Rituximab Chimeric Anti-CD20 Monoclonal Antibody Therapy for Relapsed Indolent Lymphoma: Half of Patients Respond to a Four-Dose Treatment Program.

PURPOSE: The CD20 antigen is expressed on more than 90% of B-cell lymphomas. It is appealing for targeted therapy, because it does not shed or modulate. A chimeric monoclonal antibody more effectively mediates host effector functions and is itself less immunogenic than are murine antibodies. PATIENTS AND METHODS: This was a multiinstitutional trial of the chimeric anti-CD20 antibody, IDEC-C2B8. Patients with relapsed low grade or follicular lymphoma received an outpatient treatment course of IDEC-C2B8 375 mg/m2 intravenously weekly for four doses. RESULTS: From 31 centers, 166 patients were entered. Of this intent-to-treat group, 48% responded. With a median follow-up duration of 11.8 months, the projected median time to progression for responders is 13.0 months. Serum antibody levels were sustained longer after the fourth infusion than after the first, and were higher in responders and in patients with lower tumor burden. The majority of adverse events occurred during the first infusion and were grade 1 or 2; fever and chills were the most common events. Only 12% of patients had grade 3 and 3% grade 4 toxicities. A human antichimeric antibody was detected in only one patient. CONCLUSION: The response rate of 48% with IDEC-C2B8 is comparable to results with single-agent cytotoxic chemotherapy. Toxicity was mild. Attention needs to be paid to the rate of antibody infusion, with titration according to toxicity. Further investigation of this agent is warranted, including its use in conjunction with standard chemotherapy.

Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program.

PURPOSE: The CD20 antigen is expressed on more than 90% of B-cell lymphomas. It is appealing for targeted therapy, because it does not shed or modulate. A chimeric monoclonal antibody more effectively mediates host effector functions and is itself less immunogenic than are murine antibodies. PATIENTS AND METHODS: This was a multiinstitutional trial of the chimeric anti-CD20 antibody, IDEC-C2B8. Patients with relapsed low grade or follicular lymphoma received an outpatient treatment course of IDEC-C2B8 375 mg/m2 intravenously weekly for four doses. RESULTS: From 31 centers, 166 patients were entered. Of this intent-to-treat group, 48% responded. With a median follow-up duration of 11.8 months, the projected median time to progression for responders is 13.0 months. Serum antibody levels were sustained longer after the fourth infusion than after the first, and were higher in responders and in patients with lower tumor burden. The majority of adverse events occurred during the first infusion and were grade 1 or 2; fever and chills were the most common events. Only 12% of patients had grade 3 and 3% grade 4 toxicities. A human antichimeric antibody was detected in only one patient. CONCLUSION: The response rate of 48% with IDEC-C2B8 is comparable to results with single-agent cytotoxic chemotherapy. Toxicity was mild. Attention needs to be paid to the rate of antibody infusion, with titration according to toxicity. Further investigation of this agent is warranted, including its use in conjunction with standard chemotherapy.

Laparoscopic staging of Hodgkin's disease.

The role of operative staging of patients with Hodgkin's disease continues to evolve. First described in 1969, the indications for this procedure continue to be redefined. Recent advances in surgical instrumentation have allowed procedures such as cholecystectomy, colon resection, nephrectomy, and splenectomy to be performed laparoscopically. We report a case of a complete staging procedure for Hodgkin's disease including splenectomy, performed laparoscopically. The patient had an uneventful recovery and returned to work 11 days postoperatively. While performing this operation laparoscopically does not alter the indications for the procedure, laparoscopic staging of Hodgkin's disease may result in shorter hospitalization and recovery time while providing complete pathologic staging of subdiaphragmatic disease.

Recent advances in biology and treatment of myelodysplasia.

The myelodysplastic syndromes are clonal hematopoietic stem cell disorders characterized by varying degrees of pancytopenia and often a progression to acute myeloid leukemia. Recent evidence has linked myelodysplastic syndromes to environmental and occupational genotoxic exposure. Specific cytogenetic abnormalities are well described in myelodysplastic syndromes and have been demonstrated to be useful diagnostic and prognostic tools. Activation of protooncogenes such as ras and fms have also been noted in myelodysplastic syndromes; however, their contribution to the pathogenesis of the syndrome remains to be determined. Aggressive leukemia-like induction therapy, differentiating agents (low-dose cytarabine, 13-cis-retinoic acid) have had little impact on overall survival in myelodysplastic syndromes. The recombinant hematopoietic growth factors (granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor) may be of significant benefit to patients with myelodysplastic syndromes, although it remains to be determined whether they will have a substantial impact on survival. Allogeneic bone marrow transplantation is the only potentially curable treatment of myelodysplastic syndromes. The advanced age of these patients as well as the lack of histocompatible donors restricts this modality to only a small proportion of patients.

Thrombotic thrombocytopenic purpura treated with high-dose intravenous gamma globulin.

Plasma infusion and/or plasma exchange has become standard therapy in the treatment of thrombotic thrombocytopenic purpura (TTP). The management of patients in whom such primary therapy fails is difficult and uncertain. We have described a patient who obtained a sustained remission with the use of high-dose IV gamma globulin after an initial response to aggressive plasma exchange was followed by prompt relapse. Our case and others suggest that high-dose IV IgG may induce remission in patients with TTP who do not respond to standard plasma infusion and/or exchange.

Hypereosinophilic syndrome with evolution to myeloproliferative disorder: temporal relationship to loss of Y chromosome and c-N-ras activation.

A case of hypereosinophilic syndrome is presented in which the patient was serially observed for 4 years. Transformation to a disorder resembling chronic myeloid leukemic (CML) occurred 36 months after diagnosis; at 42 months, blastic transformation and marrow failure ensued, leading to death. Marrow examination for histopathologic, cytogenetic, and molecular biologic analyses were performed during the eosinophilic, myeloproliferative, and blastic stages. These demonstrated ras activation by virtue of a codon 12 G to C transversion mutation, predicting for substitution of glycine by alanine; in addition, we observed Y chromosome loss late in the natural history of this illness, suggesting that these genetic lesions can play a role in the profound loss of myeloid differentiation characteristic of the accelerated phase commonly observed in myeloproliferative syndromes.

Pseudo-Gaucher cells preceding the appearance of immunoblastic lymphoma.

A 49-year-old white woman who presented with multiple lytic bone lesions was found to have Gaucher-like storage cells in multiple bone marrow aspirates and a percutaneous bone marrow biopsy several months before the development of overt disseminated lymphoma. Open bone biopsies of three different sites at initial presentation revealed only necrotic debris and a nondiagnostic polymorphic infiltrate. Elevated leukocyte beta-glucocerebrosidase levels ruled out the diagnosis of classic Gaucher's disease. The ultrastructural characteristics of these storage cells were found to be identical to those of pseudo-Gaucher cells found in patients with chronic myelogenous leukemia and distinctly different from those previously reported in other non-Hodgkin's lymphoma or plasma cell dyscrasias. A possible pathogenetic mechanism is suggested.

Failure of high-dose i.v. gammaglobulin in the treatment of spontaneously acquired factor VIII inhibitors.

Two patients with spontaneously acquired factor-VIII-C inhibitors were treated with high-dose i.v. gammaglobulin. Minimal inhibition of anti-VIII-C activity was demonstrated in vitro in one patient when i.v. gammaglobulin was mixed directly with his plasma. In neither patient, however, was there any significant reduction in titer of antifactor VIII-C after i.v. gammaglobulin administration, nor was there any shortening of the aPTT or reduction in bleeding. The possible mechanisms of the previously reported salutary benefits of high-dose i.v. gammaglobulin in patients with spontaneously acquired factor-VIII inhibitors as well as the potential reasons for failure in our patients are discussed. Our cases demonstrated that high-dose i.v. gammaglobulin is not uniformly successful in the treatment of patients with acquired factor-VIII-C inhibitors. The true frequency of clinically significant responses will require further clinical trials.

Procainamide-induced lupus anticoagulant.

The lupus anticoagulant, with or without other symptoms or signs of lupus, has been described in patients taking procainamide. Screening all such patients for the presence of these anticoagulants may be warranted (despite the rarity of episodes of bleeding) in view of the potentially increased risk of thrombotic events in patients who may already be predisposed. A prospective study to determine the incidence of lupus anticoagulant in procainamide-treated patients and the true frequency of thrombosis in these patients would be helpful in determining appropriate management.

Prolonged vancomycin-associated neutropenia in a chronic hemodialysis patient.

A chronic hemodialysis patient developed severe marrow granulocytic hypoplasia and peripheral blood neutropenia related to vancomycin therapy for an infected arteriovenous fistula. Neutropenia was prolonged and associated with sustained serum levels of vancomycin that persisted for more than 4 weeks following the last dose of vancomycin. No vancomycin-dependent leukoagglutinins were demonstrable in the patient's serum. Although a direct toxic effect on marrow granulocyte production seems likely, a vancomycin-dependent immune suppression of granulopoiesis cannot be ruled out.

Autoimmune neutropenia and Hodgkin's disease.

Isolated neutropenia developed in a patient who had been treated 4 years previously for Stage IIA nodular sclerosing Hodgkin's disease with mantle radiation therapy. Bone marrow revealed myeloid hyperplasia with a virtual absence of bands and polymorphonuclear leukocytes. The serum was positive for antigranulocyte antibodies. There was no evidence of recurrent Hodgkin's disease. Guidelines for the evaluation and treatment of immune neutropenia in Hodgkin's disease are suggested.

Pneumocystis carinii involvement of the bone marrow in acquired immunodeficiency syndrome.

A case of Pneumocystis carinii involvement of the bone marrow in acquired immunodeficiency syndrome is reported. The literature is reviewed for other cases of known extrapulmonary dissemination of Pneumocystis. Potential mechanisms of dissemination of Pneumocystis and its clinical implications are discussed.

Reacting appropriately to thrombocytopenia in pregnancy.

The lower limit of normal for the platelet count is considered to be 150,000/cu mm in both pregnant and nonpregnant normal adults. In the absence of preeclampsia, sepsis, drugs, or other apparent causes, the finding of asymptomatic mild thrombocytopenia in pregnant women is compatible with previously unrecognized immune thrombocytopenic purpura (ITP). Because of the risk of fetal/neonatal thrombocytopenia and the subsequent risk of neonatal intracranial hemorrhage in infants born of mothers with ITP, the optimal mode of delivery for an asymptomatic but thrombocytopenic mother is problematic. Conceivably, those gravidas with mild previously unrecognized thrombocytopenia may not have ITP and thus could be spared cesarean section. From the platelet counts of 730 antepartum patients, we found a mean value of 263,900/cu mm with a standard deviation of 66,000/cu mm, yielding 95% confidence limits of 134,500 to 393,300/cu mm. The distribution is statistically indistinguishable from a normal distribution. Of 26 asymptomatic thrombocytopenic patients with no hematologic history, none had infants with hemorrhage or platelet counts less than 100,000/cu mm. Only one patient subsequently had severe glucocorticoid-resistant thrombocytopenia requiring splenectomy several months after delivery. The remaining patients continue to be asymptomatic to date, with platelet counts greater than 100,000/cu mm. We suggest a plan for managing less than normal platelet counts in asymptomatic gravidas without a history of hematologic abnormality.

A preliminary Phase I trial of partially purified interferon-gamma in patients with cancer.

Thirty-three patients were treated in an escalating single-dose trial of partially purified nonrecombinant interferon-gamma (IFN-gamma). The first seven patients received intramuscular injections of IFN-gamma in doses up to 20 X 10(6) units/m2. When it became clear that these patients had no detectable antiviral activity in their serum, subsequent patients were treated by the intravenous route of administration, generally with 2-h infusions. A total of 26 patients received the agent intravenously in single escalating doses ranging from 0.2 to 60 X 10(6) units/m2, on a twice-weekly schedule for 4-6 weeks. The most common toxicities encountered included fever, chills, fatigue, anorexia, and occasional nausea and vomiting. No myelosuppression or hepatic toxicity was observed. A maximum tolerated dose for single-dose intravenous administration was defined as 50 X 10(6) units/m2 on the basis of unacceptable fatigue and prolonged systolic hypotension. Antiviral activity was detected in the serum following doses greater than 2 X 10(6) units/m2 when the IFN-gamma was administered intravenously. No evidence of antitumor activity was seen in this Phase I trial, although the treatment regimen employed did not lead to high or prolonged levels of serum IFN activity in the majority of patients. An accurate assessment of the antitumor activity of this particular IFN-gamma preparation will require Phase II trials employing multiple-treatment regimens.