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

SECONDARY CANCER RISK WITH to protein-conjugated vaccines can be modestly augmented with con-
Protein-conjugated
comitant use of antihistamine (H ) blockers.
366–369
CHRONIC LYMPHOCYTIC LEUKEMIA vaccines also appear to be more immunogenic than polysaccharide
2
vaccines. In the absence of definitive data of the use of vaccines in
Patients with CLL have a significantly higher risk of developing a sec- CLL we recommend following the adult immunization schedule for
ondary malignancy. This includes cancers of the skin, connective tissue immunocompromised adults for 2014, recommended by the Advisory
and peripheral nerves, eye, lip and oral cavity, lung, kidney, colorectal, Committee on Immunization Practices. This includes annual influenza
prostate, breast, and genitourinary cancers. Skin cancer is one of the vaccine and pneumococcal 13-valent conjugate (PCV-13) vaccine. 370–372
348
most common cancers seen in patients with CLL. 349–351 This includes Vaccination with live virus vaccines including the zoster, varicella and
basal cell carcinoma, squamous cell carcinoma, cutaneous melanoma, measles, mumps, and rubella (MMR) vaccine are contraindicated in
and Merkel cell carcinoma. Patients with skin cancers also appear to patients with CLL. 372
have a worse prognosis from their melanoma and Merkel cell cancer if The routine of use of granulocyte colony-stimulating factor
they also have a concomitant CLL history. 348,352 This is also true for solid (G-CSF) for patients with CLL is not recommended. G-CSF and gran-
tumors, as patients with breast, colorectal, prostate, lung, and kidney ulocyte-macrophage colony-stimulating factor (GM-CSF) can be used
cancers have an inferior prognosis if they have a preexisting diagno- to treat therapy-related neutropenia and for patients with febrile neu-
sis of CLL. We therefore recommend an annual mammogram and tropenia to shorten the duration and severity of illness. Also, please see
353
pap smear for female patients and annual prostate evaluation in male Chap. 24.
patients and annual dermatologic evaluation and screening colonos-
copy every 5 years for all patients with CLL. Multiple myeloma also
occurs at a higher frequency in patients with CLL, but appears to arise MANAGEMENT OF AUTOIMMUNE
from a separate B-cell clone. 354–356 Non-Hodgkin lymphomas are typi- COMPLICATIONS OF CHRONIC
cally not associated with CLL and appearance of a large cell lymphoma
is considered to be Richter transformation. 357 LYMPHOCYTIC LEUKEMIA
Patients with CLL have a greater risk of developing autoimmune com-
MANAGEMENT OF INFECTIOUS plications including autoimmune hemolytic anemia (AIHA; Chap. 54),
COMPLICATIONS immune thrombocytopenia (ITP; Chap. 117), and pure red cell aplasia
(PRCA; Chap. 36). In the majority of patients, the nonmalignant B-cell
Infectious complications constitute the leading cause of morbidity and clone produces the autoantibody, reflecting a dysregulation of humoral
mortality in patients with CLL. Patients with CLL develop progres- immune tolerance. 373,374 Patients who present with autoimmune cytope-
sive hypogammaglobulinemia with progressive disease that results nias may not have a worse prognosis than patients in whom cytopenias
in a higher incidence of infections with encapsulated organisms like develop because of extensive marrow infiltration by the disease. 328,375–377
Streptococcus pneumoniae and Haemophilus influenzae. This has his- AIHA can present in up to a third of patients with CLL at some time
358
torically been further compounded by the effect of cytotoxic chemo- during the course of their disease and in a small proportion of patients
therapeutics like fludarabine or antibodies like alemtuzumab that cause (10 to 15 percent) at the time of diagnosis. Patients present with signs
328
profound T-cell depletion along with worsening normal B-cell depletion and symptoms of acute onset of anemia with weakness, fatigue, lethargy,
and resultant hypogammaglobulinemia. This combined effect of dis- and shortness of breath on exertion. Physical examination reveals pal-
359
ease and therapy results in a higher incidence of opportunistic bacte- lor, jaundice, lymphadenopathy, and hepatosplenomegaly. Laboratory
rial and viral infections with herpes simplex virus, CMV, herpes zoster evaluation reveals anemia, elevated LDH, hyperbilirubinemia, positive
virus, and Listeria monocytogenes. Fungal infections with Cryptococcus direct Coombs test, and decreased serum haptoglobin. Not all patients
neoformans and Pneumocystis jiroveci are also seen in these patients and who have a positive Coombs test, however, develop hemolysis. Most
patients treated with high-dose glucocorticoids. 359–361 Patients respond to patients have warm reactive antibodies, but some patients may develop
373
appropriate antibiotics early in their disease course, but might require cold agglutinin disease. Occasionally, patients may develop concom-
prolonged and repeated courses of antibiotics later in their disease course itant ITP with AIHA or Evans syndrome. Certain miRNAs have been
and after therapy with chemotherapeutic agents. Prophylaxis for herpes correlated with the development of AIHA but their mechanistic expla-
zoster infections with acyclovir and for P. jiroveci with trimethoprim- nation in the pathogenesis of AIHA is lacking. 378
sulfamethoxazole is routinely used for patients with prior therapy with ITP results in development of sudden profound thrombocytopenia
nucleoside analogues. Fungal prophylaxis is also employed with vori- with associated bleeding diathesis. Accurate diagnosis requires a mar-
362
conazole or posaconazole for the prevention of invasive aspergillosis in row aspirate and biopsy to evaluate the extent of CLL in the marrow
patients on high-dose steroids. Patients treated with ibrutinib experience and the presence of adequate or increased numbers of megakaryocytes.
a lower incidence of infection, possibly because of effective disease con- Patients often require periodic red cell transfusions for symptom-
trol and despite a significant improvement in immunoglobulin levels. 92 atic anemia and platelet transfusions may be employed in patients with
Hypogammaglobulinemia is universally present in patients with severe thrombocytopenias with bleeding complications. Glucocorti-
CLL and progressively worsens with advancing stage of the disease. coids have been the mainstay of treatment for AIHA and ITP, However,
Intravenous immunoglobulin (IVIG) at doses of 250 to 600 mg/kg steroids need to be dosed at 0.5 to 1.0 mg/kg/day for 2 to 3 weeks fol-
administered every 4 to 6 weeks may result in a significant reduction lowed by a slow taper over several weeks. Unfortunately, a large number
of major infections requiring intensive supportive care and a modest of patients relapse after discontinuation of the steroids and may need
reduction in the incidence of clinically significant infections. However, subsequent therapy with IVIG or rituximab. The early use of IVIG and
there is no significant improvement in survival. 363–365 Consequently, we weekly rituximab for four doses may allow for better disease control and
recommend the judicious use of IVIG in patients at high risk of devel- rapid glucocorticoid withdrawal. Other immunosuppressive agents that
oping infectious complications. have been used include cyclosporine, the dose of which can be titrated
Along with the disease-related immune defects, patients with CLL to stable hemoglobin or platelet levels or serum trough levels between
also respond poorly to routine prophylactic vaccinations. Response 100 and 150 ng/mL. Erythropoiesis-stimulating agents have been
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