Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma.

BACKGROUND: Lenalidomide plus dexamethasone is a reference treatment for relapsed multiple myeloma. The combination of the proteasome inhibitor carfilzomib with lenalidomide and dexamethasone has shown efficacy in a phase 1 and 2 study in relapsed multiple myeloma. METHODS: We randomly assigned 792 patients with relapsed multiple myeloma to carfilzomib with lenalidomide and dexamethasone (carfilzomib group) or lenalidomide and dexamethasone alone (control group). The primary end point was progression-free survival. RESULTS: Progression-free survival was significantly improved with carfilzomib (median, 26.3 months, vs. 17.6 months in the control group; hazard ratio for progression or death, 0.69; 95% confidence interval [CI], 0.57 to 0.83; P=0.0001). The median overall survival was not reached in either group at the interim analysis. The Kaplan-Meier 24-month overall survival rates were 73.3% and 65.0% in the carfilzomib and control groups, respectively (hazard ratio for death, 0.79; 95% CI, 0.63 to 0.99; P=0.04). The rates of overall response (partial response or better) were 87.1% and 66.7% in the carfilzomib and control groups, respectively (P<0.001; 31.8% and 9.3% of patients in the respective groups had a complete response or better; 14.1% and 4.3% had a stringent complete response). Adverse events of grade 3 or higher were reported in 83.7% and 80.7% of patients in the carfilzomib and control groups, respectively; 15.3% and 17.7% of patients discontinued treatment owing to adverse events. Patients in the carfilzomib group reported superior health-related quality of life. CONCLUSIONS: In patients with relapsed multiple myeloma, the addition of carfilzomib to lenalidomide and dexamethasone resulted in significantly improved progression-free survival at the interim analysis and had a favorable risk-benefit profile. (Funded by Onyx Pharmaceuticals; ClinicalTrials.gov number, NCT01080391.).

Carfilzomib, lenalidomide, and dexamethasone in patients with relapsed multiple myeloma categorised by age: secondary analysis from the phase 3 ASPIRE study.

A primary analysis of the ASPIRE study found that the addition of carfilzomib to lenalidomide and dexamethasone (carfilzomib group) significantly improved progression-free survival (PFS) compared with lenalidomide and dexamethasone alone (control group) in patients with relapsed multiple myeloma (RMM). This post hoc analysis examined outcomes from ASPIRE in patients categorised by age. In the carfilzomib group, 103/396 patients were ≥70 years old, and in the control group, 115/396 patients were ≥70 years old. Median PFS for patients <70 years old was 28·6 months for the carfilzomib group versus 17·6 months for the control group [hazard ratio (HR), 0·701]. Median PFS for patients ≥70 years old was 23·8 months for the carfilzomib group versus 16·0 months for the control group (HR, 0·753). For patients <70 years the overall response rate (ORR) was 86·0% (carfilzomib group) and 66·9% (control group); for patients ≥70 years old the ORR was 90·3% (carfilzomib group) and 66·1% (control group). Within the carfilzomib group, grade ≥3 cardiovascular adverse events occurred more frequently among patients ≥70 years old compared with patients <70 years old. Carfilzomib-lenalidomide-dexamethasone has a favourable benefit-risk profile for patients with RMM, including elderly patients ≥70 years old. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT01080391.

[Low mean cell hemoglobin is a reliable marker for iron deficiency screening]. / Az alacsony átlagos vörösvértest-hemoglobin alkalmas a vashiány szurésére.

INTRODUCTION: Screening for iron deficiency, which affects a significant proportion of the population, is a burning issue in the health care system. AIM: The aim of the authors was to examine whether low mean cell hemoglobin concentration measured by automated hematology analyzers is a suitable screening parameter for iron deficiency. METHOD: The data for this study included a total of 247,705 complete blood counts and 10,840 tests with different parameters of iron metabolism. Patients were evaluated at Somogy County Kaposi Mór Teaching Hospital during a period of 30 months between January 1, 2013 and June 30, 2015. Low cell hemoglobin values were analyzed with iron metabolism parameters measured simultaneously. RESULTS: A total of 830 patients whose iron metabolism parameters were measured simultaneously had low mean cell hemoglobin (<28pg). Of the 830 patients, 679 (82%) had both low mean cell hemoglobin and iron deficiency, while in 126 hemodialysed patients (15%), 8 patients with myelofibrosis, and 5 patients with rheumatic arthritis had low mean cell hemoglobin without iron deficiency. In the remaining 6 patients the cause of low mean cell hemoglobin or iron deficiency was not identified. CONCLUSIONS: Based on these findings the authors conclude that mean cell hemoglobin may be a reliable screening marker for iron deficiency.

Targeted Venetoclax Therapy in t(11;14) Multiple Myeloma: Real World Data From Seven Hungarian Centers.

Despite the introduction of novel agents, multiple myeloma remains incurable for most patients, necessitating further therapeutic options. Venetoclax, a selective BCL-2 inhibitor, had shown promising results in patients with translocation t(11;14), but questions remain open about its optimal use. We have contacted all Hungarian haematology centers for their experience treating t(11;14) myeloma patients with venetoclax. 58 patients were reported. 37 received venetoclax in the relapsed/refractory setting with few or no other therapeutic options available. 21 patients started venetoclax as salvage after failing to achieve satisfactory response to first line therapy. In the relapsed/refractory setting objective response rate (ORR) was 94%, median progression-free survival (PFS) 10.0 months and median overall survival (OS) 14.6 months. In reinduction patients, ORR was 100%, median PFS and OS were not reached. Importantly, we found no adverse effect of high risk features such as deletion 17p or renal failure, in fact renal failure ameliorated in 42% of the cases, including three patients who became dialysis independent. Our study also reports the highest number of plasma cell leukemia cases successfully treated with venetoclax published in literature, with refractory plasma cell leukemia patients achieving a median PFS of 10.0 and a median OS of 12.2 months.

Pomalidomide Treatment in Relapsed/Refractory Multiple Myeloma Patients-Real-World Data From Hungary.

Pomalidomide is a third generation immunomodulatory drug in the treatment of refractory and relapsed multiple myeloma patients. Our aim was to investigate the efficacy and safety of pomalidomide therapy in a real world setting. Eighty-six Hungarian patients were included, 45 of whom received pomalidomide ± an alkylating agent, while in 38 of them pomalidomide was combined with a proteasome inhibitor. 56 patients (65%) showed any response to the treatment with 18 complete or very good partial remissions and 38 partial remissions. At a median duration of follow-up of 18.6 months, the median progression-free survival (PFS) was 9.03 months, while the median overall survival (OS) was 16.53 months in the whole cohort. Patients with early stage disease (R-ISS 1 and 2) had better survival results than those with stage 3 myeloma (p = 0.002). Neither the number of prior treatment lines, nor lenalidomide refractoriness had a significant impact on PFS. PFS was found similar between the cohort of patients with impaired renal function and the cohort without kidney involvement. During the study, eight mortal infections and two fatal bleeding complications occurred, however, mild hematologic and gastrointestinal toxicities were identified as the most frequent adverse events. The results of our investigations confirm that pomalidomide is an effective treatment option for relapsed/refractory MM, besides, the safety profile is satisfactory in subjects with both normal and impaired renal function.

Diagnostic pitfalls: intramyocardial lymphoma metastasis mimics acute coronary syndrome in a diffuse large B cell lymphoma patient-case report.

BACKGROUND: Cardiac tumors are very uncommon compared to other cardiac diseases. Their clinical symptoms can vary from absent to non-specific. The most common symptoms are arrhythmias, blood flow obstruction due to valvular dysfunction, shortness of breath, systemic embolization, and accumulation of pericardial fluid. Hereby, we describe a very rare case of a diffuse large B cell lymphoma patient who presented with the symptoms and signs of acute coronary syndrome (ACS) but the patient's complaints were caused by his intramyocardial lymphoma metastasis. CASE PRESENTATION: Forty-eight-year-old diffuse large B cell lymphoma patient was admitted to our emergency department with chest pain, effort dyspnea, and fever. The patient had normal blood pressure, blood oxygen saturation, sinus tachycardia, fever, crackles over the left lower lobe, novum incomplete right bundle branch block with Q waves and minor ST alterations, elevated C-reactive protein, high-sensitivity troponin-T, and d-dimer levels. Chest X-ray revealed consolidation on the left side and enlarged heart. Bed side transthoracic echocardiography showed inferior akinesis with pericardial fluid. Coronary angiography showed no occlusion or significant stenosis. Chest computed tomography demonstrated the progression of his lymphoma in the myocardium. He was admitted to the Department of Hematology for immediate chemotherapy and he reached complete metabolic remission, followed by allogeneic hematopoietic stem cell transplantation. Unfortunately, about 9 months later, he developed bone marrow deficiency consequently severe sepsis, septic shock, and multiple organ failure what he did not survive. CONCLUSIONS: Our case demonstrates a very rare manifestation of a heart metastasis. ACS is an unusual symptom of cardiac tumors. But our patient's intramyocardial lymphoma in the right atrium and ventricle externally compressed the right coronary artery and damaged the heart tissue, causing the patient's symptoms which imitated ACS. Fortunately, the quick diagnostics and immediate aggressive chemotherapy provided the patient's remission and suitability to further treatment.

Beneficial Effect of Lenalidomide-Dexamethason Treatment in Relapsed/Refractory Multiple Myeloma Patients: Results of Real-Life Data From 11 Hungarian Centers.

In Hungary, the cost of lenalidomide-based therapy is covered only for relapsed multiple myeloma (MM) patients, therefore lenalidomide is typically used in the second-line either as part of a triplet with proteasome inhibitors or as a doublet. Lenalidomide-dexamethasone is a standard treatment approach for relapsed/refractory MM, and according to recent large randomized clinical trials (RCT, the standard arm of POLLUX, ASPIRE, TOURMALINE), the progression-free survival (PFS) is expected to be approximately 18 months. We surveyed ten Hungarian centers treating MM and collected data of 278 patients treated predominantly after 2016. The median age was 65 years, and patients were distributed roughly equally over the 3 international staging system groups, but patients with high risk cytogenetics were underrepresented. 15.8% of the patients reached complete response, 21.6% very good partial response, 40.6% partial response, 10.8% stable disease, and 2.5% progressed on treatment. The median PFS was unexpectedly long, 24 months, however only 9 months in those with high risk cytogenetics. We found interesting differences between centers regarding corticosteroid type (prednisolone, methylprednisolone or dexamethasone) and dosing, and also regarding the choice of anticoagulation, but the outcome of the various centers were not different. Although the higher equivalent steroid dose resulted in more complete responses, the median PFS of those having lower corticosteroid dose and methylprednisolone were not inferior compared to the ones with higher dose dexamethasone. On multivariate analysis high risk cytogenetics and the number of prior lines remained significant independent prognostic factors regarding PFS (p < 0.001 and p = 0.005). Our results show that in well-selected patients Lenalidomide-dexamethasone can be a very effective treatment with real-world results that may even outperform those reported in the recent RCTs. This real world information may be more valuable than outdated RCT data when treatment options are discussed with patients.

Rare primary extranodal lymphomas: diffuse large B-cell lymphomas of the genital tract.

Primary non-Hodgkin's lymphoma (NHL) of the genital tract is a rare entity. Etiology and pathogenesis of these NHLs are unknown, although there might be a possible association between chronic inflammation and lymphomas. The most common histological subtype is the diffuse large B-cell lymphoma. We report two cases of uterine lymphoma and one case of prostate lymphoma in this paper. The symptoms and the differential diagnosis are also discussed. Because of the low incidence, there is no widely accepted consensus on its treatment. We demonstrate that the rituximab and CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone; R-CHOP) chemoimmunotherapy is a good and tolerable treatment option in all cases. The two young patients are disease-free nowadays; the older patient with poor prognostic histological-type lymphoma relapsed in a short time and died after second relapse. A multicenter analysis is necessary to evaluate the long-term results of chemoimmunotherapy in these rare extranodal lymphoma entities.

[Primary gastrointestinal non-Hodgkin's lymphoma in two Hungarian regions]. / Pimer gastrointestinalis non-Hodgkin-lymphoma két magyarországi régió beteganyaga alapján.

UNLABELLED: Over the past few decades, the occurrence of adult onset non-Hodgkin's lymphoma has significantly increased. The patient population involved is very heterogeneous, with different clinical and morphological manifestations. In addition to the most typical nodal involvement, extra-nodal manifestations are also frequent, affecting, most often, the gastrointestinal tract, the central nervous system and the skin. The treatment strategy for non-Hodgkin's lymphoma has changed over the past decade: chemo-immunotherapy has largely taken over surgical intervention, the dominant treatment option of the past. METHODS: The authors present their experience with 48 patients with non-Hodgkin's lymphoma, affecting the gastrointestinal tract, treated in Kaposvár, in the Kaposi Mór Teaching Hospital and in Gyula, in the Pándy Kálmán County Hospital. Demography: 27 female, 21 male; mean age: 67.8 years. Localization, pathological classification and the international prognostic index (IPI) have been analysed and correlated with the clinical response to different therapeutic strategies. RESULTS: The most frequently involved GI organ was the stomach ( n = 26), with the dominant histological type of diffuse large B-cell lymphoma. Fourty-six patients received chemo-immunotherapy, 6 received radiotherapy, 3 patients were primarily treated with Helicobacter pylori eradication therapy, and 4 patients were referred for stomach resection. A complete remission was achieved in 68% of the patients, a partial remission in 13%, while 19% did not show clinical response. Based on the international prognostic index, the majority of the patients fulfilled criteria of low or high intermediate risk categories, with an IPI average of 2.68. Patients with upper gastrointestinal tract involvement carried the best prognosis (IPI: 2.0); at the same time, patients with stomach lymphoma achieved the highest rate of remission (73%). CONCLUSIONS: With chemo-immunotherapy the chances of a complete remission have significantly improved over the past decade, thus a significant portion of non-Hodgkin's lymphomas involving the gastrointestinal tract can be cured. IPI index represents the most recognised indicator for assessing the prognosis of non-Hodgkin's lymphoma. Patients who achieved complete remission had the lowest prognostic index in this cohort; nevertheless, numerous data indicate that factors other than the IPI can also have an impact on patients' response to treatment.

Real-world data on the efficacy and safety of daratumumab treatment in Hungarian relapsed/refractory multiple myeloma patients.

Daratumumab is a human anti-CD38 monoclonal antibody used in the treatment of refractory and relapsed multiple myeloma. We investigated the efficacy and safety of daratumumab therapy in a real-world setting. Ninety-nine Hungarian patients were included; 48 received monotherapy, while lenalidomide and bortezomib combinations were administered in 29 and 19 cases, respectively. Overall response rate was assessable in 88 patients, with 12 complete, 10 very good partial, 34 partial, and seven minor responses. At a median duration of follow-up of 18.6 months, median progression-free survival (PFS) among all patients was 17.0 months. These values were inferior in the bortezomib combination and monotherapy groups. Patients with early-stage disease (ISS1) had better survival results than those with stage 2 or 3 myeloma (p = 0.009). Heavily pretreated patients had inferior PFS compared to those with 1-3 therapies (p = 0.035). Patients with impaired renal function had PFS results comparable with those having no kidney involvement. There were 10 fatal infections, and the most frequent adverse events were mild infusion-associated reactions and hematologic toxicities. Our results confirm that daratumumab is an effective treatment option for relapsed/refractory MM with an acceptable safety profile in patients with normal and impaired renal function.

[Long-term survival after nasal NK/T cell lymphoma]. / Nazális NK/T-sejtes lymphoma hosszú túlélése.

The nasal NK/T cell lymphoma is a rare, extranodal non-Hodgkin lymphoma in western civilizations, which has poor prognosis. The Epstein-Barr virus can be detected in tumor cells in nearly all cases. There are no definite treatment guidelines in our days. There is no significant difference in survival between radiotherapy and chemotherapy according to Asian studies. In this case study we show our diagnostic procedures, our treatment options and we present the summary of this illness based on the data found in the literature.

[Imatinib therapy in chronic myeloid leukemia]. / Krónikus myeloid leukaemiás betegeink imatinibkezelése.

UNLABELLED: Chronic myeloid leukemia is a malignant clonal alteration of the pluripotent hemopoietic stem cell. The genetic hallmarks of the disease are the t(9,22) (Philadelphia chromosome), registered by conventional cytogenetics in more than 90% of all chronic myeloid leukemia cases and the active tyrosine kinase protein encoded by bcr-abl fusion gene. The constitutively active tyrosine kinase is currently accepted to be the cause of chronic myeloid leukemia. The introduction of imatinib has considerably changed the treatment of chronic myeloid leukemia. Prior studies demonstrated high rates of cytogenetic responses in all phases of the disease. METHODS: The authors evaluated the cytogenetic and molecular responses of 21 chronic phase chronic myeloid leukemia patients who were consecutively admitted to their center. 13 of them were primarily treated with imatinib, and the other 7 were heavily pretreated with interferon alpha, cytarabine, all-trans-retinoic acid. Hydroxyurea pretreatment was routinely introduced in all patients until complete hematologic remission. Peripheral blood sample in every 3 months were collected for quantitative real-time polymerase chain reaction, and bone marrow aspirate in every 6 months for conventional cytogenetics. RESULTS: Hematologic remission could have been achieved with hydroxyurea pretreatment in each patient. Complete cytogenetic remission at the 6th month and major molecular response at the 12th month were observed in each patient. CONCLUSIONS: Imatinib treatment caused complete cytogenetic response and major molecular response in each chronic phase chronic myeloid leukaemia patient in our group. Hydroxyurea might have some effect on the rapid and deep cytogenetic and molecular responses, observed in the primary imatinib-treated group.

[Neutropenia and sepsis in hematologic patients]. / Neutropenia és szepszis a hematológiai osztályon: a Kaposi Mór Oktató Kórház tapasztalatai.

INTRODUCTION: The neutropenic patient's infections are challenging problems for modern medicine. The increasing number of iatrogenic neutropenia, the invasive procedures and the growing resistance to antibiotics and antimycotics make the treatment of sepsis difficult. The aim of this study was to analyse the frequency and mortality of neutropenic infections in hematologic patients. METHODS AND RESULTS: In the department of the authors 146 patients with sepsis were diagnosed out of 2173 treated patients in 24 months (67/1000 patients). 78 of them were neutropenic (absolute neutrophil count below 0,5 G/I) and 63 were severe neutropenic (absolute neutrophil count below 0,1 G/I). Sepsis occurred on the 10-11th day of neutropenia. 45% of positive hemoculture were caused by Gram positive bacteria, 30% by Gram negative bacteria, 10% by fungi and 15% were polymicrobic infections. The overall mortality was 36%, but in the severe neutropenic group it was about 60%. CONCLUSIONS: These results show that despite of the use of new, broad spectrum of antibiotics and antimycotics in neutropenic patients with sepsis, it is difficult to treat these patients.

Case report: Concomitant Chronic Lymphocytic Leukaemia and Cytogenetically Normal de novo Acute Leukaemia in a Patient.

The simultaneous occurrence of acute myeloid leukaemia with untreated chronic lymphocytic leukemia is extremely rare. We report a case of a 74-year-old man who was evaluated for macrocytic anaemia. Based on the morphology and immunophenotyping analysis of peripheral blood, a diagnosis of chronic lymphocytic leukemia was established. Subsequently, the bone marrow examination revealed the presence of two distinct, coexisting CLL and AML clones. Cytogenetic and molecular genetic analysis detected deletion 13q14.3 and unmutated immunoglobulin variable heavy-chain in the CLL clone, only. The AML and CLL clones did not share clonality, and the AML did not involve the peripheral blood. A diagnosis of cytogenetically normal de novo AML occurring concurrently with untreated CLL has not been reported previously in English literature.

Severe hemolytic anemia and acute psychosis caused by Clostridium perfringens sepsis.

BACKGROUND: Clostridium perfringens septicaemia with massive hemolysis is well known. The infection induced acute hemolytic attack frequently occur in chronic corpuscular hemolytic anemias. Alterations in mental status are common in septic patients. CASE REPORT: The case of a 39-year-old woman with a history of chronic corpuscular hemolytic anemia, experiencing weakness, pallor, somnolence is presented. Hypothermia and an acute paranoid psychotic episode subsequently developed in the hospital. C. perfringens sepsis was detected from blood cultures. The patient was cured by penicillin and clindamycin. Her symptoms disappeared and there was total resolution of toxic encephalopathy according to the brain MRI after 6 weeks. CONCLUSION: This report discusses the possible explanation of clostridial sepsis the role of brain MRI in the sepsis-induced organic psychosyndromes and underlines the need for obtain blood cultures in hypothermia suggestive to sepsis.

The association of sagittal spinal and pelvic parameters in asymptomatic persons and patients with isthmic spondylolisthesis.

Using a specialized orthopedic software package, the authors investigated the sagittal spinal shape and the position of the pelvis in the space in patients with isthmic spondylolisthesis and in persons with no such symptoms. Digitized lateral spinal radiographs of 30 healthy volunteers and 48 patients were evaluated. The absolute values and significant correlations between parameters were analyzed. The pelvic parameters correlated well with lordosis, which shows sagittal balance in the asymptomatic group. The hyperlordosis and the horizontally positioned sacrum in isthmic spondylolisthesis enlarge the tensile force component of gravity, which may cause the lysis. Finally, the authors developed a new balance between the pelvis and the spine after slipping of the vertebral body. The degree of slipping correlated well with the sacrofemoral anatomic constant (incidence), which is unique in each person.