Page 1406 - Hematology_ Basic Principles and Practice ( PDFDrive )

1252 Part VII Hematologic Malignancies

OS (94 vs. 346 months) as compared with those without transloca- How Should Staging and Biomarkers Be Used for Treatment Decisions
tions. The frequency of such translocations in untreated patients is in Chronic Lymphocytic Leukemia Patients?
less common, suggesting that such transactions accumulate with
disease progression. Our understanding of the biology of CLL has improved dramatically,
Given the limitation of standard or stimulated karyotype analysis, and many relevant biomarkers are now available for predicting when
interphase FISH has become the state-of-the-art technique for CLL patients will clinically progress. However, no study to date has
accurately distinguishing genetic subtypes of CLL. The largest study demonstrated that earlier treatment will alter the natural history of
of interphase FISH resulted in improved sensitivity to detect partial the patient in even the higher risk groups with high progression rates.
trisomies (12q12, 3q27, 8q24), deletions (13q14, 11q22-23, 6q21, Therefore, at the present time, the use of staging and predictive
6q27, 17p13), and translocations (band 14q32) in more than 80% biomarkers should be used only to provide patients with information
of all cases. In a large study of 325 patients by Dohner and colleagues, relative to the expected course of their disease. Outside of a clinical
trial, these results should never be used to initiate therapy in patients
a hierarchical model consisting of five cytogenetic subgroups was with asymptomatic disease or as an indication for treatment. Before
constructed on the basis of regression analysis of CLL patients with performing predictive tests, a detailed discussion with the patient of how
chromosomal aberrations. Patients with a 17p deletion had the short- these tests will be used should occur and the option of not performing
est median survival time (32 months) and the shortest treatment-free them should be provided. In a subset of patients, significant anxiety can
interval (TFI, months); patients with an 11q deletion followed closely be produced by identifying high-risk features for which observation,
with 79 months and 13 months, respectively. Whereas the favorable without therapeutic intervention, remains the standard of care. Table
13q14 deletion group had a long TFI of 92 months and a median 77.4 provides an example of the initial evaluation provided by our group
survival of 133 months, the group without detectable chromosomal when seeing a newly diagnosed patient. Because lymphocyte-doubling
anomalies and those with trisomy 12 fell into the intermediate group time is a prognostic feature in the progression of CLL, our approach
is to follow patients every 3 months during the first year following
with median survival of 111 and 114 months, respectively, and TFI diagnosis; if little change in clinical or laboratory parameters occurs at
of 33 and 49 months, respectively. According to this pivotal study, this point, we extend this time period to every 6 months in the absence
CLL patients are prioritized in a hierarchical order (deletion 17p13 of new complaints.
> deletion 11q22-q23 > trisomy 12 > no aberration > deletion
13q14). The hierarchical model of cytogenetic abnormalities in
predicting disease progression by FISH has been further confirmed
by other studies. Of interest, patients with high-risk interphase deferred (41.6%). Thus, patients with asymptomatic or early-stage
cytogenetic abnormalities or other complex abnormalities are almost disease derive no therapeutic benefit from early alkylating agent
always found to have IGHV-unmutated CLL. therapy. However, in these studies, chlorambucil was administered as
initial therapy, and chlorambucil achieves complete response (CR) in
few patients. Similarly, fludarabine when used early for patients who
Mutational Analysis do not meet the conventional criteria for treatment resulted in higher
response rate but failed to demonstrate a survival advantage. A
Numerous recurrent mutations and or deletions have been described recently completed trial from the German CLL study group of high
in CLL that are often associated with IGHV mutational status. While risk CLL patients did not demonstrate an advantage of even more
the majority of these mutations do not impact the clinical outcome aggressive chemoimmunotherapy with fludarabine, cyclophospha-
of CLL patients, several including p53, ATM, NOTCH1, SF3B1, mide, and rituximab in improving overall survival. It is now well-
XPO1, and BIRC3 have been shown to predict time to initiation of established that CLL undergoes genetic clonal evolution over time
treatment and also overall survival. Outside of p53 mutations, the with greater frequency in IGHV-unmutated CLL, resulting in
frequency of these mutations are often low and therefore prevent increasing resistance to therapy. Thus, the issue of early treatment
definitive independent determination of their impact on outcome needs to be reconsidered, particularly in patients with high-risk
with respect to other features. The presence of several other mutations biological or molecular markers predicting a poor long-term progno-
including ERK1, BRAF, and MYD88 have served as a rationale for sis, such as IGHV-unmutated disease and especially with the advent
therapeutic targeting with novel agents that are U.S Food and Drug of kinase inhibitors that may be associated with limited toxicities.
Administration (FDA) approved or are being evaluated in clinical To establish uniform clinical practice standards and ensure repro-
trials. However, none of these drugs have been shown to be effective ducible eligibility criteria for entrance into clinical studies, the
in CLL. Despite routine mutational tests being available, it is not our IWCLL established guidelines for initiation of treatment. Indications
practice to examine these broadly at diagnosis or at time of treatment. to begin therapy included nonautoimmune cytopenias (Rai stage III
The exception to this is p53 mutations for which there may be value and IV), bulky or symptomatic lymphadenopathy or hepatospleno-
although their independence of del(17)(p13.1) as a negative bio- megaly, disease-related B symptoms or fatigue, extreme lymphocytosis
9
marker has only rarely been demonstrated because of the common (>300 × 10 /L) or a rapid lymphocyte-doubling time, and auto-
association of these two aberrations. immune hemolytic anemia (AIHA) or thrombocytopenia not con-
trolled with steroids. A rapidly rising lymphocyte doubling time was
TREATMENT recently removed from the National Comprehensive Cancer Network
(NCCN) criteria as an indication to treat as it commits many patients
Initiation of Treatment of Newly Diagnosed or to earlier intervention, which may not be necessary in the absence of
other symptoms. It is imperative to determine if a patient’s symptoms
Previously Untreated Patients are attributable to CLL or a comorbid medical condition because
constitutional symptoms such as fatigue are nonspecific and can be
Many patients are incidentally diagnosed with CLL on routine attributed to many causes in elderly patients with comorbid illnesses.
complete blood count examination and are asymptomatic with a In addition to the official IWCLL 2008 criteria for therapy, an
normal hemoglobin and platelet count at the time of initial diagnosis. increasing frequency of infections and slowly progressive anemia are
Expectant observation without therapy is the standard practice for other indications that can aid the practicing physician in deciding
such asymptomatic patients, and patients receive treatment only when to initiate therapy in patients with CLL. A summary of the
when their disease progresses. This practice is based on several studies IWCLL 2008 guidelines for treatment is provided in Table 77.5 with
that failed to show an improvement in OS when early therapeutic some minimal modifications used by our group.
intervention with chlorambucil was administered to asymptomatic A useful paradigm for clinical practice is to institute treatment in
patients. A metaanalysis of 2048 patients participating in six trials CLL only for cytopenias or directly referable symptoms. When treat-
demonstrated no difference in death rate between patients who were ment is necessary, a variety of agents have been examined in clinical
randomized to early therapy (42.6%) and those with treatment trials (outlined below). Previously identified biomarkers are used in