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© 2003 American Society for Clinical Oncology Pentostatin and Cyclophosphamide: An Effective New Regimen in Previously Treated Patients With Chronic Lymphocytic Leukemia
From the Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, and Cornell University Medical College, New York, NY; and the Greenebaum Cancer Center, University of Maryland, Baltimore, MD. Address reprint requests to Mark Weiss, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021; email: weissm{at}mskcc.org.
Purpose: Purine analogs and alkylators are important agents in the treatment of chronic lymphocytic leukemia (CLL). Previously, combinations of fludarabine and chlorambucil were abandoned because of increased toxicity from overlapping myelosuppression and immunosuppression. Of the purine analogs active in CLL, pentostatin may be least myelosuppressive. We hypothesized that combining pentostatin with cyclophosphamide would have less myelotoxicity than combinations using other purine analogs. Patients and Methods: We studied 23 patients with previously treated CLL. All patients received pentostatin 4 mg/m2. Seventeen patients received cyclophosphamide 600 mg/m2, and six patients received cyclophosphamide 900 mg/m2. Both drugs were administered on day 1 of each cycle, and cycles were repeated every 3 weeks for six treatments. Filgrastim, sulfamethoxazole/trimethoprim, and acyclovir were administered prophylactically. The median number of prior treatment regimens was three (range, one to five) with 13 patients (57%) refractory to prior fludarabine therapy. Results: The cyclophosphamide 900 mg/m2 dose level was associated with moderate to severe nausea, and we chose cyclophosphamide 600 mg/m2 as the dose for further study. There were 17 responses (74%; 95% confidence interval, 63% to 85%), including four complete responses. The response rate was 77% in fludarabine-refractory patients. Myelosuppression was acceptable with grade 3/4 neutropenia and thrombocytopenia, seen in 35% and 30% of patients, respectively. The relative sparing of thrombopoiesis can be seen in that only one patient (5%) with an initial platelet count of more than 20,000 required platelet transfusions while receiving therapy. Conclusion: Pentostatin 4 mg/m2 with cyclophosphamide 600 mg/m2 is safe and effective in previously treated patients with CLL. On the basis of these results, we are currently studying pentostatin, cyclophosphamide, and rituximab (PCR) therapy in patients with CLL.
TRADITIONALLY, PATIENTS with chronic lymphocytic leukemia (CLL) have been treated in a palliative fashion. Conventional therapy with oral alkylating agents with or without corticosteroids produced clinical improvement in most patients but rarely induced complete responses (CRs).1–3 In general, these responses were not durable, and patients ultimately succumbed to progressive resistant disease. The introduction of three structurally related purine analogs, fludarabine,4,5 cladribine,6,7 and pentostatin,8,9 renewed interest in developing more aggressive treatment programs for selected patients with CLL. Of these drugs, fludarabine has been the most widely studied. The ability of fludarabine to induce CRs in a minority of previously untreated patients10,11 led to investigation of combination chemotherapy with corticosteroids12,13 or chlorambucil.3,14,15 The results from these initial attempts of combining fludarabine with a second agent were disappointing because increased toxicity limited dose-intensity and because there was no clear-cut improvement in frequency of response. More recently, combinations of fludarabine with cyclophosphamide have been successfully administered to patients, but such regimens require careful attention to the dose of the alkylating agent because this synergistic combination has potent immunosuppressive and myelosuppressive effects leading to a risk of infection and hemorrhage.16–18 Of the purine analogs active in CLL, pentostatin may be the least myelosuppressive.19,20 We therefore hypothesized that the combination of pentostatin and cyclophosphamide might have less myelosuppression than combinations with either fludarabine or cladribine, and that this improved therapeutic index would allow us to exploit the antileukemic activity of this synergistic combination.21 Despite evidence that pentostatin has activity in CLL, as seen in the early phase II trials, the use of pentostatin in this disease has been extremely limited. To the authors’ knowledge, this article represents the first peer-reviewed report of combination therapy with pentostatin in patients with CLL.
Patients Patients with previously treated B-cell CLL or small lymphocytic lymphoma (SLL) were recruited for enrollment on this study between September 1998 and December 2000. All patients with CLL were required to have Rai intermediate- or high-risk disease and to meet the criteria for active disease as defined by the National Cancer Institute (NCI) Working Group.22 All patients gave written informed consent. This study was reviewed and approved by the institutional review board of Memorial Sloan-Kettering Hospital. Patients were defined as experiencing fludarabine treatment failure if they failed to respond to their last treatment with fludarabine (or a fludarabine-based regimen) or if they progressed within 6 months of a partial response (PR) or CR.
Trial Design After three cycles of therapy, patients who did not achieve at least PR were considered treatment failures 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, complete blood count, BM aspirate, and biopsy. In addition, 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 as assessed by FISH pretreatment were also tested at the time of response assessment. These evaluations were performed after three and six cycles of therapy.
CR required a normal physical exam; a peripheral blood lymphocyte count less than 4,000/µL, neutrophils
PR was defined as at least a 50% reduction in size of enlarged lymph nodes, spleen, and liver and at least a 50% decrease in peripheral blood lymphocyte count. In addition, patients achieving PR were required to have an ANC Progression of disease was defined as appearance of new lymphadenopathy or hepatosplenomegaly, or a more than 50% increase in lymph node, liver, or spleen size. In addition, a more than 50% increase in peripheral blood lymphocyte count constituted progression of disease. Patients who fit none of the above response categories were considered to have stable disease. Patients with either stable or progressing disease constituted treatment failures. After completion of therapy (until documented relapse), patients were typically followed at 2- to 3-month intervals for at least 1 year to assess duration of response. Response duration was measured from the time of maximal response to relapse. Time to treatment failure was measured from the start of protocol therapy to the first nonprotocol therapy (or death), and survival was measured from the start of protocol treatment. Flow cytometric analysis was evaluated separately as an indication of residual disease but was not included in the definition of response. A patient was considered to have no flow cytometric evidence of disease (flow cytometric CR) if immunophenotypic analysis of peripheral blood and BM revealed a normal kappa/lambda ratio (no clonal excess) and a normal number of CD5/CD19 (or CD5/CD20) dual-staining cells (< 5% of the lymphocyte gate). All patients had pretreatment blood and/or BM assessed for trisomy 12 by FISH analysis using a centromeric probe for chromosome 12. Patients with trisomy 12 as assessed by this methodology had subsequent blood and/or BM followed 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 Tumor lysis syndrome was defined as hyperkalemia, hyperphosphatemia, or hyperuricemia that developed after institution of chemotherapy.
Patient Characteristics Twenty-three patients were treated on this study. Twenty-one patients had CLL (15 patients with high-risk disease and six patients with intermediate-risk disease). Two patients had SLL; histologically (and immunophenotypically), 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. Patient characteristics including sex, age, prior therapy, blood counts, and beta-2 microglobulin are detailed in Table 1  . Table 2 summarizes the prior treatment received by patients treated on this study. On average, these patients had received substantial prior therapy (median of three prior regimens), with most patients having previously received therapy with fludarabine (87%) and alkylating agents (78%). In addition, 26% of patients had previously received therapy with rituximab. Seventeen patients were treated with cyclophosphamide 600 mg/m2 (dose level 1), and six patients were treated with cyclophosphamide 900 mg/m2 (dose level 2).
Response Of the 23 patients treated, there were 17 responses (74%; 95% confidence interval, 63% to 85%), including four CRs (17%) and 13 PRs (57%). One of the patients (4%) assessed as PR met the criteria for nodular PR. The six patients assessed as having experienced treatment failure included five with disease progression during therapy and one with stable disease (Table 3 ). In 17 patients, we had sufficient data to determine responses to their prior treatment regimens. In seven (41%) of these 17 patients, the response to treatment on the current regimen was superior to the response seen on any prior treatment. Thirteen patients had previously experienced failure of fludarabine-based therapy. In this group there were 10 responses (77%), including one CR. These responses appear to have been clinically meaningful because there was only one death within 6 months of completing therapy, and median survival from start of protocol therapy was 16 months in this typically poor-risk group of patients. Responses assessed according to fludarabine status and other pretreatment characteristics are listed in Table 4.
Patients achieving CR by standard criteria were also assessed for minimal residual disease by flow cytometry and, where appropriate, by FISH. Flow cytometric evaluation of blood and BM was performed on the four patients characterized as CRs. In three of the four patients who achieved CR, residual disease was not detected by flow cytometry (flow cytometric CR), which confirmed the high quality of these responses. In addition, two of the patients who achieved CR were known to have trisomy 12, as detected by FISH in pretreatment samples. In both of these patients, FISH analysis was unable to detect residual trisomy 12 at the conclusion of therapy.
For the 17 responding patients, median response duration was 7 months (Fig 1
The cytotoxic effects of this combination were rapid, as evidenced by the fact that mild, asymptomatic tumor lysis syndrome was detected in 39% 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 (Fig 3 ) was manifested as a prompt decline in the number of circulating lymphocytes, with a median reduction of 84% seen with the first cycle of chemotherapy. After two cycles of chemotherapy, both the median WBC count (7,800/µL) and lymphocyte count (3,200/µL) normalized.
Toxicity In general, this regimen was well tolerated. Toxicities encountered during the study are summarized in Table 5 . The most common adverse effects were mild fatigue (91%) and nausea (78%), which was typically well controlled with antiemetics. Despite the rapid decline in WBC count, the regimen was relatively platelet sparing. Myelosuppression, particularly thrombocytopenia, frequently complicates therapy of CLL. In this study, only 30% of patients experienced grade 3 (26%) or grade 4 (4%) thrombocytopenia, with a median duration of 7 days (range, 1 to 38 days). In fact, 44% of patients who were thrombocytopenic pretreatment did not suffer further decline in their platelet count while receiving therapy, and only one patient (5%) with an initial platelet count more than 20,000 required platelet transfusions while receiving therapy with pentostatin and cyclophosphamide.
Grade 3 or 4 neutropenia was encountered in eight patients (35%) but was typically of brief duration (median, 1 day; range, 1 to 16 days), which helped limit the frequency of severe infections. Overall, 15 patients (65%) developed infections while receiving treatment. Thirteen of these infections were grade 1 or 2, including five patients with mild viral upper respiratory infections. Other mild infections included cellulitis and paronychial infections. Only two patients (9%) had serious (grade 3 or 4) infections. Both of these infections were pneumonias that developed in heavily pretreated patients. One of these patients ultimately died of progressive pneumonia, and the other patient (with Pseudomonas pneumonia) recovered and ultimately achieved PR. In addition to the single death from pneumonia, one other patient died while enrolled onto the study; this patient experienced treatment failure and died of fulminant (transformed) disease. This patient also had grade 3 nephrotoxicity and cardiac toxicity (atrial fibrillation) that occurred as preterminal events. Other grade 3/4 toxicities were rare and included one instance of grade 3 nausea and vomiting in a patient receiving the cyclophosphamide 900 mg/m2 dose that was successfully treated with parenteral granisetron. Initially, three patients were accrued at the cyclophosphamide 600 mg/m2 dose level. The dose was then escalated to cyclophosphamide 900 mg/m2 for the next six patients. Given the somewhat more severe nausea encountered at the cyclophosphamide 900 mg/m2 dose level and the activity of this regimen seen at the lower dose level, we chose cyclophosphamide 600 mg/m2 as the phase II dose for further study. Fourteen additional patients were then accrued at the cyclophosphamide 600 mg/m2 dose level to more accurately assess frequency of response.
The results of a large intergroup trial that randomly assigned patients to receive fludarabine, chlorambucil, or combination chemotherapy with fludarabine and chlorambucil were recently reported.3 That study demonstrated a superior frequency of response and progression-free survival for the patients randomly assigned to receive fludarabine compared with those randomly assigned to receive chlorambucil as initial therapy. That study, however, was unable to demonstrate a significantly improved survival for those treated initially with fludarabine, but this may be the result of both the cross-over design of the study and the relatively small fraction of patients (20%) achieving CR in the fludarabine arm. Because other studies have indicated that patients achieving CR have improved survival compared with those achieving PR,17,24 it is possible that a regimen that produces a higher fraction of CRs might ultimately lead to improved survival for patients with CLL. In an attempt to improve the frequency of CR for patients with CLL, several strategies have been used to study combination therapy in this disease. Initial studies combining fludarabine with either prednisone or chlorambucil were abandoned because of increased toxicity associated with combination therapy.3,12–15 More recent combinations, particularly fludarabine with cyclophosphamide, have been tested in clinical trials and shown to be highly active.16–18 Because of the synergistic nature of the combination and the overlapping toxicities of myelosuppression and immunosuppression, these agents cannot be used at the single-agent maximum-tolerated dose when administered concomitantly, and careful attention to dosing is required for their safe coadministration. A review of early phase II studies of pentostatin indicates that this agent may be less myelosuppressive than either fludarabine or cladribine.19,20 We hypothesized that the combination of an alkylating agent with pentostatin would have less severe overlapping toxicities than combinations with either fludarabine or cladribine and that this combination would be active in patients with CLL. We chose cyclophosphamide as our alkylating agent because we expected a narrow therapeutic window with this combination and decided that the issues of variable bioavailability inherent in using an oral agent (chlorambucil) would further complicate the trial design. Pentostatin, which is produced by Streptomyces antibioticus, has a somewhat distinct mechanism of action compared with fludarabine or cladribine. Pentostatin is an irreversible inhibitor of adenosine deaminase, whereas fludarabine and cladribine are halogenated analogs resistant to deamination by adenosine deaminase. The exact mechanism of cytotoxic action of pentostatin in CLL is not fully known. It is recognized that lymphocytes have a high ratio of the phosphorylating enzyme deoxycytidine kinase to the dephosphorylating enzyme 5-nucleotidase, whereby adenosine and deoxyadenosine are converted to triphosphate metabolites. It is believed that the accumulation of these metabolites inhibits ribonucleotide reductase, which in turn inhibits DNA synthesis. This may well be the key for explaining the enhanced cytotoxic effect of combining pentostatin with an alkylating agent.21 Presumably, DNA damaged by the alkylator in what may otherwise be a sublethal insult may not be able to be adequately excised and repaired in the presence of the purine analog. In this manner, relatively low doses of alkylating agent may result in cell death. Early trials with pentostatin were plagued by significant toxic complications. The toxicity profile was markedly improved by using lower doses and paying attention to renal function.25 This decrease in toxicity through close monitoring of renal function probably occurs because pentostatin is both cleared by and toxic to the kidney. Previously, occasional patients may have suffered mild deteriorations in renal function with their initial dose of pentostatin, but because serum creatinine was not routinely measured pretreatment, subsequent dosing with pentostatin was administered. Even a mild loss of glomerular filtration rate would lead to an increased area under the curve of pentostatin, and therefore, subsequent dosing would have ever-increasing negative effects on kidney function and further increase the area under the curve of pentostatin, which would ultimately lead to renal failure and profound adverse systemic effects.26 In this study, we measured serum creatinine in all patients on the day of treatment and deferred treatment in patients with an increase in serum creatinine of more than 20% over baseline. To further minimize the risk of nephrotoxicity, all patients received at least 1.5 L of intravenous fluid on their day of treatment. In this study of heavily pretreated patients, we noted that the combination of pentostatin and cyclophosphamide led to a prompt cytotoxic effect, with a rapid decline in WBC and evidence of mild tumor lysis syndrome in approximately one-third of patients. This rapid cytotoxic effect translates into a measurable response in a high proportion of patients. The different mechanism of action of pentostatin compared with fludarabine may be clinically relevant in that the incidence of response was similar in patients who were sensitive to fludarabine (74%) and patients who were previously resistant to fludarabine (77%). There was, however, a greater incidence of CR in fludarabine-sensitive patients (30%) compared with fludarabine-refractory patients (8%). The activity of this combination in fludarabine-refractory patients is particularly encouraging because this group typically has poor survival and few available options for cytotoxic therapy.27–29 This regimen was designed, in part, to test the hypothesis that the combination of pentostatin and cyclophosphamide might have less myelosuppression than combinations that included fludarabine or cladribine as the purine analog. Without a randomized trial it is difficult to assess the relative myelosuppression of this regimen compared with other regimens. Perhaps the regimen most suitable for comparison with this study would be the combination of fludarabine and cyclophosphamide reported by O’Brien et al.18 In that trial of 128 patients (94 previously treated patients and 34 previously untreated total patients) myelosuppression and infection were noted to be the main complications, with grade 3/4 thrombocytopenia seen in 19% of patients, grade 3/4 neutropenia seen in 75% of patients, and serious infections (pneumonia and sepsis) occurring in 25% of patients. In this study, 30% of patients experienced grade 3/4 thrombocytopenia, 35% of patients experienced grade 3/4 neutropenia, and 9% of patients suffered serious infectious complications. This comparison supports the possibility that the current regimen may be less myelosuppressive, but other differences including the routine use of prophylactic filgrastim on this study (but not in the trial by O’Brien et al18) and possible differences in patient mix make it difficult to conclusively compare the two approaches. Our favorable experience with this active, well-tolerated regimen even at the lowest dose level of cyclophosphamide tested has led to the recent initiation of a trial that tests a new three-drug combination, pentostatin, cyclophosphamide, and rituximab (PCR therapy), in previously treated patients with CLL. The ultimate goal of this approach is to develop a well-tolerated regimen that will achieve CR in a majority of previously untreated patients and to then conduct a randomized trial of this regimen compared with standard therapy with fludarabine. In this way, we will attempt to demonstrate that a regimen that produces a high frequency of CRs can lead to improved survival for patients with CLL.
Supported in part by grants from Supergen, The Beatrice Renfield Foundation, The Michael Sweig Foundation, and the Archie W. and Grace S. Berry Charitable Foundation.
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3. Rai KR, Peterson BL, Appelbaum FR, et al: Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med 343:1750–1757, 2000 4. 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]
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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
50 mL/min. 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 prochlorperazine, ondansetron, or granisetron recommended for nausea, as needed. Other supportive measures included filgrastim (300 µg for patients 
70 kg and 480 µg for patients > 70 kg administered subcutaneously daily beginning 2 days after each treatment until absolute neutrophil count [ANC] > 5,000/µL or > 1,500/µL for 2 days), sulfamethoxazole-trimethoprim (one double-strength tablet twice daily, three times per week), and acyclovir (800 mg twice daily for herpes zoster prophylaxis). 
) patients ultimately achieving complete response, and (
) patients ultimately achieving partial response. ALC, absolute lymphocyte count.
