Journal of Clinical Oncology, Vol 17, Issue 3
(March), 1999: 791
© 1999 American Society for Clinical Oncology
Rituximab Therapy in Hematologic Malignancy Patients With Circulating Blood Tumor Cells: Association With Increased Infusion-Related Side Effects and Rapid Blood Tumor Clearance
John C. Byrd,
Jamie K. Waselenko,
Thomas J. Maneatis,
Timothy Murphy,
Frank T. Ward,
Brian P. Monahan,
Melissa A. Sipe,
Sarah Donegan,
Christine A. White
From the Division of Hematology-Oncology, Walter Reed Army Medical Center, Washington, DC; Department of Medicine, Uniformed Services University of Health Sciences, Bethesda, MD; Division of Hematologic Malignancies, Johns Hopkins Oncology Center, Baltimore, MD; Genentech, Inc, South San Francisco, CA; Division of Hematology and Oncology, National Naval Medical Center, Bethesda, MD; and IDEC Pharmaceuticals Corporation, San Diego, CA.
Address reprint requests to John C. Byrd, MD, Director, Clinical Research, Hematology Oncology Service, Ward 78, Walter Reed Army Medical Center, 6900 Georgia Ave, NW, Washington, DC 20307; email john_c.byrd{at}wramaa.chcs.amedd army.mil
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ABSTRACT
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PURPOSE: Rituximab was recently approved for use in relapsed, low-grade non-Hodgkin's lymphoma; however, few data exist regarding the safety of this agent in patients with a high number of tumor cells in the blood.
METHODS AND RESULTS: After the observation at our institution of a rapid reduction of peripheral-blood tumor cells with associated severe pulmonary infusion-related toxicity in two patients with refractory hematologic malignancies, data on three additional cases were collected from physician-submitted reports of adverse events related to rituximab treatment. Five patients with hematologic malignancies possessing a high number of blood tumor cells were treated with rituximab and developed rapid tumor clearance. The median age was 68 years (range, 26 to 78 years). Patients were diagnosed with B-cell prolymphocytic leukemia (n = 2), chronic lymphocytic leukemia (n = 2), or transformed non-Hodgkin's lymphoma (n = 1). All of these patients had bulky adenopathy or organomegaly. All five patients developed a unique syndrome of severe infusion-related reactions, thrombocytopenia, rapid decrement in circulating tumor cell load, and mild electrolyte evidence of tumor lysis, and all required hospitalization. In addition, one patient developed ascites. These events resolved, and four patients were subsequently treated with rituximab without significant complications.
CONCLUSION: Rituximab administration in patients who have a high number of tumor cells in the blood may have an increased likelihood of severe initial infusion-related reactions. These data also suggest that rituximab may have activity in a variety of other lymphoid neoplasms, such as chronic lymphocytic leukemia and B-cell prolymphocytic leukemia.
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INTRODUCTION
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RITUXIMAB, A CHIMERIC antibody directed against CD20, was recently approved for use against relapsed or refractory follicular or low-grade B-cell non-Hodgkin's lymphoma (NHL). Preclinical in vitro studies demonstrated that rituximab could directly induce apoptosis in DHL-4 cell lines independent of effector cells.1 Subsequent in vivo studies demonstrated that rituximab also induces cytotoxicity via complement-mediated cytotoxicity and antibody-mediated cell cytotoxicity.2 Initial phase II studies3-6 of rituximab demonstrated high response rates (32% to 62%) in relapsed follicular low-grade NHL, mantle-cell NHL, and diffuse large-cell lymphoma. In these studies, rituximab therapy was often associated with an infusion-related symptom complex consisting of fevers, chills, and rigors, usually during the first infusion. This symptom complex usually is self-limited and generally subsides with temporary interruption of the rituximab infusion concurrent with initiation of supportive care measures (such as acetaminophen and diphenhydramine administration). Subsequent treatments with rituximab are generally well tolerated and usually associated with a reduction in the infusion-related toxicity. Severe infusion-related reactions or overt bronchospasm requiring medical intervention was noted in only 2% of patients receiving rituximab during the first treatment cycle, making outpatient administration quite feasible. Furthermore, other side effects, such as nausea, vomiting, cytopenias, infections, and therapy-induced alopecia, are absent or less frequent than those produced by combination chemotherapy regimens commonly used in lymphoproliferative disorders, making rituximab an attractive therapeutic option for patients with NHL.
Postmarketing monitoring for adverse reactions is required by the United States Food and Drug Administration (FDA). Such monitoring often identifies unusual complications that were not previously noted, owing to the small number of patients initially studied, and those that occur when the agent is administered to patients with different pretreatment characteristics as compared with those examined in the initial licensing studies. Indeed, the majority of studies performed with rituximab before FDA approval excluded patients with a high number of tumor cells in the blood. These preclinical features, however, are not uncommon in patients with relapsed NHL or related CD20-expressing low-grade lymphoproliferative disorders, such as chronic lymphocytic leukemia (CLL), prolymphocytic leukemia, splenic lymphoma with villous lymphocytes, and hairy-cell leukemia. Herein, we report a unique syndrome associated with rituximab treatment in such patients. The syndrome is characterized by early blood clearance of tumor cells concurrent with significant infusion-related reactions, thrombocytopenia, and mild electrolyte evidence of tumor lysis.
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METHODS AND RESULTS
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Example 1.
A 73-year-old man (patient no. 5) with heavily pretreated and refractory transformed B-cell lymphoma presented with bulky lymphadenopathy, B symptoms, and bone marrow involvement. The leukocyte count was 76.6 x109/L, with an abundant percentage of circulating large lymphoma cells expressing CD5, CD20 (bright), FMC7, and surface immunoglobulin (bright). Given the lack of standard chemotherapy for refractory transformed B-cell lymphoma, rituximab (375 mg/m2) therapy was initiated. The patient received intravenous alkaline hydration and allopurinol 24 hours before treatment. Dexamethasone (4 mg) by oral administration, which had been started 1 month previously for night sweats, was continued. The patient also received intravenous diphenhydramine (50 mg) and oral acetaminophen (650 mg) 30 minutes before his treatment. Within minutes of the rituximab infusion (started at 25 mg/h), the patient developed audible wheezing and hypoxemia. Therapy was interrupted, and he received bronchodilators, with resolution of his symptoms. The infusion was restarted at half the initial rate, and he again quickly developed bronchospasm, hypoxemia, fever, tachycardia, rigors, and profuse diaphoresis. Therapy was again interrupted, and he received hydrocortisone, acetaminophen, diphenhydramine, ranitidine, meperidine, bronchodilators, and supplemental oxygen, with resolution of his symptoms. Therapy was restarted at half the previous rate, but owing to the persistence and severity of subsequent reactions, including the symptoms outlined above, he was able to receive only 100 mg of the scheduled 700-mg dose of rituximab on the first day. The remaining 600 mg of rituximab was discarded because the recommended room temperature constitution time had been exceeded. The patient's peripheral WBC count rapidly fell to 10.9 x 109/L within 12 hours of this treatment, however. Also notable on his serum evaluation within 12 hours of therapy was a transient increase in uric acid, lactate dehydrogenase, and phosphate levels.
On the following day, the patient received an additional 100 mg of rituximab, after premedication, without further infusion-related toxicity and was subsequently given the remaining 500 mg of the intended total initial dose. Subsequent re-evaluation 1 week later was notable for a leukocyte count of 18 x 109/L with circulating peripheral-blood tumor cells. At this time, treatment was initiated with diphenhydramine and acetaminophen prophylaxis. This treatment was tolerated much better, with one episode of transient wheezing, rigors, and fever that resolved with cessation of the rituximab infusion and bronchodilator therapy. The patient received two additional rituximab treatments without any adverse events. Progressive disease developed after the fourth treatment, and the patient expired 1 month later.
Example 2.
A 78-year-old white male (patient no. 4) with compensated alcoholic cirrhosis (without a history of ascites and with normal serum transaminase and bilirubin levels), alkylator-refractory, Rai stage 4 CLL (WBC count, 120 x 109/L; platelet count, 25 x 109/L; diffuse bone marrow involvement), and hormone-refractory prostate cancer presented with a myelopathy judged to be due to the latter malignancy. Treatment with lumbosacral irradiation resulted in improvement of the neurologic symptoms, but the CLL continued to be clinically active (WBC count, 74 x 109/L; platelet count, 27 x 109/L). Owing to concerns regarding the potential worsening of myelosuppression with fludarabine treatment, rituximab therapy was initiated. No ascites was evident on physical examination. The patient received pretreatment hydration, oral acetaminophen, and intravenous diphenhydramine, followed by rituximab infusion at 50 mg/h. Rituximab initially was well tolerated, and the infusion rate was increased to 100 mg/h 1 hour later. Within 15 minutes, abrupt dyspnea, tachypnea, fever (39.1°C), hypoxemia (room air O2 saturation, 76%), expiratory wheezing, and confusion developed. Hematologic parameters revealed the leukocyte count to be 18.0 x 109/L and the platelet count less than 20 x 109/L. A portable chest x-ray demonstrated new, diffuse pulmonary infiltrate and stable, previously seen, small bilateral pleural effusions. The rituximab therapy was discontinued, and administration of methylprednisone, albuterol nebulizers, platelet transfusion, furosemide, O2 supplementation, and additional diphenhydramine followed. Improvement in symptoms was noted over the next several hours, but tense ascites developed on the following day, subsequently mandating two large-volume paracenteses during the next 2 days. Laboratory evaluation of the ascitic fluid revealed that it was transudative, and all cultures were negative. An ultrasound examination of the liver supported the known diagnosis of cirrhosis and excluded a hepatic vein thrombosis. The patient desired to discontinue therapy and was discharged to hospice care 6 days later. He died 3 days later of complications attributable to his CLL, hormone-refractory prostate cancer, and decompensated cirrhosis. An autopsy was not performed.
After the observation of two severe infusion-related reactions in patients receiving rituximab at Walter Reed Army Medical Center (patients no. 1 and 5), we contacted IDEC Pharmaceuticals and Genentech, Inc. Subsequent communications revealed that one similar patient adverse event had been reported to the FDA since the licensure of rituximab in the United States. Detailed clinical information relating to the pretreatment patient characteristics, clinical and laboratory features of the rapid peripheral-blood tumor cell reduction episode, and long-term consequences of the adverse event for this patient (patient no. 2) was obtained by detailed conversations between one of the coauthors (T.J.M. or C.A.W.) and the treating physician. In the preapproval rituximab studies performed in the United States and Europe (including 500 patients), one additional patient (patient no. 3) with a similar syndrome who was treated on a European study was identified and is included here. During preparation of this article, an additional adverse event was noted at the National Naval Medical Center (patient no. 4).
The specific details of these five cases are summarized in Table 1. The patients' median age at the time of receiving rituximab was 68 years (range, 26 to 78 years), and two patients were female. All patients had received prior treatment for their prolymphocytic leukemia (n = 2), CLL (n = 2), or transformed lymphoma (n = 1). All had received rituximab at a dose of 375 mg/m2, administered at a starting infusion rate of 25 mg/h (patient no. 5) or 50 mg/h (patients no. 1 to 4). A unique infusion-related reaction was noted in all patients concurrent with evidence of a rapid decline in the blood tumor cell count. Tumor cell destruction also was evident by changes in laboratory values (Table 1). Additionally, hospitalization was required for patients no. 2 and 3, and the clinical conditions observed in patients no. 1, 4, and 5 would have mandated a similar approach had rituximab therapy been administered on an outpatient basis. Four of these patients (no. 1, 2, 4, and 5) manifested symptoms of life-threatening bronchospasm with O2 desaturation, requiring rapid intervention. In all patients, this event was reversible with oxygen supplementation and bronchodilators and was not associated with laryngeal edema or urticaria. In addition to the laboratory studies outlined in Table 1, each of these patients had a significant decline in platelet counts from baseline (patient no. 1, 245 x 109/L to 75 x 109/L; patient no. 2, 57 x 109/L to 2 x 109/L; patient no. 3, 98 x 109/L to 25 x 109/L; patient no. 4, 27 x 109/L to < 20 x 109/L; and patient no. 5, 277 x 109/L to 120 x 109/L). In both patients no. 1 and 2, it was not possible to increase the infusion rate of rituximab over the initial rate of 50 mg/h during the first infusion. Patient no. 4 declined further therapy after receiving only 125 mg of rituximab. Patient no. 5 had recurrent dyspnea, rigors, fevers, and bronchospasm, requiring cessation of the infusion after administration of approximately 10 mg of rituximab. All infusion-related reactions resolved by the following day, concurrent with a marked decline in peripheral leukocyte counts. Only one patient had possible late complications of rituximab therapy, which included new transudative ascites that mandated repeated paracentesis, although this event was confounded by his known alcoholic cirrhosis. Patient no. 5 had reinitiation of the treatment on the next day, as outlined above, and he tolerated the treatment without further difficulty. Treatment of the mild laboratory findings suggestive of mild tumor lysis with hydration, urine alkalinization, and allopurinol therapy was given to patients no. 1 to 3 and 5 during week 1. All patients had subsequent reversal of electrolyte and renal abnormalities.
Rechallenge occurred in four of the patients. Patient no. 1 had mild fever and rigors, patient no. 3 had mild rigors, whereas patient no. 5 had these symptoms as well as transient bronchospasm during the second infusion. All patients tolerated subsequent infusions well. Patients no. 1 and 2 had very transient responses to rituximab, as measured by the peripheral leukocyte count decline (patients no. 1 and 2), decreased adenopathy (patient no. 2), and decreased organomegaly (patient no. 1) after eight and four treatments, respectively.
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DISCUSSION
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To our knowledge, this case series represents the first report of a unique and clinically significant infusion-related event after administration of the anti-CD20 monoclonal antibody rituximab in patients with CD20-expressing hematologic malignancies possessing high numbers of circulating blood tumor cells. Indeed, the characteristic syndrome observed in all five patients was similar, with all having a marked and rapid decline in the blood tumor cells after administration of rituximab associated with significant infusion-related side effects during the first treatment that included severe rigors, fever, bronchospasm, hypoxemia, and thrombocytopenia. Three patients included here fulfilled the definition of tumor lysis syndrome used by Cheson et al,7 whereas the other patients had findings suggestive of rapid tumor cell destruction (ie, hypocalcemia and increase in lactate dehydrogenase). The syndrome observed in these patients was different, however, from the tumor lysis syndrome observed in CLL patients after treatment with fludarabine, in which more prominent laboratory abnormalities were noted several days later without associated pulmonary and platelet toxicity.7 It is also different from the syndrome observed in patients with high-grade lymphoma, in which severe electrolyte disturbances and renal failure, sometimes requiring dialysis, are characteristic, and thrombocytopenia is less frequent.8-10 Given the less pronounced evidence of tumor lysis by rituximab, an alternate explanation for this new syndrome would include initial tumor cell agglutination in the lung, liver, and spleen producing cytokine release, followed by gradual tumor destruction by immune effector cells, producing the transient laboratory findings of mild tumor destruction. Indeed, cytokine release (tumor necrosis factor alpha, interferon gamma, and interleukin 6) with associated infusion-related toxicity has been described with other monoclonal antibody therapies11,12 and may explain the additional adverse events, such as rigors, fevers, chills, bronchospasm, and transient thrombocytopenia, observed in all of these patients. The magnitude of this adverse event mandated hospitalization of two patients (IDEC/Genentech cases) and, in the view of the treating physicians, would have mandated hospitalization if outpatient management of patients no. 1, 4, and 5 had initially been attempted at our hospitals. Despite the initial severity of the rapid tumor lysis syndrome, no permanent sequelae resulted in four of these patients. Ten days after receiving 125 mg of rituximab therapy, patient no. 4 died of causes believed to be unrelated to the therapy. Of the four patients subsequently retreated with rituximab, all tolerated the therapy well. This finding of diminishing reaction with subsequent rituximab treatments is characteristic of the infusion-related events previously noted with this agent, rather than a true anaphylactoid reaction.
The implications of our observation relate to the safety of rituximab in the treatment of patients with lymphoproliferative disorders who have a high number of circulating tumor cells in the blood. Prophylactic diphenhydramine, acetaminophen, or corticosteroid administration does not seem to prevent this initial adverse event. Because of these side effects and the relatively short time during which rituximab can safely be administered, an alternative schedule in patients with high peripheral-blood tumor cell burdens may be necessary to minimize its toxicity and to prevent wasting of this therapeutic agent. Our current approach includes administration of a small dose of rituximab (100 mg) on day 1 in the setting of prophylactic acetaminophen, diphenhydramine, allopurinol, and hydration. Patients are subjected to close observation in a clinic or inpatient ward that is well suited for rapid emergent intervention (ie, supplemental oxygen, nebulized bronchodilators, and advanced cardiac life-support equipment immediately available) for signs of severe infusion-related reactions. Patients developing rigors despite this intervention receive meperidine 12.5 to 25 mg intravenously. All patients are monitored for thrombocytopenia and evidence of rapid tumor lysis posttreatment. Administration of the intended cumulative dose of rituximab (ie, the remaining dose portion of the 375-mg/m2 total) is completed on the following day. Two CLL patients with high blood tumor counts have received rituximab at Walter Reed Army Medical Center according to this stepped-up dosing schedule, with early blood tumor cell reduction, thrombocytopenia, but minimal infusion-related toxicity.
The other potential clinical application of our observations stems from our preliminary finding of tumor cytoreduction in two patients with B-cell prolymphocytic leukemia, which to our knowledge has not been previously reported. Therapeutic options for B-cell prolymphocytic leukemia are limited, and on the basis of this preliminary observation, we believe that future studies using rituximab both as a single agent and combined with purine analogs for treatment of B-cell prolymphocytic leukemia are warranted.
In summary, we have described a new and significant clinical adverse event occurring in patients with lymphoproliferative disorders and high blood tumor counts after treatment with rituximab. The event is characterized by significant infusion-related side effects, including fever, rigors, bronchospasm, and hypoxemia, concomitant with rapid reduction and laboratory evidence of tumor destruction. Rituximab therapy in such patients should therefore be initiated with caution and close monitoring for this possible side effect. In this regard, future studies evaluating alternative schedules, such as the stepped-up dosing described here, should be considered.
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NOTES
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The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the U.S. Army, U.S. Navy, or Department of Defense.
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Rituximab Using A Thrice Weekly Dosing Schedule in B-Cell Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma Demonstrates Clinical Activity and Acceptable Toxicity
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O. W. Press, J. P. Leonard, B. Coiffier, R. Levy, and J. Timmerman
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J. D. Hainsworth
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U. Winkler, M. Jensen, O. Manzke, H. Schulz, V. Diehl, and A. Engert
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TOP
ABSTRACT
INTRODUCTION
