Complement as the enabler of carfilzomib-induced thrombotic microangiopathy.

Carfilzomib has been associated with the development of thrombotic microangiopathy (TMA) in relapsed/refractory multiple myeloma patients, a severe disease with no currently available aetiological treatment. We evaluated the potential role of terminal complement pathway in four patients with carfilzomib-induced TMA. Membrane attack complex (C5b-9) deposition on endothelial cells in culture exposed to plasma from patients during the acute phase of the disease suggests complement overactivation as a mechanism of potential endothelial damage in three out of four patients. If confirmed in larger cohorts, C5b-9 evaluation will allow early identification of patients who could benefit from complement blockade and treatment monitoring.

Baseline correlations and prognostic impact of serum monoclonal proteins in follicular lymphoma.

The presence of a serum monoclonal component has been associated with poor outcomes in some lymphomas. However, data in follicular lymphoma (FL) are scarce. We studied 311 FL patients diagnosed at a single institution, for whom information on serum immunofixation electrophoresis (sIFE) at diagnosis was available. Baseline characteristics and outcomes were compared between patients with a positive (+sIFE) and a negative sIFE (-sIFE). sIFE was positive in 82 patients (26%). Baseline features were comparable between both groups, except for an older age and higher proportion of elevated ß2 -microglobulin levels in the +sIFE group. With a median follow-up of 4.6 years, a +sIFE was associated with a higher risk of early relapse (POD24, 27% vs. 15%, P = 0·02), shorter progression-free survival (PFS; 42% vs. 52% at 5 years, P = 0·008), and shorter overall survival (OS; 59% vs. 77% at 10 years, P = 0·046). In patients >60 years, a +sIFE was an independent predictor of OS [hazard ratio (HR) = 2·4, 95% confidence interval (CI): 1·2-5·0; P = 0·02]. Approximately one quarter of patients with FL has a +sIFE at diagnosis, which is a predictor of poor outcome. These findings encourage further investigation of its relationship with B-cell biology and the tumour microenvironment.

Role of therapeutic plasma exchanges in refractory severe warm autoimmune hemolytic anemia: Presentation of two case reports.

BACKGROUND: Warm autoimmune hemolytic anemia (WAIHA) is a disorder with a usually good response to corticosteroid treatment, whereas in some cases first-line treatment's response is poor and other therapies such as intravenous immunoglobulins (IVIGs), rituximab, or splenectomy must be applied. STUDY DESIGN AND METHODS: Herein, we describe two patients with severe WAIHA treated at our center, who obtained a response after therapeutic plasma exchanges (TPEs) combined with low doses of IVIG. RESULTS: The first patient was an 18-year-old man with no relevant past medical history who was diagnosed with WAIHA. The patient presented a progressive clinical worsening despite treatment with prednisone, IVIG, and rituximab. After starting TPEs, signs of hemolysis rapidly improved and hemoglobin started to recover. The second patient was a 38-year-old man with a past history of immune thrombocytopenia and WAIHA. The patient presented a new flare of WAIHA, with no response after 2 weeks of treatment with corticosteroids, IVIG, and rituximab. After initiation of TPEs, the patient had an improvement in hemolysis biomarkers and recovery of hemoglobin concentration. CONCLUSION: Combination of TPEs with rituximab and IVIG might be considered as a therapeutic option in patients with severe WAIHA without response to corticosteroid and IVIG treatment.

Challenges in the management of patients with systemic light chain (AL) amyloidosis during the COVID-19 pandemic.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-associated coronavirus disease 2019 (COVID-19) is primarily manifested as a respiratory tract infection, but may affect and cause complications in multiple organ systems (cardiovascular, gastrointestinal, kidneys, haematopoietic and immune systems), while no proven specific therapy exists. The challenges associated with COVID-19 are even greater for patients with light chain (AL) amyloidosis, a rare multisystemic disease affecting the heart, kidneys, liver, gastrointestinal and nervous system. Patients with AL amyloidosis may need to receive chemotherapy, which probably increases infection risk. Management of COVID-19 may be particularly challenging in patients with AL amyloidosis, who often present with cardiac dysfunction, nephrotic syndrome, neuropathy, low blood pressure and gastrointestinal symptoms. In addition, patients with AL amyloidosis may be more susceptible to toxicities of drugs used to manage COVID-19. Access to health care may be difficult or limited, diagnosis of AL amyloidosis may be delayed with detrimental consequences and treatment administration may need modification. Both patients and treating physicians need to adapt in a new reality.

The renal range of the κ/λ sFLC ratio: best strategy to evaluate multiple myeloma in patients with chronic kidney disease.

BACKGROUND: Monoclonal serum free light chains (sFLC) are a well-known cause of renal impairment (RI) in patients with multiple myeloma (MM). As an indicator of monoclonality, sFLC ratio has acquired a key role in the diagnosis and monitorization of the disease. However, its interpretation is altered in patients with chronic kidney disease (CKD). This study aims to evaluate the modification of the sFLC ratio reference range in patients with CKD, and propose an optimal range for patients with CKD. METHODS: Serum FLC κ/λ ratio and estimated glomerular filtration rate (eGFR) were retrospectively analyzed in 113 control patients (without hematologic disease), 63 patients with MM in complete remission and 347 patients with active MM. The three groups included patients with CKD (eGFR < 90). RESULTS: In the group of patients without active MM (n = 176), the sFLC ratio increased at different stages of CKD without pathological significance, with an increase in the number of false positives specially when eGFR is ≤55 ml/min. An optimal range was established for patients with eGFR ≤55 ml/min/1.73 m2: 0.82-3,6 with maximum sensitivity + specificity for that group with an improvement in the Area under the curve (AUC), 0.91 (0.84-0.97) compared with the current ranges proposed by Katzmann and Hutchinson. CONCLUSIONS: This study confirms the influence of eGFR on the interpretation of the sFLC ratio, showing a decreasing specificity in progressive CKD stages when using the reference sFLC range (Katzmann), especially in patients with eFGR ≤55. According to our results, we suggest a modified optimal range (0.82-3,6) for eGFR ≤55 ml/min/1.73 m2. It is necessary to validate this modified range in larger and prospective studies.

A phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with systemic immunoglobulin light chain amyloidosis.

Immunomodulatory drugs have been shown to be of benefit in relapsed/refractory immunoglobulin light-chain (AL) amyloidosis. We designed a prospective, multicentre phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with AL amyloidosis not eligible for autologous stem-cell transplantation. Twenty-eight patients were included in the study. Cardiac involvement was present in 23 patients; 14 of them had cardiac stage III. The overall haematological response rate was 46%, including complete and very good partial responses in 25% and 18% of patients respectively. Haematological response was mainly associated with absence of cardiac stage III and lower tumour burden. Organ response was observed in 46% of patients. After a median follow-up of 24 months, median progression-free and overall survival have not been reached, both being significantly longer in responders (P < 0·001 and P = 0·001 respectively). Seventeen patients have discontinued treatment, mostly due to amyloid-related death, disease progression or lack of response. Only 14% of the patients discontinued treatment due to therapy-related adverse events. Our results support the efficacy of this regimen, with high quality responses and prolonged survival, as well as its tolerability, in patients with AL amyloidosis not eligible for stem cell transplant and without advanced cardiac involvement (clinicaltrials.gov identifier: NCT01194791).

Pulmonary tumor thrombotic microangiopathy: report of 3 cases and review of the literature.

Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare clinical entity where tumor cell embolisms in pulmonary circulation induce thrombotic microangiopathy (TMA), respiratory failure, and subacute cor pulmonale.We describe 3 cases of PTTM that presented as the initial manifestation of metastatic gastric adenocarcinoma with TMA and pulmonary infiltrates.All 3 cases had similar clinical and laboratory features, which included moderate thrombocytopenia without renal failure, hemolysis with extremely high serum lactate dehydrogenase levels, leukoerythroblastosis in peripheral blood smear, altered coagulation tests, lymphadenopathies, and interstitial pulmonary infiltrates. All patients died within 2 weeks of diagnosis. Two cases were initially misdiagnosed as idiopathic thrombotic thrombocytopenic purpura and treated with plasma exchange with no response. One patient had bone marrow infiltration by malignant cells. Autopsies revealed PTTM associated with gastric disseminated adenocarcinoma (signet-ring cell type in 2 patients and poorly differentiated type in 1).PTTM should be considered in the differential diagnosis of patients with fulminant microangiopathic hemolytic anemia, such as atypical thrombotic thrombocytopenic purpura, mainly those with pulmonary infiltrates, disseminated intravascular coagulation, or Trousseau syndrome.