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Originally published as JCO Early Release 10.1200/JCO.2005.04.3836 on March 6 2006 © 2006 American Society of Clinical Oncology. Pentostatin, Cyclophosphamide, and Rituximab Is an Active, Well-Tolerated Regimen for Patients With Previously Treated Chronic Lymphocytic Leukemia
From the Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY; Cleveland Clinic Foundation, Cleveland, OH. Address reprint requests to Mark A. Weiss, MD, Leukemia Service, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; e-mail: weissm{at}mskcc.org
PURPOSE: Purine analogs and alkylators are important agents for treating chronic lymphocytic leukemia (CLL). Early studies combining fludarabine and chlorambucil were abandoned owing to increased toxicity from overlapping myelosuppression and immunosuppression. Of the purine analogs active in CLL, pentostatin appears to be the least myelosuppressive. We previously reported that pentostatin and cyclophosphamide (PC) is active and well-tolerated in patients with relapsed or refractory CLL. Subsequently, we added rituximab, and now report on this three-drug combination. PATIENTS AND METHODS: We treated 46 patients with either previously treated CLL (32 patients) or other low-grade B-cell neoplasms (14 patients). Patients received pentostatin 4 mg/m2, cyclophosphamide 600 mg/m2, and rituximab 375 mg/m2 (PCR). All drugs were administered on the same day (rituximab omitted from cycle 1), and patients received six cycles at 3-week intervals. Filgrastim, sulfamethoxazole/trimethoprim, and acyclovir were administered prophylactically. RESULTS: The median age was 62 years (range, 30 to 80 years). The median number of prior regimens was two (range, one to seven). For CLL patients, there were 24 responses (75%), including eight complete responses (25%). In fludarabine-refractory patients, 75% responded. Toxicity was acceptable, with grade 3/4 infections (including fever of unknown origin) in 28%. The regimen was well tolerated, with 72% of patients receiving the planned treatment at full dose. CONCLUSION: PCR is safe and effective in previously treated patients with CLL. In comparison with our prior two-drug regimen, we find that rituximab did not seem to add significantly to the toxicity, but did appear to confer a survival advantage. Based on these results, we are currently studying PCR as initial therapy for patients with CLL.
The introduction of three structurally similar purine analogs—fludarabine,1,2 cladribine,3,4 and pentostatin,5,6—in the late 1980s and early 1990s dramatically reinvigorated the development of new treatments for patients with chronic lymphocytic leukemia (CLL). Fludarabine has been the most widely studied of these agents. Early studies demonstrated that single-agent fludarabine as initial treatment for patients with CLL induced responses in most patients, with a minority achieving a complete response (CR).7 This prompted investigators to combine fludarabine with prednisone8 or chlorambucil.9,10 The results of these early studies were disappointing because of increased toxicity that limited dose intensity, and overall, there was no obvious improvement in response. More recently, combinations of fludarabine and cyclophosphamide (with and without rituximab) have been successfully administered to patients, with encouraging results in terms of response. However, such regimens still require careful attention to the dose of the alkylating agent because of potent overlapping immunosuppressive and myelosuppressive effects leading to a substantial risk of infection and hemorrhage.11-13 Of the purine analogs active in CLL, pentostatin appears to be the least myelosuppressive.14-16 We hypothesized that the combination of pentostatin and cyclophosphamide might have less myelosuppression than combination therapy with either fludarabine or cladribine, and that this improved therapeutic index would allow us to exploit the antileukemic activity of this synergistic combination. Previously we tested the two-drug combination of pentostatin and cyclophosphamide (PC).17 In that study, 23 patients with heavily pretreated CLL were evaluated. There were 17 responses (74%), including four CRs (17%) with an acceptable toxicity profile. Based on the encouraging results of the two-drug combination, rituximab was added to this regimen. This report details the results of the three-drug regimen pentostatin, cyclophosphamide, and rituximab (PCR) in previously treated patients with CLL or other low-grade B-cell neoplasms.
Patients Patients with previously treated B-cell CLL or other low-grade B-cell neoplasms were enrolled between May 2001 and October 2004. All patients with CLL were required to have Rai classification intermediate- or high-risk disease and to meet the criteria for active disease as defined by the National Cancer Institute (NCI) Working Group.18 All patients gave written informed consent. This study was reviewed and approved by the institutional review boards of Memorial Sloan-Kettering Cancer Center (New York, NY) and the Cleveland Clinic Foundation (Cleveland, OH). Patients were defined as fludarabine-refractory if they failed to respond to their last treatment with fludarabine (or a fludarabine-based regimen) or if their disease progressed within 6 months of a PR or CR.17
Trial Design
Patients received pentostatin 4 mg/m2, cyclophosphamide 600 mg/m2, and rituximab 375 mg/m2. All drugs were administered on the same day in the following order: cyclophosphamide, pentostatin, and rituximab, along with at least 1.5 L of intravenous hydration. The serum creatinine was determined on the day of treatment, and chemotherapy was withheld if the serum creatinine exceeded 2.0 mg/dL or was more than 20% higher than the baseline value for the patient. In such cases, treatment was not administered until the serum creatinine had improved to these levels or to a point that the creatinine clearance was demonstrated to be
Cycles were repeated every 3 weeks if the patient had sufficient hematopoietic recovery. If necessary, therapy was delayed until the blood counts sufficiently recovered, following which, it was administered at full dose. Supportive measures included dexamethasone 20 mg and granisetron 2 mg as antiemetics administered on the day of therapy, with ondansetron or granisetron recommended for nausea, as needed. Other supportive measures included filgrastim (300 µg for patients After three cycles, patients who did not achieve at least a PR were considered to have experienced treatment failure and were removed from study. Responding patients continued on treatment for a total of six cycles.
Evaluation Criteria To assess response, patients had a complete physical examination, CBC, BM aspirate, and biopsy. Peripheral blood and/or BM samples were analyzed by flow cytometry for CD5/CD19 (or CD5/CD20) dual staining and kappa/lambda clonal excess. Patients with trisomy 12 were also tested at the time of response assessment. Patients who had abnormal computed tomography imaging pretreatment had repeat computed tomography imaging for response assessment. These evaluations were performed pretreatment, then after three and six cycles of therapy.
Criteria for Response Patients with trisomy 12 as assessed by FISH had subsequent blood and/or BM follow-up analysis performed sequentially for minimal residual disease. Patients with trisomy 12 who had no evidence of this abnormality after treatment (test results within normal limits, < 0.6%) were considered to have a "FISH CR."
Toxicity
Statistical Methods
Patient Characteristics Forty-six patients were treated. Thirty-two had CLL, 25 with Rai classification high-risk disease and seven with Rai classification intermediate-risk disease. Nine patients had SLL; histologically (and immunophenotypically), most of these patients had the "CLL type" of SLL but did not meet the NCI Working Group definition of CLL because of the degree of blood and BM involvement. Four patients had follicular lymphoma, and one had Waldenstrom's macroglobulinemia. Patient characteristics are detailed in Table 1. Table 2 summarizes prior treatments received by patients treated on this study. The CLL patients represented a poor-prognosis group, with most patients having high-risk disease (78%), CD38 expression (87%), and exposure to substantial prior therapy (median, two regimens; range, one to seven). Most patients had previously received therapy with fludarabine (78%) and alkylating agents (78%). Of those who had prior fludarabine therapy, 32% were refractory to fludarabine (or fludarabine-based combination) treatment.
Response Responses are categorized in Table 3. In the cohort of 32 patients with CLL, there were 24 responses (75%), including eight CRs (25%), one nodular response (NR; 3%), and 15 PRs (47%). The eight patients assessed as having experienced treatment failure included six patients with disease progression during therapy, one patient with stable disease, and one patient who died from infection.
All eight patients who achieved a morphologic CR had no detectable residual disease by flow cytometry (flow cytometric CR), confirming the good quality of these responses. Seven patients had trisomy 12, and in this group, there were two CRs, four PRs, and one treatment failure. In both of the patients who achieved a CR, FISH analysis was unable to detect residual trisomy 12 at the conclusion of therapy. Detection of other chromosomal abnormalities, such as 13q deletion, 11q deletion, or 17p deletion, were not required for the study and were therefore not routinely performed. The data for some patients were available, and responses for other cytogenetic subtypes were: seven patients with 13q deletion, one CR, and three PRs; three patients with 11q deletion and two PRs; and three patients with 17p deletion, one CR, and two PRs. Six (75%) of the eight patients with fludarabine-refractory disease had a response to this regimen in the salvage setting. Two (25%) of these fludarabine-refractory patients had a good response to this combination regimen, with one patient achieving a CR and another patient achieving NR.
Response Duration and Survival
Toxicity This regimen was generally well tolerated. Myelosuppression was the most frequent toxicity, with grade 3/4 neutropenia, anemia, and thrombocytopenia occurring in 53%, 9%, and 16% of patients, respectively. Grade 3/4 infections (including fever of unknown origin) occurred in nine patients (28%); eight of these patients had pneumonia. There was one death from progressive pneumonia. The only other related grade 3/4 toxicity was a single event of grade 3 nausea (without vomiting) in one patient. The cytotoxic effects of this combination were rapid, as evidenced by the fact that asymptomatic tumor lysis was detected in 56% of patients treated. This fraction may underestimate the true risk of tumor lysis syndrome because all patients received hydration and allopurinol before initiating therapy. Rapid cytoreduction was manifested as a prompt decline in the number of circulating lymphocytes, with a median reduction of 78% seen following the first cycle of chemotherapy. Twenty-three (72%) of 32 patients with CLL received the planned number of chemotherapy cycles. Five of the remaining nine patients were removed from study secondary to infections. The other four patients were removed for a variety of comorbid conditions (lung cancer, amegakaryocytic thrombocytopenia, chylous pleural effusion, and an acute confusional state of undetermined etiology).
Fludarabine, the most widely studied of the purine analogs when used as a single agent for initial therapy in patients with CLL, produces complete responses in 4.9% to 40.1% of patients.7,12,21-24 Despite producing a higher frequency of CR compared to alkylators, to date no prospective randomized trial has demonstrated a survival advantage for patients receiving fludarabine as initial therapy.21,23,24 It is recognized, however, that patients who achieve a CR have an improvement in survival compared to those who achieve a PR. Therefore, many investigators have focused on developing regimens that can induce high frequencies of CR12,25,26 by examining purine-analog–based combination therapy for patients with CLL. Many of the initial combination studies were abandoned because of the increased toxicity associated with combination therapy.8-10,21,27 More recently, combinations of fludarabine and cyclophosphamide with or without rituximab have been shown to be highly active.11-13,28,29 However, these combinations need careful attention to dose and schedule, as overlapping myelosuppression and immunosuppression can lead to severe toxicity, often necessitating dose reductions in order to maintain safe coadministration of these agents. Because pentostatin is less myelosuppressive14-16 than fludarabine, we hypothesized that the combination of an alkylating agent with pentostatin would have less myelosuppression than combinations with fludarabine, and would thus produce a regimen with equivalent activity but less toxicity than fludarabine- (or cladribine-) based regimens. In our initial study, pentostatin was combined with cyclophosphamide, and the degree of myelosuppression seemed to be favorable (compared with fludarabine-based combinations), with grade 3/4 neutropenia, thrombocytopenia, and anemia noted in 35%, 29%, and 0% of patients, respectively.17 Grade 3/4 infections were noted in only 9% of patients treated with the PC combination. The addition of rituximab may increase myelotoxicity, with increased neutropenia (53%) and infections, including fever of unknown origin (28%), as compared with the two-drug regimen. However, the difference in the degree of myelosuppression and the risk of infection for PC and PCR was not statistically significant (P > .05 for all comparisons). An increase in myelosuppression is not surprising, as the addition of rituximab to fludarabine has previously been noted to result in increased myelotoxicity.30 Obviously, only a prospective randomized comparison can accurately assess the effect of rituximab on this regimen. Though response frequencies are similar between PC and PCR (74% v 75%; CR, 19% v 25%, respectively), response duration (9 v 25 months, respectively) and survival (17 v 44 months, respectively; Fig 1 ) seem to be improved by the addition of rituximab. This is consistent with previous reports whereby the addition of rituximab to fludarabine-based treatments also suggested a survival advantage compared with the same regimen without rituximab.22,28 Though this survival advantage has been reported by others, to date, no biologically valid hypothesis has been offered to explain this benefit. In part, however, the very long half-life of rituximab may contribute to the improved response duration and overall survival associated with rituximab-containing regimens. The group at the M.D. Anderson Cancer Center (Houston, TX) recently reported on their combination of FCR in patients with previously treated CLL.28 We have compared those published results with our results with the PCR regimen (Table 4). However, we recognize that it is not possible to fully account for differences in patient mix between these clinical trials, and a prospective randomized trial will be required to truly compare these regimens. In the comparison of the pretreatment characteristics between PCR and FCR, we note that age and number of prior regimens are comparable. Other pretreatment characteristics are not, and these include the frequency of: high-risk disease (PCR 78% v FCR 50%, P = .003), ß-2 microglobulin greater than 4 mg/L (PCR 44% v FCR 57%, P = .13), and CD38 expression greater than 20% (PCR 87% v FCR 41%, P = .0001). Recognizing the inherent limitations in these comparisons, we note that responses are virtually identical, with an overall frequency of 75% for PCR compared with 73% for FCR, and CRs seen in 25% of patients treated with either PCR or FCR. The median survivals for all patients are also comparable, at 44 months for PCR and 42 months for FCR. PCR seems to compare favorably with FCR in terms of the frequency of grade 3/4 toxicity encountered including neutropenia (53% with PCR v 81% with FCR, P = .0007), thrombocytopenia (PCR 16% v FCR 34%, P = .04), anemia (PCR 9% v 24%, P = .06), and infectious complications including fever of unknown origin (28% with PCR v 47% with FCR, P = .05). Moreover, PCR may be better tolerated, as indicated by the fraction of patients receiving all planned therapy at full dose (72% with PCR v 38% with FCR, P = .0004). Rituximab infusion–related toxicity (any grade) was also less (9% with PCR v 63% with FCR, P = .001). An important caveat, however, in these comparisons, which will likely affect the degree of neutropenia and possibly the frequency of infectious complications, is that myeloid growth factor was routinely administered to patients on the PCR study but was not routinely administered to patients treated with FCR.
Another concern regarding alkylator-fludarabine–based combinations is that there may be an increased incidence of therapy-related myeloid leukemias.28,31 In the Intergroup study, this was noted in five (3.5%) of 142 patients who received combination fludarabine and chlorambucil at a median of 34 months following therapy.30 One case was observed in 188 patients treated with fludarabine alone, and no cases were observed in the 191 patients treated with chlorambucil only (P = .007). A comparable incidence was reported by the M.D. Anderson group for their FCR regimen, with five patients (2.8%) developing myelodysplasia or acute myelogenous leukemia.28 To date, we have not yet observed the development of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) in any of the 69 patients treated with PC or PCR. Though the numbers are small and the follow-up limited (maximum, 6.5 years), we believe it possible that because pentostatin is less myelotoxic (and therefore perhaps less toxic to the hematopoietic stem cells) than fludarabine, we may see fewer cases of therapy-related MDS or AML when compared with fludarabine-based therapy. Ultimately, only a prospective randomized study comparing a pentostatin-based regimen such as PCR, with a fludarabine-based regimen such as FCR, can optimally evaluate these two regimens and control for differences in patient populations often observed among different phase II studies. This is an exciting era for patients with CLL. Modern combination regimens are producing responses in most patients, even in the salvage setting. However, in our attempt to produce ever more active regimens, we must be cognizant of the increased toxicity that these combination regimens can impart to our patients. Therefore, we must continue to not only improve the efficacy, but also limit the toxicity of these active combinations.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amonut Codes (A) < $10,000 (B) $10,000-$99,900 (C)
Supported by grants from SuperGen, the Michael Sweig Foundation, The Beatrice Renfield Foundation, and the Lymphoma Foundation. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Grever MR, Kopecky KJ, Coltman CA, et al: Fludarabine monophosphate: A potentially useful agent in chronic lymphocytic leukemia. Nouv Rev Fr Hematol 30:457-459, 1988[Medline] 2. Keating MJ, Kantarjian H, Talpaz M, et al: Fludarabine: A new agent with major activity against chronic lymphocytic leukemia. Blood 74:19-25, 1989 3. Juliusson G, Liliemark J: High complete remission rate from 2-chloro-2'deoxyadenosine in previously treated patients with B-cell chronic lymphocytic leukemia: Response predicted by rapid decrease of blood lymphocyte count. J Clin Oncol 11:679-689, 1993[Abstract] 4. Saven A, Lemon RH, Kosty M, et al: 2-Chlorodeoxyadenosine activity in patients with untreated chronic lymphocytic leukemia. J Clin Oncol 13:570-574, 1995 5. Grever MR, Leiby JM, Kraut EH, et al: Low-dose deoxycoformycin in lymphoid malignancy. J Clin Oncol 3:1196-1201, 1985 6. Dillman RO, Mick R, McIntyre OR: Pentostatin in chronic lymphocytic leukemia: A phase II trial of Cancer and Leukemia Group B. J Clin Oncol 7:433-438, 1989[Abstract] 7. Keating MJ, Kantarjian H, O'Brien S, et al: Fludarabine: A new agent with marked cytoreductive activity in untreated chronic lymphocytic leukemia. J Clin Oncol 9:44-49, 1991 8. O'Brien S, Kantarjian H, Beran M, et al: Results of fludarabine and prednisone therapy in 264 patients with chronic lymphocytic leukemia with multivariate analysis-derived prognostic model for response to treatment. Blood 82:1695-1700, 1993 9. Elias L, Stock-Novack D, Head DR, et al: A phase I trial of combination fludarabine monophosphate and chlorambucil in chronic lymphocytic leukemia: A Southwest Oncology Group study. Leukemia 7:361-365, 1993[Medline] 10. Weiss M, Spiess T, Berman E, et al: Concomitant administration of chlorambucil limits dose intensity of fludarabine in previously treated patients with chronic lymphocytic leukemia. 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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
50 mL/min. Given concerns that infusion reactions to rituximab tend to be more severe in patients with hyperleukocytosis
70 kg and 480 µg for patients > 70 kg administered subcutaneously daily beginning 2 days after each treatment and continued until the absolute neutrophil count exceeded 5,000/µL or 1,500/µL for 2 days), sulfamethoxazole-trimethoprim (one double-strength tablet twice daily, three times per week for Pneumocystis carinii prophylaxis), and acyclovir (800 mg twice daily for herpes zoster prophylaxis). 
2 analysis. 
