Page 1408 - Hematology_ Basic Principles and Practice ( PDFDrive )

1254 Part VII Hematologic Malignancies

other nucleoside analogs, fludarabine and cladribine, were subse- in previously untreated CLL patients, with the goal of improving
quently found to be clinically active in CLL. Phase II–III studies of response rates and hopefully long-term survival. The German CLL
cladribine monotherapy achieved similar clinical responses as alkylat- Study Group randomized 375 previously untreated patients (age
ing agent–based treatment but were associated with more cytopenias younger than 65 years) to standard fludarabine or Flu/Cy (fludarabine
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and immune suppression. The FDA approved fludarabine for the 30 mg/m IV and cyclophosphamide 250 mg/m IV daily for 3 days)
treatment of CLL, and thus most studies of purine analog–based every 28 days for six cycles. The ORR (94% vs. 83%), CR rate (24%
therapy in CLL have focused on fludarabine. The remainder of this vs. 7%), median PFS (48 vs. 20 months), and duration of treatment-
section focuses predominantly on clinical trials of fludarabine. free survival (37 vs. 25 months) all favored Flu/Cy, although there
Fludarabine was initially approved by the FDA for alkylating were more patients with cytopenias in the combination arm. Further-
agent–resistant CLL in 1991 based on two phase II studies demon- more, no difference in OS was observed. ECOG randomized 278
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strating a high response rate to fludarabine in this patient subset, patients to single-agent fludarabine or fludarabine 25 mg/m on days
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prompting several additional trials of fludarabine as monotherapy in 1–5, cyclophosphamide 600 mg/m on day 1, and granulocyte
relapsed and previously untreated CLL. After the observation of high colony-stimulating factor (G-CSF) support every 28 days for six
response rates and a 33% CR rate in previously untreated CLL by cycles. Flu/Cy therapy achieved a superior ORR (74% vs. 59%), rates
Keating and colleagues, several large prospective randomized studies of CR (23% vs. 5%), and duration of PFS (32 vs. 19 months),
in previously untreated CLL patients compared alkylating agent– although no OS advantage was observed. The United Kingdom LRF
based regimens with fludarabine. These studies collectively established CLL4 study randomized 777 patients to oral chlorambucil, fludara-
fludarabine as an accepted standard first-line therapy for CLL based bine, or Flu/Cy. Patients randomized to Flu/Cy enjoyed superior
on improved response rates and PFS. A multicenter European study ORR, CR rates, and 5-year PFS rates (94%, 39%, and 33%, respec-
randomized 196 evaluable patients to fludarabine or cyclophospha- tively) as compared with patients who received chlorambucil (72%,
mide, doxorubicin, and prednisone (CAP). The ORR favored 7%, and 9%, respectively) or fludarabine (80%, 15%, and 14%,
fludarabine (60% vs. 44%), and this benefit was observed in both respectively).
relapsed (n = 96; 48% vs. 27%) and previously untreated (n = 100; These three large, prospective, randomized, multicenter studies in
71% vs. 60%) patients, although the difference was not statistically the United States and Europe have clearly demonstrated that Flu/Cy
significant in the untreated group. Fludarabine achieved a longer therapy is associated with better response rates and duration of PFS
median duration of response than did CAP, with a tendency toward than single-agent fludarabine. However, no OS advantage for upfront
longer OS in previously untreated patients. A randomized, multi- Flu/Cy has been observed to date. Although toxicity has generally
center American study confirmed these findings in 509 previously been manageable, greater hematologic toxicity has been observed
untreated CLL patients. Patients were randomized to receive fluda- with Flu/Cy. In addition, patients older than 65 or 70 years, who
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rabine 25 mg/m IV daily for 5 days every 28 days, chlorambucil make up the majority of CLL patients receiving therapy in clinical
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40 mg/m PO every 28 days, or fludarabine 20 mg/m daily for 5 practice, have either been excluded or minimally represented in these
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days and chlorambucil 20 mg/m PO every 28 days, for up to 12 trials. Further studies are needed to determine if Flu/Cy is as well
cycles. Patients who failed to respond or relapsed were allowed to tolerated and active in older patients as it is in younger patients.
cross over to the other arm. The combination arm was closed because Finally, of these patients, long-term follow up is required to determine
of excessive toxicity. Fludarabine achieved a superior CR rate, ORR, the duration of remission, OS, and the incidence of potential late
median duration of remission, and median duration of PFS (20%, complications such as therapy-related myeloid neoplasia (tr-MN) to
63%, 25 months, 20 months, respectively) than did chlorambucil fully assess the utility of the Flu/Cy regimen. Indeed, the U.S.
(4%, 37%, 14 months, 14 months, respectively). However, there was Intergroup study of Flu/Cy versus Flu suggested an increased risk of
no statistically significant difference in OS even after 10 years of tr-MN in the Flu/Cy arm. Examination of outcome by cytogenetic
follow up (66 vs. 56 months), possibly because of the crossover risk groups showed that patients with high-risk cytogenetic abnor-
design. A multicenter French study randomized 938 patients with malities, including del(17p13.1), had a significantly shorter remission
previously untreated Binet stage B and C CLL to fludarabine, CHOP, than patients in the groups with good- or intermediate-risk cytoge-
or CAP. Although fludarabine achieved better response rates than netic findings. Therefore, the addition of alkylating agents to fluda-
CAP, OS (67–70 months) was identical for all three treatment groups. rabine does not appear to alter the poor prognosis associated with
Thus, single-agent fludarabine achieves superior response rates and high-risk cytogenetic abnormalities except for patients with
duration of PFS than alkylating agent–based regimens. The impact del(11q22.3).
of prognostic factors on response rates and duration of PFS to
fludarabine was recently examined; patients with high-risk cytoge-
netic abnormalities, including del(11q22.3) and del(17p13.1), have Rituximab
significantly shorter PFS in response to fludarabine-based therapy
than patients with other cytogenetic abnormalities. Rituximab is a chimeric murine monoclonal antibody that targets the
However, the benefit of fludarabine does not apply to patients older CD20 antigen on the surface of normal and malignant B-lymphocytes,
than the age of 65 years. A phase III trial by the German CLL Study and is the best studied and most widely used monoclonal antibody
Group randomized 193 previously untreated CLL patients older than for the treatment of CLL and B-NHL. CD20, a calcium channel that
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65 years to fludarabine 25 mg/m IV for 5 days every 28 days for six interacts with the BCR complex, is an ideal target, because CD20 is
cycles or chlorambucil 0.4–0.8 mg/kg PO every 15 days for 12 months. expressed in 90% to 100% of cases of CLL and B-NHL and is only
Fludarabine achieved higher OR (72% vs. 51%) and CR rates (7% vs. minimally internalized or shed. Rituximab induces antibody-
0%) and longer time to treatment failure (19 vs. 18 months). However, dependent cellular cytotoxicity (ADCC) and complement-dependent
PFS was similar in both arms (19 months vs. 18 months), and OS was cytotoxicity (CDC), activates caspase 3, and induces apoptosis in
46 months for fludarabine compared with 64 months for chlorambucil CLL and B-NHL cells. These multiple mechanisms of action likely
arm (p = .15). Thus, the results achieved in younger patients do not contribute to rituximab’s effectiveness in CLL.
necessarily apply to older patients with comorbid diseases or who In phase I clinical studies in indolent B-NHL rituximab, 375 mg/
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otherwise cannot tolerate more aggressive therapies. m IV was administered weekly for four doses, although the dose and
length of treatment were empirically determined. The pivotal phase
Combining Fludarabine With Alkylating II trial of rituximab was pursued in 166 patients with relapsed or
refractory indolent B-NHL, including SLL. Although an ORR of
Agent Therapy 60% was achieved in indolent follicle center B-NHL, only four of
30 patients (13%) with SLL/CLL responded. Similarly, disappointing
Fludarabine was combined with cyclophosphamide (Flu/Cy) in three results were obtained in several other small studies. Responses in each
randomized phase III studies, based on two promising pilot studies of these studies were predominantly in the blood and nodal