Ralph M. Meyer

Systematic Review: Efficacy and Safety of Rituximab for Adults with Idiopathic Thrombocytopenic Purpura

Idiopathic thrombocytopenic purpura (ITP) is a common hematologic disorder characterized by platelet autoantibodies, low platelet counts, and bleeding. Rituximab is a chimeric, monoclonal anti-CD20 antibody that targets B lymphocytes and causes Fc-mediated cell lysis (14). It is currently indicated for the treatment of lymphoma (58), but because of its ability to deplete autoantibody-producing B lymphocytes and its favorable toxicity profile (9), it has been used in patients with various autoimmune diseases (1012), including ITP. In some patients with ITP, rituximab has been associated with a reduction in specific platelet-associated autoantibodies and an increase in platelet count (13). Early success with rituximab in ITP has lead to its widespread use and incorporation into recent treatment algorithms (14, 15). However, the evidence to support the use of rituximab in ITP is uncertain. We performed a systematic review of the literature to evaluate the efficacy and safety of this treatment. Methods Search Strategy One hematologist and one internist independently searched the literature in June 2005 and updated the search in April 2006. The electronic databases of MEDLINE (from 1966) and EMBASE (from 1980) were searched by using the explode function for the Medical Subject Heading (MeSH) terms antibodies, monoclonal and purpura, thrombocytopenic, idiopathic and the textwords rituximab, rituxan, mabthera, anti CD20, anti CD20 antibody, immune thrombocytopenic purpura, and idiopathic thrombocytopenic purpura. The MEDLINE database was also searched with the PubMed search engine by using the MeSH term purpura, thrombocytopenic, idiopathic and the textwords rituximab and rituxan. The Cochrane Registry for Controlled Trials was searched by using the terms rituximab, immune thrombocytopenic purpura, and ITP. Scientific abstracts were identified by searching the electronic databases of the American Society of Hematology and the American Society of Clinical Oncology from 1997 (the year of licensure of rituximab) to 2005 by using the search terms ritux*, thrombocytopenic, and ITP. Bibliographies of relevant articles and reviews were manually searched, and authors were canvassed for additional citations. Eligibility Criteria and Study Selection Exclusion criteria were secondary causes of thrombocytopenia, including splenomegaly, hepatitis B or C virus infection, HIV infection, lupus, antiphospholipid antibody syndrome, bone marrow failure syndromes, and drug-induced thrombocytopenia; malignancy, including chronic lymphocytic leukemia and lymphoma; the Evan syndrome; and rituximab re-treatments. Children (<16 years of age) were excluded because the biology and natural history of ITP in children were believed to differ considerably from those in adults. There was no restriction on study design or language of publication. Reports published only in abstract form were eligible. Where duplicate or redundant publications were uncovered, the latest and most informative version was retained. Initially, titles and abstracts of all articles were evaluated independently by 2 reviewers. Full-text articles were retrieved when they were judged by at least 1 reviewer to possibly contain relevant original data. Final article selection was done independently by both reviewers, and disagreements were resolved by consensus in all cases. Data Extraction The following data were collected in duplicate: proportion of patients with complete, partial, or minimal platelet count responses (and their definitions); time to platelet count responses; duration of platelet count responses; dose and schedule of rituximab administration; toxicities; previous ITP treatments; baseline platelet count; duration of ITP before rituximab treatment; study design and use of controls; and sources of funding. Individual-patient data were used where possible. Assessment of Methodologic Quality Study quality was assessed independently by 2 hematologists with expertise in research methods. Reviewers evaluated 4 key design features for each study: prospective data collection, consecutive patient enrollment, a clearly stated duration of follow-up, and a description of losses to follow-up. Assessors were blinded to study author, journal, publication date, and main results. Disagreements were resolved by independent adjudication. Statistical Analysis Patient demographic characteristics and platelet count responses were analyzed only from those studies enrolling 5 or more patients because we felt that smaller studies may be subject to extreme reporting bias. To determine estimates of response, we defined complete response as the achievement of a platelet count greater than 150109 cells/L; partial response as a platelet count between 50 and 150109 cells/L; and overall response as a platelet count greater than 50109 cells/L. These definitions were chosen to reflect the most common criteria used in primary reports. Toxicities were considered from all studies, including those enrolling fewer than 5 patients each, to provide the most thorough description of safety. We determined estimates of effect of rituximab by calculating the weighted mean proportion by using a random-effects model. This model estimated the between-study variance by using the method of moments and assumed that the proportion from each study was sampled from the normal distribution, with variance calculated from the data. Continuous variables, including time to response, response duration, and follow-up, were summarized with medians, minimum and maximum values, and interquartile ranges assuming a normal distribution of the data. Unweighted chance-corrected values were used to assess agreement between reviewers for study selection (16). Role of the Funding Source This systematic review had no external source of funding. The organizations that fund the individual authors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, and approval of the manuscript. Results Study Selection We identified 599 citations through our comprehensive literature search, of which 60 were retrieved for detailed review (Figure 1). Agreement between reviewers for initial study inclusion was excellent (= 0.87). After exclusion of ineligible studies, redundant or duplicate publications, and reports that did not contain original data, 31 reports were included. Nineteen studies (313 patients) enrolled at least 5 patients each and were included in the efficacy analysis (13, 1734), and 29 studies (306 patients) reported toxicity data (13, 1719, 2128, 3046). Of the 19 reports describing efficacy outcomes, 9 were published in abstract form only. Abstracts were carefully scrutinized, and authors were contacted when necessary to ensure that redundant publications were excluded. Figure 1. Article selection. Results of article search and selection conducted in accordance with guidelines on reporting systematic reviews of observational studies (56). ITP = idiopathic thrombocytopenic purpura. Study Designs and Sources of Funding There was 1 dose-finding phase II study (28) and 18 single-arm cohort studies (13, 1727, 2934). Source of funding was not reported in 26 of 31 reports; of the remaining 5, 1 was industry-sponsored (19), 3 were funded by nonprofit organizations (21, 31, 41), and 1 reported that it had no funding information to disclose (32). Description of Patients Patients were 16 to 89 years of age, had had ITP for 1 to 360 months, and had a platelet count that ranged from 1 to 89109 cells/L before rituximab treatment (Table 1). Nearly all (99.0%) patients had received corticosteroids, and 158 (50.5%) had had splenectomy. Other previous treatments were immunosuppressants, including cyclosporine, azathioprine, or mycophenylate (n= 26); cyclophosphamide (n= 12); vinca alkaloids (n= 18); and danazol (n= 17). The number of previous treatments varied between and within reports. Table 1. Characteristics of Patients with Idiopathic Thrombocytopenic Purpura in Rituximab Studies Enrolling 5 or More Patients Each (n= 313)* Rituximab Dose and Schedule Rituximab was administered as a weekly infusion of 375 mg/m2 for 4 consecutive weeks in 16 of 19 studies. Of the remaining 3 studies, 1 did not report the dosing schedule (30); 1 used a schedule of 1 to 8 infusions of 325 mg/m2 per dose (29); and 1 used a low dose of rituximab (50 mg/m2 on day 1, then 150 mg/m2 on days 8 and 15), an intermediate dose (150 mg/m2 on day 1, then 375 mg/m2 weekly for 3 weeks), and a standard dose (28). Platelet Count Response In most reports, complete response and partial response were defined according to the achievement of predefined platelet count thresholds; however, these thresholds varied. Certain reports used additional criteria to define a response, including the discontinuation of steroid therapy (32) and the resolution of bleeding symptoms (26). One report defined complete response as the achievement of a platelet count that was adequate for hemostasis (25); in 2 reports, neither complete response nor partial response was defined (22, 27). The timing of platelet count measurements in the definitions of a response was specified in 2 reports: 12 weeks after the first rituximab infusion (29) and 2 weeks after the last infusion (30). In 1 report, a response was considered only if it lasted at least 30 days (21), and in another, at least 4 months (13). Where reporting of studies included homogenous criteria to define platelet count responses to therapy, treatment with rituximab resulted in a complete response (platelet count> 150109 cells/L) in 46.3% of patients (95% CI, 29.5% to 57.7%), partial response (50 to 150109 cells/L) in 24.0% (CI, 15.2% to 32.7%), and overall response (>50109 cells/L) in 62.5% (CI, 52.6% to 72.5%). Rates of complete, partial, and overall response were based on 191, 284, and 313 eligible patients, respectively (Table 2). In a sensitivity analysis that exclud

ABVD Alone versus Radiation-Based Therapy in Limited-Stage Hodgkin's Lymphoma

BACKGROUND Chemotherapy plus radiation treatment is effective in controlling stage IA or IIA nonbulky Hodgkins lymphoma in 90% of patients but is associated with late treatment-related deaths. Chemotherapy alone may improve survival because it is associated with fewer late deaths. METHODS We randomly assigned 405 patients with previously untreated stage IA or IIA nonbulky Hodgkins lymphoma to treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) alone or to treatment with subtotal nodal radiation therapy, with or without ABVD therapy. Patients in the ABVD-only group, both those with a favorable risk profile and those with an unfavorable risk profile, received four to six cycles of ABVD. Among those assigned to subtotal nodal radiation therapy, patients who had a favorable risk profile received subtotal nodal radiation therapy alone and patients with an unfavorable risk profile received two cycles of ABVD plus subtotal nodal radiation therapy. The primary end point was 12-year overall survival. RESULTS The median length of follow-up was 11.3 years. At 12 years, the rate of overall survival was 94% among those receiving ABVD alone, as compared with 87% among those receiving subtotal nodal radiation therapy (hazard ratio for death with ABVD alone, 0.50; 95% confidence interval [CI], 0.25 to 0.99; P=0.04); the rates of freedom from disease progression were 87% and 92% in the two groups, respectively (hazard ratio for disease progression, 1.91; 95% CI, 0.99 to 3.69; P=0.05); and the rates of event-free survival were 85% and 80%, respectively (hazard ratio for event, 0.88; 95% CI, 0.54 to 1.43; P=0.60). Among the patients randomly assigned to ABVD alone, 6 patients died from Hodgkins lymphoma or an early treatment complication and 6 died from another cause; among those receiving radiation therapy, 4 deaths were related to Hodgkins lymphoma or early toxic effects from the treatment and 20 were related to another cause. CONCLUSIONS Among patients with Hodgkins lymphoma, ABVD therapy alone, as compared with treatment that included subtotal nodal radiation therapy, was associated with a higher rate of overall survival owing to a lower rate of death from other causes. (Funded by the Canadian Cancer Society and the National Cancer Institute; HD.6 ClinicalTrials.gov number, NCT00002561.).

Diagnosis of iron-deficiency anemia in the elderly.

PURPOSE To determine the value of serum ferritin, mean cell volume, transferrin saturation, and free erythrocyte protoporphyrin in the diagnosis of iron-deficiency anemia in the elderly. PATIENTS AND METHODS We prospectively studied consecutive eligible and consenting anemic patients over the age of 65 years, who underwent blood tests and bone marrow aspiration. The study consisted of 259 inpatients and outpatients at two community hospitals in whom a complete blood count processed by the hospital laboratory demonstrated previously undiagnosed anemia (men: hemoglobin level less than 12 g/dL; women: hemoglobin level less than 11.0 g/dL). RESULTS Thirty-six percent of our patients had no demonstrable marrow iron and were classified as being iron-deficient. The serum ferritin was the best test for distinguishing those with iron deficiency from those who were not iron-deficient. No other test added clinically important information. The likelihood ratios associated with the serum ferritin level were as follows: greater than 100 micrograms/L, 0.13; greater than 45 micrograms/L but less than or equal to 100 micrograms/L, 0.46; greater than 18 micrograms/L but less than or equal to 45 micrograms/L, 3.12; and less than or equal to 18 micrograms/L, 41.47. These results indicate that values up to 45 micrograms/L increase the likelihood of iron deficiency, whereas values over 45 micrograms/L decrease the likelihood of iron deficiency. Seventy-two percent of those who were not iron-deficient had serum ferritin values greater than 100 micrograms/L, and in populations with a prevalence of iron deficiency of less than 40%, values of greater than 100 micrograms/L reduce the probability of iron deficiency to under 10%. Fifty-five percent of the iron-deficient patients had serum ferritin values of less than 18 micrograms/L, and in populations with a prevalence of iron deficiency of greater than 20%, values of less than 18 micrograms/L increase the probability of iron deficiency to over 95%.

A randomized controlled trial comparing the frequency of acute reactions to plasma-removed platelets and prestorage WBC-reduced platelets

BACKGROUND: Removal of the plasma supernatant from platelets before transfusion is effective in preventing acute reactions to platelets caused by cytokines. Prestorage WBC reduction of platelets may be even more effective at preventing reactions as the WBCs are removed and WBC‐derived cytokines do not accumulate in this component. This study evaluates the effectiveness of plasma removal and two methods of prestorage WBC reduction for preventing acute reactions to platelets.

Flavopiridol in Untreated or Relapsed Mantle-Cell Lymphoma: Results of a Phase II Study of the National Cancer Institute of Canada Clinical Trials Group

Purpose: To determine the response rate and toxicity of flavopiridol in patients with previously untreated or relapsed mantle-cell lymphoma.Patients and Methods: Adult patients with previously untreated or in first or second relapse of previously responsive mantle-cell lymphoma were given flavopiridol 50 mg/m2/d by intravenous bolus for 3 consecutive days every 21 days with antidiarrheal prophylaxis. Flavopiridol was continued until disease progression, unacceptable toxicity, or stable disease for four cycles. Disease was reassessed every two cycles.Results: From 33 registered patients, 30 were eligible after pathology review, 30 were assessable for toxicity, and 28 were assessable for response. A median of four cycles of treatment was administered; 90% of patients received at least 90% of planned dose-intensity. No complete responses were seen; three patients had a partial response (11%), 20 patients had stable disease (71%), and five patients had progressive disease (18%). The median duration of respons...

Randomized phase II comparison of standard CHOP with weekly CHOP in elderly patients with non-Hodgkin's lymphoma.

PURPOSE To determine whether modifying the standard regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) from full doses given every 3 weeks to one-third doses given weekly (chop) increases the received chemotherapy dose-intensity in elderly patients with advanced-stage intermediate-grade lymphoma. PATIENTS AND METHODS Consenting patients, age > or = 65 years who had acceptable cardiac, renal, and liver function and an Eastern Cooperative Oncology Group (ECOG) performance status less than 4, were stratified by bone marrow and performance status and randomized to receive standard CHOP or weekly chop. Drug doses were attenuated or escalated according to a defined dose-modification schedule. The primary outcome was average relative received dose-intensity. Secondary outcomes included response, progression-free and overall survival, toxicity, and performance status. RESULTS Nineteen patients were allocated to each group. No difference in received dose-intensity was seen. When dose-intensity was calculated for the first six cycles of therapy, average relative received dose-intensity was .92 with CHOP versus .89 with weekly chop (P = .5); when calculated for the first 18 weeks of therapy, values were .88 with CHOP versus .89 with weekly chop (P = .8). The complete response rate was 68% with CHOP versus 74% with weekly chop (P = .9). At 2 years, the progression-free survival rate was 57% with CHOP versus 46% with weekly chop (P = .16) and the survival rate was 74% with CHOP versus 51% with weekly chop (p = .05). More myelotoxicity was seen with CHOP. CONCLUSION We conclude that CHOP can be given in sufficient doses to elderly patients and that weekly chop does not increase received dose-intensity. Progression-free and overall survival are unlikely to be superior with weekly chop, and may be worse. CHOP should remain the standard against which new therapies for elderly patients with intermediate-grade lymphoma are compared.

A randomized controlled trial comparing plasma removal with white cell reduction to prevent reactions to platelets.

BACKGROUND: Recent data suggest that most reactions to platelets are caused by white cell (WBC)‐derived cytokines that accumulate in the plasma portion of the component during storage. On the basis of this theory, the effectiveness of two interventions to prevent reactions, poststorage WBC reduction and plasma depletion, were compared.

Single versus multiple fractions of repeat radiation for painful bone metastases: a randomised, controlled, non-inferiority trial

BACKGROUND Although repeat radiation treatment has been shown to palliate pain in patients with bone metastases from multiple primary origin sites, data for the best possible dose fractionation schedules are lacking. We aimed to assess two dose fractionation schedules in patients with painful bone metastases needing repeat radiation therapy. METHODS We did a multicentre, non-blinded, randomised, controlled trial in nine countries worldwide. We enrolled patients 18 years or older who had radiologically confirmed, painful (ie, pain measured as ≥2 points using the Brief Pain Inventory) bone metastases, had received previous radiation therapy, and were taking a stable dose and schedule of pain-relieving drugs (if prescribed). Patients were randomly assigned (1:1) to receive either 8 Gy in a single fraction or 20 Gy in multiple fractions by a central computer-generated allocation sequence using dynamic minimisation to conceal assignment, stratified by previous radiation fraction schedule, response to initial radiation, and treatment centre. Patients, caregivers, and investigators were not masked to treatment allocation. The primary endpoint was overall pain response at 2 months, which was defined as the sum of complete and partial pain responses to treatment, assessed using both Brief Pain Inventory scores and changes in analgesic consumption. Analysis was done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00080912. FINDINGS Between Jan 7, 2004, and May 24, 2012, we randomly assigned 425 patients to each treatment group. 19 (4%) patients in the 8 Gy group and 12 (3%) in the 20 Gy group were found to be ineligible after randomisation, and 140 (33%) and 132 (31%) patients, respectively, were not assessable at 2 months and were counted as missing data in the intention-to-treat analysis. In the intention-to-treat population, 118 (28%) patients allocated to 8 Gy treatment and 135 (32%) allocated to 20 Gy treatment had an overall pain response to treatment (p=0·21; response difference of 4·00% [upper limit of the 95% CI 9·2, less than the prespecified non-inferiority margin of 10%]). In the per-protocol population, 116 (45%) of 258 patients and 134 (51%) of 263 patients, respectively, had an overall pain response to treatment (p=0·17; response difference 6·00% [upper limit of the 95% CI 13·2, greater than the prespecified non-inferiority margin of 10%]). The most frequently reported acute radiation-related toxicities at 14 days were lack of appetite (201 [56%] of 358 assessable patients who received 8 Gy vs 229 [66%] of 349 assessable patients who received 20 Gy; p=0·011) and diarrhoea (81 [23%] of 357 vs 108 [31%] of 349; p=0·018). Pathological fractures occurred in 30 (7%) of 425 patients assigned to 8 Gy and 20 (5%) of 425 assigned to 20 Gy (odds ratio [OR] 1·54, 95% CI 0·85-2·75; p=0·15), and spinal cord or cauda equina compressions were reported in seven (2%) of 425 versus two (<1%) of 425, respectively (OR 3·54, 95% CI 0·73-17·15; p=0·094). INTERPRETATION In patients with painful bone metastases requiring repeat radiation therapy, treatment with 8 Gy in a single fraction seems to be non-inferior and less toxic than 20 Gy in multiple fractions; however, as findings were not robust in a per-protocol analysis, trade-offs between efficacy and toxicity might exist. FUNDING Canadian Cancer Society Research Institute, US National Cancer Institute, Cancer Council Australia, Royal Adelaide Hospital, Dutch Cancer Society, and Assistance Publique-Hôpitaux de Paris.

A randomized phase 3 trial of thalidomide and prednisone as maintenance therapy after ASCT in patients with MM with a quality-of-life assessment: the National Cancer Institute of Canada Clinicals Trials Group Myeloma 10 Trial

We conducted a randomized, controlled trial comparing thalidomide-prednisone as maintenance therapy with observation in 332 patients who had undergone autologous stem cell transplantation with melphalan 200 mg/m2. The primary end point was overall survival (OS); secondary end points were myeloma-specific progression-free survival,progression-free survival, incidence of venous thromboembolism, and health-related quality of life (HRQoL). With a median follow-up of 4.1 years, no differences in OS between thalidomide-prednisone and observation were detected (respective 4-year estimates of 68% vs 60%, respectively; hazard ratio = 0.77; P = .18); thalidomide-prednisone was associated with superior myeloma-specific progression-free survival and progression-free survival (for both outcomes, the 4-year estimates were 32% vs 14%; hazard ratio = 0.56; P < .0001) and more frequent venous thromboembolism (7.3% vs none; P = .0004). Median survival after first disease recurrence was 27.7 months with thalidomide-prednisone and 34.1 months in the observation group. Nine second malignancies were observed with thalidomide-prednisone versus 6 in the observation group. Those allocated to thalidomide-prednisone reported worse HRQoL with respect to cognitive function, dyspnea, constipation, thirst, leg swelling, numbness, dry mouth, and balance problems. We conclude that maintenance therapy with thalidomide-prednisone after autologous stem cell transplantation improves the duration of disease control, but is associated with worsening of patient-reported HRQoL and no detectable OS benefit.

Randomized Comparison of Gemcitabine, Dexamethasone, and Cisplatin Versus Dexamethasone, Cytarabine, and Cisplatin Chemotherapy Before Autologous Stem-Cell Transplantation for Relapsed and Refractory Aggressive Lymphomas: NCIC-CTG LY.12

PURPOSE For patients with relapsed or refractory aggressive lymphoma, we hypothesized that gemcitabine-based therapy before autologous stem-cell transplantation (ASCT) is as effective as and less toxic than standard treatment. PATIENTS AND METHODS We randomly assigned 619 patients with relapsed/refractory aggressive lymphoma to treatment with gemcitabine, dexamethasone, and cisplatin (GDP) or to dexamethasone, cytarabine, and cisplatin (DHAP). Patients with B-cell lymphoma also received rituximab. Responding patients proceeded to stem-cell collection and ASCT. Coprimary end points were response rate after two treatment cycles and transplantation rate. The noninferiority margin for the response rate to GDP relative to DHAP was set at 10%. Secondary end points included event-free and overall survival, treatment toxicity, and quality of life. RESULTS For the intention-to-treat population, the response rate with GDP was 45.2%; with DHAP the response rate was 44.0% (95% CI for difference, -9.0% to 6.7%), meeting protocol-defined criteria for noninferiority of GDP (P = .005). Similar results were obtained in a per-protocol analysis. The transplantation rates were 52.1% with GDP and 49.3% with DHAP (P = .44). At a median follow-up of 53 months, no differences were detected in event-free survival (HR, 0.99; stratified log-rank P = .95) or overall survival (HR, 1.03; P = .78) between GDP and DHAP. Treatment with GDP was associated with less toxicity (P < .001) and need for hospitalization (P < .001), and preserved quality of life (P = .04). CONCLUSION For patients with relapsed or refractory aggressive lymphoma, in comparison with DHAP, treatment with GDP is associated with a noninferior response rate, similar transplantation rate, event-free survival, and overall survival, less toxicity and hospitalization, and superior quality of life.