Page 1417 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 77 Chronic Lymphocytic Leukemia 1263

factor that can be modulated by H2 receptor antagonists. Thus, autoimmune cytopenias. However, our practice is to first control the
responses to vaccines may be further enhanced by adjuvant treatment autoimmune process with steroids or other therapies before consider-
with H2 blockers. Studies have shown that response to protein- ing treatment of the underlying CLL. Supportive therapy with
conjugated vaccines may be enhanced by ranitidine in CLL patients periodic RBC transfusions is also important in the management of
to as much as 90% compared with 43% in the control group. AIHA. Ibrutinib has also been shown to reduce the incidence of
Unfortunately, this response is not seen with polysaccharide vaccines. autoimmune complications in patients who initiate therapy for
Other studies have indicated that protein-conjugated vaccines may progressive disease and provides an exciting option for these patients.
be more immunogenic, as shown by a more significant immune Unfortunately, ibrutinib has not been shown to be effective when
response to Haemophilus influenzae type b conjugate vaccine than to treating active AIHA.
plain polysaccharide antigen. In light of the paucity of data on an Pure RBC aplasia (PRCA) is a relatively rare T-cell–dependent
appropriate immunization schedule, we suggest a modified immuni- complication associated with CLL, with an incidence as high as 6%
zation plan based on the recommendations of the Advisory Commit- having been reported. PRCA was first described by Dameshek and
tee on Immunization Practices. This includes use of Prevnar-13 for colleagues in 1967. It is characterized by a hypoproliferative anemia
pneumococcal prophylaxis and avoiding live vaccines, including the that can be detected even in early-stage CLL patients and is thought
varicella zoster virus. to be caused by the cytotoxic effects of suppressor T cells on erythroid
Growth factors such as G-CSF or granulocyte macrophage progenitor cells. Increased numbers of cells coexpressing CD3, CD8,
colony-stimulating factor can be used prophylactically in high-risk, and CD57 have been shown to gradually accumulate in the BM of
severely neutropenic patients to shorten the duration and severity of patients with PRCA. Abeloff and Waterbury described the first remis-
neutropenia. sion of PRCA with cyclophosphamide therapy in 1974, and Chik-
kappa and colleagues described the first case of response to CSA.
AUTOIMMUNE COMPLICATIONS OF CHRONIC Subsequent larger studies have shown a response rate as high as 63%
with 300 mg/day of oral CSA. Mild reversible nephrotoxicity may
LYMPHOCYTIC LEUKEMIA warrant dose adjustment in some patients. Most patients exhibit a
response by having reticulocytosis within the first 10–14 days of the
Patients with CLL have a greater predisposition to develop auto- initiation of therapy, but maximal response may occur on average
immune hematologic complications, including AIHA, idiopathic after 10 weeks. Steroid therapy at a dose of 1 mg/kg per day of
thrombocytopenia purpura (ITP), and pure RBC aplasia. AIHA prednisone remains the first line of treatment. If a response is not
occurs in up to 37% of CLL patients at some time during the course obtained in 4 weeks, CSA should be added to the regimen. Other
of their disease. A small proportion (10–15%) of patients may present agents that have shown promising activity in treating PRCA include
with AIHA at diagnosis. AIHA can have a varied presentation, rituximab, IVIG, alemtuzumab, and antithymocyte globulin. Packed
with patients developing signs of anemia, including weakness, leth- RBC transfusions are usually indicated in patients who are clinically
argy, dyspnea on exertion, and dizziness over a period of months. symptomatic from severe anemia.
Examination may reveal pallor, jaundice, hepatosplenomegaly, and A number of other complications, most of which are autoimmune
lymphadenopathy. Hemolysis can cause mild to moderate indirect in nature, have been reported in patients with CLL. These complica-
hyperbilirubinemia, elevated LDH levels, and hemoglobinuria. The tions include paraneoplastic pemphigus, angioedema caused by
direct antiglobulin Coombs test result is positive in up to 74% of acquired C1-inhibitor deficiency, and nephrotic syndrome. As a result
patients with CLL, but not all patients develop hemolysis. Most of of autoimmune involvement of various organs, patients with CLL
the antibodies produced are warm reactive, but patients can occasion- may have abnormal serum chemistry profiles and liver function tests.
ally present with cold agglutination syndrome. The antibodies are
mostly polyclonal and usually a product of normal B cells rather than
the leukemic clone. FUTURE DIRECTIONS
In contrast to the high frequency of AIHA in CLL, ITP or ITP
and AIHA, or Evans syndrome, occurs less frequently in CLL. These Advances in the understanding of molecular events associated with
events can occur throughout the entire course of CLL and are much CLL over the past 2 decades has resulted into new diagnostic tests
more difficult to diagnose because of the absence of multiple impli- that allow better assessment of initial prognosis and also treatment
cating laboratory features as seen with AIHA. Given the small number assignments. In addition, multiple new therapies have been identi-
of patients with AIHA, there are no data from controlled trials to fied, and progress is being made to extend remission duration, clarify
guide the management of AIHA. Glucocorticoids have been used mechanisms of resistance, develop stopping rules for therapies and
since the 1940s and are considered the first line of therapy. Most improve the quality of life of CLL patients. In addition, medications
patients will respond to prednisone at a dose of 1 mg/kg for 10–14 and interventions to overcome complications that arise from CLL
days followed by a slow taper over 2–3 months, depending on the have also been introduced. Overall, the future for patients with CLL
extent of hemolysis. ORRs of up to 90%, with 65% CRs, have been remains brighter based on such efforts and likely will continue to
reported with the use of steroids. Unfortunately, approximately 60% improve with additional laboratory and clinical research. In particular,
of patients relapse when steroid therapy is stopped. Rituximab the use of kinase inhibitors have transformed treatment approaches
2
375 mg/m weekly for 4 weeks is often effective for steroid-resistant and the outcome of patients with CLL which will likely alter the
AIHA or ITP and if steroid withdrawal is not possible. Because of natural history of the disease.
the long-term morbidity of prolonged steroid administration in CLL
and data demonstrating benefit to concurrent steroids and rituximab
for rapid withdrawal of corticosteroids in ITP, our group gives these FINANCIAL SUPPORT
two agents concurrently at diagnosis of ITP or AIHA unless contra-
indicated (e.g., hepatitis B). IVIG, the next line of treatment, induces This work was supported by the National Cancer Institute P01
responses in 40% of patients for both AIHA and ITP. Thrombopoi- CA95426, R01 CA095241, the American Cancer Society, the Leu-
etin agonists are effective for refractory ITP in CLL and could also kemia and Lymphoma Society, the Lymphoma Research Foundation
be considered at this time. Cyclosporine A (CSA) at 5 mg/kg per day and the D. Warren Brown Foundation.
given in divided doses twice daily has been used for refractory AIHA
and ITP of CLL. The dose should be adjusted to maintain a serum
level of around 100–150 µg/dL. Other treatment modalities include SUGGESTED READINGS
splenectomy or splenic irradiation, alkylating agents, or therapy
(FCR or FR directed at the disease if active). Treatment of the Awan FT, Byrd JC: New strategies in chronic lymphocytic leukemia: shifting
underlying CLL is generally required for long-term control of treatment paradigms. Clin Cancer Res 20:5869, 2014.