Irinotecan in Relapsed or Refractory Non-Hodgkin’s Lymphomas

ABSTRACT: Because irinotecan (CPT-11, Camptosar) is a topoisomerase I inhibitor with a broad spectrum of antitumor clinical activity, we investigated its activity in relapsed or refractory non-Hodgkin’s lymphomas (NHLs). Irinotecan at 300 mg/m² IV was administered every 21 days with intensive loperamide management of diarrhea. Responders received up to six treatment cycles. Of 44 registered patients, 32 are evaluable for response. Seventeen patients had received one previous regimen, and 15 patients had received two. Disease was refractory to the regimen preceding irinotecan in 12 patients. At baseline, serum lactate dehydrogenase levels were high in 47% (14/30), and beta-2-microglobulin levels were higher than 3.0 mg/L in 29% (8/28) of patients. Responses were seen in 12 of 32 (38%) patients (95% confidence interval [CI] = 21%-56%). Response rates were 43% for seven indolent (95% CI = 10%-82%), 0% for three mantle cell (95% CI = 0%-71%), 44% for 18 relapsed aggressive (95% CI = 22%-69%), and 20% for five refractory aggressive NHLs (95% CI = 1%-72%). Grade 3/4 toxicities included myelosuppression, neutropenic fever, and diarrhea. Irinotecan appears active and relatively well tolerated in patients with relapsed aggressive or indolent NHL. Accrual to this study is continuing for better determination of response rates in all histologic subtypes of NHL.[ONCOLOGY 16(Suppl 7):27-31, 2002]

Camptothecin is an alkaloidobtained from the Camptotheca acuminata tree. The original clinical preparation,camptothecin sodium, was evaluated in clinical trials in the late 1960s andearly 1970s, but was abandoned due to severe and unpredictable hemorrhagiccystitis.[1-3] A semisynthetic derivative of camptothecin is irinotecan (CPT-11,Camptosar), with higher water solubility, greater in vitro and in vivo activity,and milder and more predictable toxicity than camptothecin.[4-6]

Camptothecin and its derivative, irinotecan, are potent inhibitors oftopoisomerase I, an enzyme normally active during DNA replication. TopoisomeraseI induces transient breaks in a single strand of DNA, which release thetorsional strain caused by synthesis of a new strand of DNA or RNA around adouble helix. The campthothecins target this topoisomerase I-DNA complex,stabilize it, and inhibit the reannealing of the parent DNA. When an advancingreplication 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 using several schedules and dosages, the mostfrequent being weekly for 4 weeks with 1- or 2-week treatment breaks.Alternatively, in Europe, where the drug has also been developed primarily forthe treatment of colorectal cancer, single doses of 350 mg/m² have been givenevery 3 weeks with response rates ranging from 14% to 18%, depending on theextent of previous therapy.[9,10] The every-21-days irinotecan schedule is moreattractive for the treatment of lymphoma because it will be easier to combinewith other myelosuppressive drugs that are active in lymphoma, which are alsousually given every 21 days, and can be supported by hematopoietic growthfactors to minimize or prevent neutropenia.

Based on these considerations, we decided to investigate the clinicalactivity of irinotecan administered at 300 mg/m² every 21 days[11] in patientswith relapsed or refractory non-Hodgkin’s lymphoma (NHL).

Patients and Methods

Eligibility Criteria

Patients were eligible for study entry if they had histologically confirmedrelapsed or refractory NHL. Relapsed disease indicates recurrence after acomplete or partial response to the initial regimen. Refractory diseaseindicates less than a partial response or progression during the initialregimen. Eligible patients had bidimensionally measurable disease, a Zubrodperformance status ≤ 2, normal serum creatinine and bilirubin levels, serumtransaminase levels £ 4 times the upper normal limit, absolute granulocytecount ³ 1,500/µL, and platelet count ³ 100,000/µL. Patients with centralnervous system involvement or human immunodeficiency virus infection, or who hadbeen treated with three or more previous regimens or with transplantation ofstem cells or bone marrow, were ineligible. The study was approved by theInvestigational Review Board and the National Cancer Institute for activation tothe Cancer Community Oncology Program. All patients signed informed consent.

Treatment Plan

Irinotecan was infused intravenously at a dose of 300 mg/m² in 250 mL ofnormal saline over 30 minutes. No steroids were allowed during treatment.Antiemetic premedication was prochlorperazine at 10 mg orally 30 minutes priorto chemotherapy. Treatment was repeated every 21 days in the absence ofdose-limiting toxicity or disease progression. Responders received up to sixinjections. Dose reduction at multiples of 25 mg/m² was employed fordose-limiting toxicity. All patients were counseled on the use of intensiveloperamide for control of delayed diarrhea, as previously described.[11]

Study Staging andResponse Determination

Staging consisted of physical examination, including routine neurologicexamination, tumor measurements, complete blood cell count, bone marrow aspirateand biopsy, serum chemistries, beta-2-microglobulin serum level, andcomputerized axial tomography of the chest, abdomen, and pelvis. Tomography ofthe head and neck and gallium scan were performed at the discretion of thetreating physician. Baseline staging was performed within 21 days of treatment,and was repeated after two cycles of irinotecan. Response criteria werestandard.

Treatment failure was any response less than a partial response after twocycles, or progressive disease at any time during therapy. Patients who achieveda complete or partial response after two cycles received a maximum of sixcycles, with complete restaging every two cycles.

Statistical Considerations

The primary goal of this study was to evaluate the response rate of this doseand schedule of irinotecan in patients with relapsed or refractory NHL. Threecategories of NHL patients were analyzed separately because of differences inthe biology of NHL histotypes and responses to treatment. These separatecategories were clinically classified as aggressive, indolent, and mantle cell.Mantle cell lymphoma was considered separately from other aggressive lymphomasbecause it has a low response rate and tends to be overrepresented in relapsedlymphoma series.

Patients with aggressive NHL were stratified by achievement of previousresponse (complete or partial remission) or no response to the initial therapy(refractory lymphoma). Therefore, the following arms were used: (1) refractoryaggressive NHL, (2) relapsed aggressive NHL, (3) relapsed indolent NHL, and (4)mantle cell NHL. The optimal Simon two-stage design was used for eachstratum.[12] The plan was constructed so that if the true response rate were nomore than 10%, the probability of recommending the regimen would be 0.05 (type Ierror). Similarly, if the true response rate were at least 25%, the probabilityof detecting such a result would be 0.80 (power).

During the first stage of the study, 18 patients were to be accrued to eachof these four arms. If only one or two patients in an arm responded, that armwould be closed with the conclusion that the true response rate is not likely tobe greater than 10%. The probability of this occurrence was to be 0.734. If atleast three patients in an arm responded, an additional 25 patients would beaccrued in that arm during the second stage of the study. The probability thatthis will occur is 0.864 if the true probability of response is 25%. With 43patients, the true response rate would be calculated along with approximate 95%confidence limits of ± 13%. The criterion for further study of this agent isthe observation in a given stratum of eight responses among 43 evaluablepatients (19% response rate).

Results and Discussion

A total of 44 patients have been registered in this study, of whom 32 areevaluable for response and toxicity. Their presenting clinical and laboratoryfeatures are shown in Table 1. Despite the limit of two previous regimens, thispatient population had some unfavorable characteristics. For example, 12 of 32patients (38%) did not achieve complete or partial response during the regimenimmediately preceding irinotecan. This was reflected in the frequent elevationsof serum levels of lactate dehydrogenase and beta-2-microglobulin, which havebeen associated with lower response rates in relapsed NHL.[13]

As shown in Table 2, 44% of patients with relapsed aggressive and 43% withindolent NHL responded to irinotecan. Surprisingly, 20% of patients withaggressive NHL who had been refractory to the initial regimen also achieved aresponse to irinotecan. However, the 95% confidence intervals of thesecategories overlap, at least in part because of the small patient number, soaccrual is ongoing. Based on the statistical rules described previously, a totalof 35 patients will be accrued in each category of relapsed aggressive andrelapsed indolent NHL. It is not yet clear whether the categories of refractoryaggressive NHL or mantle cell lymphomas will pass the early stopping rule.

As shown in Figure 1, progression-free survival for responders is a median of7.1 months, and ranges from 1.4 to 27 months. Three patients remain in remissionmore than 1 year after beginning irinotecan treatment. Their presentingcharacterisitics and past therapies are shown in Table3.

Grade 3 and 4 toxicities are shown in Table4. Serious nausea and vomitingwere rare. Early diarrhea was uncommon, occurring after only 3% of treatmentcycles. Late diarrhea, occurring 48 hours or later after irinotecanadministration, occurred more commonly (after 12% of doses). However, this wasmanageable with intensive loperamide support. Only one patient requiredhospitalization for intravenous hydration for delayed diarrhea and management ofconcurrent non-neutropenic fever. Diarrhea was controlled but the patient diedof septic complications (see below for details). The frequency of nonhematologictoxicity was similar to that previously reported with this dose and schedule inpatients with colorectal cancer.[11]

Neutropenia (< 1,000/µL) was common (42% of cycles) but severe (<100/µL) after only 17% of irinotecan cycles. Even then, it was usuallytransient; consequently, neutropenic fever was seen in 8% of cycles, especiallysince hematopoietic growth factor support was permitted at the discretion of thetreating physician. Thrombocytopenia (< 100,000/µL) was less frequent thanneutropenia (20% of cycles), but platelet counts were rarely less than20,000/µL(5% of cycles). One patient with colonic involvement by mantle cell lymphoma hada hemorrhagic episode associated with thrombocytopenia (melena) when plateletcount was 87,000/µL. Colonoscopy revealed oozing of blood around thelymphomatous polyps. The patient received transfusions of packed red cells andplatelets, and recovered.

One toxic death occurred in association with thrombocytopenia in a patient(also previously described) who was admitted to the hospital 5 days afterinitiation of the first irinotecan treatment cycle. Evaluation revealeddehydration caused by 2 days of diarrhea and fever with an absolute neutrophilcount of 1,000/µL. Diarrhea was controlled in the hospital with loperamide, anddehydration was corrected with intravenous fluids. The patient receivedbroad-spectrum antibiotics, but developed multisystem organ failure and expired.No infectious organism was identified in all cultures.

Conclusion

In conclusion, irinotecan shows promising activity in patients with relapsedaggressive and relapsed indolent NHL. Because of the small number of patients inthis study, it is unclear whether irinotecan is active among patients withmantle cell lymphoma or refractory aggressive NHL. Accrual is continuing in allarms for better determination of the response rate in various NHL subcategories.

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