy for the acute myeloid leukemia.

OBJECTIVE: The hospitalization of the patient during the critical myelosuppressive period after chemotherapy is often complicated by infections caused by nosocomial pathogens, what is associated with a high antibiotics consumption and with prolongation of the period of hospitalization. These findings have led many centres to change their policy from "in-hospital" to "out-hospital care". In this retrospective study we tried, on the basis of our experiences, to identify the feasibility and safety of this approach. PATIENTS AND METHODS: We studied 56 patients with the acute myeloid leukemia treated in our clinic with the consolidation chemotherapy. We compared two groups of patients. In the first group, the patients were discharged upon completion of chemotherapy, consequently followed up as outpatients. Patients in the second group were observed in hospital during the entire nadir. Following 41 courses, patients were discharged and instructed to return immediately if fever or any other change of their clinical status occurred. RESULTS: In 24 cases after chemotherapy, the patients returned to the hospital after a discharge (in 23 cases because of fever), in 17 cases of nadir periods the hospitalisation was not necessary at all. Seven patients were readmitted in septic shock, but rapidly recovered. Two other patients died, one due to an irreversible shock within 12 hours of readmission and one due to bacterial meningitis within 48 hours after readmission. In 10 cases of rehospitalization, patients responded to the first line of antibiotics. In the second group of the patients, only 2 courses of consolidation from a total of 15 were not complicated. In contrast to the first group, we detected only poor effectiveness of broad-spectrum antibiotics in the group of inpatients. CONCLUSIONS: For AML patients in a good clinical status without any complicating medical conditions, the early discharge is feasible, safe and cost saving option (Tab. 2, Fig. 2, Ref. 7).

Abnormal cardiomarkers in leukemia patients treated with allogeneic hematopoietic stem cell transplantation.

OBJECTIVE: Clinical cardiac complications in oncologic patients may develop from subclinical myocardial damage. Biomarkers N-terminal pro brain natriuretic peptide (NT-proBNP) and troponin T (cTnT) have been hypothesized to reflect preclinical cardiotoxicity earlier than echocardiography. The aim of this study was to assess prospectively the serial values of these cardiomarkers in leukemia patients treated with allogeneic hematopoietic stem cell transplantation (HSCT). PATIENTS: Twenty-one patients who were treated with allogeneic HSCT for acute leukemia at mean age of 32.8 years (range: 19-58) were studied. The conditioning regimen included high-dose cyclophosphamide in combination with total body irradiation (TBI) or busulphan. All patients were treated with anthracyclines earlier (median cumulative dose 250 mg/m, range: 150-580). METHODS: Cardiomarkers were measured before the preparative regimen (PR) and on days 1, 14 and 30 after HSCT. Their cardiac systolic function was assessed before PR, and 1-2 months after HSCT by echocardiography. RESULTS AND CONCLUSION: The differences in NT-proBNP before PR and after HSCT were statistically significant (p<0.001). The values of cTnT before and after HSCT were also significantly different (p=0.005). Persistent abnormalities (30 days after HSCT) of NT-proBNP levels were found in 19/21 patients (90.5 %) and of cTnT levels in 10/21 patients (47.6 %). The median cTnT concentrations were higher in patients treated with TBI than in patients without TBI (p=0.013). The median NT-proBNP values were higher in patients pretreated with higher cumulative doses of anthracyclines (>250 mg/m vs ≤250 mg/m) Cardiac symptoms developed in 3/21 (14.3 %) patients (Tab. 1, Fig. 3, Ref. 36).

Secondary malignancies after hematopoietic stem cell transplantation.

Hematopoietic stem cell transplantation (HSCT) offers patients with malignant and nonmalignant diseases the oportunity to pursue life-prolonging therapy. The number of survivors after successful HSCT is continually increasing. However, HSCT can induce tissue and organ damage that occurs not only "on treatment" , but long after completing therapy. Secondary malignancies belong to serious late complications after HSCT. A significant association of certain risk factors with increased likelihood of secondary malignancies after HSCT has been published over the last ten years. Better knowledge of pathogenesis of these complications, their early identification and treatment may contribute to better health outcomes of allogeneic and autologous hematopoietic stem cell transplantation recipients. We review here the incidence and risk factors of secondary malignancies after hematopoietic stem cell transplantation.

[The late effects in patients treated with allogeneic hematopoietic stem cell transplantation]. / Neskoré následky u pacientov liecených alogénnou transplantáciou kmenových krvotvorných buniek.

BACKGROUNDS: Allogeneic hematopoietic stem cell transplantation (HSCT) has become a curative treatment option for a variety of malignant and non-malignant hematological disorders. The number of long-term survivors after HSCT is continuously increasing and quality of their life represents a multidisciplinary concern. The aim of this study was to evaluate the prevalence of the late effects in long-term allogeneic HSCT survivors. PATIENTS AND METHODS: The study included 45 patients aged 12-63 years who survived at least two years after allogeneic HSCT for a hematological disorder. Twelve (26.7%) patients received an irradiation-based conditioning regimen. Median follow-up was 6 years (range 2-18 years). RESULTS: Toxicity varied from subclinical to life-threatening. The prevalence of at least one late toxic effect was 88.9%. Endocrine and metabolic complications included thyroid abnormalities in 12 (26.7%) patients, bone and joints complications in 13 (28.8%) and metabolic syndrome in 13 (28.8%). Ocular complications were diagnosed in 20 (44.4%), cardiovascular abnormalities in 15 (33.3%), pulmonary dysfunction in 6 (13.3%) and secondary malignancies in 3 (6.67%) survivors. The number of complications per patient increased with time from HSCT. Chronic graft-versus-host disease was the most significant risk factor associated with ocular, pulmonary and osteoarticular complications. CONCLUSION: Late toxicity of allogeneic HSCT in patients surviving for more than 2 years after this procedure may facilitate conduct of longer follow-up studies and an implementation of interventions to prevent late effects among survivors of serious hematological diseases

[Cardiovascular effects after hematopoietic stem cell transplantation]. / Kardiovaskulárne následky po transplantácii kmenových krvotvorných buniek.

Increasing numbers of patients now survive long-term following hematopoietic stem cell transplantation (HSCT). Hematopoietic stem cell transplantation can induce damage of various organs and tissues--from minimal potentially progressive subclinical changes to life-threatening conditions. These potential complications and effects include endocrine, respiratory, skeletal, neurological and other complications, as well as cardiotoxicity and secondary malignancies. Cardiovascular effects belong to life-threatening. There is a possibility of decreasing these effects--by their prevention, earlier diagnosis and treatment. It is necessary for the patient to receive lifelong care including cardiology follow-up after such intensive oncologic treatment.