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© 2002 American Society for Clinical Oncology Campath-1H Treatment of T-Cell Prolymphocytic Leukemia in Patients for Whom at Least One Prior Chemotherapy Regimen Has FailedByFrom the M.D. Anderson Cancer Center, Houston, TX; Hôpital Claude Huriez, Lille; Cvitkovic & Associés Consultants, Kremlin-Bicêtre, France; Stanford University Medical Center, Stanford, CA; Marshfield Clinic, Marshfield, WI; Lausanne University Hospital, Lausanne, Switzerland; Evangelic Hospital, Essen-Werden, Germany; McMaster University/Hamilton Health Sciences Corporation, Hamilton, Ontario, Canada; Velindre Hospital, Cardiff, United Kingdom; Long Island Jewish Medical Center, New York, NY; and National Hospital, Oslo, Norway. Address reprint requests to Patrice Hérait, MD, Cvitkovic & Associés Consultants, 18-20 rue Pasteur, 94278 Kremlin-Bicêtre, France; email: p.herait{at}cvitkovic-ac.fr
PURPOSE: We conducted a retrospective analysis to evaluate the safety and efficacy of Campath-1H, an anti-CD52 humanized monoclonal antibody, in previously treated T-prolymphocytic leukemia (T-PLL) patients in a compassionate-use program. PATIENTS AND METHODS: Seventy-six patients with T-PLL (including four chemotherapy-naive patients) received 3, 10, and 30 mg of Campath-1H on sequential days, followed by 30 mg three times weekly, as 2-hour intravenous infusions, for 4 to 12 weeks. RESULTS: Median patient age was 60 years (range, 35 to 84). Spleen liver, lymph node, and skin involvement were present in 64%, 40%, 54%, and 18% of patients, respectively. All tested patients had CD2, CD7, CD4, and/or CD8 positivity, whereas CD5 and CD3 were positive in 98% and 96% of tested patients, respectively. The objective response rate was 51% (95% confidence interval [CI], 40% to 63%), with a 39.5% complete response (CR) rate (95% CI, 28% to 51%). The median duration of CR was 8.7 months (range, 0.13+ to 44.4), and median time to progression was 4.5 months (range, 0.1 to 45.4) compared with 2.3 months (range, 0.2 to 28.1) after first-line chemotherapy. The median overall survival was 7.5 months (14.8 months for CR patients). The most common Campath-1H–related adverse events were acute reactions during or immediately after infusions. Fifteen infectious episodes occurred during treatment in 10 patients (13%), leading to treatment discontinuation in three. Eight patients experienced possibly related, late-onset infections. Severe thrombocytopenia and/or neutropenia occurred in six patients (8%), leading to treatment discontinuation in four. Two treatment-related deaths occurred. CONCLUSION: Campath-1H is an active drug in T-PLL patients for whom first-line therapy has failed. It has a favorable risk/benefit ratio and should be prospectively investigated in chemotherapy-naive patients.
T-CELL PROLYMPHOCYTIC leukemia (T-PLL) is a rare lymphoproliferative disorder, representing approximately 3% of T-lymphocyte disorders.1 When determination of the B- or T-cell nature of lymphocytes was introduced in the medical practice approximately 30 years ago,2 it was recognized that approximately 95% of chronic lymphocytic leukemia (CLL) patients exhibit a B phenotype and 5% exhibit a T phenotype. At the same time, a subset of CLL cells, called prolymphocytes because of their less mature cell morphology, was identified, based on cytologic examination and the presence of significant splenomegaly.3 It was generally acknowledged that both T-CLL and cytologically defined prolymphocytic leukemia had a poorer prognosis than the more prevalent typical B-CLL. Most patients with phenotypically defined T-CLL have prolymphocytic cell morphology, whereas a small lymphocyte variant also exists.4 Most experts now agree that the term CLL should apply to B-CLL only, that T-PLL should be considered a specific entity, regardless of the cytologic features, and that the diagnosis of T-CLL should be discarded.4,5 There is currently no approved standard treatment for T-PLL. The most investigated treatment for this condition is deoxycoformycin (DCF/pentostatin), with a 40% to 50% objective response rate, including approximately 10% complete responses.6-8 The purine analog, 2-chlorodeoxyadenosine (CdA, cladribine), has been reported to be sporadically active in T-PLL,9-11 but no formal assessment of its use in T-PLL has been performed so far. There are few other published single case reports of therapeutic approaches, including chlorambucil and prednisolone,12 fludarabine,13 splenectomy,14 and allogenic bone marrow transplantation.15 Furthermore, after failure of first- or second-line chemotherapy, no other alternative active treatments are currently available. Campath-1H is a humanized immunoglobulin G1 rat monoclonal antibody directed against the CD52 antigen, a lymphocyte differentiation antigen present on the majority of both normal and leukemic B- and T-cells, monocytes, and macrophages. In vitro, Campath-1H is active in both complement-mediated cell lysis and antibody-dependent cellular cytotoxicity. In vivo, the proven cytotoxic effect of various rat or human anti-CD52 antibodies against lymphoproliferative disorders,16,17 as well as the immunosuppressive effect18 of Campath-1H, makes it a potentially attractive new therapy. Campath-1H is clinically active in previously treated19,20 and newly diagnosed21 B-CLL. The use of Campath-1H to treat T-PLL has been reported for 24 patients.22,23 Pawson et al22 administered Campath-1H to 15 patients, most of whom had previously received the purine analog DCF. Major responses occurred in 11 (73%) of these Campath-1H–treated patients and complete responses (CRs) were documented in nine (60%), with a median survival of 8 months. Cazin et al23 presented a preliminary report on nine patients, among whom six (67%) experienced a CR. The CRs with Campath-1H were long-lasting, and re-treatment resulted in second CRs in some patients who had experienced relapse. The patients reported in these two publications have been reviewed in the present series. The safety profile of Campath-1H, established from two phase II studies including CLL patients, is marked by acute reaction of short duration during infusion (77% of patients), including hypotension, fever, rigors/chills, nausea/vomiting, and rashes.19-21 However, many patients developed tolerance to these effects with continued treatment. The most serious adverse effects were neutropenia, thrombocytopenia, and the occurrence of opportunistic infections owing to the profound and prolonged drug-induced lymphocytopenia. However, the incidence and severity of these infections has been reduced with the systematic use of anti-infective prophylaxis. To date, after failure of first- or second-line chemotherapy in T-PLL, no alternative active treatments have been systematically assessed, making Campath-1H an attractive therapeutic approach after failure of treatment with purine analogs/alkylators.
Patient Population A compassionate-use program for Campath-1H was initiated by Burroughs Wellcome Co (Greenford Middlesex, United Kingdom) and continued by Ilex Oncology (San Antonio, TX) for patients with either PLL previously treated with at least one chemotherapy regimen or B-CLL who had relapsed after a first response with Campath-1H therapy. A total of 100 patients were treated with Campath-1H in this program between May 1992 and October 1999 in 57 centers worldwide. They were retrospectively reviewed on-site by two independent hemato-oncologists (M.B. and P.H.). Twenty-four patients were considered ineligible because the T-PLL diagnosis was not confirmed (B-CLL, 15 patients; B-PLL, seven patients; and non-Hodgkin’s lymphoma, two patients). The remaining 76 patients had confirmed T-PLL on the basis of clinical and cytologic features and immunophenotype. Eligibility criteria included failure of at least one prior regimen; age at least 18 years; World Health Organization performance status (PS) of 0, 1, or 2; creatinine and conjugated bilirubin levels of no more than twice the upper limit of normal unless deemed secondary to direct infiltration of the liver with leukemic cells; and written informed consent. Patients were ineligible if they were human immunodeficiency virus–positive, had an active infection or a past history of anaphylaxis after exposure to rat- or mouse-derived humanized monoclonal antibodies, had received prior chemotherapy within 3 weeks of the study, were pregnant or breast feeding, or had severe concurrent diseases or mental disorders. Four T-PLL patients were given Campath-1H as first-line treatment. Though they were ineligible, their data are reported separately in the present series.
Dosage and Administration of Campath-1H
Treatment Evaluation
Statistical Methods
Patient Characteristics The baseline characteristics of the 76 confirmed T-PLL patients are listed in Table 1. Note that because this was a compassionate-use cohort with retrospective data collection, some data were not available. The median age was 60 years (range, 35 to 84 years), with 70% of patients being male and 30% female. Performance status was formally assessed in only 38 patients (50%). Eight had a PS of 0 (21%), 11 had a PS of 1 (29%), 13 had a PS of 2 (34%, and six had a PS of more than 2 (16%). Most patients had aggressive and/or treatment-refractory disease. Four patients had not been given prior chemotherapy. The most frequently prescribed treatment as first-line chemotherapy was pentostatin, given to 31 patients (41%). Among the other 41 previously treated patients, 18 (24%) had received another nucleoside analog (cladribine and/or fludarabine). Forty-one patients (54%) had been given second-line treatment, and 19 patients (25%) had received three lines or more of prior chemotherapy, with the whole population having received a median of two lines (range, 0 to 5).
The response rate to first-line chemotherapy in the 72 pretreated patients was 32%, including 6% of patients achieving CRs. In the 31 patients treated initially with pentostatin, the response rate was 26%, all of which were PRs. In the 40 assessable patients treated with drugs other than pentostatin, there was a 37% response rate, which included four patients (10%) with CRs. The median TTP in first-line therapy was 2.3 months (range, 0.2 to 28.1 months). Prior second-line chemotherapy yielded a 22% response rate in the 40 assessable patients, equivalent to that observed in first line, but the majority of these responses were observed in patients who had not responded to first-line therapy. No responses were observed with any further treatments. The baseline symptoms were characteristic of patients with T-PLL8 (Table 1); 22% of patients had "B" symptoms, 64% of the patients without prior splenectomy presented with splenomegaly, and 40% of patients had liver enlargement. Diffuse lymph node involvement was present in 54% of patients, and 18% had skin lesions (half of which were confirmed histologically). Pleural effusion and/or ascites were present in 13% of patients. The most common disease-specific characteristic was hyperleukocytosis, with a median count of 74.8 x 109/L (range, 3.5 to 850 x 109/L). Only 11 patients (15%) had WBC counts less than 15 x 109/L, most of them as a result of prior chemotherapy, whereas 40% of patients had WBC counts greater than 100 x 109/L. This hyperleukocytosis consisted of leukemic lymphocytes, classified as prolymphocytes in all cases by the local hematologist. The immunophenotype of tumor lymphocytes was characteristic of mature, postthymic, T lymphocytes, with 100% of the tested patients having CD2 and CD7 positivity, whereas CD5 was positive in 98% of tested cases and CD3 in 96%. CD4 and/or CD8 were positive in 100% of cases, with CD4+/CD8- phenotype in 53%, CD4+/CD8+ in 25%, and CD4-/CD8+ in 22%. CD45(RO) was positive in 95% of the tested cases, and CD38 was positive in 80%. Almost all tested patients were negative for non-T and immature antigens, including CD1, CD10, CD11 CD16, CD19, CD20, CD34, CD56, terminal-deoxyribonucleotidyl transferase, HLA-DR, and surface immunoglobulin. In the 18 tested cases, the T-cell receptor was positive (15 with the alpha/beta and three with the gamma/delta phenotype). Bone marrow aspiration or trephine biopsy was not routinely performed at baseline, as organomegaly and elevated peripheral leukocyte counts allowed assessment of the initial effect of therapy. In the 41 cases in which a marrow aspiration was performed, the median percentage of lymphocyte infiltration was 67% (range, 16% to 100%).
Efficacy
Specific organ CRs were seen in bone marrow in 30 (39%) of 76 patients, in spleen in 14 (33%) of 42 patients with splenomegaly, in lymph nodes in 13 (32%) of 41 patients with adenomegaly, in liver in nine (30%) of 30 patients with hepatomegaly, and in skin in six (43%) of 14 patients. The time to reach lymphocyte nadir in complete responders was 30 days (range, 5 to 94 days) and to reach a WBC count of less than 100 x 109/L was 14 days (range, 1 to 94 days). Among the 31 patients who had received prior pentostatin in first-line therapy, 14 achieved a CR with Campath-1H (45.2%) versus 13 among the 41 who had not received prior pentostatin (31.7%). Among the 72 pretreated patients, of the 27 who achieved a CR with Campath-1H in this study, only 11 (41%) had achieved objective responses with prior chemotherapy (one CR and 10 PRs), whereas nine (33%) had PD as best response. All of these prior responses to chemotherapy occurred in either first-line (six of 27 patients; 22%) or in second-line treatment (six of 15 patients; 40%), including five instances in patients with PD in first line, and none occurred in the five patients given third-line treatment. Time-related parameters. All time-related parameters were calculated with a median follow-up of 18.2 months (range, 4.6 to 96.5 months). The median duration of complete response was 8.7 months (range, 0.1+ to 44.4 months). The median TTP for all patients was 4.5 months (range, 0.1 to 45.4 months), which was longer than that observed with prior first-line chemotherapy (median, 2.3 months; range, 0.2 to 28.1 months). In each patient achieving CR (except one censored patient), the TTP with Campath-1H was longer than the TTP with the prior first-line chemotherapy. As of March 31, 2000, 21 patients (27.6%) were still alive. The overall median survival for all patients was 7.5 months (range, 0.1 to 53.6 months) (Fig 1). For CR patients, the median survival was 14.8 months (range, 0.8 to 53.6 months).
Thirteen CR patients were given Campath-1H at relapse. One of them experienced a second CR after a disease-free interval of almost 3 years. Three patients had stable disease (SD), one of whom had clearance of blood prelymphocytes and who died from infection. One patient had PR in the blood and skin but had persistence of CNS disease, six had PD and three had not yet been assessed.
Safety Major adverse events occurring during treatment, regardless of their relationship to study treatment, are presented in Table 3. The main toxicities seen during Campath-1H treatment were acute reactions during or immediately after infusions. Fever occurred in 47 patients (62%) for a total of 116 episodes and chills/rigors occurred in 41 patients (54%) for a total of 90 episodes, sometimes occurring several times in the same patient despite premedication. Transient skin rashes were also frequent, occurring in 16 patients (21%) during or immediately after the infusions. Hypotension occurred in 17% of patients, and nausea, vomiting, and diarrhea occurred in 14% each. Other acute effects were rare and were usually short-lived and mild to moderate in intensity. Their incidence decreased with increasing numbers of infusions. Severe acute reactions occurred in only three patients (pulmonary edema [one patient], hypotension with syncope [one patient], and atrial fibrillation with tachycardia and hypotension [one patient]). Acute reaction was responsible for treatment discontinuation in only one patient.
Fifteen infectious events occurred in 10 patients (13%) during therapy, including seven episodes of viral infection in five patients (7%; Table 4). Among the three patients with cytomegalovirus infection, one had grade 2 and the severity of the other two patients was not documented. Two discontinued treatment and resolved in 1 to 3 months. In addition, 23 patients (30%) experienced 30 episodes of late-onset infections after treatment discontinuation. In eight patients (11%) the infectious episodes were likely to be related to Campath-1H–induced immunosuppression, including three during re-treatment after relapse. All other episodes occurred in patients with progressive disease who were receiving cytotoxic or immunosuppressive therapy at the time of infection, or in responding patients having undergone consolidation high-dose chemotherapy with or without radiation therapy with hematopoietic stem-cell support.
As a consequence of Campath-1H treatment, a transient decrease in neutrophil and platelet counts was observed in most patients. However, most patients who experienced severe cytopenia during the study had severe cytopenia at baseline (Table 2). It was sometimes difficult to distinguish between disease-related and treatment-related myelosuppression. For instance, 27 patients had a lower grade of neutropenia during treatment than at baseline, but 13 of them experienced SD or PD as best response. Similarly, 46 patients had a lower grade of thrombocytopenia during treatment than at baseline, among whom 21 had SD or PD as best response. Thrombocytopenia and/or neutropenia were clinically severe in six patients (8%), leading to treatment discontinuation in four of them. Three patients had grade 3 or 4 thrombocytopenia, one experienced grade 4 neutropenia, and two patients had pancytopenia leading to treatment discontinuation. All six of these patients received 30 mg, and the median cumulative dose was 532 mg (range, 340 to 863 mg).
Among the CR patients, 10 had neutropenia less than 1.5 x 109/L at baseline or during treatment, and recovered an absolute neutrophil count Campath-1H induced profound and prolonged lymphocytopenia, even after treatment discontinuation, especially in responders. The probability of recovering a lymphocyte count of at least 1.0 x 109/L (consisting of morphologically normal lymphocytes) is presented in Fig 2. Only eight of 29 assessable CR patients recovered an absolute lymphocyte count of at least 1 x 109/L during a period of 500 days, reflecting the prolonged lymphosuppression related to Campath-1H. The phenotype of the lymphocyte population was not assessed, and it is not known whether it reflected an immunocompetent population of patients. The occurrence of a late Pneumocystis carinii pneumonia in one patient with a normal lymphocyte count suggested a prolonged immunodeficiency beyond the mere recovery of normal lymphocyte count. Only one non-CR patient recovered a normal lymphocyte count of greater than 1.0 x 109/L, with prolymphocyte clearance.
Two treatment-related deaths occurred during the study. One patient died as a result of sepsis and pneumonia related to Campath-1H–induced severe neutropenia. The second patient died from pneumonia during a second course of Campath-1H, given as a result of disease progression occurring after the patient had achieved PR with the first treatment course. Six other fatal events, not obviously related to Campath-1H, also occurred: one patient had a deterioration of general condition, two episodes of cerebral hemorrhage in patients with disease-related grade 4 thrombocytopenia occurred, one cerebral infarction without thrombocytopenia was reported, one patient experienced renal failure, and one patient had pneumonia (both latter events were considered to be due to specific leukemic infiltrates).
T-PLL is a rare disease and the present series is one of the largest ever published. Matutes et al8 has reported a series of 78 patients; however, the treatment administered in their report was heterogeneous. The diagnosis of T-PLL in the 76 patients included in the present analysis was confirmed on the basis of blood involvement with a T-cell population sharing a common mature T phenotype with CD2, 3, 5, and 7 positivity and either CD4+/CD8- (54%), CD4+/CD8+ (25%), or CD4-/CD8+ (22%) and no B-cell markers.1,8 Three patients had a CD3- phenotype previously reported in T-PLL when tested in suspension,8 and one patient had a CD5- phenotype. In all cases the leukemic cells were morphologically prolymphocytes. Furthermore, patient characteristics at baseline were consistent with those reported for T-PLL in the literature.8 These include high leukocyte count (median, 74.8 x 109/L), massive splenomegaly in 64%, hepatomegaly in 40%, lymphadenopathy in 54%, and skin involvement in 18% of patients. Of note, some patients treated in this compassionate-use program had a poor performance status (> 2). Such patients are normally excluded from clinical trials in which investigators are usually more compliant with inclusion criteria. The response rate to prior treatment with pentostatin was 26%, slightly lower than but consistent with the range reported in the literature (33% to 48%).8 Prior second-line treatment yielded a 22% response rate, and most of these responses were observed in patients who had not responded to first-line therapy. No responses were observed with prior third-line or later treatment given before Campath-1H. It should be noted that 84% of pretreated patients had been previously exposed and were initially or had become resistant to pentostatin and/or other purine interacting agents, ie, the agents considered to be the most active in this disease. All of these facts strongly suggest that this patient population was resistant to standard cytotoxic chemotherapy. The response rate to Campath-1H in all 76 treated patients was 51%, with 39.5% of patients achieving CRs. This antitumor activity (notably the high CR rate) compares favorably with that reported for pentostatin in the literature (33% to 48% overall response rate with 10% CRs) and with that observed with prior chemotherapy in the present series (26% with zero CRs). The CRs reported here were clinically meaningful, as all signs of disease disappeared, and were long-lasting (median response duration, 8.7 months) without maintenance therapy. Long-lasting CRs were seen even in patients with severe disease-related bone marrow failure. According to strict CR criteria, four patients should not have been qualified as CR because of a CR duration of less than 2 months. These four patients underwent early hematopoietic stem-cell transplantation while in CR, so the duration of CR was censored at 0.13+, 0.83+, 0.85+, and 1.44+ months. Two of these patients died early from transplantation-associated toxicity, and two remained in CR for more than 2 months. Nevertheless, even if these responses were not taken into account, the CR rate in pretreated patients would be 32% and would not modify the conclusions of the present report. The time to achieve CR was variable between patients, depending notably on the initial tumor burden. Thus no recommended treatment duration can be made, and patients must be treated until tumor shrinkage gives CR. The longest treatment duration reported here was 161 days (48 infusions). In addition, four patients, classified as achieving a PR because they did not fulfill all criteria for CR, benefited from a prolonged antitumor effect (data not shown). The higher response rate in patients with a CD4+/CD8- phenotype previously reported with pentostatin8 was not found with Campath-1H in this series, as all phenotypes responded equally. The median TTP of 4.5 months (range, 0.1 to 45.4 months) obtained with Campath-1H compares favorably with that experienced by the same patients with their first-line treatment (2.3 months; range, 0.2 to 28.1 months). Importantly, the TTP in CR patients receiving Campath-1H was always longer than that observed with first-line therapy in the same patients. These findings, with each patient being his/her own control, strongly suggest that Campath-1H is a more effective therapy than those used previously. Generally, the effects of salvage therapies are less than those observed with first-line treatment, in terms of response likelihood and response duration. Notably, this was not the case with Campath-1H. Twenty-one patients were still alive at the cutoff date (range, 8.5+ to 90+ months). The overall survival was 7.5 months, and this figure compares favorably with that reported in the literature with pentostatin (8 months) in less heavily pretreated patients. Although it is likely that the population of pretreated patients may have selected a subset of long-term survivors, this plateau effect on survival, whereby a significant proportion of patients appear as long-term, disease-free survivors, is a further argument in support of Campath-1H efficacy. The level of Campath-1H activity observed in T-PLL seems to be even higher than that observed in B-CLL.19-21 This may be explained by different levels of expression of CD52, the Campath-1H target antigen. Although this antigen is expressed on both B and T lymphocytes, the level of expression has been reported to be higher on normal and leukemic T lymphocytes than on B lymphocytes.25 Furthermore, the level of expression correlates with Campath-1H response in vivo.25 Although it would have been interesting to study the surface expression of CD52 on the malignant lymphocytes at baseline to examine its potential role in the prediction of response to Campath-1H, these data were only available in a few patients. The safety profile of Campath-1H in this series was dominated by acute reactions with fever in 62% of patients, rigors in 54%, skin rash in 21%, hypotension in 17%, and diarrhea, nausea, and vomiting in 14%. These adverse events were usually mild to moderate and their incidence decreased with exposure, though some patients experienced repeated acute side effects. The incidence of acute reactions was lower than that previously reported with Campath-1H in B-CLL,19-21 especially grade 3 to 4. However, the occurrence of severe reactions could not have been ignored during on-site review. One hypothesis is that patients with T-PLL have reactions that are different from those with B-CLL. Alternatively, the premedication may have been more standardized at the time when the T-PLL patients were treated. Moreover, corticosteroids were often administered in this series prophylactically. The incidence of infections (13% of patients during treatment and 11% of patients with delayed onset episodes possibly related to study treatment) is lower than that observed in previous studies in B-CLL. This fact may be linked to different disease-related immunosuppression in T-PLL and/or to the systematic prescription, in the present series, of prophylactic cotrimoxazole and famciclovir in accordance with the current recommendations for use. The prescribed prophylaxis did not prevent the occurrence of one episode of P carinii pneumonia and three cytomegalovirus infections. However, it was not possible to determine whether the patients had been compliant with their prophylaxis. Most severe late-onset infections occurred in patients with concomitant PD and/or those treated with other cytoreductive/immunosuppressive therapies (including hematopoietic stem-cell transplantation), making the direct relationship to Campath-1H difficult to establish. Late-onset infections occurred in three patients in whom treatment with Campath-1H was resumed. This observation, together with the fact that only one of 13 patients who received a second course of Campath-1H achieved a response, indicates that re-treatment with Campath-1H is not recommended in this patient population. Thus, given the poor prognosis of patients with T-PLL, the lack of effective standard therapy as confirmed by the poor activity of previous treatment regimens in the present series, and the prevalence of elderly and/or fragile (16% of patients with PS > 2) and/or heavily pretreated patients due to the extended access program of this series, the results observed with Campath-1H in patients having failed prior chemotherapy are impressive. Because T-PLL is a very uncommon entity, these retrospective data support the use of Campath-1H for this population of patients. Furthermore, given the magnitude of the CR rate, response duration, and TTP in previously treated patients compared with first-line therapy, and that three CRs were observed among four patients without prior chemotherapy, a prospective study is warranted in chemotherapy-naïve patients, either alone or in combination with chemotherapy.
Eighteen patients from the current study were also reported in the following article: Dearden CE, Matutes E, Cazin B, et al: High remission rate in T-cell prolymphocytic leukemia with CAMPATH-1H. Blood 98:1721-1726, 2001
We thank the following physicians for providing access to their patient records: D. Catovsky, P. Avanzini, R. Billstrom, H. Birgens, K. Bouabdallah, D. Bunjes Carter, A. Cortelezzi, R.G. Dalton, A. Duncombe, C. Emmanouilides, I. Flinn, C. Fruchart, M. Garcia-Marco, B. Grant, J. Greeve, V. Gressler, J. Hernandez, M. Hedenus P. Hillmen, E. Hoppin M. Howard, R. Ireland, S. Johnson N. Ketley, E. Kimby D. Krahl, P. Leoni, M. Ojeda-Uribe, B. Mahe, M. Mangi, B. Monahan, E. Montserrat, G. Morgan, F. Morschhauser, R. Nagourney, S. Rassam, S. Reykdal, Simoyi, D. Soligo, K. Speed, R. Stewart, A. Wahlin, J.M Zijilmans. We also thank Dr Sarah Mackenzie for help in editing the manuscript.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
50% reduction in detectable disease. Objective response (CR + PR) had to have lasted at least 2 months. Safety was assessed using the National Cancer Institute common toxicity criteria. Duration of response was measured from the time the patient exhibited the maximum response until evidence of progressive disease (PD). Time to progression (TTP) was measured from study entry until the first report of disease progression. Survival duration was measured from study entry until death. 
