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© 2003 American Society for Clinical Oncology Flavopiridol in Untreated or Relapsed Mantle-Cell Lymphoma: Results of a Phase II Study of the National Cancer Institute of Canada Clinical Trials Group
From the Hamilton Regional Cancer Centre, Hamilton; Princess Margaret Hospital, Toronto; National Cancer Institute of Canada, Clinical Trials Group, Queen’s University, Kingston; London Regional Cancer Centre, London; Northeastern Ontario Regional Cancer Centre, Sudbury, Ontario; Cross Cancer Institute, Edmonton, Alberta; and British Columbia Cancer Agency, Vancouver Cancer Centre, Vancouver, British Columbia, Canada. Address reprint requests to C. Tom Kouroukis, MD, Hematology-Oncology, Hamilton Regional Cancer Centre, 699 Concession Street, Hamilton, Ontario L8V 5C2 Canada; email: tom.kouroukis{at}hrcc.on.ca.
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 response was 3.3 months (range, 2.8 to 13.2 months). The most common toxicities were diarrhea (97%), fatigue (73%), nausea (47%), and vomiting (27%). At least one nonhematologic grade 3 or 4 toxicity was seen in 14 patients (47%). Hematologic toxicity was modest. Conclusions: Flavopiridol given as a daily bolus for 3 consecutive days every 3 weeks has modest activity as a single agent for mantle-cell lymphoma. The number of stable and partial responses that was seen indicates that it is biologically active and may delay progression. Future studies in mantle-cell lymphoma should test this agent with other active agents and using different schedules.
MANTLE-CELL LYMPHOMA, which comprises 5% to 10% of cases1 of non-Hodgkin’s lymphoma, has been a recognized entity under the Revised European American Lymphoma Classification2 and the World Health Organization Classification of Hematopoietic Malignancies.3 Patients now recognized as having mantle-cell lymphoma would have previously been diagnosed as having centrocytic,4 intermediate lymphocytic,5 intermediately differentiated,6 small cleaved cell, or small lymphocytic lymphoma.7 The term mantle-cell lymphoma was coined by Banks8 in 1992. The majority of patients with mantle-cell lymphoma demonstrate overexpression of cyclin D1,9 which regulates transition from G1 to S phase of the cell cycle. This overexpression results from the t(11;14)(q13;q32) translocation, which approximates the bcl-1 oncogene at locus 11q13 to the immunoglobulin heavy-chain locus at 14q32.10,11 Mantle-cell lymphoma is considered incurable, as are other indolent lymphomas, but with a shorter median survival.12–14 It has, therefore, the worst features of both indolent and aggressive histology lymphomas. Patients with mantle-cell lymphoma frequently present with adverse prognostic factors15 as outlined in the International Prognostic Index.16 In addition, other investigators have found that the presence of a leukemic phase, the blastoid variant, and a number of other factors predict for a poorer prognosis.17,18 A variety of chemotherapy regimens have been tested in patients with mantle-cell lymphoma. A randomized trial could not detect any differences in outcomes between patients receiving doxorubicin in addition to cyclophosphamide, vincristine and prednisone.4 The long-term success rates of high-dose chemotherapy, autologous stem-cell transplantation with and without rituximab, and allogeneic transplantation are unclear, in part because of the small numbers of patients treated in single institutions and with limited follow-up (see a recent review in19). Patients with relapsed disease typically have incomplete and brief responses to salvage chemotherapy. The overexpression of cyclin D1 in mantle-cell lymphoma makes inhibition of this step in cell cycle regulation an attractive target for potential therapeutic agents. Flavopiridol, a synthetic N-methylpiperidinyl, chlorophenyl flavone compound has a number of reported cellular effects that may contribute to its antitumor activity. It has been found to induce cell cycle arrest by direct inhibition of cyclin-dependent kinases (cdks) by a competitive mechanism with respect to adenosine triphosphate;20 by preventing phosphorylation of cdks caused by inhibition of cdk7 and cyclin H; and by downregulating cyclin D1 and D3 expression, which leads to G1 arrest.20,21 There is also evidence that flavopiridol has antiangiogenic properties.22–24 In some hematopoietic models, bcl-2 may be downregulated.25,26 Exposure of mantle-cell lymphoma cell lines to flavopiridol induced apoptosis, decreased cyclin D1 expression, and inhibition of cdk4 and cdk6 activity.27 Exposure to flavopiridol induces apoptosis in HL-60 leukemia cells,28 myeloma cells,29 B-cell chronic lymphocytic leukemia cells,25,26 and other hematopoietic cell lines.30 Regression in malignant hematopoietic tissue was seen in human leukemia and lymphoma xenografts in animals treated with flavopiridol.31 In one animal study, marked regression in subcutaneous HL-60 xenografts was seen when flavopiridol was administered in a bolus schedule compared with a continuous infusion schedule.31 This experimental work indicated that peak flavopiridol concentrations are required to produce maximal antitumor effect. A phase I study32 demonstrated that flavopiridol was well tolerated when given at 50 mg/m2/d by continuous infusion for 3 days in patients with refractory neoplasms, and a minor response was observed in a patient with non-Hodgkin’s lymphoma. Another phase I study in which patients with advanced neoplasms were administered a short infusion regimen of flavopiridol33 resulted in a recommended dose of 50 mg/m2/d given as a 1-hour infusion for 3 days every 21 days. The short infusion regimen was selected for our study because of the preclinical data indicating that flavopiridol-related apoptosis was dependent on peak concentration and that those levels could be achieved with the short infusion schedule. The purpose of this study was to measure the response rate and toxicity of bolus flavopiridol given for 3 consecutive days every 3 weeks in patients with newly diagnosed or relapsed mantle-cell lymphoma.
Patients were accrued from participating centers of the National Cancer Institute of Canada Clinical Trials Group. The study was approved by the research ethics boards of participating institutions, and all patients provided written informed consent before registration. Patients were eligible for this study if they were at least 18 years old and had previously untreated or relapsed mantle-cell lymphoma with no more than two previous courses of treatment, not counting rituximab. The pathologic diagnosis of mantle-cell lymphoma was confirmed by central review in all cases (by R.D.G.). Routine immunohistochemistry was performed in all cases and included stains for CD5 and cyclin D1. Patients were required to have bidimensionally measurable disease, an Eastern Cooperative Oncology Group performance status of less than 3, and no CNS involvement. In previously treated patients, at least 6 weeks had to have elapsed since the last dose of chemotherapy and 4 weeks had to have elapsed since the last radiation treatment. Adequate organ and bone marrow function was required, defined as follows: an absolute granulocyte count of at least 1.5 x 109/L; platelets of at least 75 x 109/L (amended from 100 x 109/L at the start of the study after 16 patients); serum creatinine no more than 1.5 times the upper normal limit or a creatinine clearance of greater than 60 mL/min; bilirubin of no more than 1.5 times the upper normal limit; and an AST of no more than 2.5 times the upper normal limit. Patients were not permitted to have had documented progression while receiving a previous chemotherapy regimen, to be receiving concurrent anticancer treatment, or to have been treated previously with radioactive monoclonal antibodies or high-dose chemotherapy with stem-cell transplant. Prior treatment with rituximab was allowed. Patients could not have uncontrolled infection or serious comorbid disease or be pregnant or lactating. Baseline studies included a complete blood count with differential, blood urea nitrogen, serum creatinine, fasting glucose, electrolytes, bilirubin, alkaline phosphatase, AST, lactate dehydrogenase, urinalysis, and computed tomography of the chest, abdomen, and pelvis. Bone marrow studies were optional unless necessary for definitive diagnosis or if a biopsy had never been done.
Treatment Plan Vital signs were recorded before and at 30, 60, 90, and 120 minutes after the start of each daily infusion in the first two cycles to check for hypotension. Clinical examination, performance status, and lymph node measurements were documented every 3 weeks; interim follow-up was left to the discretion of the treating physician, but patients were required to have weekly complete blood counts and bilirubin and AST level analyses. Computed tomography of the chest, abdomen, and pelvis was done every two cycles (6 weeks). Patients with a complete response, partial response, or stable disease were followed up every 3 months until relapse or death. All patients who received at least one cycle and had their disease re-evaluated were considered assessable for response. All patients were assessable for toxicity from the time of their first dose of flavopiridol. Response was classified according to the definitions recommended by the International Workshop to Standardize Response Criteria for Non-Hodgkin’s Lymphomas.34 Antitumor response was categorized as complete (disappearance of all clinical and radiological evidence of lymphoma confirmed at least once by repeat examination not < 4 weeks later), probable complete response (where residual nodal abnormalities persist with regression by at least 75% in sum of products), partial response (a 50% or greater decrease in the sum of products of diameters of the six largest nodal masses, or liver or splenic lesions, confirmed by repeat examination at least 4 weeks later), stable disease (less than partial response or progression less than progressive disease, without the appearance of new lesions), and progressive disease (at least a 50% increase in the sum of the product of measured lesions, with no prior period of stability or response, or the appearance of new lesions). Nonmeasurable disease (eg, pleural effusion, ascites, bone marrow involvement) was not considered in response assessments except in the instance of new disease (progression) or disappearance (complete response). Relapse was determined after a complete response when new disease was identified, or in patients with probable complete response, partial response, or stable disease when at least a 50% increase from the nadir in the products of any previously identified individual abnormal nodes or with the appearance of any new lesions was seen. Response duration was measured from the time measurement criteria were first met until disease relapse. Stable disease duration was measured from the time of start of therapy until disease relapse. In this study, tissue was not obtained for molecular analysis. For patients with a complete response, therapy was to continue for two cycles after complete response criteria were first met. Patients with a partial response were to continue receiving therapy until progression or for two cycles after documentation of stable partial response (no further tumor shrinkage documented). Patients with stable disease were initially given treatment for a maximum of three cycles, later amended to four cycles. Patients with progressive disease were taken off study at the time progression was documented and treated at the discretion of their attending physician. Patients were assessed for toxicity 4 weeks after protocol therapy ended. Toxicities were evaluated throughout the time patients received therapy and graded using the National Cancer Institute Common Toxicity Criteria version 2.0.35 Doses of flavopiridol were reduced by 25% for hematologic and other toxicities (to 37.5 mg/m2/d or, if a second reduction was needed, to 28 mg/m2/d). Dose reductions were required in patients with diarrhea associated with mucus or dehydration, and in patients with nadir absolute neutrophil counts of less than 0.5 x 109/L or nadir platelet counts of less than 25 x 109/L. For other toxicities, dose reductions were used when toxicities of grade 3 or 4 were seen.
Sample Size
A total of 33 patients were registered from January 2000 to October 2001. Pathology review confirmed the diagnosis of mantle-cell lymphoma in 30 of 33 patients. Three patients were excluded for the following reasons: diagnosis other than mantle-cell lymphoma, no pathology material available for review, and inadequate sample for accurate classification. All 30 patients included in the study were shown to express both CD5 and cyclin D1 by immunohistochemistry. In some patients the diagnosis was complemented by conventional cytogenetic analysis revealing the presence of a t(11;14) translocation. Histologic review showed that 17 patients had a diffuse architecture, nine patients had nodular disease, two patients had a mantle zone pattern, and two patients were unclassifiable (one patient had splenic histology and one patient had a needle core biopsy in which the architecture could not be discerned). Classic cytology was seen in 26 patients, with blastoid features in the remaining four patients. Thirty patients were assessable for nonhematologic toxicity, 29 patients were assessable for hematologic toxicity (blood work was not repeated in one patient), and 28 patients were assessable for response (disease was not reassessed in two patients). Baseline characteristics of the 30 eligible patients are summarized in Table 1  .
Response A total of 116 cycles of treatment were administered, with a median of four cycles per patient (Table 2 ). The median received dose-intensity was 49.7 mg/m2/d, and 90% of patients received at least 90% of planned dose-intensity. There were no complete responses. Three patients achieved a partial response (11%; 95% confidence interval, 2% to 28%), 20 patients had stable disease (71%), and five patients had progressive disease (18%). None of the three patients who had been previously treated with rituximab experienced a response. The median durations of partial response and stable disease were 3.3 (range, 2.8 to 13.2 months) and 3.4 months (range, 1.4 to 10.3 months), respectively. Time to progression is shown in Fig 1. The response rate appeared to be higher in patients who had not received prior therapy (Table 3).
Toxicity The most common drug-related nonhematologic toxicities (Table 4 ) were diarrhea (97%), fatigue (73%), nausea (47%), and vomiting (27%). The frequency of diarrhea did not vary greatly when the first and last cycles were compared (90% v 77%); however, it may have been somewhat less severe (16 of 30 patients with grade 2 and 3 in cycle 1 v nine of 23 patients in the last cycle). Fourteen patients (47%) experienced at least one grade 3 or 4 nonhematologic toxicity. No grade 5 toxicity was seen. Hematologic toxicity was modest and is summarized in Table 5; lymphocyte subset testing was not performed. One patient experienced febrile neutropenia (grade 3); no systemic opportunistic infections were seen. Alterations in biochemistry were minimal; all were grade 1 with the exception of one grade 2 hyperglycemia. One patient required dose reductions for two cycles because of grade 4 fatigue and grade 3 nausea and anorexia. In three patients, four cycles were interrupted for bradycardia (grade 1), hypotension (grade 2), chest heaviness (grade 2), and another reason not specified. In the first three of these cycles, diarrhea of grades 1, 2, and 2, respectively, was documented. One patient missed one dose because of dyspnea believed probably to be related to disease (grade 4). In one patient with a pre-existing history of hypertension and stable coronary artery disease, tumor lysis syndrome developed on day 2 of the first cycle. The patient was treated with intravenous hydration; however, on day 3 congestive heart failure was noted, which promptly resolved with intravenous furosemide. This patient also developed grade 2 diarrhea but was able to complete a total of four cycles with a best response of stable disease. Two patients were hospitalized for treatment of weakness, diarrhea, vomiting, and dehydration. Another patient with pre-existing bilateral pleural effusions developed worsening dyspnea, with the third cycle of flavopiridol requiring thoracentesis.
There was no evidence of any relationship between response and toxicity, as assessed by examination of neutropenia and diarrhea (the two most commonly observed severe toxic effects). The nadir absolute neutrophil counts in the three responders were 1.7, 0.7, and 0.8 x 109/L (median, 1.1 x 109/L for all 29 assessable patients), representing grades 1, 3, and 3 toxicities, respectively. The grades of diarrhea toxicity in the first cycle in the three responders were 2, 2, and 0, and in the worst cycle with diarrhea were 2, 2, and 1, respectively. Thus there was no evidence that patients responding to flavopiridol had a substantially worse or better toxicity pattern than the study population as a whole. The search for such relationships is, however, hampered by the size of the sample and the limited number of responders.
Mantle-cell lymphoma is characterized by the presence of the t(11;14) translocation in which approximation of the immunoglobulin heavy-chain locus at 14q32 and the bcl-1 oncogene at 11q13 results in overexpression of cyclin D1. Cyclin D1 regulates transition from G1 to S phase of the cell cycle,10 and detection of cyclin D111 overexpression is one of the criteria used in making a diagnosis of mantle-cell lymphoma.9 When cyclin D1 is coupled to cdk4, the complex is capable of phosphorylating the retinoblastoma protein and relieving its growth-suppressive effects. Flavopiridol is a potent inhibitor of cyclin D1, cdk4, and other cdks, and in preclinical testing, it has resulted in cell cycle arrest and apoptosis in a number of hematologic cell lines. The overexpression of cyclin D1 in mantle-cell lymphoma therefore indicates that it is rational to study flavopiridol in this disease. This phase II trial assessed the response rate and toxicity of a bolus infusion of flavopiridol daily for 3 days every 3 weeks in patients with untreated or relapsed mantle-cell lymphoma. The majority of patients had advanced stage disease and were previously treated. The activity of flavopiridol as a single agent in this schedule was modest; the response rate was 11% and the median duration of response was 3.4 months. Stable disease was seen in 71% of patients. The response rate in previously untreated patients may be higher than in previously treated patients (18% v 6%), although the numbers of patients in either group are small. Despite the low response rate, some patients did experience transient decreases in the size of palpable lymph nodes, often within the first week of treatment. However, tumor regrowth was observed by the time the next cycle was due. This observation, along with the observed number of patients with a partial response or stable disease, supports the hypothesis that targeted cell cycle inhibition by flavopiridol leads to an antitumor effect. Because this effect is brief and incomplete, the responses are unlikely to be meaningful to patients, and further study of this dose and schedule of flavopiridol as a single agent is not believed to be worthwhile in patients with mantle-cell lymphoma. Our data do, however, indicate that further study of this drug and other agents that inhibit cyclin D1 may provide insights into potential new treatment strategies. As expected, diarrhea was the most common adverse event, but no patients required a dose reduction for this effect. Clinically apparent thromboembolic disease was not seen, and hematologic toxicity was modest. In another phase I to II study in patients with mantle-cell lymphoma in first relapse, flavopiridol 50 mg/m2/d was administered by continuous infusion over 72 hours37 repeated every 14 days to 10 patients. The median age of the patients was 61.5 years; 90% of them previously had been treated with cyclophosphamide, doxorubicin, vincristine, and prednisone with or without rituximab; and three patients had had no response to previous treatment. Dose escalation was possible in two patients. Diarrhea was seen in all patients, although mostly grades 1 and 2. Although flavopiridol was well tolerated, no responses were seen; three patients maintained stable disease and seven patients had progressive disease. Therefore, the study was terminated early. The lack of responses with the continuous-infusion schedule may be explained by an increased binding of flavopiridol to serum proteins.38 In addition, preclinical experiments have suggested that peak flavopiridol concentrations are required for maximal antitumor effect, something that is more apt to be achieved with bolus, rather than continuous, intravenous administration.31 Flavopiridol has been shown to enhance the induction of apoptosis by chemotherapy.39–42 Several studies in patients with solid tumors have tested combinations of flavopiridol with paclitaxel alone,43 cisplatin alone,44 and paclitaxel and cisplatin.45 The feasibility of combining flavopiridol with traditional chemotherapy was demonstrated in a phase I study,43 which also indicated some clinical activity in patients with esophageal, lung, and prostate cancer who had progressed while taking paclitaxel. The sequence of administration appears to be important in studies in which flavopiridol has been combined with other agents; pretreatment with flavopiridol induces a G1 arrest that prevents cycling cancer cells from entering the M phase of the cell cycle, where they may be susceptible to the actions of other antineoplastic agents.40 In summary, flavopiridol has modest activity as a single agent in mantle-cell lymphoma. The number of patients with stable disease, the few partial responses, and the transient tumor shrinkage in some patients provide evidence for its biologic effect and indicate that it may delay progression. Future studies with this agent should examine its use in combination with other active agents in different schedules in patients with mantle-cell lymphoma. Furthermore, it would be of interest to evaluate other agents targeting cdks in this disease.
We thank the following study participants: Stephen Caplan, John Matthews, Louis Fernandez, Colin Germond, Kang Howson-Jan, Kevin Imrie, Michael Kovacs, Richard Klasa, Leona Rudinskas, Chaim Shustik, and Scott Young. We also thank Wendy Walsh at the National Cancer Institute of Canada, Clinical Trials Group, for her excellent work in preparing data summaries.
Supported by a grant from the National Cancer Institute of Canada.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
