331Personalized Management of Chronic Lymphocytic Leukemia
Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western
world with the majority of cases occurring in patients over the age of 55. It usually
progresses slowly and is characterized by the accumulation of lymphocytes, which
can overwhelm the bone marrow and invade the blood stream, eventually spreading
to the spleen, liver and other solid organs. CLL, however, has a highly variable clini-
cal course: slowly progressive in some, whereas others have an aggressive disease.
In the last quarter of twentieth century, prognosis and treatment decisions were
based on clinical staging systems. In the twenty-fi rst century, biomarkers have
enabled a more refi ned prognostic stratifi cation. In spite of advances in whole
genome sequencing, CLL is not associated with a specifi c genetic abnormality.
However, B cell receptor signaling, which may be constitutively expressed, antigen-
induced, or both, plays a critical role in driving cell proliferation in CLL and their
survival through the cascade of protein kinases. Elimination of CLL to an extremely
low level may improve the overall and treatment-free survival. Patients with no
detectable CLL cells after receiving Campath (alemtuzumab) usually survive for
5 years. CLL patients who relapse from or are refractory to chemotherapy have the
poorest prognosis with a median survival of 10 m. A test to detect MRD in patients
with B cell CLL to complement the treatment with Campath ® is an example of com-
bining diagnostics with therapy to improve the treatment.
The pathognomonic genetic alteration in CML is the formation of the BCR-
ABL1 fusion gene, which produces a constitutively active tyrosine kinase (TK) that
drives leukemic transformation. Targeted TK inhibitor treatment with imatinib,
nilotinib, dasatinib, bosutinib, and ponatinib is the cornerstone of modern therapy
for this hematologic malignancy. Ibrutinib, an oral inhibitor, has shown activity in a
small series of patients with relapsed or refractory CLL or small lymphocytic lym-
phoma (Advani et al. 2013 ). In a phase Ib clinical trial, ibrutinib was associated with
a high frequency of durable remissions in patients with relapsed or refractory CLL
and small lymphocytic lymphoma, including patients with high-risk genetic lesions
(Byrd et al. 2013 ). This is an example of trend in management of hematologic can-
cers, which is shifting from a chemotherapy-based approach to treatments aimed at
mechanisms of disease. New prognostic subgroups in CLL based on integrated
mutational and cytogenetic analysis are (Rossi et al. 2013 ):
- High risk (10-years survival <30 %): TP53 abnormalities, BIRC3 abnormalities,
or both. - Intermediate risk: NOTCH1 mutations, SF3B1 mutations, or both, with or with-
out 11q22.3 deletion. - Low risk: trisomy 12 or normal cytogenetic profi le.
- Very low risk (10-years survival ~70 %): 13q14 deletion only.
RT-qPCR of BCR-ABL1 RNA is a necessary laboratory technique for monitor-
ing the effi cacy of TK inhibitor therapy and quantitatively assessing MRD. The
molecular response measured by BCR-ABL1 RT-qPCR assists in identifying sub-
optimal responses and can help the decision to switch to alternative therapies that
Personalized Management of Cancers of Various Organs