A prospective multicenter study of paroxysmal nocturnal hemoglobinuria cells in patients with bone marrow failure.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH), a rare clonal hematopoietic stem cell disorder, is characterized by chronic, uncontrolled complement activation leading to intravascular hemolysis and an inflammatory prothrombotic state. The EXPLORE study aimed to determine the prevalence of undiagnosed PNH in patients with aplastic anemia (AA), myelodysplastic syndrome (MDS), and/or other bone marrow failure (BMF) syndromes and the effect of PNH clone size on hemolysis. METHODS: Patients, selected from medical office chart reviews, had blood samples collected for hematologic panel testing and for flow cytometry detection of PNH clones. RESULTS: Granulocyte PNH clones ≥ 1% were detected in 199 of all 5,398 patients (3.7%), 93 of 503 AA patients (18.5%), 50 of 4,401 MDS patients (1.1%), and 3 of 130 other BMF patients (2.3%). Higher-sensitivity analyses detected PNH clones ≥ 0.01% in 167 of 1,746 patients from all groups (9.6%) and in 22 of 1,225 MDS patients (1.8%), 116 of 294 AA patients (39.5%), and four of 54 other BMF patients (7.8%). Among patients with PNH clones ≥ 1%, median clone size was smaller in patients with AA (5.1%) than in those with MDS (17.6%) or other BMF (24.4%), and the percentage of patients with lactate dehydrogenase levels (a marker for intravascular hemolysis) ≥ 1.5 × upper limit of normal was smaller in patients with AA (18.3%) than in those with MDS (42.0%). CONCLUSIONS: These results confirm the presence of PNH clones in high-risk patient groups and suggest that screening of such patients may facilitate patient management and care.

A Prospective Multicenter Study of Paroxysmal Nocturnal Hemoglobinuria Cells in Patients with Bone Marrow Failure.

Background: Paroxysmal nocturnal hemoglobinuria (PNH), a rare clonal hematopoietic stem cell disorder, is characterized by chronic, uncontrolled complement activation leading to intravascular hemolysis and an inflammatory prothrombotic state. The EXPLORE study aimed to determine the prevalence of undiagnosed PNH in patients with aplastic anemia (AA), myelodysplastic syndrome (MDS), and/or other bone marrow failure (BMF) syndromes and the effect of PNH clone size on hemolysis. Methods: Patients, selected from medical office chart reviews, had blood samples collected for hematologic panel testing and for flow cytometry detection of PNH clones. Results: Granulocyte PNH clones ≥ 1% were detected in 199 of all 5398 patients (3.7%), 93 of 503 AA patients (18.5%), 50 of 4401 MDS patients (1.1%), and 3 of 130 other BMF patients (2.3%). Higher-sensitivity analyses detected PNH clones ≥ 0.01% in 167 of 1746 patients from all groups (9.6%) and in 22 of 1225 MDS patients (1.8%), 116 of 294 AA patients (39.5%), and 4 of 54 other BMF patients (7.8%). Among patients with PNH clones ≥ 1%, median clone size was smaller in patients with AA (5.1%) than in those with MDS (17.6%) or other BMF (24.4%), and the percentage of patients with lactate dehydrogenase levels (a marker for intravascular hemolysis) ≥ 1.5 × upper limit of normal was smaller in patients with AA (18.3%) than in those with MDS (42.0%). Conclusions: These results confirm the presence of PNH clones in high-risk patient groups and suggest that screening of such patients may facilitate patient management and care. © 2013 Clinical Cytometry Society.

Increased C-kit intensity is a poor prognostic factor for progression-free and overall survival in patients with newly diagnosed AML.

C-kit, a tyrosine kinase receptor, is expressed on most myeloid blasts and is thought to be important in the pathogenesis of AML. Activation of the c-kit receptor leads to phosphorylation and activation of downstream signaling proteins, which are important for cell survival and proliferation. Here, we discuss the prognostic impact of c-kit intensity, measured using the mean fluorescent index (MFI) in patients with newly diagnosed AML. On multivariate analysis, c-kit MFI>20.3 correlated with a decreased progression-free survival and overall survival, independent of known prognostic factors (age, white blood count at diagnosis and cytogenetics). Whether inhibiting c-kit in patients with AML will alter prognosis is the basis of ongoing clinical trials.

Impact of socioeconomic status and distance from treatment center on survival in patients receiving remission induction therapy for newly diagnosed acute myeloid leukemia.

BACKGROUND: While socioeconomic status (SES) and the distance patients travel to a treatment center (DTC) impact survival of certain solid tumors, little is known of their influence in acute myeloid leukemia (AML). METHODS: We retrospectively reviewed patients receiving remission induction therapy for AML at the Cleveland Clinic between January 1997 and December 2005. Demographic data were obtained from medical records. Income and DTC were determined using online databases. Known prognostic factors (age, WBC count at diagnosis, cytogenetics, AML etiology) were collected and controlled for in Cox proportional hazards analysis. RESULTS: Induction chemotherapy was administered to 281 patients; 91% were Caucasian (C), 8% were African American (AA), and 1% were neither (non-AA non-C). The median DTC was 24 miles (range, 0.9-2058), and median annual household income was USD 38,972 (range, USD17,496-143,220). With a median follow up of 22.6 months, the median overall survival (OS) was 11.3 months. In multivariable analyses, age >or=60 years, unfavorable cytogenetics, initial WBC count and secondary AML significantly influenced survival (p<0.001, p<0.001, p=0.035, and p=0.010, respectively). OS was similar for AAs and non-AA non-Cs compared to Cs (HR=1.12, 95% CI=.61-2.07, p=.71, and HR=0.87, CI=0.21-3.62, p=.84, respectively). Neither DTC (HR=1.00, 95%CI=0.98-1.01, p=.96 per 20 mile increment) nor SES (HR=1.02, 95%CI=0.92-1.13, p=.77 per USD10,000 annual income increase) had an impact on OS. CONCLUSION: Unlike with many solid tumors, SES and DTC are not predictive of outcome in AML patients.

Impact of remission induction chemotherapy on survival in older adults with acute myeloid leukemia.

BACKGROUND: Significant controversy surrounds the use of remission induction chemotherapy (IC) in older adults with acute myeloid leukemia (AML). Earlier clinical trials have yielded conflicting results and possibly a minor survival benefit, often offset by a longer hospitalization time. METHODS: To evaluate the role of IC in patients with AML, a case control study of patients 60 years or older treated at the Cleveland Clinic Taussig Cancer Center between 1997 and 2005 was conducted. Forty-four patients who did not receive IC were matched by a propensity analysis to 138 patients who received an anthracycline-based regimen. RESULTS: The unadjusted median survival of patients who did not receive IC was 53 days, compared with 197 days (P < .001) for those who did. After further adjusting for age, gender, race, leukocyte count at presentation, AML cytogenetics, history of prior hematologic disorder, and assessing for comorbidities, not receiving IC was still associated with worse survival (hazards ratio of 1.88; 95% confidence interval, 1.15-3.05 [P = .01]). Additional predictors of poor outcomes in older adults with AML included higher leukocyte count at presentation, poor-risk cytogenetics, and African-American race (compared with Caucasians). CONCLUSIONS: The study suggests improved outcomes in older adults with AML who undergo remission induction therapy.

The role of aspirin in the prevention of thrombotic complications of thalidomide and anthracycline-based chemotherapy for multiple myeloma.

OBJECTIVE: To study the efficacy of daily low-dose aspirin (81 mg orally) in decreasing the incidence of venous thromboembolic events (VTEs) in patients with multiple myeloma receiving pegylated doxorubicin, vincristine, and decreased-frequency dexamethasone, plus thalidomide (DVd-T). PATIENTS AND METHODS: In this phase 2 clinical trial of DVd-T, conducted by the Cleveland Clinic Foundation from August 2001 to October 2003, 105 patients were enrolled. The first 35 patients experienced increased numbers of VTEs. von Willebrand levels and platelet aggregation to ristocetin before and after treatment with DVd-T increased significantly, suggesting a pathophysiology involving platelet-endothelial interaction. Aspirin was added to the regimen, thus generating 3 patient groups: group 1 received aspirin from the start of DVd-T treatment before the study began (58 patients), group 2 received aspirin after the start of DVd-T treatment and after the study began (26 patients), and group 3 did not receive daily low-dose aspirin during the study (19 patients). Two patients being treated with warfarin for other indications were excluded from the study. The primary end point for this study was the incidence of VTE in the form of either deep venous thrombosis or pulmonary embolism. Secondary end points were the time to the first VTE, time to the composite end point of death or first VTE, and incidence of bleeding complications. RESULTS: After a median follow-up of 24 months, on an intent-to-treat basis, 26 posttreatment VTEs occurred after a median of 90 days, with 19% occurring in group 1, 15% in group 2, and 58% in group 3. Following multivariate time-to-event analysis, aspirin use continued to be associated with lower relative risk of VTE (hazard ratio, 0.22; confidence interval, 0.10-0.47; P<.001) and of the composite end point (hazard ratio, 0.28; confidence interval, 0.15-0.51; P<.001). CONCLUSION: Daily low-dose aspirin (81 mg orally) given to patients with newly diagnosed and relapsed/refractory multiple myeloma who were receiving DVd-T reduced the incidence of VTEs without an increase in bleeding complications.