Irinotecan in Relapsed or Refractory Non-Hodgkin’s Lymphoma

Introduction

Camptothecin is an alkaloid obtained from the Camptotheca acuminata tree. The original clinical preparation, camptothecin sodium, was evaluated in clinical trials in the late 1960s and early 1970s, but was abandoned due to severe and unpredictable hemorrhagic cystitis.[1-3] Irinotecan(Drug information on irinotecan) (CPT-11, Camptosar) is a semisynthetic derivative of camptothecin that has higher water solubility and greater in vitro and in vivo activity, and is associated with less severe and more predictable toxicity than camptothecin.[4-6]

Both camptothecin and irinotecan are potent inhibitors of topoisomerase I, an enzyme normally active during DNA replication. Topoisomerase I induces transient breaks in a single strand of DNA that release the torsional strain caused by synthesis of a new strand of DNA or RNA around a double helix. The camptothecins target this topoisomerase I/DNA complex, stabilize it, and inhibit the reannealing of the parent DNA. When an advancing replication fork collides with the camptothecin-topoisomerase I/DNA complex, double-stranded DNA breaks occur that lead to cell death.[7,8]

Irinotecan has been evaluated in several schedules and dosages. Commonly, it has been given weekly for 4 weeks with a 1- to 2-week break. In the United States, this schedule is commonly used for patients with colorectal cancer. Alternatively, in Europe, where the drug has also been developed primarily for treatment of colorectal malignancy, single dose of 350 mg/m2 has been studied every 3 weeks with resulting response rates ranging from 14% to 18%, depending on whether patients had been previously treated.[9-11]

This latter irinotecan schedule may be more attractive for the treatment of lymphoma, because it may be easier to combine irinotecan with other myelosuppressive drugs that are active in lymphoma. These are usually administered every 21 days, and can be supported by growth factors. Based on these considerations, we investigated the clinical activity of irinotecan 300 mg/m² administered every 21 days[11] in patients with relapsed or refractory non-Hodgkin’s lymphoma.

Patients and Methods

Eligibility Criteria

Patients were eligible for study entry if they had histologically confirmed relapsed (complete or partial remission during initial therapy) or refractory (no response or progression during initial therapy) non-Hodgkin’s lymphoma. Eligible patients had bidimensionally measurable disease, Zubrod performance status ≤ 2, normal serum creatinine and bilirubin levels, serum transaminase levels ≤ 4 times the upper normal limit, absolute granulocyte count ³ 1,500/mL, and platelet count > 100,000/mL. Patients with central nervous system involvement, human immunodeficiency virus (HIV) infection, and treatment with three or more previous chemotherapy regimens or transplantation of stem cells or bone marrow were ineligible. The study was approved by the clinical research council and the investigational review board of The University of Texas M. D. Anderson Cancer Center and the National Cancer Institute for activation in the Community Clinical Oncology Program. A signed, witnessed informed consent was required of all patients entering the study.

Treatment Plan

Irinotecan was infused intravenously at a dose of 300 mg/m² (calculated on actual body weight) in 250 mL normal saline over 30 minutes. No steroids were allowed during treatment. Oral antiemetic premedication was given 30 minutes prior to chemotherapy. Treatment was repeated every 21 days in the absence of dose-limiting toxicity or disease progression. Responders received up to six injections. Dose reduction in increments of 25 mg/m² was used for limiting toxicity. All patients were counseled on the use of intensive loperamide(Drug information on loperamide) for control of delayed diarrhea, as previously described.[12]

Study Staging, Response Determination

Staging included physical examination, including routine neurologic examination, tumor measurements, complete blood count, bone marrow aspirate and biopsy, serum chemistries, b₂-microglobulin serum levels, and computed tomography (CT) of chest, abdomen, and pelvis. Tomography of the head and neck and a gallium scan were performed at the discretion of the treating physician. Baseline staging was performed within 21 days of treatment and was repeated after two cycles of irinotecan.

Complete response was defined as complete disappearance of all disease on physical or radiographic examination. Partial response was ³ 50% reduction, and progressive disease was ³ 25% increase of bidimensional tumor area or appearance of disease in any new sites. All other changes were considered stable disease. Response to therapy was defined as achievement of complete or partial remission. Treatment failure was progressive or stable disease after two cycles or progressive disease at any time.

Patients who achieved a complete or partial response after two cycles received a maximum of six cycles, with complete restaging every two cycles. Progression-free survival was measured from the time treatment was started to the last follow-up, treatment failure, or disease progression, and was estimated according to Kaplan and Meier.

Statistical Considerations

The primary goal of this study was to evaluate the response rate of this dose and schedule of irinotecan in patients with relapsed or refractory non-Hodgkin’s lymphoma. Three categories of non-Hodgkin’s lymphoma were analyzed because of differences in biology and response to treatment. These were clinically classified as aggressive, indolent, and mantle cell non-Hodgkin’s lymphoma. Mantle cell lymphoma was considered separately from other aggressive lymphomas because it has a low response rate and tends to be overrepresented in relapsed lymphoma series. For the aggressive and indolent non-Hodgkin’s lymphoma categories there was a stratification for achievement of previous response (complete or partial remission) or for no response to the initial therapy (refractory lymphoma).

Therefore, the following arms were used: (1) refractory aggressive non-Hodgkin’s lymphoma, (2) relapsed aggressive non-Hodgkin’s lymphoma, (3) refractory indolent non-Hodgkin’s lymphoma, (4) relapsed indolent non- Hodgkin’s lymphoma, and (5) mantle cell lymphoma. The optimal Simon two-stage design was used for each stratum.[12]

The plan was constructed so that if the true response rate were no more than 10%, the probability of recommending the regimen would be 0.05 (type I error). Similarly, if the true response rate were at least 25%, the probability of detecting such a result would be 0.80 (power). During the first stage, 18 patients were to be accrued to each of these five arms. If only one or two patients were to have a response, that arm of the trial would be closed with the conclusion that the true response rate was not likely to be > 10%. The probability of this occurrence was to be 0.734. If at least three patients were to have a response, an additional 25 patients would be accrued in that particular arm during stage II. The probability that this will occur if the true probability of response is 25% is 0.864. With 43 patients the true response rate would be calculated along with approximate 95% confidence limits of ± 13%. The criterion for further study of this agent is the observation in a given stratum of eight responses among 43 evaluable patients (19%).

Results and Discussion

As of May 2000, 25 patients were registered, 22 of whom were evaluable for response and toxicity and are the subject of this early report. Their presenting clinical and laboratory features are shown in Table 1. Ten of 22 patients did not achieve complete or partial response during the regimen immediately preceding irinotecan. This was reflected in the frequent elevations of serum levels of lactate dehydrogenase and b₂-microglobulin, which have been associated with lower response rates in relapsed non-Hodgkin’s lymphoma.[13]

Responses according to clinical grade are shown in Table 2, and are promising for patients with relapsed aggressive non-Hodgkin’s lymphoma, 45% of whom responded. Because of the small number of patients, the 95% confidence intervals are still wide. According to the study design, the arm of relapsed aggressive non-Hodgkin’s lymphoma will continue accrual until 45 patients are entered. The other arms will continue accrual to 18 patients before the statistical design can determine which of them will continue.

Toxicity is shown in Table 3. Myelosuppression was relatively common but transient. Neutropenic fevers were seen in only 8% of cycles. Grade 3 or 4 delayed diarrhea was seen in only 10% of treatment cycles, a frequency similar to that previously reported with this irinotecan dose and schedule in patients with colorectal cancer.[11]

Conclusions

In conclusion, this ongoing trial of irinotecan shows promising activity in patients with relapsed aggressive non-Hodgkin’s lymphoma. Accrual is continuing in all arms for better determination of the response rate in the various non-Hodgkin’s lymphoma subcategories.