NcXHF

MANAGEMENT OF CLL
Up-Front Management of Advanced Stage, Symptomatic
Patients with an Indication for Treatment
Conventional chemoimmunotherapy regimens. The current
up-front standard of care in physically fıt patients with CLL
who require treatment based on IWCLL criteria 1 is fludarabine,
cyclophosphamide, and rituximab (FCR; Fig. 1). 17,18,23
This is based on high response rates (40% to 50% complete
response [CR]), prolongation of median progression-free
survival (PFS), and, notably, median overall survival (OS)
compared with FC. However, many patients with CLL cannot
tolerate FCR because of age (e.g., age 65 to 70), decreased
fıtness (e.g., Cumulative Illness Rating Scale [CIRS]
score 6) and decreased renal function (e.g., creatinine
clearance 30 to 50 mL/min). In these patients, recent trials
have suggested that other regimens could be more tolerable.
The German CLL Study Group (GCLLSG) CLL10 study
compared FCR versus bendamustine/rituximab (BR) among
fıt (CIRS 6, creatinine clearance 70 mL/min) patients
without 17p-, and showed that overall BR was inferior to FCR
in terms of response rate and PFS. 24 However, FCR was associated
with markedly increased toxicity without substantially
better outcomes in patients over age 65, suggesting that
BR is a reasonable alternative treatment for this population.
There are now new monoclonal antibody–based treatment
options for patients who are not considered fıt for FCR-type
KEY POINTS
Careful observation for disease progression and
complications, together with appropriate preventative
interventions, remains the standard of care for patients
with early-stage, asymptomatic, chronic lymphocytic
leukemia. Patients with very high-risk chronic lymphocytic
leukemia should not receive treatment until they meet
standard criteria for progressive disease.
The most critical determinants of treatment choice are the
presence of 17p-/TP53mut, physical fitness/age, and
duration of prior response in patients who have received
previous treatment. In addition, 17p-/TP53mut analysis
should be repeated before initiation of therapy.
The combination of anti-CD20 antibody (rituximab,
ofatumumab, or obinutuzumab) and chemotherapy (FC,
bendamustine, or chlorambucil) is the standard up-front
treatment for the majority of patients with chronic
lymphocytic leukemia, with the specific choice of agents
mostly determined by fitness of the patient. Based on the
dramatic efficacy and favorable toxicity profile of the BCR
and BCL2 inhibitors compared with historic
chemoimmunotherapy regimens, these agents are the
preferred treatment approach for very high-risk chronic
lymphocytic leukemia (17p-/TP53mut and early relapse).
Ongoing and future clinical trials are essential to further
improve treatment efficacy, determine treatment duration,
and eventually develop curative therapy.
The role of allogeneic stem cell transplant in the management
of chronic lymphocytic leukemia requires careful and early
discussion in patients who are very high-risk.
treatment. Ofatumumab in combination with bendamustine
or chlorambucil was licensed based on the randomized,
phase III COMPLEMENT-1 trial that compared chlorambucil
with ofatumumab/chlorambucil and showed substantially
higher effıcacy with only moderately increased toxicity
for the combination therapy. 25 The phase III CLL11 trial
compared chlorambucil, rituximab/chlorambucil, and obinutuzumab/chlorambucil
in a three-arm design. Obinutuzumab/chlorambucil
showed higher effıcacy compared with
both chlorambucil and rituximab/chlorambucil with an acceptable
safety profıle, which led to the approval of obinutuzumab/chlorambucil
for the up-front treatment of patients
with CLL who are less fıt. 26 Therefore, the combination of
anti-CD20 antibody (rituximab, ofatumumab, or obinutuzumab)
and chemotherapy (FC, bendamustine, or chlorambucil)
is the standard up-front treatment for the vast majority
of patients with CLL.
Initial therapy of patients with 17P-/TP53mut. Patients with
17p-/TP53mut CLL have markedly inferior outcomes with
both chemotherapy and chemoimmunotherapy. 6,16,18,19,27 In
the subset of patients with 17p- CLL enrolled in the randomized
CLL8 study that compared FC with FCR, FCR was superior
in terms of overall response rate (ORR, 68% for FCR
vs. 34% for FC; p 0.03) and PFS (median 11.3 months for
FCR vs. 6.5 months for FC; p 0.02), but there was no difference
in complete remission rates (CRR, 5% for FCR vs. 0%
for FC) or 3-year OS (38% for FCR vs. 37% for FC). 18,27
TP53mut and 17p- were the two markers that had the strongest
independent effect on PFS and OS in a multivariable
analysis after FC and FCR treatment. 27 These unacceptable
outcome data were clearly inferior to all other disease subgroups.
In the British CLL4 trial, TP53 mutation was identifıed
as an adverse prognostic marker after treatment with
chlorambucil, fludarabine, and FC. 19 These fındings of inferior
response and poor prognosis are supported by the reported
results for 17p- patients undergoing initial treatment
of active CLL in studies conducted by MD Anderson Cancer
Center/Mayo Clinic, 22 the Spanish Group for CLL, 28 and the
Memorial Sloan Kettering Cancer Center 29 which showed
that only about 25% of patients with 17p- CLL achieve remissions
of 3 years or longer after treatment with purine analog–
containing chemoimmunotherapy.
There is limited data on bendamustine containing chemoimmunotherapy
for the fırst-line treatment of patients CLL
with 17p-. The GCLLSG CLL2M phase II study of front-line
BR enrolled only eight patients with 17p- CLL, of which three
responded; all responses were partial, and the median PFS
was only 7.9 months. 30 Therefore, BR is likely inferior to FCR
as initial therapy in 17p- CLL. In the relapsed/refractory setting,
both FCR and BR were unsatisfactory, with response
rates of 35% and 7%, respectively, and median PFS of 5
months and 7 months, respectively.
The value of using other recurrently mutated genes in the
defınition of high-risk disease and the treatment of patients
with CLL is less well defıned. There is data from heteroge-
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK 165