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1534 Part XI: Malignant Lymphoid Diseases Chapter 92: Chronic Lymphocytic Leukemia 1535

DEVELOPMENT OF CHEMOTHERAPY FOR However, PFS and OS advantage was not shown in another randomized
THE TREATMENT OF CHRONIC LYMPHOCYTIC trial of elderly patients older than age 70 years treated with fludarabine
on chlorambucil despite the higher overall and complete response (CR)
LEUKEMIA rate in the fludarabine-treated patients. 174
Alkylating Agents The use of fludarabine and similar nucleoside analogues is associ-
Chlorambucil has been used as the prominent alkylating agent for the ated with significant hematologic and immunologic toxicities. Patients
treatment of CLL for the last 60 years. Chlorambucil is taken orally and can experience prolonged cytopenias and especially neutropenia, which
is generally well-tolerated but does have multiple side effects, includ- can result in a significant increase in the risk of infectious complica-
ing nausea, vomiting, and cytopenias. Various doses and schedules tions. These drugs are also exquisitely toxic to T cells, especially to
have been used with different responses and tolerability profiles. Older CD4+ T cells. This effect may last for an extended period of time and
studies compared chlorambucil to conventional high-grade lymphoma predisposes patients to acquiring opportunistic infections. 175,176 Neuro-
therapy, including cyclophosphamide, vincristine, and prednisone logic toxicities have also been observed in patients receiving the usual
177
(CVP) and cyclophosphamide, doxorubicin, vincristine, and predni- dose of fludarabine. Patients treated with fludarabine occasionally
sone (CHOP), and found no improvement in survival outcomes with develop autoimmune hemolytic anemia. In this situation, further use of
the use of high-grade lymphoma-like therapies. Multiple doses of fludarabine is contraindicated. 178–180 Fludarabine is also poorly tolerated
159
chlorambucil have been evaluated in various clinical trials with differing in patients with compromised renal function as a significant percentage
but similarly modest overall response rate (ORR) and PFS. No single- of the metabolites are cleared via the renal system. Hemodialysis is a
dosing regimen has been shown to be superior to another. One dosing useful tool to limit fludarabine toxicity in patients who develop acute
181
regimen that has been used in cooperative group studies is 40 mg/m oral renal failure while receiving treatment. Moreover, fludarabine treat-
2
dose every 28 days for 12 cycles. An argument, however, can be made ment in patients older than age 65 years was poorly tolerated and did
163
that escalating the dose of chlorambucil in younger patients might not result in improvements in PFS and resulted in a trend toward infe-
result in a higher response rate. Despite its ease of use and reasonable rior OS outcome when compared to chlorambucil. 174
164
tolerability, chlorambucil is not very commonly used today because of Other nucleoside analogues used in the treatment CLL include
the availability of better and potentially safer alternatives. Moreover, cladribine and pentostatin which have similar outcomes and toxicities
responses observed with chlorambucil are modest and not durable. as fludarabine. 182–185 A phase III trial comparing fludarabine, cladrib-
165
Nevertheless, chlorambucil is potentially an option for treatment of ine, and chlorambucil showed similar ORR and CR rate with all three
elderly patients with multiple comorbidities and limited other options agents, but median PFS was superior with cladribine (25 months) versus
186
for treatment. It should, however, not be used for asymptomatic patients 10 and 9 months with fludarabine and chlorambucil, respectively. No
with early stage disease. 160 advantages, however, were observed in OS. Cytarabine has also shown
Cyclophosphamide is also approved for the use in patients with modest activity, especially in combination with oxaliplatin, fludarabine,
CLL and has moderate efficacy and reasonable tolerability. Care should and rituximab (OFAR regimen) in patients with refractory disease and
be taken to avoid nighttime dosing and aggressive hydration should patients with Richter transformation. 187,188
encouraged to avoid hemorrhagic cystitis. Low-dose etoposide, either
166
as a single agent or in combination with cladribine, also shows modest COMBINATION CHEMOTHERAPY
responses in patients with relapsed and refractory disease. Treatment Multiple chemotherapeutic combinations have been studied in patients
with etoposide is associated with significant myelosuppression and with CLL. One of the earlier combinations to be used was chlorambucil
resultant infectious complications. 167,168 and prednisone with ORR of approximately 80 percent with CR rates
Bendamustine was approved for the treatment of patients with CLL of approximately 10 to 15 percent. 165,189 This regimen was also found
in 2008. This was based on a phase III trial that demonstrated the supe- to be as effective as other combination regimens like CVP, cyclophos-
rior efficacy of bendamustine as compared to chlorambucil with regards phamide, melphalan, and prednisone (CMP), CAP, or CHOP. 159,190–192
to response rate and PFS. Structurally, bendamustine has features A meta-analysis comparing lymphoma-like combination therapies found
169
common with alkylating agents and purine analogues, but its activity no improvements in survival outcomes over chlorambucil alone.
159
is primarily derived from the alkylating agent moiety. Bendamustine High-dose combination therapies like CAP, CHOP, and CVP have no
170
appears to be generally better tolerated than fludarabine but causes role in the routine management of patients with CLL.
significant myelosuppression, requiring dose reductions, especially in Given the improvement in outcomes with single-agent fludarabine
elderly and infirm. Tolerability is better in patients with impaired renal as compared to chlorambucil, multiple combinations were developed
function since excretion is primarily through the feces. 171 with fludarabine to improve on its efficacy. Both the combination of
fludarabine and chlorambucil and fludarabine and prednisone were
Nucleoside Analogues found to be similar to fludarabine and not developed further. 172,193,194
Nucleoside analogues have also been used for the treatment of patients Fludarabine was combined with cyclophosphamide (FC) and resulted
with CLL for the last 25 to 30 years. Fludarabine has been the most com- in encouraging responses even in patients with heavily pretreated dis-
195
monly used agent from this class of drugs. Fludarabine has moderate ease. Multiple phase III trials were subsequently conducted in pre-
activity especially in the younger patients with good nutritional status dominantly younger patients, comparing fludarabine with FC and
and with untreated, early stage disease. After demonstrating prom- revealed an ORR of 74 to 94 percent with CR rates of 23 to 38 percent
172
ising activity as a single agent in early phase clinical trials, fludarabine and median PFS of 33 to 48 months, all significantly better with the
was compared to chlorambucil in a randomized phase III study for the combination. 87,196,197 Early toxicities were mostly related to cytopenias
initial treatment of patients with CLL. Patients treated with fludarabine secondary to myelosuppression and the resultant increase in infectious
demonstrated improvement in PFS and OS compared to chlorambucil, complications resulted in a slight dose adjustment and a dose of flu-
2
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albeit with a higher rate of infectious complications; however, all patients darabine 25 to 30 mg/m for 3 days and cyclophosphamide 250 mg/m
163
ultimately had recurrent disease. Similar to chlorambucil, fludarabine for 3 days every 28 days for six cycles was used for subsequent studies.
was also more effective compared to combination chemotherapy regi- Notably, the combination of FC was the first regimen that was able to
173
mens like cyclophosphamide, doxorubicin, and prednisone (CAP). overcome the adverse prognostic impact of del 11q. 86

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