Experience of Daratumumab in Relapsed/Refractory Multiple Myeloma: A Multicenter Study from Türkiye

Objective: This study aimed to evaluate patients with relapsed/refractory multiple myeloma (RRMM) who underwent daratumumab (DARA) therapy. Materials and Methods: This multicenter retrospective study included 134 patients who underwent at least two courses of DARA from February 1, 2018, to April 15, 2022. Epidemiological, disease, and treatment characteristics of patients and treatment-related side effects were evaluated. Survival analysis was performed. Results: The median age at the start of DARA was 60 (range: 35-88), with 56 patients (41.8%) being female and 48 (58.2%) being male. The median time to initiation of DARA and the median follow-up time were 41.2 (5.1-223) and 5.7 (2.1-24.1) months, respectively. The overall response rate after DARA therapy was 75 (55.9%), and very good partial response or better was observed in 48 (35.8%) patients. Overall survival (OS) and progression-free survival (PFS) for all patients were 11.6 (7.8-15.5) and 8.0 (5.1-10.9) months, respectively. OS was higher for patients undergoing treatment with DARA and bortezomib-dexamethasone (DARA-Vd) compared to those undergoing treatment with DARA and lenalidomide-dexamethasone (DARA-Rd) (16.9 vs. 8.3 months; p=0.014). Among patients undergoing DARA-Rd, PFS was higher in those without extramedullary disease compared to those with extramedullary disease (not achieved vs. 3.7 months; odds ratio: 3.4; p<0.001). The median number of prior therapies was 3 (1-8). Initiation of DARA therapy in the early period provided an advantage for OS and PFS, although it was statistically insignificant. Infusion-related reactions were observed in 18 (13.4%) patients. All reactions occurred during the first infusion and most reactions were of grade 1 or 2 (94.5%). The frequency of neutropenia and thrombocytopenia was higher in the DARA-Rd group (61.9% vs. 24.7%, p<0.001 and 42.9% vs. 15.7%, p<0.001). Conclusion: Our study provides real-life data in terms of DARA therapy for patients with RRMM and supports the early initiation of DARA therapy.

Determination of serum imatinib and its' metabolite in patients chronic myeloid leukemia.

INTRODUCTION: Imatinib has favorable pharmacokinetic properties, but primary and secondary resistance mechanisms may cause a decrease in clinical response over time. There is a positive correlation between serum imatinib concentrations and treatment response. Our aim was to develop a method for the measurement of imatinib and its' active metabolite N-desmethyl imatinib. METHODS: Serum imatinib and N-desmethyl imatinib levels were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and validation studies were carried out according to CLSI (The Clinical & Laboratory Standards Institute) protocols. Serum samples were collected from 40 patients with chronic myeloid leukemia (CML) and analyzed with LC-MS/MS and ultra high-performance liquid chromatography (UHPLC) methods. RESULTS: The linearity range and correlation coefficient were 12.2-12,500 ng/mL and 0.9987 for LC-MS/MS method, respectively. Limit of quantitation was determined as 24.4 ng/mL. The retention times of imatinib and N-desmethyl imatinib were 1.66 and 1.60 min, respectively. There was no statistically significant difference between the results of both methods. DISCUSSION: This LC-MS/MS method is cost-effective and has adavantages such as using low serum volumes, requiring simple pretreatment steps (only protein precipitation) and reduced turnaround times for analysis.

Evaluation of bone mineral density (BMD) and indicators of bone turnover in patients with hemophilia.

A decrease in bone mass is observed in hemophilic patients. The aim of this study was to evaluate bone mineral density (BMD), parathyroid hormone (PTH), 25-hydroxy vitamin D (vitamin D), and a bone formation and resorption marker, procollagen type I N-terminal propeptide (PINP) and urinary N-terminal telopeptide (uNTX) respectively, in hemophilic patients and healthy controls. Laboratory parameters related to the pathogenesis of bone loss such as neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) were also evaluated. Thirty-five men over 18 years of age, with severe hemophilia (A and B) and receiving secondary prophylaxis, were included in the study. The same number of age-, sex-, and ethnicity-matched healthy controls were evaluated. Anthropometric, biochemical, and hormonal parameters were determined in both groups. No significant difference in anthropometric parameters was found between the two groups. The BMD was low in 34% of hemophilic patients. Vitamin D, calcium, and free testosterone levels were significantly lower (p < 0.001, p = 0.011, p < 0.001, respectively), while PTH, PINP, and activated partial thromboplastin time (aPTT) levels were significantly higher (p < 0.014, p = 0.043, p < 0.001, respectively), in hemophilic patients compared to controls. There was no significant difference between the two groups in NLR, PLR, phosphorus, thyroid-stimulating hormone, and uNTX level. The reduction of bone mass in hemophilic patients may be evaluated using the markers of bone formation and resorption, enabling early detection and timely treatment.

Autoimmune hepatitis-primary biliary cirrhosis overlap syndrome concomitant with immune hemolytic anemia and immune thrombocytopenic purpura (Evans syndrome).

Autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) associated with Evans syndrome; combination of autoimmune hemolytic anemia (AIHA) and immune thrombocytopenic purpura (ITP) has rarely been reported. We report the case of a 53-year-old patient who presented with weakness, myalgia, arthralgia, shortness of breath and purpura. Initial laboratory investigations revealed liver dysfunction, anemia and thrombocytopenia. Anti-nuclear (ANA) and antimitochondrial M2 (AMA M2) antibodies were positive. Diagnose of PBC-AIH overlap was made by clinical, serological and histological investigations. AIHA and ITP was identified with clinical-laboratory findings and bone marrow puncture. She was treated with IVIG followed by prednisolone and ursodeoxycholic acid. Hemoglobin-thrombocytes increased rapidly and transaminases improved at day 8. We have reported the first case in the literature with AIH-PBC overlap syndrome concurrent by ITP and AIHA which suggest the presence of shared genetic susceptibility factors in multiple autoimmune conditions including AIH, PBC, ITP and AIHA.

Global fibrinolytic capacity increased exponentially in metastatic colorectal cancer.

Colorectal cancers are one of the most common malignancies associated with coagulation abnormalities ranging from asymptomatic laboratory changes to massive thromboembolism or hemorrhage. It was previously shown that global fibrinolytic was increased in non-metastatic colorectal cancer. In this study global fibrinolytic capacity was measured in patients with colorectal cancer and metastatic liver disease, which always more commonly displays various coagulation disorders. Nineteen patients with biopsy-proven colorectal cancer, 30 patients with metastatic colorectal cancer, and 20 healthy control subjects were involved into the study. Using standart silicated fibrin pellets and tissue plasminogen activator, fibrinolytic capacity of the plasmas was detected with the amount of d-dimer produced before the reaction was stopped by adding aprotinin to the medium. Mean global fibrinolytic capacity (GFC) was increased to higher levels in patients with metastatic disease compared to levels in non-metastatic disease (p<0.05). Fibrinogen/GFC ratio correlated to the increase of d-dimer levels. Global fibrinolytic capacity was much higher in metastatic disease, reflecting a progression to overt disseminated intravascular coagulation.

Cardiac dysfunction in cirrhosis.

In cirrhosis, cardiac symptoms and physical signs occur as the liver functions worsen. Cirrhosis is associated with hyperdynamic circulation and beta-adrenergic system activation responsible for the cardiovascular changes. The purpose of the present study was to explore the cardiovascular response to exercise in cirrhotic patients. A total of 20 patients (16 men, four women) with cirrhosis of hepatitis B or C without any cardiac dysfunction were included in the study. Ten people (eight men, two women) were enrolled in the control group. Plasma noradrenaline and adrenaline concentrations, blood pressures in supine and standing positions, exercise echocardiography and exercise radionuclide ventriculography were carried out. In cirrhotics, the exercise capacity was lower and also there was an impaired cardiovascular response to exercise with lower than expected peak heart rate without any cardiac dysfunction, which may have important clinical implications for the ability of these patients to withstand cardiovascular stress.

Global fibrinolytic capacity in colorectal cancer: a new clue to occult fibrinolysis.

Hemostatic disorders in cancer patients range from asymptomatic laboratory changes to massive thromboembolism or hemorrhage. Routine laboratory tests often fail to identify patients at high risk for hemostatic complications. The postoperative risk of thromboembolic events in colorectal cancer was reported as approximately 2% to 5%. A new diagnostic test was used to assess global fibrinolytic activity, which may detect occult fibrinolysis or disseminated intravascular coagulation in patients with colorectal cancer. Twenty patients with colorectal cancer and 20 healthy control subjects were involved. Using standard silicated fibrin pellets and tissue plasminogen activator, the fibrinolytic capacity of the plasma samples was detected with the amount of D-dimer produced before the reaction was stopped by adding aprotinin to the medium. Mean global fibrinolytic capacity was increased in patients before and after surgery when compared to controls (p = 0.002, p = 0.001, respectively). In conclusion, a hemostatic imbalance was detected toward primary fibrinolysis in the preoperative period and low-grade disseminated intravascular coagulation postoperatively.

Monitoring of peripheral blood CD34+ cell counts on the first day of apheresis is highly predictive for efficient CD34+ cell yield.

The purpose of this study was to evaluate the correlation of preleukapheresis circulating CD 34+ cells/micro L, white blood cells (WBC), and platelet counts on the first day of apheresis with the yield of collected CD 34+ cell counts in 40 patients with hematological malignancies (n = 29) and solid tumors (n = 11). The median numbers of apheresis cycles, numbers of CD 34+ cells, peripheral blood (PB) mononuclear cells, and total nucleated cells collected were 2 (range, 1-4), 5.5 x 106/kg (range, 0.05-33.78), 2.59 x 108/kg (range, 0.04-20.68), and 7.36 x 108/kg (range, 0.15-28.08), respectively. There was a strong correlation between the number of preleukapheresis circulating CD 34+ cells/micro L and the yield of collected CD 34+ cells per kilogram (r = 0.962, p < 0.001). The threshold levels of PB C 34+ cell/micro L to obtain > or =1 x 106/kg and > or =2.5 x 106/kg CD 34+ cell in one collection were 12/micro L and 34/ micro L, respectively. Fifteen of 17 (88%) patients who had > or =34 CD 34+ cells/ micro L in the PB before collection reached the level of > or =2.5 x 106/kg in a single apheresis. Despite a low r value, WBC and platelet counts on the first day of apheresis also correlated with the yield of collected daily CD 34+ cells per kilogram (r = 0.482, p < 0.01 and r = 0.496 p < 0.01, respectively). These data suggest that preleukapheresis circulating CD 34+ cells/ micro L correlated significantly better with the yield of collected CD 34+ cells than WBC and platelet counts on the first day of apheresis. Using a value of 34/micro L preleukapheresis circulating CD 34+ cells as a guide for the timing of peripheral blood stem cells collections can be time saving and cost-effective.

Increased erythropoietin levels in reactive thrombocytosis.

Erythropoietin, the major humoral regulator of red cell production, was reported to stimulate various levels of megakaryocytopoiesis. We investigated levels of thrombopoietin (TPO) and erythropoietin (EPO) in patients with reactive thrombocytosis (RT) and clonal thrombocytosis (CT). 17 patients with RT and 18 patients with CT and 15 healthy subjects were enrolled into the study. TPO levels were higher in both patient groups than the controls. EPO levels were significantly higher than these in reactive thrombocytosis and in controls (p < 0.05). We suggest that besides TPO, EPO may play an important role in the pathogenesis of RT.

Influence of post-transplant recombinant human granulocyte colony-stimulating factor administration on peritransplant morbidity in patients undergoing autologous stem cell transplantation.

This study evaluated of the effect of post-transplant recombinant human granulocyte colony-stimulating factor (rhG-CSF) administration on the parameters of peritransplant morbidity. Three sequential and consecutive cohorts of 20 patients each received either post-transplant rhG-CSF at a dose of 5 micro g/kg/d i.v. in the morning, starting on d 0, d 5, or no rhG-CSF. Patients who received rhG-CSF starting on d 0 and 5 recovered granulocytes more rapidly than those not receiving rhG-CSF (P < 0.001 for ANC >or= 0.5 and 1 x 10(9)/l). RhG-CSF administration was not significantly associated with more rapid platelet engraftment. RhG-CSF administration starting on d 0 and 5 was significantly associated with a decreased duration of fever (P = 0.002 and 0.001 respectively), antibiotic administration (P < 0.001 and 0.006 respectively) and shorter hospitalization (P < 0.001 and 0.001 respectively) compared with the reference group. There was no difference between the d 0 and d 5 arms regarding the parameters of peritransplant morbidity. In conclusion, rhG-CSF administration was associated with a faster granulocyte recovery, shorter hospitalization, and shorter period of fever and non-prophylactic antibiotic administration. This study also showed that starting rhG-CSF administration on d 5 may be as effective as d 0 on the clinical outcome and may be an economical approach in routine clinical practice in this cost-conscious era.