Results of fludarabine and prednisone therapy in 264 patients with chronic lymphocytic leukemia with multivariate analysis-derived prognostic model for response to treatment [see comments]

Abstract

Two hundred sixty-four patients with chronic lymphocytic leukemia were treated with fludarabine 30 mg/m2 intravenously for 30 minutes each day for 5 days and with prednisone 30 mg/m2 orally each day for 5 days. Courses were repeated monthly. Of the 264 patients. 125 patients (47%) had Rai stage III-IV disease; 169 patients (64%) were previously treated with a median of 3 prior regimens; and 138 of them (82%) were refractory to therapy with alkylating agents. The overall response (OR) and complete response (CR) rates in the 169 previously-treated patients were 52% and 37%; these were 74% and 63%, respectively, in Rai stage O- II patients and declined to 64% and 46%, respectively, in Rai III-IV disease. Among the previously untreated patients, the OR and CR rates were 79% and 63%, these being 85% and 70%, respectively, in Rai O-II patients, and declining to 64% and 46%, respectively, in Rai III-IV disease. The incidence of minor infections or fever of unknown origin was similar in all patient groups and occurred in 22% of courses. The incidence of sepsis and/or pneumonia was significantly correlated with the extent of prior therapy and with Rai stage, and ranged from 3% of courses in the previously untreated Rai O-II patients, to 13% of courses in the previously treated Rai III-IV patients. Listeria sepsis or Pneumocystis carinii pneumonia was noted in 14 patients. With therapy, CD4 levels were uniformly depressed from a median 1,015/microL pretreatment to a median 159/microL after 3 months of fludarabine therapy. Median time to progression in previously treated patients was 22 months. In previously untreated patients, median time to progression was 30 months for patients who achieved a partial remission and has not been reached in patients who achieved a CR with a median follow-up of 2 years. The median survival was 18 months for previously treated patients and has not been reached for previously untreated patients. Response rates in previously treated and untreated patients, as well as infection rates, were identical to those seen in 110 patients treated with the same dose schedule of fludarabine alone. Logistic regression analysis selected 4 factors to be significantly associated with worse response: Rai III-IV stage disease, prior therapy, older age, and low albumin levels. The regression equation was used to derive a probability of response based on the 4 characteristics. When the model was applied to the same population, patients could be divided into 4 prognostic groups with different outcomes.

Due to low infection rates no routine anti‐infective prophylaxis is required in younger patients with chronic lymphocytic leukaemia during fludarabine‐based first line therapy

“…This result is remarkable since FC induced a significantly higher rate of severe leucopenia compared with fludarabine alone. Within previous trials, fludarabine alone resulted in a 4-16% rate of major infections (O'Brien et al, 1993;Johnson et al, 1996;Rai et al, 2000;Leporrier et al, 2001), which is comparable with our results. However, our findings differ from two previous studies that reported a 77% overall infection rate with a 29-34% incidence of severe infections (Anaissie et al, 1998;Morrison et al, 2001).…”

“…The main infection site in the fludarabine arm was the respiratory tract. This observation has been made in previous trials during fludarabine treatment as well as in CLL patients in general (Molica et al, 1993;O'Brien et al, 1993;Morrison et al, 2001). With FC therapy, FUO was the most prominent cause of infection, which might be related to the higher incidence of severe leucopenia after FC treatment followed by transient bacteremia.…”

“…Pneumocystis jiroveci pneumonia or listeriosis were not observed in this study. This result might be related to the relatively short observation period, since these opportunistic infections have been described to occur with a delay after fludarabine based therapy (O'Brien et al, 1993;Anaissie et al, 1998). The 6% incidence rate of herpes or varicella zoster virus infection after fludarabine treatment in our trial was also very low compared with previous results, which might be explained by the short observation period and the age limitations used in this trial (Byrd et al, 1999;Morrison et al, 2001).…”

A prognostic model for survival in chronic lymphocytic leukaemia based on p53 expression

“…These investigators reported that expression of p53 protein, as measured by IHC (deemed positive if ‡ 1% of lymphocytes showed 'strong' nuclear staining), was strongly associated with p53 gene mutations, advanced disease, progressive disease, refractoriness to therapy and reduced survival. Univariate analyses of prognostic features in the study population confirmed the importance of b 2 M, prior therapy and Rai stage (O'Brien et al, 1993;Zwiebel & Cheson, 1998). The level of p53 expression joined these established factors as being a significant predictor of survival.…”

Peripheral blood stem cell (PBSC) mobilization and transplantation after fludarabine therapy in chronic lymphocytic leukaemia (CLL): a report of the European Blood and Marrow Transplantation (EBMT) CLL subcommittee on behalf of the EBMT Chronic Leukaemias Working Party (CLWP)

“…the purine analogues¯udarabine (Hiddemann et al, 1991;Keating et al, 1993;O'Brien et al, 1993;Robertson et al, 1995;Montserrat et al, 1996), deoxycorfomycin (Kefford & Fox, 1982), 2-chlorodeoxyadenosine (2-CDA) (Juliusson et al, 1992) and pentostatin (Dillman et al, 1989) have been introduced into CLL therapeutic strategies. Increasingly, udarabine is being used as initial therapy for patients with CLL Saven et al, 1995;Keating et al, 1998).…”