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Chapter 77 Chronic Lymphocytic Leukemia 1261

6 months of completing such a regimen. Several retrospective studies clone may arise from the bone or an extranodal site. Laboratory
have documented a short survival time (9–12 months) and a particu- abnormalities including anemia, neutropenia, and thrombocytopenia
larly high frequency of both bacterial and opportunistic infections in which may be caused by large-cell transformation in the BM. A rapid
this patient population. With the introduction of chemoimmuno- increase in the serum LDH is seen in the majority of patients. The
therapy as initial therapy, another poor prognostic group includes diagnosis is generally made after examining the histology of a rapidly
patients relapsing within 2 years of FCR- or FR-based therapy. These enlarging lymph node, which typically reveals large-cell lymphoma.
patients have a significantly shorter PFS with subsequent therapies. PET scans can be helpful in these patients to localize the most hyper-
Other therapeutic agents such as bendamustine, ofatumumab, and metabolic node for biopsy. Historically, RS has been treated with regi-
alemtuzumab have been evaluated in this setting and have modest mens similar to those used for the treatment of large-cell lymphomas
activity and produce relatively short remissions. Newer kinase inhibi- involving multiple agents such as methotrexate, doxorubicin, cyclo-
tors have resulted in impressive responses and PFS and are the recom- phosphamide, vincristine, prednisone, bleomycin, dexamethasone,
mended therapeutic option for the vast majority of patients with cytarabine, and cisplatin (e.g., methotrexate with leucovorin rescue,
relapsed disease. Currently there is no consensus about the manage- doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomy-
ment of patients relapsing after kinase inhibitor therapy and these cin [MACOP-B], CHOP-B, dexamethasone, high-dose cytarabine
patients should be considered for participation on clinical trials. The [ara-C], and cisplatin [Platinol] and vincristine, doxorubicin, dexa-
complexities of complications, poor therapeutic options, and acute methasone [VAD]) in combination with rituximab. Other regimens
features of this advanced form of CLL can put great strain on the incorporating oxaliplatin have been reported, although their benefit
patient, family members, and general hematologist alike. Referral of in RS is uncertain over traditional lymphoma regimens. Our institu-
such patients to tertiary CLL centers for access to clinical trials and tion prefers dose-adjusted infusional therapy (R-EPOCH) for the
treatment of these specialized needs should be considered for patients initial treatment of these patients. The duration of response and the
with fludarabine-refractory, short remission after chemoimmuno- OS rates are dismal, with most patients likely to die within 6 months
therapy and relapsed disease after kinase inhibitors. of their diagnosis despite aggressive therapy. Long-term remissions and
survival have been reported in a few patients after allogeneic SCT, but
this approach is associated with a high TRM. When Richter transfor-
Patients Relapsing After Kinase Inhibitors mation occurs, treatment on a clinical trial and consolidation with
allogeneic SCT is the preferred treatment.
The use of kinase inhibitors has significantly transformed the man- Similar to RS, prolymphocytic transformation (PT) occurs in fewer
agement of CLL, and patients are now experiencing prolonged than 10% of patients with CLL. PT is characterized by the appearance
progression-free intervals. Less than 5% of patients with previously of large, immature prolymphocytes in the peripheral blood, which
untreated disease who have been treated with ibrutinib in the front- make up >55% of the peripheral circulating malignant lymphoid cells.
line setting have experienced disease progression at 3-years of These patients may be older with advanced disease and have more
follow-up. However, a larger proportion of patients have disease pronounced lymphadenopathy and splenomegaly. PT is associated
progression when they were treated with either ibrutinib or idelalisib with a poor outcome, with limited survival beyond 1 year. These
in the relapsed setting. The majority of these patients have high-risk patients often have del(17p13.1) but do appear to respond to many of
disease and have failed prior chemoimmunotherapy based treatments. the newer therapies coming forward for treatment of CLL. Allogeneic
Moreover, patients also experience transient disease flares if they have SCT may also be used as a potentially curative therapeutic option.
to temporarily hold therapy for routine surgical or unrelated medical Hodgkin lymphoma can also manifest as a form of RS and may
procedures. There is limited data to guide management of these have a better outcome provided patients are treated appropriately.
patients and multiple trials are currently underway to address these Identification of this diagnosis can sometimes be challenging because
issues. Early experience with these patients indicate that switching of its localization to the bone marrow, lower standardized uptake value
kinase inhibitors for progressive disease is a feasible option in a subset (SUV) readings on PET scan, and also more insidious onset as com-
of these patients. Similarly, there is no direct comparative data pared with the diffuse large B-cell lymphoma (DLBCL) presentation
comparing the efficacy of these agents and a formal recommendation of RS. Hodgkin lymphoma disease in the setting of CLL can be treated
cannot be made regarding the choice for initial kinase inhibitor as de novo disease with some individuals attaining long-term remis-
therapy. Therapy should be tailored to patient needs and comorbid sions. Unlike DLBCL transformation of CLL to RS where reduced
conditions and special consideration should be made for patients who intensity allogeneic SCT is recommended, we generally do not pursue
require long-term anticoagulation in which idelalisib might be a this in individuals with Hodgkin lymphoma transformation.
better option, and for patients with lung, liver, or gastrointestinal
issues in whom ibrutinib might be more suitable.
Secondary Malignancies in Chronic
Lymphocytic Leukemia
Richter Syndrome
Chronic lymphocytic leukemia is associated with an increased risk
Richter syndrome (RS), the development of high-grade lymphoma in of secondary malignancies. These include not only hematologic
patients with CLL, was described by Maurice Richter in 1928. Over malignancies such as MDS and AML associated with the use of che-
the years, the classification of RS has expanded to include lymphoid motherapeutic agents but also solid tumors such as Kaposi sarcoma,
malignancies such as Hodgkin disease, lymphoblastic lymphoma, malignant melanoma, and laryngeal and lung cancers. The increased
PLL, and hairy cell leukemia (see Fig. 77.4A–C). Incidence estimates incidence of secondary malignancies may be attributable to multiple
range from 2.8% to 10.7%. Recent studies have suggested that the reasons, including the immune dysfunction associated with CLL, the
development of RS may be related to the evolution of an abnormal frequent infectious complications, the carcinogenic side effects of the
clone unrelated to the underlying CLL clone. Clearly identifiable risk various chemotherapeutic agents, and the increased and close medical
factors for the development of RS are lacking, and its development surveillance that patients with CLL receive from trained oncologists.
has been shown to be independent of disease stage, duration of disease,
type of therapy, or response to therapy. However, the presence of
diffuse lymphomatous involvement, advanced Rai stage, IGHV- Hypersensitivity in Chronic Lymphocytic Leukemia to
unmutated disease, ZAP-70 expression, high LDH, del(17p13.1), Mosquitoes and Insect Bites and Treatment
high serum β 2 M levels, and recently NOTCH1 mutations may predict
the development of RS. RS is characterized by sudden onset of B Patients with chronic lymphocytic leukemia commonly exhibit an
symptoms (fever, night sweats, weight loss) and rapidly progressive exaggerated cutaneous response to insect bites. This was first reported
lymphadenopathy at any anatomic site. Rarely, the lymphomatous in 1965 by Robert Weed, who documented a hypersensitivity