Targeted IV busulfan and fludarabine followed by post-allogeneic hematopoietic cell transplantation rituximab demonstrate encouraging activity in CD20+ lymphoid malignancies without increased risk of infectious complications.
ABSTRACT We examined pharmacokinetic-targeted IV busulfan (75-170 mg/m(2), with target AUC of 3500-6000 μmol min) and fludarabine (40 mg/m(2)) × 4 days with rituximab (t-IV Bu/Flu + rituximab) 375 mg/m(2) on days +1 and +8 followed by allogeneic hematopoietic cell transplantation in 19 patients (median age 56, range 35-68 years) with CD20+ lymphoid malignancies. Median time to neutrophil and platelet engraftment was 15 and 12 days. The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was 58% (95% confidence interval, CI 39-85%), and chronic GVHD was 50% (95% CI 28-88%). With a median follow up of 7 (range 1-31) months, overall response was observed in 15, and stable or progressive disease in 4. Overall survival at 1 year was 67%. Engraftment, chimerism, and infectious complications did not differ significantly from a contemporaneous non-rituximab containing comparator group. The addition of rituximab 375 mg/m(2) to t-IV Bu/Flu does not appear to adversely affect engraftment, donor chimerism, or increase the risk of infectious complications.
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ABSTRACT: This consensus document is intended to serve 3 functions. First, it standardizes the criteria for diagnosis of chronic graft-versus-host disease (GVHD). Second, it proposes a new clinical scoring system (0-3) that describes the extent and severity of chronic GVHD for each organ or site at any given time, taking functional impact into account. Third, it proposes new guidelines for global assessment of chronic GVHD severity that are based on the number of organs or sites involved and the degree of involvement in affected organs (mild, moderate, or severe). Diagnosis of chronic GVHD requires the presence of at least 1 diagnostic clinical sign of chronic GVHD (e.g., poikiloderma or esophageal web) or the presence of at least 1 distinctive manifestation (e.g., keratoconjunctivitis sicca) confirmed by pertinent biopsy or other relevant tests (e.g., Schirmer test) in the same or another organ. Furthermore, other possible diagnoses for clinical symptoms must be excluded. No time limit is set for the diagnosis of chronic GVHD. The Working Group recognized 2 main categories of GVHD, each with 2 subcategories. The acute GVHD category is defined in the absence of diagnostic or distinctive features of chronic GVHD and includes (1) classic acute GVHD occurring within 100 days after transplantation and (2) persistent, recurrent, or late acute GVHD (features of acute GVHD occurring beyond 100 days, often during withdrawal of immune suppression). The broad category of chronic GVHD includes (1) classic chronic GVHD (without features or characteristics of acute GVHD) and (2) an overlap syndrome in which diagnostic or distinctive features of chronic GVHD and acute GVHD appear together. It is currently recommended that systemic therapy be considered for patients who meet criteria for chronic GVHD of moderate to severe global severity.Biology of Blood and Marrow Transplantation 01/2006; 11(12):945-56. · 3.94 Impact Factor
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ABSTRACT: Myeloablative doses of BU and fludarabine followed by allogeneic hematopoietic cell transplantation offer effective therapy for AML. We anticipated that pharmacokinetic targeting of i.v. BU to 5300 μM/L min/day × 4 (targeted i.v. BU and fludarabine (t-i.v. BU/Flu)) would limit nonrelapse mortality (NRM) in adults up to 70 years of age. We assessed the safety and efficacy of t-i.v. BU/Flu in a series of 100 adults (median age 48, range 22-69 years) with AML in the first CR (CR1) with high risk of treatment failure (n=49), second CR (CR2, n=25), relapsed disease (REL, n=9), primary induction failure (PIF, n=16) and untreated (n=1). NRM was 3% at 100 days and 15% at 1 year. The cumulative incidence of relapse was 30.6% for CR1, 41.7% for CR2, 55.6% for REL and 58.6% for PIF. OS for primary AML in CR1 was 66% (95% confidence interval (CI): 46-80%) at 1 year, and 62% (95% CI: 42-77%) at 2 years. On multivariable modeling, remission status, moderate/severe chronic GVHD and day-90 BM chimerism ≥90% predicted improved OS. Importantly, there was no effect of age. t-i.v. BU/Flu provides effective disease control with encouraging NRM in patients up to age of 70 years.Bone marrow transplantation 05/2011; 46(5):641-9. · 3.00 Impact Factor
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ABSTRACT: The year 2007 marks the 10th anniversary of approval by the U.S. Food and Drug Adminstration of the first monoclonal antibody for the treatment of cancer. Rituximab, an anti-CD20 chimeric monoclonal antibody, was approved for the treatment of patients with relapsed/refractory low-grade B-cell non-Hodgkin lymphomas. From an immunologic perspective, this therapeutic indication provided the long-elusive validation of immunotherapy as the fourth modality of treatment for patients with cancer. From a clinical perspective, it was hard to imagine then that this nonchemotherapeutic approach would dramatically impact the management of patients with almost every type of B-cell malignancy and that it would even find a place as a therapeutic option for patients with non-malignant disorders. Although thousands of patients have been treated worldwide with rituximab, there is still debate regarding its mechanism(s) of action. The demonstration that a number of patients do not benefit with this treatment and that no cures have been achieved with single-agent rituximab prompted several investigators to identify those barriers limiting the efficacy of this monoclonal antibody. Here, we summarize what we have learned in the past 10 years about rituximab efficacy and its mechanisms of action and resistance. We also discuss the new generation of monoclonal antibodies, the development of which has been spurred by the widespread success of anti-CD20 MAb therapy.Hematology 02/2007; · 1.49 Impact Factor