Paroxysmal nocturnal hemoglobinuria (PNH) is a debilitating and life-threatening disease in which lysis of PNH red blood cells frequently manifests with chronic hemolysis, anemia, and thrombosis. Renal damage in PNH is associated with chronic hemosiderosis and/or microvascular thrombosis. We determined the incidence of renal dysfunction or damage, defined by stages of chronic kidney disease (CKD), in a large cohort of PNH patients and evaluated the safety and efficacy of the complement inhibitor eculizumab in altering its progression. Renal dysfunction or damage was observed in 65% of the study population at baseline with 21% of patients with later stage CKD or kidney failure (glomerular filtration rate [GFR] 60 ml/min/1.73 m 2 ; Stage 3, 4, or 5). Eculizumab treatment was safe and well-tolerated in patients with renal dysfunction or damage and resulted in the likelihood of improvement as defined as categorical reduction in CKD stage (P < 0.001) compared with baseline and to placebo (P 5 0.04). Improvement in renal function was more commonly seen in patients with baseline CKD Stages 1-2 (67.1% improvement, P < 0.001) although improvement was also observed in patients with CKD Stages 3-4 (P 5 0.05). Improvements occurred quickly and were sustained for at least 18 months of treatment. Patients categorized at CKD Stages 3-5 did not worsen during treatment with eculizumab. Overall, 40 (21%) of 195 patients who demonstrated renal dysfunction or damage at baseline were no longer classified as such after 18 months of treatment. Administration of eculizumab to patients with renal dysfunction or damage was well tolerated and was usually associated with clinical improvement. Am. J. Hematol. 85:553-559, 2010. V
Background: Cardio-Oncology (CO) is a new subspecialty that thrives mostly in large academic quaternary centers. This study describes how to establish a successful cardio-oncology program, with limited resources, in order to effectively manage the unique care required by this patient population. Methods: Clinical data was collected from 25 consecutive months. There were four foundational elements to establish a CO program: 1. Clinical program: integrating staff and resources from the Heart and Vascular, and Cancer Centers; 2. Education Program: establishing a platform to educate/advocate with respect to CO; 3. Engagement with professional societies: active engagement allowed for the successful establishment of the proposed CO program; and 4. Research program: establishing data collection modalities/cooperation with other institutions. Results: 474 consecutive patients were treated by our CO program during the first 25 months of operation. Clinical data, information about cancer treatment, cardiovascular co morbidities, cardiac testing and impact of CO management are reported. Conclusions: A successful CO program can be established utilizing existing resources without the need for significant additional assets. Integration with professional societies, advocacy, education and research, provide a platform for learning and growth. This model improves access to care and can be reproduced in a variety of settings.
PNH is a debilitating and life-threatening clonal hematopoietic disease in which lysis of PNH RBCs manifests with chronic hemolysis, anemia and thrombosis. Incidence of progression to chronic renal insufficiency (CRI; GFR < 60 ml/min/1.73 m2) has not been previously examined in a controlled trial. Renal damage in PNH has been associated with chronic hemolysis and subsequent hemosiderosis and/or microvascular thrombosis. A previous study showed that 9/9 hemolytic PNH patients had renal hemosiderin by MRI [Hill et al., 48th Annual ASH meeting, Dec. 9, 2006]. All patients entering into the recently completed eculizumab multinational studies in hemolytic PNH patients (Phase 2, TRIUMPH, SHEPHERD; n=195) were screened for CRI and for a previous clinical diagnosis of CRI and acute renal failure (ARF). The median GFR was 81 ml/min/1.73 m2 (63–97). The incidence of CRI at screening was 21% (40/195) with 10/40 patients having severe CRI (GFR ≤30ml/min). Of 195 patients, 7% (14/195) had previously experienced episodes of ARF which showed at least partial recovery and 21% (3/14) of these patients subsequently developed CRI. Only 25% (10/40) of patients with pre-study CRI had been clinically diagnosed with CRI. Most patients (68%, 27/40) who developed CRI had not previously been clinically diagnosed with either ARF or CRI. Median disease duration and median time from first thrombosis to study entry were increased in CRI patients vs non-CRI patients (8.8 yrs vs 5.1 yrs and 4.6 yrs vs 3.2 yrs, respectively). Proportions of patients with PNH for 10 or more years and 10 or more years since first thrombosis were increased in CRI patients vs non-CRI patients (48%, 19/40 vs 28%, 43/155, P=.02; and 13%, 5/40 vs 3%, 5/155, P=.03, respectively). Eculizumab was safe and well-tolerated in patients with CRI including 1 patient receiving dialysis, with AEs similar to those in patients without CRI. Eculizumab was associated with a reduction in median LDH from 1783 to 331 U/L (P<.0001) and reduction in thrombosis from 5.34 to 0.00 thrombotic events/100 pt-years (P<.0001) in patients with CRI. For patients with baseline CRI, GFR remained stable (median increase 0.47 ml/min/1.73m2) and 10% of patients were no longer classified as CRI, with eculizumab treatment. For the 14 patients with ARF pre-eculizumab, only one patient was reported with ARF during eculizumab (P<.001). CRI is a common finding in PNH as the observed prevalence in hemolytic PNH patients is increased 5-fold compared to the prevalence in the overall U.S. population [NEJM2006;354:2473–83]. ARF is a specific risk factor for development of CRI, although it is not a sensitive risk indicator as most patients with CRI did not previously have ARF. These data suggest that all PNH patients should be closely monitored for CRI and that hemolysis and/or microvascular thrombosis are risk factors for CRI. In the current studies of hemolytic PNH patients, CRI was associated with both increased duration of PNH and duration of exposure to thrombotic events. Eculizumab is safe and effectively reduces hemolysis and thrombosis in PNH patients with ARF and CRI. Moreover, as eculizumab controls hemolysis, reduces thrombosis, and reduces re-occurrence of ARF, the long-term impact of eculizumab on the prevention of renal pathology and CRI in patients with PNH will continue to be evaluated.
Primary plasma cell leukemia (PCL) is a rare and aggressive variant of multiple myeloma (MM). PCL is characterized by peripheral blood involvement by malignant plasma cells and an aggressive clinical course leading to poor survival. There is considerable overlap between MM and PCL with respect to clinical, immunophenotypic, and cytogenetic features, but circulating plasma cell count exceeding 20% of peripheral blood leukocytes or an absolute plasma cell count of >2000/mm3 distinguishes it from MM. After initial stabilization and diagnosis confirmation, treatment of PCL in a fit patient typically includes induction combination chemotherapy containing novel agents typically, with proteasome inhibitors (such as bortezomib) and immunomodulatory drugs (eg, lenalidomide), followed by autologous hematopoietic stem cell transplant (HSCT) and multidrug maintenance therapy using novel agents post-HSCT. Long-term outcomes have improved employing this strategy but the prognosis for non-HSCT candidates remains poor and new approaches are needed for such PCL patients not eligible for HSCT. Here, we report a case of primary PCL, and a comprehensive and up to date review of the literature for diagnosis and management of PCL. We also present the findings of Positron Emission Tomography (PET) scan. Since PCL is often associated with extra-medulary disease, including PET scan at the time of staging and restaging may be a novel approach particularly to evaluate the extra-medullary disease sites.
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