Pocket Drug Guide

Posts Tagged ‘PR’

Overview

Immunotoxins use MAb technology conjugated to natural toxins. Monoclonal antibodies are well established in cancer therapy. Immunotoxins have a lack of encouraging data in non-Hodgkin’s lymphoma, but their activity in blood-based tumors versus solid tumors may prove more efficacious.

Mechanism Of Action

Immunotoxins comprise peptides, usually an antibody or growth factor, which are linked to toxins such as diphtheria toxin, Pseudomonas exotoxin, or ricin. This “magic bullet” mechanism is designed to target the toxic moiety to a specific cell by binding the growth factor/antibody portion of the immunotoxin to its cell surface receptor. Upon internalization, the toxin is cleaved into an active form and causes cell death.

Denileukin Diftitox

Ligand Pharmaceuticals is developing denileukin diftitox (Ontak) for the treatment of chronic lymphocytic leukemia. Phase II trials are underway in the United States. This agent has already been launched in the United States and preregis-tered in Western Europe for the treatment of cutaneous T-cell lymphoma.

Denileukin diftitox is an interleukin-2 (IL-2) diphtheria toxin fusion protein; it is designed to direct the cytocidal action of diphtheria toxin to cells that express the IL-2 receptor. The human IL-2 receptor exists in three forms: low (CD25), intermediate (CD122/CD132), and high (CD25/CD122/CD132) affinity, the last of which is expressed on activated T and B lymphocytes and activated macrophages.

Researchers presented data from a Phase II trial in which heavily pretreated, fludarabine-refractory chronic lymphocytic leukemia patients received denileukin diftitox at a dose of 18 µg/kg/day or 9 µg/kg/day (if older than 70) intravenously for 5 days every 21 days. The mean age of patients enrolled in this study was 61.8 years and included 14 males and 4 females with Rai stages I (n = 2), II (n = 6), and IV (n = 10) who had received a mean of 4.5 prior treatments. Eleven out of 12 patients who received three or more courses of denileukin diftitox showed a reduced chronic lymphocytic leukemia cell count, and 6 of the 11 showed a >95% reduction. Seven of 12 patients showed a reduction in all lymph node diameters, with 1 patient showing 60% and another 80% shrinkage. Pre- and post-bone marrow biopsies performed on 11 patients showed a reduction in chronic lymphocytic leukemia marrow index; 7/11 had>50% reduction, including >98% in 3 patients.

In the study, denileukin diftitox produced 2/12 (17%) PRs and 7/12 (58%) minimal responses. Progression-free intervals ranged from 1 to more than 19 months. Toxicities were mild to moderate and included asymptomatic transient transaminasemia, fever, hypoalbuminemia, nausea, vomiting, elevated creatinine kinase, and vascular leak syndrome. The results suggest this agent has some biologic activity in this difficult-to-treat group of patients.

Previous published data have reported that immunotoxins directed against CD25 are more effective in treating malignancies where the expression of surface CD25 is high, such as in hairy-cell leukemia. Research has determined that chronic lymphocytic leukemia cells can be sensitized to CD25-directed immunotoxins by treating them with an agent that upregulates CD25 expression. A follow-up study is investigating denileukin diftitox therapy in combination with bexarotene (Ligand’s Tagretin), a retinoid X receptor (RXR) selective agonist known to upregulate IL-2 receptor expression.

Another study of denileukin diftitox therapy also presented data on a small number of heavily pretreated fludarabine-refractory patients. Their median age was 63, and patients had received three to eight prior therapies. Of the five evaluable patients, the median number of denileukin diftitox cycles received was three. Therapy was stopped after one cycle because of grade 4 hepatitis, diarrhea, and disseminated herpes simplex with fatal pneumonia and after two cycles because of grade 4 vascular leak with microangiopathy/cardiac tamponade or lack of efficacy. Other toxicities included grade 1 and 2 fatigue and myalgias; grade 4 anorexia; and grade 1, 2, and 4 raised liver function. Two of the five patients achieved a PR, both of which were ongoing at 12+ months, and two achieved minor responses (1 month and ongoing at 6+ months). CD25-positive and -negative patients were treated, and PR was observed in both groups. Furthermore, therapy with denileukin diftitox resulted in reduced lymphocytosis (median pre = 55 and post = 3.7) and a more normalized range of hemoglobin, neutrophils, and platelets.

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.

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.

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.

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.

Overview

The clinical efficacy of purine analogues first became apparent in the late 1980s, and a progressive shift toward their use in first-line therapy has occurred. Fludarabine (Schering AG/Berlex’s Fludara) is approved for the treatment of chronic lymphocytic leukemia in patients who have failed prior therapy, but physicians report this agent forms the basis of first-line regimens in patients with a good performance status. Fludarabine is the leading cytotoxic agent throughout our study period in terms of market share.

Mechanism Of Action

Fludarabine is a purine analogue and is metabolized rapidly to F-Ara-ATP, which restricts DNA synthesis by inhibition of DNA polymerases and prevents elongation of DNA strands through direct incorporation into the DNA molecule.

Clinical Performance

Three large-scale, randomized trials have investigated single-agent fludarabine in previously untreated chronic lymphocytic leukemia patients. A three-arm study compared fludarabine (25 mg/m² on days 1-5, every 28 days), chlorambucil (40 mg/m² every 28 days), and a fludarabine (20 mg/m² on days 1-5 every 28 days)/chlorambucil (20 mg/m² every 28 days) combination in untreated patients with intermediate- and high-risk disease.

The overall response rate was markedly improved in patients receiving fludarabine compared with chlorambucil (63% versus 37%). Complete and partial responses were 20% and 43%, respectively, in the fludarabine arm compared with 4% and 33%, respectively, in the chlorambucil arm. The median duration of response was 25 and 14 months, and median survival was 66 months and 56 months in patients receiving fludarabine versus chlorambucil, respectively. However, a significantly higher incidence of grade 3 and 4 toxicities, specifically neutropenia and infection rate, was observed in patients receiving fludarabine compared with chlorambucil. The combination of fludarabine and chlorambucil produced response rates similar to those of fludarabine alone but with greater toxicity. Despite the improved response rates, at a median follow-up of five years, overall survival was not significantly different between the three arms of the study.

The response rates for single-agent fludarabine in untreated patients are in agreement with results gained from two other large-scale trials.

The dose and schedule of chlorambucil in the Rai study have been criticized as not optimal, yet a study in which high-dose chlorambucil (15 mg daily for up to six months) was administered produced a median survival of 68 months, which is not significantly different from the 56 months achieved in the three-arm study. A more recent study compared high-dose chlorambucil (10 mg/m² daily for 18 weeks) with fludarabine and found complete remissions (CRs) of 47% versus 33%, respectively, and partial remissions (PRs) of 41% versus 42%. Hematological toxicity was significantly higher in the chlorambucil arm, and infections were more common in the fludarabine arm. Survival data are not yet available.

In addition to its efficacy as a first-line agent, fludarabine works in the second-line setting, following failure with alkylating and/or anthracycline agents. More than 15 studies including a total of 1,400 patients have published results showing a wide range of response rates due to the heterogeneity of patient characteristics. Overall response rates are approximately 40%, including 10% CR and 20% nodular PR (nPR).

The major limitation of fludarabine is the high level of myelotoxicity, resulting in an increased infection rate. Elderly patients and those with a poor performance status are often unable to cope with these adverse side effects and are therefore limited to chlorambucil therapy.