Posts Tagged ‘CR’
Cell-Cycle Inhibitors
Mechanism Of Action
Progression through the cell cycle depends on numerous signaling pathways and checkpoints (e.g., the cyclin families of proteins, the cyclin-dependent kinases [CDKs]). Deregulation of these key cell-cycle checkpoints is observed in most cancer cells. Inhibition of these enzymes can result in cell-cycle arrest and, ultimately, cell death, usually by apoptosis. Targeting the machinery involved in the cell cycle aims to directly attack cells with a high turnover, such as cancer cells.
Alvocidib
Aventis and the National Cancer Institute (NCI) were developing alvocidib (Flavopiridol) together until Aventis discontinued its involvement in
February 2004. This synthetic flavenoid inhibits CDKs and is the first CDK inhibitor to enter trials; it is in Phase II trials for chronic lymphocytic leukemia. It has reached Phase III in France.
Preclinical research has demonstrated alvocidib’s ability to enhance both the radio- and chemosensitivity of a variety of cell lines and animal tumors. Ongoing experiments are analyzing this mechanism of action as well as further delineating alvocidib’s activity when administered alone. In a syngeneic mouse model of lym-phoma, alvocidib enhanced the tumor response to radiation, and in H460 human lung cancer cells, alvocidib enhanced the effects of docetaxel and radiation. Researchers examined the molecular pathway of alvocidib activity and found that this agent interacts synergistically with the tumor necrosis factor-related apoptosis-induced ligand (TRAIL). Alvocidib does so through a mechanism involving the downregulation of XIAP (X-linked inhibitor of apoptosis protein), resulting in apoptosis of human leukemia cells.
A Phase II study of alvocidib in patients with fludarabine-refractory chronic lymphocytic leukemia is complete. This trial was an open-label, multicenter study aiming to accrue up to 37 patients. Those registered before September 2000 received intravenous (IV) alvocidib continuously on days 1-3, and treatment was repeated every 14 days for a total of 12 courses in the absence of disease progression or unacceptable toxicity. Patients who were registered after September 2000 received IV alvocidib over one hour daily on days 1-3. Treatment was repeated every three weeks for a total of eight courses. Patients were to be followed every three months for the first year and then every six months for five years. The study aimed to assess toxicity, CR, PR, progression-free and overall survival, and the impact of alvocidib on normal T-cell subsets and immunoglobulinlevels. No data from this trial have been published.
A Phase I dose-escalation study is examining alvocidib combined with fludarabine and rituximab in patients with various lymphoproliferative disorders, including chronic lymphocytic leukemia. No data have been published.
Given the lack of data on the use of alvocidib for chronic lymphocytic leukemia, we examined results from Phase I and II studies of alvocidib as a single agent or in combination with chemotherapy in the treatment of other cancers. In a Phase II trial of single-agent alvocidib in patients with hormone-refractory metastatic prostate cancer, no objective responses were observed and only 11% of patients achieved stable disease as the best response. In addition, alvocidib administered at 40 or 50 mg/m2/day for a total of 72 hours was associated with significant toxicities that resulted in a high withdrawal rate from the study. A single-agent Phase II study of alvocidib therapy involving 33 renal-cell carcinoma patients resulted in 1 CR, 2 PRs, and 13 stable disease, but the study’s response criteria were not met. Alvocidib is being investigated in a variety of combination regimens with agents such as irinotecan, docetaxel, 5-FU and leucovorin, and paclitaxel and carboplatin. The majority of trials completed have set out to establish alvocidib’s safety and maximum tolerated dose.
Rituximab
Rituximab (Rituxan, MabThera) is under development by Biogen Idee and Genentech in collaboration with Roche, Chugai, and Zenyaku Kogyo. This antibody is in Phase III clinical trials in the United States and Europe.
Rituximab is a mouse/human chimeric MAb directed against the cluster of differentiation (CD) 20 molecule. CD20 is a calcium channel that interacts with the B-cell immunoglobulinreceptor complex and is expressed on both normal and malignant B cells, making it an ideal target for monoclonal antibodies therapy in B-cell disorders. After binding to CD20, rituximab is thought to deplete B cells in a number of ways, including antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and alteration of calcium flux and factors involved in apoptosis. This antibody has been launched for the treatment of relapsed or refractory low-grade or follicular, CD20-positive B-cell non-Hodgkin’ s lymphoma (B-NHL).
Rituximab is under investigation in many chronic lymphocytic leukemia clinical trials both as a single agent and in combination with chemotherapy as well as in first- and subsequent-line settings.
The role for rituximab as a single agent in chronic lymphocytic leukemia is controversial. Previous studies showed an overall response rate of only 11% and 25%, comparing poorly with the rate of 40-60% reported for follicular NHL. However, a recent Nordic multicenter study yielded improved results. Twenty-four chronic lymphocytic leukemia patients of median age 57 (47-72) with active disease (3 Binet A, 7 Binet B, 14 Binet C) who had previously been heavily treated with a variety of chemotherapy regimens were given the standard dose of 375 mg/m2 rituximab once weekly for four doses. The primary objectives this study addressed were response rate, quality, and duration; secondary objectives were to analyze the feasibility and tolerability of rituximab therapy.
Eight of 23 evaluable patients (35%) achieved a partial response (PR), with a median duration of 12.5 weeks. A drop of at least 50% in blood lymphocyte count occurred in 17/21 (81%) patients who had pretreatment lymphocytosis, and 10 patients achieved a normal blood lymphocyte count (< 3 x 109 L_1). Of the 15 patients who did not achieve a PR with rituximab, 9 had at least a 50% drop in lymphocyte count and 3 achieved a normal count.
TABLE. Emerging Therapies in Development for Chronic Lymphocytic Leukemia
| Compound | Development
Phase |
Marketing Company |
| Monoclonal antibodies | ||
| Rituximab (Rituxan, MabThera) | ||
| United States | III | Biogen Idec/Genentech |
| Europe | III | Roche/Chugai/Zenyaku Kogyo |
| Japan | — | — |
| Lumiliximab (IDEC-152) | ||
| United States | II | Biogen Idee |
| Europe | — | — |
| Japan | — | — |
| Antisense oligonucleotides | ||
| Oblimersen (Genasense) | ||
| United States | Ill | Genta/Aventis |
| Europe | — | — |
| Japan | — | — |
| Cell-cycle inhibitors | ||
| Alvocidib (Flavopiridol) | ||
| United States | II | National Cancer Institute |
| Europe | III | — |
| Japan | — | — |
| Immunostimulatory therapies | ||
| Xcellerate | ||
| United States | I/I I | Invitrogen (formerly with Xcyte Technology) |
| Europe | — | — |
| Japan | — | — |
| ISF-154 | ||
| United States | II | Tragen/University of California at San Diego |
| Europe | — | — |
| Japan | — | — |
| Immunotoxins | ||
| Denileukin diftitox (Ontak) | ||
| United States | II | Ligand Pharmaceuticals |
| Europe | — | — |
| Japan | — | — |
| Apoptosis inducers | ||
| SDX-101 | ||
| United States | Ib/lla | Salmedix |
| Europe | — | — |
| Japan | — | — |
| Motexafin gadolinium (Xcytrin) | ||
| United States | II | Pharmacyclics |
| Europe | — | — |
| Japan | — | — |
| Selective apoptotic antineoplastic drugs | ||
| OSI-461 | ||
| United States | Ila | OSI Pharmaceuticals |
| Europe | — | — |
| Japan | — | — |
Seventy-five percent of patients experienced rituximab-related side effects, half of which were related to the first infusion only. The most common toxicities were World Health Organization (WHO) grade 1/2 chills and grade 2 fever. In previous studies, the severe infusion-related toxicities reported had been specifically linked to a high tumor burden. Mainly mild/moderate side effects were observed in this study, even in patients with extremely high lymphocytosis (223 x 109 L_1). This study demonstrates that single-agent rituximab does have some activity in heavily pretreated chronic lymphocytic leukemia patients, although the response is minor and of short duration.
The reasons rituximab is more effective in NHL than in chronic lymphocytic leukemia are unclear. Circulating soluble CD20 and a high tumor burden, both of which “mop up” rituximab, are potential mechanisms/states by which the antibody is rapidly cleared from the blood; this theory is supported by the observation of altered pharmacokinetics and increased response rates with higher doses of rituximab in chronic lymphocytic leukemia. In addition, chronic lymphocytic leukemia cells have a much lower density of surface CD20 than do NHL cells, although no correlation between density and response to therapy has been found.
Rituximab has been used as a first-line, single-agent therapy, and limited clinical data suggest it may be more effective than as second- or third-line therapy. In one trial, treatment-naive patients with stage II — IV small lymphocytic lymphoma or chronic lymphocytic leukemia received 375 mg/m2 rituximab weekly for four doses. Patients who achieved an objective response (PR or complete response [CR]) or stable disease at reevaluation after six weeks continued maintenance courses of rituximab using the standard four-week schedule every six months for a maximum of four courses. Twenty-two of forty-three patients (51%) had an objective response at week 6, and the remaining patients had stable disease.
Twenty-eight patients (65%) went on to receive maintenance rituximab therapy. With a median follow-up of 24 months, the response rate was 58% (9% CR). Median progression-free survival (PFS) was 19 months with a one- and two-year actuarial PFS of 63% and 49%, respectively. Two patients had a reversible grade 3 infusion-related toxicity with the first course of rituximab. The increase in overall response rate is encouraging, but the small CR indicates that single-agent rituximab will not result in long-term survival in chronic lymphocytic leukemia.
Treatment for chronic lymphocytic leukemia is generally reserved for patients with symptoms of advanced disease, although rituximab therapy may be effective in early-stage disease for those at risk of progression. The overall response rate in 21 evaluable patients with Rai stage 0-11 and beta-2 microglobulin levels >2 mg/dL was 90% (19% CR, 19% nodular PR [nPR], 48% PR). The clinical significance of these results is unclear because a longer follow-up is required to analyze time to progression and long-term survival.
The dose and schedule of administration for single-agent rituximab therapy as both first and subsequent lines of therapy are under investigation in dose-escalation studies in an attempt to increase response rates. Researchers have reported using doses of up to 2,000 mg/m2/week in four patients. Such studies are ongoing to optimize clinical responses.
The most active area of research involving rituximab is in combination with chemotherapy. A randomized Phase II study of fludarabine in combination with concurrent rituximab versus sequential rituximab was conducted in 104 previously untreated chronic lymphocytic leukemia patients. The treatment schedule for sequential therapy involved patients receiving 25 mg/m2 fludarabine for 5 days, repeated every 28 days for six cycles. Four weekly doses of 375 mg/m2 rituximab were administered to patients who achieved stable disease or better, following a two-month rest period and restaging. The concurrent schedule followed the same pattern as the sequential schedule, with the addition of rituximab to each fludarabine cycle. It is important to note that patients receiving concurrent administration received 11 doses of rituximab (seven in combination with fludarabine and four as consolidation after this therapy) compared with only 4 doses in the sequential arm.
Concurrent administration of these two agents demonstrated superior response rates when compared with the sequential arm (47% CR versus 28% CR, 43% PR versus 49% PR, respectively). Neutropenia was more common in the concurrent arm, but infectious complications occurred at similar frequencies in both schedules. Additional data presented at the American Society of Hematology (ASH) meeting in 2003 determined that adding rituximab to fludarabine did not significantly increase the risk of infection.
This encouraging study establishes that concurrent administration of rituximab and fludarabine produces CR rates superior to those achieved with fludarabine alone. To date, the impact of rituximab on improving progression-free survival and overall survival compared with fludarabine monotherapy has not been analyzed in a randomized trial. A retrospective comparison with data from 179 patients enrolled in the North American Intergroup Study CALGB 9011 who received fludarabine monotherapy showed that CR, PR, and two-year performance-free and overall survival rates were significantly superior in the fludarabine/rituximab group.
The triple-drug regimen fludarabine/cyclophosphamide/rituximab (FCR) is also under intense investigation. In one study, 202 previously untreated chronic lymphocytic leukemia patients received FCR (25 mg/m2/day F for three days; 250 mg/m2/day C for three days; 375-500 mg/m2 R on day 1). Results showed 68% CR, 18% nPR, and 14% PR. The study also analyzed patients for the presence of minimal residual disease (minimal residual disease) and found that the FCR regimen produced a high level of minimal residual disease-negative complete remissions. A longer follow-up will determine whether minimal residual disease-negative CR is more durable than minimal residual disease-positive CR.
At the 2003 ASH meeting, the results of a sequential FCR program also were presented. Thirty treatment-naive chronic lymphocytic leukemia patients received six cycles of standard fludarabine therapy, then 3 g/m2 cyclophosphamide every three weeks for three cycles, and finally standard rituximab therapy. CR and PR rates of 57% and 29% (10% nPR and 19% PR), respectively, were achieved.
The FCR regimen has also succeeded in patients with relapsed or refractory chronic lymphocytic leukemia. In one trial, 179 patients who had already received between one and three courses of therapy were treated with FCR and achieved responses of 25% CR, 16% nPR, and 32% PR. Minimal residual disease (analyzed by polymerase chain reaction) was absent in 33% of CR patients. Therapy was well tolerated, and 62% of patients completed four or more cycles of this regimen. Forty-one percent of patients experienced fever and chills with the first rituximab infusion, and a minority experienced hypotension, nausea, and dyspnea (6%, 9%, and 3%, respectively). Hematologic toxicities included neutropenia in 30% of cycles and thrombocytopenia in 12%.
A comparative, retrospective analysis of patients treated with fludarabine (plus or minus prednisone), fludarabine/cyclophosphamide, or FCR demonstrated increased CR, overall response, and median survival in patients treated with FCR.
The purine analogue pentostatin (SuperGen Warner-Lambert’s Nipent) has shown significant activity and minimal toxicity when combined with cyclophos-phamide in chronic lymphocytic leukemia patients. In one trial, rituximab was added to this combination (known as the PCR regimen) and administered to previously untreated chronic lymphocytic leukemia patients. Preliminary data on 15 patients presented at ASH 2003 revealed 40% CR, 13% complete clinical response, and 47% PR. Most toxicities were grade 1 or 2, although eight patients suffered grade 3 anemia and hypotension and one patient developed grade 4 sinus bradycardia.
In another trial, 20 patients with relapsed or refractory disease were treated with the PCR regimen; the response rates were 20% CR, 10% nPR, and 50% PR. Grade 3/4 neutropenia occurred in 45% of patients, grade 3/4 thrombocytopenia in 5%, and infections in 15%. Preliminary data suggest this regimen is well tolerated, but further analysis is needed to determine both response rates and toxicity profiles compared with those associated with fludarabine-containing regimens.
The combination of rituximab and another MAb, alemtuzumab is under investigation for relapsed and refractory chronic lymphocytic leukemia. Nine patients underwent treatment with this combination, and preliminary data showed a 44% CR and 23% PR rate. Nonhematologic toxicities were grade 2 or less, and infection occurred in 44% of patients. Another study presented at ASH 2003 failed to show any complete or partial remissions in 11 patients with relapsed or refractory chronic lymphocytic leukemia who were treated with alemtuzumab and rituximab in combination. Further investigation into the combination of these antibodies is needed to determine their potential efficacy.
In an attempt to improve upon the success seen in FCR, the M.D. Anderson Cancer Center is pioneering a trial examining a regimen consisting of cyclophosphamide, fludarabine, alemtuzumab, and rituximab (known as the CFAR regimen). Only two relapsed/refractory patients have completed all courses, and both achieved PRs. Four patients on continuing therapy were evaluated after three courses, and responses included one CR, one nPR, and two PRs. Seven patients came off therapy because of treatment failure (n = 2), infection (n = 1), noncompliance (n = 1), or at their own request (n = 2); one death occurred as a result of disease-related liver failure. Early analysis indicates good response with substantial but expected toxicities.
Rituximab enjoys extensive off-label usage in the United States, mainly in the first- and second-line chronic lymphocytic leukemia settings in combination with chemotherapy. In Europe, however, the use of rituximab is restricted by a lack of reimbursement owing to its experimental status and high cost.
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Alemtuzumab (Single Agent)
Overview
Alemtuzumab (Schering AG’s Mab Campath, Berlex Laboratories’ Campath) was launched for third-line therapy of chronic lymphocytic leukemia in the United States and Europe in 2001. Early pilot studies indicated that alemtuzumab could cause tumor regression in advanced non-Hodgkin’s lymphoma. However, subsequent studies showed that the therapeutic effect was confined mainly to tumor cells in the blood and bone marrow rather than in lymph nodes, a finding that paved the way for trials in chronic lymphocytic leukemia. Patients who are refractory to fludarabine are left with few treatment options. These difficult-to-treat patients are therefore candidates for therapies such as monoclonal antibodies, whose uptake is growing.
Mechanism Of Action
Alemtuzumab is a chimeric, humanized monoclonal antibodies directed against the cluster of differentiation (CD) molecule 52, a glycosylphosphatidy-linositol-anchored glycoprotein expressed on all mature lymphocytes, monocytes, and spermatozoa but not on hematopoietic stem-cell progenitors. The physiological function of CD52 is unknown. The binding of alemtuzumab to cell-surface CD52 leads to complement-mediated lysis, antibody-dependent cellular cytotoxicity, and opsonization, resulting in cell death. The efficacy of alemtuzumab has been correlated with the density of CD52 on the target cell surface.
Clinical Performance
An international study investigated the efficacy of alemtuzumab in 93 chronic lymphocytic leukemia patients who had failed at least one alkylating-based regimen and fludarabine treatment. FDA approval was granted largely on the basis of this study’s initial results. Longer-term follow-up reported that 33 out of 93 patients responded (33%), experiencing 2 CRs (2%) and 29 PRs (31%). The authors noted that this result significantly exceeded their target response rate of 20%, and responses were seen in all prognostic subsets: both those who had failed fludarabine and those who had previously had a short response to this agent. However, patients with Rai stage IV and those who had at least one lymph node greater than 5 cm in diameter were less likely to respond. Median TTP among responders was 9.5 months; median survival was 16 months in all patients, which is longer than for historical controls.
Infusion-related reactions were commonly reported adverse events and were mostly grade 1/2. They included rigors (90% in total, 14% grade 3); fever (85% in total, 17% grade 3, 3% grade 4); nausea (53% grade 1/2); vomiting (38% in total, 1% grade 3); and rash (33% grade 1/2). These events declined over the time of treatment. Most patients experienced transient cytopenias. Neutropenia was most common during weeks 5 and 6 (30% of patients) and thrombocytopenia occurred in the first two weeks. These problems had resolved in the majority of patients by two-month follow-up.
This study recorded a high rate of infection (51 patients, 55%), although 53% of patients had a prior history of infection and 33% had infection in the month before alemtuzumab therapy. Twenty-five of 51 patients had a grade 3/4 infection. Grade 3/4 sepsis occurred in ten patients and led to death in two of these cases. A total of nine deaths occurred during treatment or within 30 days of the last alemtuzumab dose, of which five were related to treatment, comparing favorably with the 22% death rate observed in fludarabine trials.
Although alemtuzumab is approved as third-line therapy in chronic lymphocytic leukemia, the literature reports that it has been investigated in previously untreated chronic lymphocytic leukemia patients. Forty-one patients, the majority (90%) of whom were in Rai stage II-IV, were enrolled in a dose-escalation Phase II study of subcutaneous alemtuzumab. Of the 38 evaluable patients, 7 (19%) achieved a CR and 26 (68%) achieved a PR, giving an overall response rate of 87%. The response rate was almost as high in Rai stage III-IV patients as it was in stage I-II, possibly because this antibody is effective in eradicating bone marrow disease, thereby improving or normalizing peripheral blood counts. In addition, the response rates were equally high among older patients.
Acute administration-related reactions such as rigor, nausea, hypotension, and bronchospasm were rare or absent. These reactions are commonly seen when alemtuzumab is administered intravenously, and the reason for the discrepancy is unclear. Hematologic toxicity included transient grade IV neutropenia in 21% of patients; in some patients, repeated or more prolonged episodes required the use of G-CSF so that further treatment was not delayed.
Alemtuzumab is also under investigation in combination with chemotherapy and other monoclonal antibodies. Data presented at the American Society of Clinical Oncology (ASCO) conference in 2003 described the combination of fludarabine and alemtuzumab in relapsed chronic lymphocytic leukemia patients who had received a median number of two prior courses of therapy. Of 14 patients, 9 (64%) achieved a CR and 3 (21%) achieved a PR. Transient grade 3 and 4 hematologic toxicities were observed. Other investigations include using alemtuzumab as consolidation therapy following chemotherapy to further improve responses and eradicate minimal residual disease.
Alemtuzumab’s major limitation is the high level of hematologic toxicity and subsequent infection it induces in these already fragile patients. Physicians are wary of these side effects, but in light of alternative options, alemtuzumab is a popular therapy choice in the third-line setting. Continued investigation is evaluating its worth in earlier treatment settings.
Cladribine (Single Agent)
Overview
Cladribine (Ortho Biotech’s Leustatin, Japananssen-Cilag’s Leustatin/ Leustatine/Leustat, generics; also known as chlorodeoxyadenosine and 2-CDA) is primarily used to treat hairy-cell leukemia. Cladribine is used much less frequently than fludarabine for chronic lymphocytic leukemia because many more, and larger, randomized trials have evaluated the latter agent. It has now been approved.
Mechanism Of Action
Cladribine is a purine analogue that closely resembles fludarabine; it inhibits DNA synthesis by interfering with DNA polymerases, thereby preventing the elongation of DNA strands.
Clinical Performance
A multicenter, randomized prospective study analyzed the efficacy and toxicity of cladribine plus prednisone versus chlorambucil plus prednisone in previously untreated patients with progressive or symptomatic chronic lymphocytic leukemia. As with other study designs, patients were randomized to receive either therapy; evaluated after a certain number of courses (in this case, three); and switched to the alternate therapy arm if they had not responded. As mentioned previously, this method obscures the interpretation of long-term survival data. However, in the initial evaluation following three courses of therapy, 59/126 (47%) patients receiving cladribine plus prednisone achieved a CR and 50/126 (40%) achieved a PR, giving a total response rate of 87%. In the chlorambucil plus prednisone arm, 12/103 (12%) patients achieved a CRs and 46/103 (45%) of patients achieved a PR, giving an overall response rate of 57%. In addition, early relapses occurred more frequently in the chlorambucil arm than in the cladribine arm.
Patients who did not respond to first-line treatment with either regimen were switched to the alternate arm of the study. Second-line treatment with cladribine plus prednisone was found to be more effective (10/43 CR, 19/43 PR) than chlorambucil plus prednisone (0/26 CR and 7/26PR).
Response rates in the cladribine arm were comparable to responses obtained in patients receiving fludarabine. Although both the overall response rates and progression-free survival improved in the cladribine arm, this improvement did not translate into a significant difference in terms of overall survival rates. This effect may be associated with the switching of patients from one arm to another early on in the study.
Analysis of the drug-induced toxicity confirmed cladribine’s myelosuppressive effects, which resulted in a high incidence of neutropenia and infections compared with patients in the chlorambucil arm. Thrombocytopenia occurred with equal frequency in both arms.
Several Phase II studies have examined the efficacy of cladribine in combination chemotherapy in regimens such as cladribine/cyclophosphamide and cladribine/cyclophosphamide/mitoxantrone. In untreated patients, the former regimen produced overall response rates of 88%, with a CR of 29%. Large-scale, randomized trial data are lacking for this drug.
Pentostatin/Cyclophosphamide
Overview
Pentostatin (SuperGen{/Wyefh/Pfizer}’s Nipent) was first administered to patients with acute leukemia in the 1970s, but it was associated with severe extramedullary toxicity, and enthusiasm for its use declined. However, patients with hairy-cell leukemia and chronic lymphocytic leukemia have shown responses at lower doses, so pentostatin is being investigated again as part of a combination regimen. This agent will garner an increasing, but modest, off-label share of sales throughout the study period owing to current investigation into its use in chronic lymphocytic leukemia by investigators at the Mayo Clinic College of Medicine and the Memorial Sloan-Kettering Cancer Center.
Mechanism of Action
• Pentostatin, a purine analogue, is a potent, irreversible inhibitor of adenosine deaminase produced by Streptomyces ontibioticus. adenosine deaminase is a vital enzyme in the purine salvage pathway, and its inhibition results in the accumulation of adenosine and deoxyadenosine metabolites, which inhibit ribonucleotide reductase. The depletion of the nucleotide pool leads to the inhibition of DNA synthesis and subsequent toxicity to the cell. adenosine deaminase is a ubiquitous enzyme but is found in higher concentrations in lymphoid tissue.
• Cyclophosphamide is an alkylating agent. These agents alkylate DNA bases, thereby producing “cross-links” that covalently link the two DNA strands and prevent cell replication.
Clinical Performance
Pentostatin is thought to be the least myelosuppressive of the purine analogues in use to treat chronic lymphocytic leukemia. Its usage, though, is not widespread and few trial data are available.
A study published in 2003 describes the combination of pentostatin with cyclophosphamide in 21 patients with intermediate- or high-risk chronic lymphocytic leukemia and 2 patients with small-cell lymphoma who had received substantial prior therapy (median of three regimens) including fludarabine (87% of patients), chlorambucil (78%), and rituximab (26%). Responses were seen in 17 patients and included 4 CRs (17%), 1 nPR (4%), and 12 PRs (57%). When analyzing the responses in comparison with patients’ responses to previous therapies, where sufficient data were available, investigators in this trial determined that seven patients achieved their best response on this regimen. In addition, 13 patients who had previously failed fludarabine-based treatment responded, including 1 CR. (This latter group of patients is particularly difficult to treat and is left with few therapy options.) The median response duration of all 17 responders was 7 months (13 months for those in CR and 6 months for those in PR). As expected, median survival was longer for responders versus nonresponders (17 versus 8.5 months).
Mild, asymptomatic tumor lysis syndrome (the release of cellular breakdown products into the blood) was detected in 39% of patients, demonstrating the rapid cytotoxic effects of this combination, which resulted in a sharp decline in white blood cell count following the first cycle of chemotherapy. Pentostatin’s different mechanism of action may be clinically relevant in fludarabine-treated patients. The incidence of response was similar among both sensitive and refractory patients, although a higher rate of CR occurred in fludarabine-sensitive patients (30% versus 8%, respectively).
One of the major reasons for using pentostatin versus fludarabine is the potential for reducing myelosuppression. Grade 3/4 thrombocytopenia, neutropenia, and serious infections were observed in 30%, 35%, and 9% of patients in this study. The rates of thrombocytopenia and neutropenia are higher and lower, respectively, than those observed in a study of fludarabine/cyclophosphamide
(19% and 75%), and the rate of infection is lower. However, it is difficult to compare these trials because of different variables, including the use of G-CSF support in the pentostatin/cyclophosphamide study.
Ongoing studies are attempting to determine the efficacy of pentostatin combinations in chronic lymphocytic leukemia patients, particularly combination therapy with monoclonal antibodies.
Fludarabine/Cyclophosphamide/Mitoxantrone (FCM)
Overview
The fludarabine, cyclophosphamide, and mitoxantrone (Serono/Wyeth/Takeda’s Novantrone, Baxter’s Onkotrone, generics) regimen is under investigation in clinical trials and is used as the standard of care in some hospitals in Germany and Spain.
Mechanism of Action.
• Fludarabine is a purine analogue and is metabolized rapidly to F-Ara-ATP, which inhibits DNA synthesis by inhibition of DNA polymerases and prevents elongation of DNA strands through direct incorporation into the DNA molecule.
• Cyclophosphamide is an alkylating agent. These agents alkylate DNA bases, thereby producing “cross-links” that covalently link the two DNA strands and prevent cell replication.
• Mitoxantrone is a synthetic antineoplastic anthracenedione. It is a DNA-reactive agent that intercalates with DNA by hydrogen bonding,causing cross-links and strand breaks. It also reacts with RNA and is a potent inhibitor of topoisomerase II.
Clinical Performance
In vitro studies have demonstrated fludarabine’s synergistic effect with both cyclophosphamide and mitoxantrone. On the basis of these results, a clinical trial was designed to test the efficacy of these agents in previously treated chronic lymphocytic leukemia patients. Of the 60 patients treated with FCM, 34 had received one prior therapy, 18 had received two, and 8 had received three or more. Previous therapies included chlorambucil with or without prednisone (70%), cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) (32%), and fludarabine monotherapy (8%). FCM was administered following relapse in 25 cases (42%) and following development of resistance to prior therapy in 35 (58%) patients.
Thirty patients (50%) achieved a CR and 17 patients (28%) achieved a PR. Of the 30 patients in CR, 10 were found to be negative for minimal residual disease by flow cytometry and polymerase chain reaction (PCR; so-called molecular remission). The CR and PR rate was significantly higher among patients who had relapsed (32% and 40%, respectively) compared with those who were resistant to prior treatment (6% and 28%, respectively). None of the five patients previously treated with fludarabine achieved a CR, although they did respond to FCM therapy. The median duration of response was 19 months in patients who achieved a CR, similar to that achieved with other fludarabine combinations, and was not significantly different if patients were minimal residual disease-negative (17 versus 21 months) or between relapsed and resistant cases.
Hematologic toxicities and infections were the most significant side effects, as reported in other fludarabine-based regimens. Sixty-three percent of patients suffered from grade 3 or 4 neutropenia, and this toxicity was greater in patients who had prior chlorambucil treatment (81% versus 47%). Grade 3/4 thrombocytopenia and anemia were observed in 16% and 17% of cases, respectively, and grade 3/4 infections/fever occurred in 23% of patients.
Although no large-scale trials describing the use of FCM in first-line therapy of chronic lymphocytic leukemia have been performed, the regimen is being used in this setting in some European countries.
Fludarabine/Cyclophosphamide (FC)
Overview
Several recent studies have investigated the combination of fludarabine with cyclophosphamide (Bristol-Myers Squibb’s Cytoxan, Baxter’s Endoxan/Endoxana, Pfizer’s Neosar/Cyclostin, generics), and this regimen is used in both first and subsequent lines of treatment.
Mechanism of Action
• Fludarabine is a purine analogue and is metabolized rapidly to F-Ara-ATP, which inhibits DNA synthesis by inhibition of DNA polymerases and prevents elongation of DNA strands through direct incorporation into the DNA molecule.
• Cyclophosphamide is an alkylating agent. These agents alkylate DNA bases, thereby producing “cross-links” that covalently link the two DNA strands and prevent cell replication.
Clinical Performance
A trial published in 2003 investigated this combination in both treated and untreated patients of performance status 0,1, or 2. The untreated patient cohort contained 15 patients with Rai stage III-IV chronic lymphocytic leukemia or stage II with bulky disease. Within this group, 60% of patients achieved CR and 40% achieved PR status. Seventeen patients had received previous therapy, 6 of whom received fludarabine or fludarabine combinations. Response rates were lower in the previously treated group: 29% achieved CR and 59% achieved PR.
The median time to progression (TTP) (median follow-up = 24 months) for the entire population was 25 months (median TTP in untreated patients had not yet been reached versus 18 months in treated patients). The median survival was 35 months (median survival in the untreated group had not yet been reached versus 20 months in treated patients). The program of six courses of fludarabine/cyclophosphamide was administered in 75% of patients and reduced in 19% of patients because of severe myelosuppression and/or sepsis, which was fatal in one patient. Two patients discontinued therapy after two courses because of primary resistance; both patients had been heavily pretreated and had been refractory to previous chemotherapy.
Toxicities included severe neutropenia in 31% of patients, which delayed subsequent courses of therapy and required the use of prophylactic granulocyte colony-stimulating factor (G-CSF). Red cell transfusions were required in 22% of cases because of decreased hemoglobin. No cases of grade 3/4 thrombocytopenia were observed. Infections, including seven cases of pneumonia and two of sepsis — one of which was fatal — occurred in 28% of patients.
In another study, the efficacy of fludarabine/cyclophosphamide in a population of chronic lymphocytic leukemia patients was accurately determined by analyzing response rates according to the patients’ treatment history. Patients were divided into four cohorts:
• No prior treatment.
• Prior therapy with alkylating agents either alone or in combination.
• Prior therapy with alkylating agents and fludarabine. Initial response to fludarabine therapy followed by relapse.
• Prior therapy with alkylating agents and fludarabine. Patients relapsed after or were refractory to alkylating agents and failed to achieve a PR with their last fludarabine-based therapy.
Patients who had not received prior therapy (n = 34) had an overall response rate of 88%, which comprised 35% CR, 29% nPR, and 24% PR. Their median TTP and overall survival had not yet been reached after a follow-up of 41 months. Previously untreated patients receiving fludarabine monotherapy reportedly achieved an overall response rate of 60-80%, similar to the data presented in this trial. The CR rate was also not significantly different from that reported for fludarabine alone. However, these authors suggested that CRs achieved with fludarabine/cyclophosphamide may be more durable because the percentage of patients with CD5+ B cells still present in their bone marrow at the time of CR was less than that found in patients receiving fludarabine with or without prednisone (8% versus 33%).
The combination of fludarabine/cyclophosphamide was significantly more efficacious as salvage therapy for previously treated patients than was single-agent fludarabine. Previous Phase II studies have reported response rates of 45-65% in patients receiving fludarabine following failure of therapy with alkylating agents.
In one such study. In this study, patients (n = 20) achieved an overall response rate of 85% (15% CR, 25% nPR, 45% PR) and estimated median overall survival of 38 months. In the group of patients who had previously received both drug therapies, those who were fludarabine-sensitive (n = 46) showed an overall response rate of 80% (12% CR, 17% nPR, 51% PR) and a median overall survival of 21 months. Fludarabine-resistant patients have an extremely poor prognosis and a median survival of less than one year, with most combination regimens providing less than or equal to 15% response. In this trial, patients achieved a response rate of 38% and a median overall survival of 12 months. However, the majority of these remissions were partial (3% CR, 13% nPR, 26% PR), and median TTP was less than a year.
Significant toxicities were observed with this regimen, resulting in dose reductions of cyclophosphamide and 25% of patients unable to complete the planned number of six courses of therapy. Both alkylating agents and purine analogues are known to cause myelosuppression, which can result in a high infection rate. The dose of cyclophosphamide was reduced from 500 mg/m2 to 300 mg/m2 daily for three days because of the occurrence of grade 3/4 neutropenia occurring in 88% of patients and grade 3/4 thrombocytopenia in 30% of patients at the highest dose. Even at 300 mg/m2 of cyclophosphamide combined with fludarabine, 75% of patients had grade 3 and 48% grade 4 neutropenia. Infections were common, and serious infections including bacteremia and/or pneumonia occurred in 25% of patients.