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Blood, Vol. 92 No. 4 (August 15), 1998:
pp. 1165-1171
Long-Term Follow-Up of Patients With Chronic Lymphocytic Leukemia
(CLL) Receiving Fludarabine Regimens as Initial Therapy
By
M.J. Keating,
S. O'Brien,
S. Lerner,
C. Koller,
M. Beran,
L.E. Robertson,
E. J Freireich,
E. Estey, and
H. Kantarjian
From the Department of Hematology, The University of Texas, M.D.
Anderson Cancer Center, Houston, TX.
 |
ABSTRACT |
One hundred seventy-four patients with progressive or advanced
chronic lymphocytic leukemia (CLL) have received initial therapy with
fludarabine as a single agent or fludarabine combined with prednisone.
The overall response rate was 78% and the median survival was 63 months. No difference in response rate or survival was noted in the 71 patients receiving fludarabine as a single agent compared with the 103 patients who received prednisone in addition. The median time to
progression of responders was 31 months and the overall median survival
was 74 months. Patients over the age of 70 years had shorter survivals.
Patients with advanced stage disease (Rai III and IV) had a somewhat
shorter survival than earlier stage patients. More than half the
patients who relapsed after fludarabine therapy responded to salvage
treatment, usually with fludarabine-based regimens. Second remissions
were more common in patients who had achieved a complete remission on
their initial treatment. The CD4 and CD8 T-lymphocyte subpopulations
decreased to levels in the range of 150 to 200/µL after the first 3 courses of treatment. Although recovery towards normal levels was slow, the incidence of infections was low in patients in remission (1 episode
of infection for every 3.33 patient years at risk) and decreased with
time off treatment. There was no association of infections or febrile
episodes with the use of corticosteroids or the CD4 count at the end of
treatment and a poor correlation with the increase in CD4 counts during
remission. Infectious episodes were less common in patients who had a
complete response compared with partial responders. Richter's
transformation occurred in 9 patients and Hodgkin's disease occurred
in 4 patients. Five other patients died from other second malignancies.
Fludarabine appears to be an effective initial induction therapy with a
reasonable safety profile for patients with CLL.
© 1998 by The American Society of Hematology.
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INTRODUCTION |
THE TRADITIONAL MANAGEMENT of patients
with chronic lymphocytic leukemia (CLL) needing therapy is the use of
chlorambucil with or without corticosteroids.1-4 Other
alkylating agent-based regimens that have been used are
cyclophosphamide, vincristine, and prednisone (CVP)5;
cyclophosphamide, vincristine, prednisone, and adriamycin with or
without ara-C (CHOP, POACH)6,7; cyclophosphamide,
adriamycin, and prednisone (CAP)8; or multiple alkylating
agent regimens such as the M2 regimen.9 Comparative studies
have been performed that have not demonstrated superiority of any one
regimen in previously untreated patients. The response rates to therapy
have varied from 50% to 80%, with the majority of the responses being
partial remissions.1-9
More recently, the purine analogs, fludarabine,10-16
2-chlorodeoxyadenosine,17 and
pentostatin,18 have been explored in previously treated
patients with CLL. Fludarabine, in particular, had a very high response
rate, with a substantial number of complete remissions in previously
treated patients with CLL.10-16 Increasingly purine analogs
are being used as initial therapy for patients with
CLL.11,18,19 Two reports from the M.D. Anderson Cancer Center (MDACC; Houston, TX) using fludarabine with or without prednisone have already been published, but long-term follow-up data of
these studies are not available.11,20 In particular, little
information has been provided regarding time to progression in
responding patients and the results of re-treatment with fludarabine or
other regimens. Randomized comparisons between fludarabine and
chlorambucil or between fludarabine, CAP, and CHOP
regimens21-23 have recently been conducted in the United
States and Europe.
The purpose of this report is to present an overall evaluation of the
response to fludarabine regimens as initial therapy of patients with
CLL, the response rate, toxicity, time to progression, results of
re-treatment, and long-term survival.
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PATIENTS AND METHODS |
Three different fludarabine studies form the basis of this report. The
first used fludarabine at 25 to 30 mg/m2 daily for 5 days
every 4 weeks administered as part of a phase I/II clinical trial
(FLU-PhI-II).10 The next regimen was the combination of
fludarabine at 30 mg/m2/d for 5 days combined with
prednisone at 30 mg/m2/d for 5 days every 4 weeks
(FLU+Pred).11 After completion of the fludarabine + prednisone protocol, subsequent patients were treated with fludarabine
at 30 mg/m2/d for 5 days every 4 weeks on a current
practice research protocol (FLU-CP) and are classified as FLU together
with the phase I-II protocol patients. In the phase I-II protocol, the
number of courses was not specified. In the latter 2 protocols, all
patients were projected to receive 6 cycles of therapy and continue
therapy until complete response or treatment failure. However, some
patients discontinued treatment after achieving complete remission in
less than 6 courses. Some patients who had not achieved a complete remission after 6 courses but were continuing to improve their clinical
status had additional therapy. The median number of courses was 6 (range, 2 to 11). Patients were eligible for treatment if they
fulfilled the National Cancer Institute (NCI) recommendations for
therapy, having advanced stage disease (Rai III and IV) or progressive
stage I and II disease.24
One hundred seventy-four patients fulfilled the criteria for treatment
with Rai stage I-IV disease. The median age of the 174 Rai III-IV
patients was 61 years (Table 1). Two-thirds
of the patients were male and 38% had Rai stage III and IV disease. The range of times from diagnosis to treatment was wide, but the median
time was 9 months. Few patients had B symptoms, and the majority of
patients had performance status 0 to 1 using the Zubrod performance
scale. Less than 10% of patients had a history of prior infection
(Table 1).
Patients were started on treatment between 1986 and 1993. Informed
consent was obtained according to institutional guidelines. All
patients had a workup including history and physical examination; complete blood counts; differential and platelet counts; sequential multiple analysis-12 (SMA-12), including liver and renal function studies; bone marrow aspiration and biopsy; and blood and marrow samples for immunophenotyping and molecular studies. The
criteria required for a confirmation of the diagnosis were a monotypic expansion of lymphoid cells  5 × 103/µL
morphologically consistent with CLL (small lymphocytes) in the blood
for 2 months before treatment and greater than 30% lymphocytes in the
bone marrow. One hundred fifty patients were proven to be
CD5+, 18 were CD5 (<20%), and 6 had
no immunophenotyping studies performed. Normal renal and hepatic
functions (creatine <2 mg% and bilirubin <2 mg%) were required.
Patients were evaluated for marrow response after each 3 courses. NCI
Working Group criteria for response were used.24 Complete
remission (CR) required disappearance of all palpable disease, a
neutrophil count greater than 1,500/µL, a platelet count greater than
100,000/µL, a hemoglobin level greater than 11 g/dL, and a bone
marrow aspirate lymphocyte percentage of less than 30%. Patients
fulfilling the criteria noted above but with persistent lymphoid
aggregates or nodules in the bone marrow biopsy were classified within
the partial remission (PR) group as PR-Nod. Other PRs required 50%
decrease in palpable disease as well as 50% improvement of all
abnormal blood parameters. No bone marrow evaluation was required for
determination of PR. Computerized tomography scans were not required to
stage patients or evaluate response.
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STATISTICAL CONSIDERATIONS |
Associations between patient characteristics and response to outcome
were evaluated using the  2 test. Cut-points for
quantitative variables were those defining abnormal levels or other
cut-points in common use. Distributions of survival and time to
progression were estimated by the method of Kaplan-Meier. Survival
intervals were measured from the first day of chemotherapy to death
from any cause. Time to progression was measured from the first day of
chemotherapy to the first detection of relapse from CR (defined as
>10,000 lymphocytes/µL in the peripheral blood, development of
anemia or thrombocytopenia, or more than 50% lymphocytes in the bone
marrow aspirate), reappearance of lymphadenopathy, hepatomegaly,
splenomegaly, or extramedullary disease. Development of Richter's
transformation was considered to be a relapse. Time to progression in
PR patients was defined as 50% increase in size of residual
abnormalities in liver, spleen, or lymph nodes, a consistently
increasing lymphocyte count to a level of at least greater than
10,000/µL, or development of anemia or thrombocytopenia.
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RESULTS |
Response to induction regimen.
The overall response rate for 174 patients treated with fludarabine
regimens was 78% (29% CR, 32% PR-Nod, and 17% PR), and the overall
median survival was 63 months. Five patients were considered to be
early deaths, having died without time to recover from at least 3 courses of chemotherapy. There was no significant difference in the
overall response rate for the regimens, FLU (57/71 [80%]) compared
with the FLU+Pred group (79/103 [77%]). However, the CR rate for
FLU+Pred (24/103 [23%]) was significantly less than for FLU (27/71
[38%]; P = .04). The vast majority of the 38 patients
classified as nonresponders had a significant response in the
peripheral blood lymphocytes (69%), nodes (57%), spleen (67%), liver
(60%), and bone marrow (36%). Two of 8 patients who had a tumor CR or
PR but failed to respond to treatment because of persistent cytopenia
are still alive at 48 and 68 months. The survival curves show no
significant difference in survival for the 3 regimens, with the median
values being 74, 55, and 47+ months. All patients receiving FLU-PhI-II
have completed 98 months of follow-up; the median follow-up of the
FLU+Pred group is 62 months and that of the FLU-CP protocol is 39 months. The curve for FLU+Pred versus the other 2 protocols combined is
shown in Fig 1.
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| Fig 1.
Survival of CLL patients treated with fludarabine alone
or with prednisone. P value, log rank; NB median survival, 63 months.
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Time to progression.
The median time to progression for CR, PR-Nod, and PR patients was 31 months, being significantly longer for the true CR patients (37 months)
compared with PR-Nod (30 months; Fig 2). No
other pretreatment characteristic (shown in
Table 2) was associated with the time to
progression. There is no indication of a plateau developing on the
curve of any group to suggest a cured fraction.
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Table 2.
Response to Fludarabine Regimens and Survival in
Previously Untreated CLL by Pretreatment Characteristics
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Prognostic factors for survival.
Survival of patients with advanced Rai stage III and IV was modestly
inferior to that for Rai stage I and II
(Fig 3). There was no significant
difference in survival according to whether patients had a true CR or
PR-Nod (Fig 4). The survival of the CR and
PR-Nod groups was significantly superior to that of the PR patients
(P < .01), who, in turn, had a significantly longer survival
than the resistant patients.
Rai stage was significantly associated with survival. A hemoglobin
level of less than 11 g% was significantly associated with a shorter
survival, but no such association was noted for platelet count. There
was no significant association of measures of tumor burden such as
enlargement of liver or spleen, number of involved node sites, white
blood cell count, bone marrow cellularity, or lymphocyte percentage
with survival. Patients more than 70 years of age survived for a
shorter time than did younger patients. The level of blood urea
nitrogen in the serum was significantly associated with survival, as
was the serum  2-microglobulin. Cytogenetic analysis was performed on
161 patients before therapy, but 27 patients had insufficient
metaphases for analysis. The 100 patients with a diploid karyotype had
a significant shorter survival than the aneuploid patients (P < .01). Abnormalities (abn) in chromosome 11q were noted in 7 patients, trisomy 12 in 7 patients, abn 13q in 3 patients, abn 14q in 6 patients, and other changes in 11 patients. The small number of
patients in each group prevented meaningful statistical analysis for
response or survival. None of the other factors had a significant
impact on survival (Table 2).
Mortality.
The survival of patients on fludarabine and prednisone is slightly
inferior to the survival of patients on fludarabine as a single agent
(P = .06; Fig 1). Ninety-six patients have died. Nine of these
patients died during remission induction: 6 of infection, 1 of
progressive uncontrolled CLL, 1 of cardiac failure, and 1 with a
stroke. Five patients died in remission. Two patients died of pulmonary
infection with unknown pathogen. One patient had a myocardial
infarction. Another patient developed Hodgkin's disease and died of
this disease without recurrence of the CLL. One patient died of liver
cancer. Eighty-two patients died after progression of their disease or
failing to respond to remission induction therapy. Thirty-five of these
patients died of infection and 7 died of CLL, according to their local
physician. Five patients died of unrelated causes, being either
myocardial infarctions, cardiac arrests, or stroke. Nine patients had
developed Richter's syndrome (large-cell lymphoma) at 13 to 62 months
after the initiation of treatment and 8 have died. The cumulative
incidence of large-cell lymphomatous transformation is projected to be
8%. In addition, 3 patients developed and died from Hodgkin's
disease. Five other patients have developed cancer: 2 with lung cancer,
1 with ovarian cancer, 1 with colon cancer, and 1 with head and neck
cancer. Four patients died after receiving a transplantation, 4 more
died of hemorrhage, and 2 died with renal failure. No cause of death was established on follow-up in 9 patients.
Retreatment.
Ninety-one patients who have come off study have received salvage
therapy at MDACC. Sixty-three patients have been rechallenged with a
fludarabine-containing regimen and 41 (67%) have responded (Table 3). For patients receiving other
regimens, the response rate was 7 of 28 (25%). A number of different
treatment regimens were used, as shown in Table 3. No response was
noted for investigational agents such as Taxol or Topotecan. One
patient achieved a PR-Nod with chlorodeoxyadenosine (2-CDA) and 2 patients responded to allogeneic bone marrow transplantation (both
CRs). The CR rates were higher in patients who had achieved a true CR
(11/29 [38%]) on their initial fludarabine treatment than for PR-Nod
patients (4/30 [13%]). Seven of 16 (44%) patients who achieved a PR
on their initial fludarabine regimen responded again when challenged, but none obtained a CR. No patient who had initially failed to respond
to fludarabine had a response when retreated with a fludarabine combination. It is interesting that 4 of the 5 patients who failed to
have an initial response to fludarabine regimens but were treated with
CHOP obtained CRs (2) or PRs (2).
Immune reconstitution.
Thirty-one patients had an IgG level less than 650 mg% (the lower
limit of normal for our laboratory) and had at least 2 follow-up values
performed to evaluate the response of the Ig level to fludarabine therapy. The mean of all IgG values from start of fludarabine until the
patients commenced on another regimen was established. Of the 31 patients with a low IgG level before fludarabine, 12 (39%) returned to
a normal level. Sixteen (51%) had an increase of more than 100 mg%
from their pretreatment level and 2 patients had a decrease of 100 mg%
or more from their pretreatment value. Thirteen patients had increases
or decreases in the IgG level of lower amplitude. Fifty-three patients
had an IgA level less than 75 mg%. Fourteen (26%) had a return of the
IgA level to normal, 15 had an increase of 20 mg% or more (28%), and
2 (4%) had a decrease of 20 mg% or more. The other 36 patients had no
substantial change. The IgM level was less than 30 mg% in 23 patients.
Twelve (52%) had an increase to the normal range, 13 had an increase
of 10 mg% (56%), and 1 (4%) had a decrease of more than 10 mg%. The other 9 had no substantial change. No significant correlation appears
to exist with the response of the patients. Patients who failed to
respond had a change in their Ig levels equivalent to the CR, PR-Nod,
and PR patients.
T-cell levels.
Pretreatment CD4 and CD8 lymphocyte counts were available on 127 patients. The median CD4 count was 1,562/µL and the median CD8 count
was 510/µL. Ninety-seven patients had CD4 and CD8 estimates after the
third course and 44 patients had estimates after the sixth course of
treatment (Fig 5). The median CD4 count
after 3 courses was 172/µL and after 6 courses was 163/µL. The
median CD8 counts after the third course and after the sixth course
were 138/µL and 133/µL, respectively.
Because of concern over the low CD4 and CD8 counts, the incidence of
infections that occurred while patients were in remission off treatment
until they showed evidence of progressive disease or needed other
treatment was examined. The number of episodes has been divided by the
number of patient years at risk, which were computed by summing the
time from recovery of the last course of chemotherapy until the patient
went off study because of progressive disease or moved to some other
treatment regimen (remission time off therapy). Of the 137 patients who
achieved a CR, PR-Nod, or PR, 94 episodes occurred during remission
(Table 4). The most common single event was
dermatomal herpes zoster, occurring in 19 patients. Upper respiratory,
sinus, and bronchial infections and pneumonia (a total of 40 episodes);
6 cases of influenza (diagnosed clinically); 5 episodes of reactivation
of herpes simplex; and 10 urinary tract infections were noted. One
episode of septicemia was caused by Listeria monocytogenes. No episode
of Pneumocystis carinii pneumonia was noted during remission; 1 case of cytomegalovirus infection was seen. These 94 episodes of fever
or infection occurred in 313.2 patient years at risk, giving an overall
incidence of episodes of infection or fever of approximately 1 for each
3.3 patient years at risk.
There was a strong association with the quality of the remission and
the probability of patients developing these episodes (Table 4).
Patients who achieved PR had a greater likelihood of developing
infections or febrile episodes than did patients who had PR-Nod,
whereas the least morbidity occurred in CR patients who achieved a CR
(P < .01). No relationship was found between the CD4 count at
the end of therapy and the risk of fever/infection during remission
(Table 5). In addition, infection or
febrile episodes decreased as length of remission increased, whereas
the return to normal CD4 counts was more gradual (Table
6 and Fig 5). This may explain the lower incidence of episodes in the
FLU+Pred patients who have shorter median follow-up (Table 5).
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Table 5.
Infections/Febrile Episodes During Remission of CLL
Patients Receiving Fludarabine Regimens as Initial Therapy
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DISCUSSION |
This analysis focuses on long-term outcome for patients who receive
fludarabine or fludarabine plus prednisone as initial therapy for
progressive or advanced CLL. No difference was noted for the addition
of prednisone to fludarabine in terms of response rate or survival.
Three recently described studies confirm a higher response rate for
fludarabine in comparison with chlorambucil, CAP, and French CHOP, but
no survival advantage.21-23 Smaller studies suggest a
similar response rate to 2-CDA19,25,26 without adequate
follow-up data.
Our data demonstrate a long time to progression in CR (30 to 37 months)
and PR patients (27 months) that is similar to a multicenter report for
fludarabine (35+ months) and superior to CAP (<12
months).21 The duration of response reported for
chlorambucil and prednisone was 2 years and for CVP was 1.9 years in an
ECOG study.5 To date, neither of the fludarabine
comparative trials has defined a survival advantage for
fludarabine.21,23 Comparison of the data in this report
with our previous 2 studies of CAP and POACH (median survival of 5 years in both) shows only a modest increase in overall
survival.7,8
The only component of the Rai and Binet staging systems associated with
survival was the hemoglobin level. The 28 Rai stage IV patients had an
excellent survival in this study (71+ months). A high blood urea
nitrogen (BUN) level was associated with a short survival
and high early death rate. Because fludarabine is excreted largely by
the kidneys, modification of dosage may be recommended, perhaps using a
3-day schedule.12 Unfortunately, the 2-microglobulin level before therapy was not available on all patients, because it
appears to be the characteristic most strongly associated with survival.27
The risk of administering fludarabine as initial therapy for CLL has
been addressed, and deaths in the first year were associated with
well-known adverse features such as age, stage, tumor burden, and
myelosuppression.10,11 There was no increase in toxicity or
early death reported in comparative studies with chlorambucil or
CAP.21,23 Thus, fludarabine used with appropriate levels of
caution is safe and effective as induction therapy in previously untreated patients with CLL.
Depression of CD4 and CD8 counts was marked in this study, occurring
mainly during the first 3 courses of therapy, as reported in other
studies.10-12 No difference in these values was noted between patients treated with or without prednisone. Recovery from this
effect after fludarabine was discontinued was slow. Despite the
persistent T-cell suppression, infections and febrile episodes were
uncommon during remission and decreased with time of follow-up. No
association was noted between infection rate and the CD4 level at the
end of fludarabine treatment. Thus, the risk of infection appears to be
low during remission, but vigilance for opportunistic infections is
always necessary.28 The improvement of IgG, IgA, and IgM
levels in many patients after therapy was encouraging and may
contribute to the low incidence of opportunistic infections.
Concern has been expressed about the responsiveness to salvage therapy
after relapse in patients who receive fludarabine as initial therapy.
As we have shown, most patients achieve a second remission. Second
remissions are more likely in patients achieving CR with initial
therapy than in patients achieving PR or failing to respond to
induction therapy. Surprisingly, the salvage response rate was not
associated with the length of the first remission. Most patients were
rechallenged with a fludarabine-based regimen. Combination therapies
tended to be administered to patients with the shortest initial
response and to those with evidence suggestive of transformation. Some
fludarabine-resistant patients responded to CHOP-like regimens but not
to new agents such as Taxol or Topotecan.
Responsiveness of patients to salvage therapy raises the question of
the optimum duration of fludarabine treatment. If patients are still
responding without toxicity, should patients be treated until there is
no evidence of disease using techniques such as two-parameter flow
cytometry or polymerase chain reaction29,30? Should
maintenance therapy with fludarabine (perhaps an oral formulation),
alkylating agents, or biologic agents be attempted? These are
appropriate questions for subsequent clinical trials. In conclusion,
fludarabine is effective and relatively safe as initial therapy for CLL
with no evidence yet for a survival advantage over previous regimens.
Future studies should be planned to increase the incidence of true CRs
in an attempt to prolong survival in patients with this disease.
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FOOTNOTES |
Submitted April 30, 1997;
accepted April 9, 1998.
Address reprint requests to M.J. Keating, MD, Department of Hematology,
Box 92, The University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
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Abstract
Introduction
Abstract
