Robert C. Wolf

Rituximab for Immune Cytopenia in Adults: Idiopathic Thrombocytopenic Purpura, Autoimmune Hemolytic Anemia, and Evans Syndrome

OBJECTIVE To evaluate the efficacy of rituximab for the treatment of adult patients with immune cytopenia, including idiopathic thrombocytopenic purpura (ITP), autoimmune hemolytic anemia, and Evans syndrome. PATIENTS AND METHODS We retrospectively reviewed the medical charts of all patients treated with rituximab for immune cytopenia at the Mayo Clinic in Rochester, Minn, through January 1, 2003. Fourteen patients (median age at first diagnosis, 51 years; range, 21-79 years) were identified who received 1 or more treatment courses of rituximab for treatment of refractory ITP (12 patients), autoimmune hemolytic anemia (AIHA) (5 patients), or both ITP and AIHA (classified as Evans syndrome) (4 patients). Data regarding age, diagnosis, date of diagnosis, previous treatments, comorbid conditions, blood cell counts before taking rituximab, number of rituximab treatments, and response to treatment were extracted and analyzed. RESULTS Of 12 patients treated for ITP, 6 were receiving corticosteroid-based treatment either alone or combined with other immunosuppressive therapy at the time they received rituximab. Complete remission occurred in 5 (42%) of 12 patients with ITP and in 2 (40%) of 5 patients with AIHA. Response to rituximab in patients with Evans syndrome was seen in either ITP or AIHA, but not both. Complete response was often durable in ITP. Responses were seen in both splenectomized and nonsplenectomized patients. CONCLUSIONS Our findings, considered with the results of other studies, suggest that rituximab deserves early consideration as salvage therapy for immune cytopenias that are refractory to both corticosteroid treatment and splenectomy. This series represents the largest series of adult patients with AIHA and Evans syndrome.

Prognostic model for disease‐specific and overall mortality in newly diagnosed symptomatic patients with Waldenstrom macroglobulinaemia

We sought to define prognostic factors for survival in Waldenstrom macroglobulinaemia (WM). Of 585 patients diagnosed with WM and seen at Mayo Clinic between 1960 and 2001, 337 symptomatic patients met the inclusion criteria and were analysed for overall and disease‐specific survival. The median survival from the time of diagnosis was 6·4 years. The median disease‐specific survival was 11·2 years. Univariate analysis for overall survival identified the following adverse prognostic factors: age >65 years (P < 0·001), organomegaly (P < 0·001), elevated β2‐microglobulin (<0·001), anaemia (Hb < 10·0 g/dl) (P = 0·01), leucopenia (<4·0 × 109/l) (P = 0·03), thrombocytopenia (<150 × 109/l) (P = 0·01), serum albumin <40 g/l (P = 0·001), and quantitative IgM < 0·4 g/l (P = 0·04). On multivariate analysis, age >65 years and organomegaly were associated with poor prognosis. A prognostic model was built based on these two variables. Patients at high risk (1–2 risk factors, median survival 4·2 years) experienced worse survival than patients at low risk (0 risk factors, median survival 10·6 years), P < 0·001. The prognostic model was validated in 204 patients who were not included in the analysis cohort. β2‐microglobulin ≥4 mg/l was associated with a threefold increase in the risk of death when added to the prognostic model. We describe a simple prognostic model for overall survival for newly diagnosed patients with WM.

Autologous Stem Cell Transplant in 716 Patients With Multiple Myeloma: Low Treatment-Related Mortality, Feasibility of Outpatient Transplant, and Effect of a Multidisciplinary Quality Initiative

We report on the feasibility of outpatient transplant in 716 patients undergoing autologous stem cell transplant for multiple myeloma at Mayo Clinics site in Rochester, MN, from January 1, 2000, through October 31, 2007. We also report on the development and effect of a multidisciplinary quality initiative implemented by the Mayo Clinic Blood and Marrow Transplant Program involving physicians, nurses, pharmacists, dietitians, and financial specialists for outpatient management of patients undergoing stem cell transplant. This approach uses an electronic ordering system for diagnostic tests and chemotherapy to minimize medical errors. Analysis of hospitalization trends since inception of the program showed that 278 (39%) of the 716 patients treated completed the transplant procedure as outpatients. The median duration of hospitalization for all patients was 4 days; age and serum creatinine levels were predictive of the need for and duration of hospitalization. We also assessed recent treatment-related mortality rates during a 33-month period after implementation of the program (between January 1, 2005, and October 1, 2007). The 100-day survival rate was 99.5% for patients with low-risk myeloma (transplant during first plateau; n=201) and 97.2% for patients with high-risk myeloma (refractory, relapsing or second or greater plateau; n=71). The overall 100-day survival rate was 98.9%. Our experience shows that outpatient transplant is feasible for all patients with multiple myeloma and results in shorter hospital stays and low treatment-related mortality rates.

Cost-Effectiveness Analysis of a Risk-Adapted Algorithm of Plerixafor Use for Autologous Peripheral Blood Stem Cell Mobilization

Historically, up to 30% of patients were unable to collect adequate numbers of peripheral blood stem cells (PBSCs) for autologous stem cell transplantation (ASCT). Plerixafor in combination with granulocyte colony-stimulating factor (G-CSF) has shown superior results in mobilizing peripheral blood (PB) CD34+ cells in comparison to G-CSF alone, but its high cost limits general use. We developed and evaluated risk-adapted algorithms for optimal utilization of plerixafor. In plerixafor-1, PBSC mobilization was commenced with G-CSF alone, and if PB CD34 on day 4 or day 5 was <10/μL, plerixafor was administered in the evening, and apheresis commenced the next day. In addition, if on any day, the daily yield was <0.5 × 10(6) CD34/kg, plerixafor was added. Subsequently, the algorithm was revised (plerixafor-2) with lower thresholds. If day-4 PB CD34 <10/μL for single or <20/μL for multiple transplantations, or day-1 yield was <1.5 × 10(6) CD34/kg, or any subsequent daily yield was <0.5 × 10(6) CD34/kg, plerixafor was added. Three time periods were analyzed for results and associated costs: January to December 2008 (baseline cohort; 319 mobilization attempts in 278 patients); February to November 2009 (plerixafor-1; 221 mobilization attempts in 216 patients); and December 2009 to June 2010 (plerixafor-2; 100 mobilization attempts in 98 patients). Plerixafor-2 shows a significant improvement in PB CD34 collection, increased number of patients reaching minimum and optimal goals, fewer days of apheresis, and fewer days of mobilization/collection, albeit at increased costs. In conclusion, although the earlier identification of ineffective PBSC mobilization and initiation of plerixafor (plerixafor-2) increases the per-patient costs of PBSC mobilization, failure rates, days of apheresis, and total days of mobilization/collection are lower.

Clinical impact and resource utilization after stem cell mobilization failure in patients with multiple myeloma and lymphoma

High-dose chemotherapy in conjunction with auto-SCT is the preferred treatment of relapsed Hodgkin disease and non-Hodgkin lymphoma and newly diagnosed multiple myeloma. Failure to achieve optimal stem cell mobilization results in multiple subsequent attempts, which consumes large amounts of growth factors and potentially requires antibiotics and transfusions. We retrospectively reviewed the natural history of stem cell mobilization attempts at our institution from 2001 to 2007 to determine the frequency of suboptimal mobilization in patients with hematologic malignancy undergoing autologous transplant and analyzed the subsequent resource utilization in patients with initially failed attempts. Of 1775 patients undergoing mobilization during the study period, stem cell collection (defined by the number of CD34+ cells/kg) was ‘optimal’ (⩾5 × 106) in 53%, ‘low’ (⩾2–5 × 106) in 25%, ‘poor’ (<2 × 106) in 10%, and ‘failed’ (<10 CD34+ cells/μl) in 12%. In the 47% of collections that were less than optimal, increased resource consumption included increased use of growth factors and antibiotics, subsequent chemotherapy mobilization, increased transfusional support, more apheresis procedures, and more frequent hospitalization. This usually unappreciated resource utilization associated with stem cell mobilization failure highlights the need for more effective mobilization strategies.

Thromboembolism in Adults with Acute Lymphoblastic Leukemia During Induction with L-Asparaginase-containing Multi-agent Regimens: Incidence, Risk Factors, and Possible Role of Antithrombin

Thromboembolism (TE) is a known complication of L-asparaginase (ASP) therapy of acute lymphoblastic leukemia (ALL), possibly attributable to reduced synthesis of natural anticoagulants, in particular antithrombin (AT). This retrospective single institution study was performed to determine the TE incidence among adults undergoing induction with contemporary, ASP-containing regimens. Ten of 54 (18.5%) consecutive adults developed symptomatic, objectively confirmed TE, at a median of 5.5 days after the first ASP dose. These were notable for CNS and upper extremity localization, varied significantly according to ALL immunophenotype (precursor B: 11% vs. T cell: 33%), without apparent effect of schedule or total dose of ASP. Median baseline AT level was 94% and fell to a nadir of 47% (P < 0.0001) during ASP therapy. Prophylactic AT had been given to 17 during ASP therapy. None of these developed TE vs. 10/37 (27%) without replacement (P = 0.021). These observations merit further study to gain insight into disease and/or therapy-specific pathogenesis of TE in this population and call for the prospective evaluation of appropriate prophylactic interventions.

Omission of day +11 methotrexate after allogeneic bone marrow transplantation is associated with increased risk of severe acute graft-versus-host disease

The combination of CYA and short-course MTX is commonly used for GVHD prophylaxis after allogeneic BMT. Severe mucositis and organ dysfunction early after transplantation often lead to omission of the day +11 dose of MTX. To examine whether this omission increases the risk of acute or chronic GVHD, we reviewed 135 allogeneic BMTs performed at our institution in which CYA and short-course MTX prophylaxis were used. Patients receiving less than three doses of MTX and those who died before day +11 were excluded. Of the 123 eligible patients, 84 received all four doses and 39 received three doses, with the fourth dose withheld because of severe mucositis (n = 27) or hepatic or renal dysfunction (n = 12). Acute GVHD of any grade developed in 23 patients (59%) in the three-dose group compared with 57 patients (68%) in the four-dose group (P = 0.33). Chronic GVHD developed in 15 patients (38%) in the three-dose group compared with 31 patients (37%) in the four-dose group (P = 0.87). There was no difference in the overall rate of acute or chronic GVHD between the groups. However, the three-dose group was more likely to develop grade III or IV acute GVHD (12 of 39 (31%) ) compared with the four-dose group (12 of 84 (14%); P = 0.03). Relapse-free survival was similar for the two groups. We conclude that omitting day +11 MTX appears to increase the risk of severe acute GVHD.

Therapeutic Options in Patients With Lymphoma and Severe Liver Dysfunction

OBJECTIVES To determine the long-term outcome of patients presenting with synchronous lymphoma and severe liver dysfunction and to describe the outcome of patients treated with initial mechlorethamine-based therapy used as a bridge to more conventional chemotherapy. PATIENTS AND METHODS We reviewed the clinical course of all patients diagnosed as having lymphoma who presented with severe liver dysfunction and received intravenous mechlorethamine between September 1988 and February 2003 at the Mayo Clinic in Rochester, Minn. RESULTS Forty-one patients were identified, 33 (80%) of whom had newly diagnosed, previously untreated lymphoma. Thirty-seven (90%) had non-Hodgkin lymphoma, and 4 (10%) had Hodgkin disease. Thirty-four patients (83%) had stage IV disease, and 31 (84%) of 37 had an intermediate-high International Prognostic Index. The median total bilirubin level before therapy was 10.7 mg/dL (range, 2.5-30.2 mg/dL), and the median alkaline phosphatase level was 982 U/L (range, 233-3415 U/L). In addition to mechlorethamine, 34 patients (83%) received concomitant corticosteroids, and 12 (29%) received concomitant rituximab. Twenty-two patients (54%) had sufficient improvement in liver function to receive subsequent standard chemotherapy. Nine patients (22%) are alive and disease-free at a median of 31 months (range, 4 to > or = 87 months) after mechlorethamine treatment. Factors associated with improved overall survival included improvement in bilirubin levels (P < .001) and receiving subsequent standard chemotherapy (P = .001). CONCLUSION Mechlorethamine, high-dose corticosteroids, and rituximab are useful therapeutic interventions for this unique group of patients with lymphoma and severe liver dysfunction. Substantial clinical improvement and long-term survival are possible.

The incidence of invasive fungal infections in neutropenic patients with acute leukemia and myelodysplastic syndromes receiving primary antifungal prophylaxis with voriconazole

The objective of this study is to characterize the outcomes of primary antifungal prophylaxis with voriconazole in patients receiving intensive chemotherapy for acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS). We conducted a single center, retrospective, cohort study of consecutive adult patients with AML or MDS at Mayo Clinic between January 1, 2006 and July 1, 2010. The study included patients undergoing induction or first relapse combination chemotherapy who received voriconazole 200 mg orally twice daily as prophylaxis during the neutropenic phase. Patient records were evaluated until 30 days after neutrophil recovery for development of invasive fungal infection (IFI) as defined per EORTC/MSG 2008 criteria with computed tomography scans independently reviewed by a radiologist. Therapeutic drug monitoring and reasons for voriconazole discontinuation were documented. Twenty four episodes of IFI were detected among 165 consecutive patients for an overall incidence of 145 per 1000 patients. The incidence of IFI was 24, 42, and 78 per 1000 patients for proven, probable, and possible infection, respectively. Four patients developed proven IFI (n = 2 Aspergillus spp., n = 2 Rhizopus spp.). Serum voriconazole trough concentrations were available in 39 patients, and no statistically significant difference in voriconazole trough level was observed between those with versus without an IFI. Voriconazole prophylaxis was discontinued in 81 patients due to suspected IFI (n = 24), fever of unknown origin (n = 19), adverse events (n = 23), and other causes (n = 17). Voriconazole as primary IFI prophylaxis is safe and may be beneficial in AML/MDS patients receiving intensive chemotherapy. Am. J. Hematol. 88:283–288, 2013.

Imatinib and type 2 diabetes.

OBJECTIVE To characterize the effect, if any, of imatinib mesylate, an inhibitor of abl tyrosine kinase used in the treatment of chronic myeloid leukemia, on type 2 diabetes. METHODS The centralized pharmacy database was used to identify all patients who had received imatinib at the Mayo Clinic in Rochester, Minnesota, during a 5-year period. The electronic medical records were subsequently reviewed to identify which of these patients had type 2 diabetes. In addition, relevant biochemical data, prior to, during, and after imatinib treatment, were abstracted from the electronic laboratory database and medical records. RESULTS At the Mayo Clinic in Rochester, Minnesota, a total of 164 patients received imatinib during the period of study (1999 to 2004). Of these 164 patients, 7 had preexisting type 2 diabetes, and diabetes developed in 2 patients during treatment with imatinib. Despite 2 previous reports of improvement in glycemic control with use of imatinib in patients with type 2 diabetes, no net effect on glycemic control or diabetes therapy was noted in our study cohort. CONCLUSION On the basis of our current study, it seems unlikely that imatinib substantially affects glycemic control in patients with type 2 diabetes.