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.

Long-term Results of Imatinib Discontinuation in Patients with Chronic-phase Chronic Myeloid Leukemia: A National Multicenter Prospective Study

Objective: The discovery of imatinib was a milestone for chronic myeloid leukemia (CML). As the life expectancy of CML patients has approached that of the general population, research has shifted towards improving quality of life and economic considerations. After 2010, it was shown that some patients could maintain molecular response even after discontinuing imatinib. This national multicenter prospective cohort study aimed to observe the long-term consequences of discontinuing imatinib therapy in adult chronic-phase CML patients. Materials and Methods: We enrolled 41 CML patients from 4 different centers in this non-randomized single-arm trial. Molecular responses of all patients were re-evaluated using real-time polymerase chain reaction at a single center. The median follow-up time after imatinib discontinuation was 48 months (minimum-maximum: 6-81 months). Results: The rate of molecular relapse-free survival at 48 months was 33.2% (confidence interval: 48.2-18.2). Twenty-seven of 41 patients lost their major molecular response, treatment was started again, and deep molecular response was re-achieved with imatinib in all cases. There was no significant relationship between molecular relapse and clinical factors such as duration of treatment or molecular response status. Discontinuing imatinib resulted in savings of approximately 4,392,000 Turkish lira or 245,150 US dollars. Conclusion: Tyrosine kinase inhibitor discontinuation with close molecular monitoring is a safe option and provides important national economic benefits for chronic phase CML patients. This approach should be considered for all eligible patients. This is the first tyrosine kinase inhibitor discontinuation study from Türkiye.

Utility of Different Scoring Systems for the Diagnosis of Thrombotic Microangiopathies.

OBJECTIVE:  To investigate the appropriateness of Bentley and plasmic scores and ADAMTS-13 activity to distinguish between primary thrombotic microangiopathies (TMA) syndromes and other thrombotic microangiopathies, as well as primary thrombotic microangiopathies (TTP, complement-related TMA, etc). STUDY DESIGN:  Descriptive study. Place and Duration of the Study: Department of Hematology, Faculty of Medicine, from February 2013 to February 2020. METHODOLOGY: Data of patients with non-immune hemolytic anaemia (MAHA) and thrombocytopenia who had ADAMTS-13 test, were analysed. Clinical and laboratory findings, Bentley and plasmic scores, and ADAMTS activity levels were compared. RESULTS: The patients were grouped as primary (n = 27) and secondary (n = 28) TMA, the age was median 38.0 (18-63) years in the primary TMA group and 49.5 (20-84) years in the secondary TMA group. Neurological findings were less in the secondary TMA group (p = 0.008). Plasmic score, lactate dehydrogenase, and total and indirect bilirubin levels were high and D-dimer levels were low in the primary TMA group. In the primary TMA group, a greater number of patients with high plasmic scores were found, whereas all patients in the secondary TMA group had low risk according to Bentley score. Calcium levels were high and platelet levels were low in those with ADAMTS activity level <10% (p = 0.006). The evaluation of primary TMAs demonstrated significant differences in platelet, urea, creatinine, and sodium values between the two groups. CONCLUSION: Laboratory data and clinical scores are valuable in differentiating primary and other TMA. KEY WORDS: Bentley score, Complement, Plasmic score, Thrombotic microangiopathy, Thrombotic thrombocytopenic purpura, ADAMTS-13.

Pneumonitis associated with bortezomib in a patient with multiple myeloma.

INTRODUCTION: Bortezomib, which is widely used in the treatment of multiple myeloma (MM), is a proteasome inhibitor and acts by inducing apoptosis. Bortezomib has many side effects, mainly hematological, neurological, and gastrointestinal. A few cases of bortezomib-induced pneumonitis (BIP) have been reported in the literature. CASE REPORT: A 51-year-old male patient who was newly diagnosed with MM received bortezomib, cyclophosphamide, and dexamethasone as first-line therapy. In the first cycle, the patient developed dyspnea, tachypnea, and hypoxia after the fourth day of administration of bortezomib monotherapy according to the treatment protocol. MANAGEMENT AND OUTCOME: Infection and pulmonary involvement of MM were excluded after radiological evaluations, and a diagnosis of BIP was made. Clinical control was achieved quickly with steroid therapy and oxygen support, and radiological findings improved with treatment. Due to this rare side effect of bortezomib, the treatment regimen containing bortezomib was changed. The patient is still receiving treatment that does not contain bortezomib and does not have any pulmonary problems. DISCUSSION: In cancer patients receiving treatment, infection and metastasis should be quickly ruled out when pulmonary problems occur, and drug-induced pneumonitis should be considered. This diagnosis, which often responds dramatically to steroids, has the potential to have serious consequences when not considered. In this case, we present bortezomib-associated pneumonitis, a rare side effect of bortezomib. The most important feature of this case is the development of this side effect at the beginning of the treatment, unlike other cases reported in the literature.

Ibrutinib and panitumumab used in combination safely in a patient with metachronous colorectal cancer and chronic lymphocytic leukemia.

Ibrutinib is a Bruton tyrosine kinase inhibitor used in the treatment of chronic lymphocytic leukemia (CLL). Panitumumab, an mAb for epidermal growth factor receptor, is used in the treatment of metastatic colorectal cancer (CRC). We wanted to present our case where we used ibrutinib and panitumumab in combination in a patient with metachronous CLL and CRC. A 58-year-old male patient with a diagnosis of CLL was receiving ibrutinib treatment and primary rectal cancer was detected. FOLFOX + panitumumab were started when metastasis was detected in the lung after neoadjuvant chemoradiotherapy for rectal cancer. The patients used ibrutinib and panitumumab in combination. There was no cumulative or unexpected toxicity due to the combination of both antineoplastic agents. The most important point to be considered in the use of combined drugs is the evaluation of drug-drug interactions. Toxic effects of the combination of ibrutinib and cetuximab have been reported in a patient with metastatic CRC. We used ibrutinib together with panitumumab in our case and we did not encounter any cumulative or unexpected side effects during the treatment.

Castleman Disease: A Multicenter Case Series from Turkey

Objective: Castleman disease (CD) is a rare disease also known as angiofollicular lymph node hyperplasia. The two main histological subtypes are the hyaline vascular and plasma cell variants. It is further classified as unicentric CD (UCD) or multicentric CD (MCD) according to the anatomical distribution of the disease and the number of lymph nodes involved. The aim of this multicenter study was to evaluate all cases of CD identified to date in Turkey to set up a national registry to improve the early recognition, treatment, and follow-up of CD. Materials and Methods: Both adult (n=130) and pediatric (n=10) patients with lymph node or involved field biopsy results reported as CD were included in the study. Patients' demographic information, clinical and laboratory characteristics, imaging study results, treatment strategies, and clinical outcomes were evaluated retrospectively. Results: A total of 140 patients (69 male and 71 female) with a diagnosis of UCD (n=73) or MCD (n=67) were included. The mean age was 39 years in the UCD group and 47 years in the MCD group. Female patients were more common in the UCD group. The most common histological subtype was hyaline vascular for both UCD and MCD patients. Asymptomatic patients were more common in the UCD group. Anemia, elevations of acute phase reactants, and hypoalbuminemia were more common in the MCD group. The most commonly used treatment strategies for UCD were surgical excision, rituximab, and radiotherapy, respectively. All UCD patients were alive at a median of 19.5 months of follow-up. The most commonly used treatment strategies for MCD were methyl prednisolone, R-CHOP, R-CVP, and rituximab. Thirteen MCD patients had died at a median of 34 months of follow-up. Conclusion: This study is important in presenting the patient characteristics and treatment strategies for CD from Turkey, with the potential of increasing awareness about CD. Treatment data may help in making decisions, particularly in countries that do not have access to siltuximab. However, larger prospective studies are needed to make definitive conclusions.

Anaplastic Multiple Myeloma with Multiple Genetic Anomalies.

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Treatment with doxorubicin-based protocol in cardiac involvement diffuse large B-cell lymphoma: A case report.

INTRODUCTION: Cardiac involvement in diffuse large B-cell lymphoma is a rare entity in non-Hodgkin lymphomas. Symptoms are usually related to heart failure. Patients who are severely symptomatic due to cardiac mass could be considered treatment as soon as possible. In this report, we present a patient diagnosed with diffuse large B-cell lymphoma with cardiac involvement. CASE REPORT: A 61-year-old female patient was admitted to our unit with gastric biopsy diffuse large B-cell lymphoma. Computerized tomography of the chest and positron emission tomography/computed tomography demonstrated a neoplastic mass in the intra-atrial septum extended to inferior vena cava (5 × 4 cm in size and standardized uptake value maximum 24.6). She was in stage III and in the high-risk group. Because of pronounced heart failure findings associated with the mass-specific chemotherapy was planned early. MANAGEMENT & OUTCOME: Although a fraction of ejection was 60% by echocardiography before the treatment, she had a cardiac risk for doxorubicin due to being over 60 years old and hypertension. Complete remission was achieved after three cycles of rituximab-cyclophosphamide-doxorubicin-vincristine and methylprednisolone protocol including doxorubicin. Treatment was completed with six cycles and she was followed up for three months. DISCUSSION: Because of the cardiotoxicity of doxorubicin-based protocols, patients should be evaluated according to cardiac functions before and during the chemotherapy.

Clinical Characteristics and Outcomes of COVID-19 in Turkish Patients with Hematological Malignancies

Objective: Patients with solid malignancies are more vulnerable to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection than the healthy population. The outcome of SARS-CoV-2 infection in highly immunosuppressed populations, such as in patients with hematological malignancies, is a point of interest. We aimed to analyze the symptoms, complications, intensive care unit admissions, and mortality rates of patients with hematological malignancies infected with SARS-CoV-2 in Turkey. Materials and Methods: In this multicenter study, we included 340 adult and pediatric patients diagnosed with SARS-CoV-2 from March to November 2020. Diagnosis and status of primary disease, treatment schedules for hematological malignancies, time from last treatment, life expectancy related to the hematological disease, and comorbidities were recorded, together with data regarding symptoms, treatment, and outcome of SARS-CoV-2 infection. Results: Forty four patients were asymptomatic at diagnosis of SARS-CoV- 2 infection. Among symptomatic patients, fever, cough, and dyspnea were observed in 62.6%, 48.8%, and 41.8%, respectively. Sixty-nine (20%) patients had mild SARS-CoV-2 disease, whereas moderate, severe, and critical disease was reported in 101 (29%), 71 (20%), and 55 (16%) patients, respectively. Of the entire cohort, 251 (73.8%) patients were hospitalized for SARS-CoV-2. Mortality related to SARS-CoV-2 infection was 26.5% in the entire cohort; this comprised 4.4% of those patients with mild disease, 12.4% of those with moderate disease, and 83% of those with severe or critical disease. Active hematological disease, lower life expectancy related to primary hematological disease, neutropenia at diagnosis of SARS-CoV-2, ICU admission, and first-line therapy used for coronavirus disease-2019 treatment were found to be related to higher mortality rates. Treatments with hydroxychloroquine alone or in combination with azithromycin were associated with a higher rate of mortality in comparison to favipiravir use. Conclusion: Patients with hematological malignancy infected with SARS-CoV-2 have an increased risk of severe disease and mortality.

Dynein axonemal heavy chain 9 M4374I variation may have an effect on imatinib mesylate resistance in CML.

Chronic myelogenous leukemia (CML) is a myeloproliferative neoplasm caused by a translocation between the breakpoint cluster region (BCR) and Abelson murine leukemia 1 (ABL1) genes. Tyrosine kinase inhibitors (TKIs) are used in the treatment of CML. TKIs, bind the ABL1 kinase domain of hybrid BCR-ABL1 protein and inhibit its function. However, resistance can occur due to the pathogenic variations in the ABL kinase domain or BCR-ABL1-independent mechanisms. In the present study, genetic variations possibly related to imatinib resistance in CML were explored. A total of five single nucleotide polymorphisms [SNPs; MORN2 rs3099950, PTCRA rs9471966, ANKRD35 rs11579366, dynein axonemal heavy chain 9 (DNAH9) rs1990236 and MAGEC1 rs176037] were investigated in imatinib sensitive and in resistant CML patients. Additionally, sequencing of the ABL1 kinase domain was also performed. The frequency of DNAH9 M4374I (NP_001363.2)/M686I (NP_004653.2) (rs1990236) was found to be significantly higher in the imatinib-resistant group. However, the other SNPs did not exhibit any statistically significant differences and no new variant was detected in the ABL1 kinase domain. Considering the frequency difference of the DNAH9 rs1990236 between imatinib-sensitive and imatinib-resistant groups, DNAH9 gene may play a role in TKI resistance. Due to the limited amounts of literature available on this subject, further studies on DNAH9 and related genes may prove to be beneficial for the elucidation of the association between DNAH9 and TKI resistance. Moreover, further larger studies are required to support the current findings. This may aid in the development of novel treatment protocols for patients with CML with DNAH9 genetic polymorphisms.

Bing-Neel syndrome: A case reports.

INTRODUCTION: Bing-Neel syndrome (BNS) is a rare complication of of Waldenström macroglobulinemia (WM) identified by involvement of central nervous system (CNS) lymphoplasmacytic cells. CASE REPORT: We present a patient who was diagnosed with Bing-Neel syndrome four years after the diagnosis of Waldenström macroglobulinemia. MANAGEMENT & OUTCOME: The patient was admitted with neurological symptoms. There were lesions associated with WM involvement on brain imaging. The diagnosis was made by brain biopsy. High dose methotrexate treatment was given. DISCUSSION: CNS infiltrating agents such as fludarabine, methotrexate and cytarabine are often used in BNS treatment. Ibrutinib, which is a new bruton tyrosine kinase inhibitor, has recently started to be used in BNS treatment, as it has been shown to be effective and penetrate the CNS.

Solitary Plasmacytoma of the Mandible: An Uncommon Entity.

INTRODUCTION: Plasma cell dyscrasias are characterized by a monoclonal neoplastic proliferation of plasma cells. Solitary bone plasmacytoma (SBP) is a local form of the disease with the vertebrae and long bones being the most frequently encountered sites. Its prevalence in the maxillofacial area is extremely rare. CASE PRESENTATION: A 70-year-old Caucasian male patient was referred for the extraction of his mobile premolar tooth with a poorly-defined radiolucent lesion. Histopathological analysis revealed an SBP and no distant lesion or serum M protein was noted on radiological and hematological examinations. The patient was under follow-up care with no recurrence at 2 years of follow up. CONCLUSIONS: Diagnosis of an SBP is based on local radiological and neurological symptoms and similar systemic manifestations of multiple myeloma that are also distinctive for SBP. Skeletal radiological analysis including CT and PET-CT, bone marrow biopsy, and serum protein electrophoresis are essential for confirmation of the diagnosis. Although surgery, chemotherapy, and radiation, or a combination of these modalities, have been successfully used in the treatment of SBP, it should be managed in relation to its possible long-term evolution.

Value of 18F-fluorodeoxyglucose uptake in positron emission tomography/computed tomography in predicting survival in multiple myeloma.

PURPOSE: We assessed the role of the maximum standardized uptake value (SUV(max)) of bone marrow and the extramedullary lesion with the highest SUV(max) in positron emission tomography/computed tomography (PET/CT) of newly diagnosed multiple myeloma (MM) patients in predicting overall survival (OS). METHODS: A total of 61 newly diagnosed patients (55 MM and 6 plasmacytoma) were enrolled in the study [37 men and 24 women with a median age of 57 years (range 28-80 years)]. The SUV(max) of bone marrow and the extramedullary lesion in PET/CT was correlated with the levels of ß(2)-microglobulin, C-reactive protein (CRP), albumin, creatinine, per cent of bone marrow plasma cells, serum free light chain (FLC) ratio, International Staging System (ISS) score and Durie-Salmon stage. RESULTS: The extramedullary lesion with the highest SUV(max) showed significant correlation with bone marrow fluorodeoxyglucose (FDG) uptake (p = 0.027) and near significant correlation with ISS (p = 0.048). Bone marrow SUV(max) correlated significantly with the per cent of bone marrow plasma cell count (p = 0.024), CRP (p = 0.012) and ISS (p = 0.013). In stage III MM the mean values of SUV(max) in extramedullary lesions were significantly higher than stages I and II (6.23 ± 6.32 vs 2.85 ± 3.44, p = 0.023). The serum FLC ratio did not show any correlation with SUV(max) of lesions and bone marrow (p > 0.05). Forty-four MM patients with FDG-positive lesions in PET/CT showed inferior 5-year estimated survival (61.73%) when compared to 11 patients without FDG-positive lesions, all of whom were alive (p = 0.01). In multivariate analysis an extramedullary lesion with the highest SUV(max) was the only independent predictor of OS (p = 0.03). CONCLUSION: PET/CT allows identification of high-risk myeloma patients, and extramedullary lesions with the highest SUV(max) independently predict inferior OS.

Hepatitis B-related events in autologous hematopoietic stem cell transplantation recipients.

AIM: To investigate the frequency of occult hepatitis B, the clinical course of hepatitis B virus (HBV) reactivation and reverse seroconversion and associated risk factors in autologous hematopoietic stem cell transplantation (HSCT) recipients. METHODS: This study was conducted in 90 patients undergoing autologous HSCT. Occult HBV infection was investigated by HBV-DNA analysis prior to transplantation, while HBV serology and liver function tests were screened prior to and serially after transplantation. HBV-related events including reverse seroconversion and reactivation were recorded in all patients. RESULTS: None of the patients had occult HBV prior to transplantation. Six (6.7%) patients were positive for HBV surface antigen (HBsAg) prior to transplantation and received lamivudine prophylaxis; they did not develop HBV reactivation after transplantation. Clinical HBV infection emerged in three patients after transplantation who had negative HBV-DNA prior to HSCT. Two of these three patients had HBV reactivation while one patient developed acute hepatitis B. Three patients had anti-HBc as the sole hepatitis B-related antibody prior to transplantation, two of whom developed hepatitis B reactivation while none of the patients with antibody to HBV surface antigen (anti-HBs) did so. The 14 anti-HBs- and/or anti-HBc-positive patients among the 90 HSCT recipients experienced either persistent (8 patients) or transient (6 patients) disappearance of anti-HBs and/or anti-HBc. HBsAg seroconversion and clinical hepatitis did not develop in these patients. Female gender and multiple myeloma emerged as risk factors for loss of antibody in regression analysis (P < 0.05). CONCLUSION: Anti-HBc as the sole HBV marker seems to be a risk factor for reactivation after autologous HSCT. Lamivudine prophylaxis in HbsAg-positive patients continues to be effective.

Autonomic nervous system dysfunction and serum levels of neurotoxic and neurotrophic cytokines in patients with cobalamin deficiency.

OBJECTIVE: The imbalance between neurotoxic cytokine tumor necrosis factor-α (TNF-α) and neurotrophic cytokines epidermal growth factor (EGF) and interleukin-6 (IL-6) plays a role in the pathogenesis of cobalamin (Cbl) deficiency-induced neuropathy. The aim of this study was to evaluate autonomic nervous system dysfunction and to look for any relationship between autonomic nervous system disturbances and serum cytokine levels (TNF-α, EGF, IL-6) in patients with Cbl deficiency. METHODS: Serum levels of TNF-α, EGF and IL-6 were studied in patients with Cbl deficiency (n=41) and a healthy control group (n=17) and after 3 months in patients who underwent Cbl replacement therapy (n=22). All patients with Cbl deficiency underwent electrophysiological studies (EPS) for the diagnosis of neuropathy. Statistical analysis was performed using SPSS for Windows 11.5 software. RESULTS: With EPS, 29 of 41 Cbl-deficient patients (70.73%) demonstrated neurological dysfunction [3 (7.32%), 19 (46.34%) and 7 (17.07%) patients with sensorimotor peripheral neuropathy, parasympathetic, and sympathetic autonomic dysfunction, respectively]. Although there was no significant difference in serum levels of EGF and IL-6 between patients with versus without autonomic dysfunction, levels were significantly lower in Cbl- deficient patients than healthy controls. CONCLUSION: Presence of autonomic dysfunction seems to be a frequent neurological finding in patients with Cbl deficiency. However, we could not find any relationship between serum cytokine levels and autonomic dysfunction by EPS.

Atraumatic osteonecrosis after estrogen replacement therapy associated with low protein S level in a patient with Turner syndrome.

Atraumatic osteonecrosis has been associated with a variety of clinical conditions including corticosteroid usage, alcoholism, infections, hyperbaric events, storage disorders, marrow-infiltrating diseases, coagulation defects, and some autoimmune diseases. Osteonecrosis due to thrombophilia is an extremely rare condition with only few cases reported previously in the literature. Hormone-replacement therapies cause increased risk of venous thrombosis, probably by causing a synergistic effect with inherited clotting defects. In this article, we report a young female with Turner syndrome, who developed avascular necrosis of the femoral head during treatment with oral estrogen, which was associated with low protein S levels.

Evaluation of superoxide dismutase enzyme activity of polymorphonuclear leucocytes, erythrocytes and thrombocytes in patients with chronic myeloproliferative disorders.

This study aimed to investigate the activity of the antioxidant enzyme superoxide dismutase (SOD) in the three main cell types in chronic myeloproliferative disorders (CMPD) patients, i.e. polymorphonuclear leucocytes (PMNLs), erythrocytes and thrombocytes, prior to therapy. Patients with reactive neutrophilia (RN) and healthy volunteers were included as controls. The SOD activity of PMNLs was significantly decreased in CMPD and RN patients compared with healthy volunteers, whereas the SOD activity of erythrocytes was found to be significantly increased in patients with CMPD and RN compared with healthy volunteers. There were no significant differences in the SOD activity of thrombocytes between CMPD patients, RN patients or healthy volunteers. This study indicates that the activity of the SOD enzyme in two cell types is different in CMPD patients compared with healthy subjects. Thus, SOD activity may be altered dependent on cell type and due to specific cell function.