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1540 Part XI: Malignant Lymphoid Diseases Chapter 92: Chronic Lymphocytic Leukemia 1541

RADIATION interval as compared to people with a more conventional partial
Involved field radiation therapy is an extremely useful treatment modal- remission. 275
ity for the management of locally symptomatic lymphadenopathy and
isolated Richter transformation. Splenic irradiation can be used in EVALUATION FOR MINIMAL RESIDUAL
patients with symptomatic splenomegaly, but its efficacy is limited and
short-lived with significant and sometimes prolonged myelosuppres- DISEASE
sion. 332–334 Systemic radiation or extracorporeal photopheresis has no CLL is currently considered incurable, but a subset of patients who
role in the routine management of patients with CLL. 335–337 achieve a complete remission will have undetectable disease even after
using highly sensitive techniques. The evaluation for MRD is now
LEUKAPHERESIS fairly well established and can be performed by either flow cytome-
try or allele-specific oligonucleotide polymerase chain reaction–based
Patients with CLL will very rarely experience hyperviscosity-related methods. 342–345 Both these tests have excellent comparable sensitivity and
signs and symptoms secondary to hyperleukocytosis. However, this are able to identify one leukemia cell in 10,000 leukocytes. These tests
343
modality can be used for the occasional patient who becomes symp- can be performed on blood but sensitivity is higher when performed on
tomatic from hyperleukocytosis. When this is initiated, it should be marrow aspirate, especially with the current use of monoclonal antibod-
performed in conjunction conventional therapy, to cytoreduce the CLL. ies that are able to effectively clear the circulating blood of the disease
Leukapheresis has been used in the past for patients with refractory but are not equally effective in eliminating disease from the marrow or
disease as a therapeutic option, but it results in modest and transient lymph nodes. Patients with MRD-negative disease at the completion
benefits. 338–340 With the advent of modern therapeutic options, the role of therapy experience longer treatment-free and OS periods. 346,347 This
of leukapheresis is limited in the management of routine CLL patients advantage in outcomes has been shown both for chemotherapy-based
with hyperleukocytosis. While the BCR signaling agents can cause pro- regimens and for regimens based primarily on antibodies. 262,347 The
found hyperleukocytosis in some patients, it virtually never results in utility of MRD assessment in the era of kinase inhibitors is currently
symptoms mandating leukapheresis. under discussion as kinase inhibitors are not typically able to induce
deep remissions as monotherapy in the majority of patients with short
followup. MRD assessment, however, can be used as a surrogate for
ASSESSMENT OF RESPONSE survival outcomes and to potentially develop a stopping rule for kinase
inhibitor-based combination approaches.
Patients who complete therapy should be assessed for response. This
involves performing a detailed history for any disease-related symp-
toms, physical examination for any palpable lymphadenopathy, and RECOMMENDATIONS FOR TREATMENT
laboratory studies to evaluate for persistent cytopenias or leukocytosis.
Outside of a clinical trial, if the patient fails to have a CR on routine OF PATIENTS WITH UNTREATED DISEASE
history, physical evaluation, and blood counts, then a CT scan and a All patients should be offered therapy on a clinical trial whenever possi-
marrow biopsy have limited utility. However, if the patient does achieve ble. This is increasingly important as therapy for CLL is evolving rapidly
a CR on clinical and laboratory evaluation, we recommend proceeding and clinical trials are required to answer the multiple questions regard-
with a CT scan of the chest, abdomen, and pelvis with contrast, along ing the best possible therapeutic option. For patients being treated off-
with a marrow aspirate and biopsy in the event that the CT scan is neg- trial, we recommend discussion of the potential risks and benefits of
ative. These patients should undergo evaluation for MRD assessment chemoimmunotherapy with FCR, particularly when low-risk disease
on the marrow aspirate. Formal response criteria for disease evalua- is present (e.g., IGHV mutated disease) that might result in prolonged
tion were revised with the advent of kinase inhibitors. Conventionally, remission. For those with IGHV unmutated disease, chemoimmuno-
patients with no evidence of disease on CT scan and marrow biopsy therapy with FCR or alternative non–chemotherapy-based regimens are
with complete hematologic count recovery would be classified as a considered. For patients older than age 65 years and those with multiple
complete remission. Patients with a CR but with persistent cytopenias comorbid conditions or renal insufficiency, we recommend therapy with
that are related to drug toxicity are classified as having CR with incom- either obinutuzumab or ofatumumab with chlorambucil. Younger and
plete count recovery (CRi). These are also detailed in the IWCLL-2008 healthier patients can be treated with chemoimmunotherapy. Patients
1
criteria. Evaluation of the marrow aspirate and biopsy is also useful in with del 17p should be treated with ibrutinib in the first-line setting.
assessing the etiology of cytopenias that can be seen frequently after
chemotherapy use. We recommend waiting until count recovery or
3 to 6 months after chemotherapy to repeat a marrow biopsy for persis- RECOMMENDATIONS FOR TREATMENT
tent cytopenias. Occasionally, patients will have no evidence of disease OF PATIENTS WITH RELAPSED DISEASE
on flow cytometry of the aspirate or on the biopsy specimen but may
have nodular lymphoid aggregates. If these aggregates are confirmed Patients who relapse after conventional chemoimmunotherapy-based
to be consistent with a collection of CLL cells by immunohistochem- approaches should, in most cases, be treated with ibrutinib unless a
ical studies, then these patients should be classified as having a nodu- need for chronic anticoagulation with warfarin (Coumadin) is required.
lar PR. Given the advent of kinase inhibitors, the response criteria are In such settings, treatment with idelalisib with or without rituximab
undergoing significant modifications especially because most patients should be considered. With both ibrutinib and idelalisib, the benefit
will not experience traditional responses as observed with chemother- of adding rituximab at this time is not known. Repeating a different
apy use despite having similar or even better outcomes. This is espe- chemoimmunotherapy regimen is also an option in younger and oth-
341
cially evident in patients with PR+L after kinase inhibitor therapy with erwise healthy patients, but is associated with higher toxicity and risk
ibrutinib who demonstrate significant and sustained improvement in of secondary neoplasms. Patients who relapse after one kinase inhibitor
clinical signs and symptoms related to CLL and in lymphadenopathy should be treated with the other and referred to a specialized center for
and organomegaly and potentially may have a longer progression-free clinical trial participation on subsequent relapses.

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