Risk for Second Nonlymphoid Neoplasms in Chronic Lymphocytic Leukemia

Constantin A. Dasanu, MD, PhD; Doru T. Alexandrescu, MD

Abstract

Major advances have occurred in understanding the biology, immunology, and modalities of treatment of chronic lymphocytic leukemia (CLL) in the last decade. B-cell CLL is the most common type of leukemia occurring in the US and Western nations. B-cell CLL is characterized by progressive defects in both cell-mediated and humoral-mediated immunity. B-lymphocyte defects, low gammaglobulin levels, and quantitative and functional T-cell defects have been documented in the setting of CLL. In concert with each other, they account for the increased susceptibility of the CLL patients to infectious agents. Moreover, several recent surveys have pointed out that CLL patients are at high risk of developing a large variety of second malignant neoplasms. Different therapeutic modalities used for CLL may further exacerbate immunosuppression by depleting both T- and B-immune effectors, thus favoring various infectious diseases and perhaps altering the immune surveillance. The occurrence of 2 or more second cancers is increasingly reported in the context of CLL. Increased awareness of this association is warranted. Future development of surveillance strategies may be needed for a growing population of surviving patients who are at risk for second nonlymphoid neoplasms.

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Population-Based Studies Looking at an Association Between CLL and Second Malignancies
Study	Site	Incidence of Cancer	Specific Cancers	Remarks
Manusow and Weinerman (1975)^[1]	University of Manitoba, Winnipeg, Manitoba, Canada	3 times that for the age- and sex-matched population	8 times for skin cancers, and 2 times for all cancers, excluding skin cancer	102 patients with CLL
Santoro, et al (1980)^[2]	Instituto Nazionale Tumori, Italy	19.5% of patients associated with neoplasm	Head and neck and breast cancers had the highest incidence	82 consecutive cases of CLL
Greene, et al (1978)^[3]	National Cancer Institute, Bethesda, Maryland	Second primary cancers in 234 patients compared with 204.9 expected	Risk was significantly elevated for malignant melanoma, soft-tissue sarcomas, and lung cancer	4869 patients with CLL
Mellemgaard, et al (1994)^[4]	Danish Cancer Society, Copenhagen, Denmark	SIR 2.0 for men and 1.2 for women	Lung (RR = 2.0) and prostate (RR = 1.5) in men Nonmelanoma skin cancer (RR = 4.7 for men, RR = 2.4 for women) Renal cell carcinoma (RR = 2.8 for men, RR = 3.6 for women) Sarcomas (RR = 3.3 for men, RR = 2.8 for women) in both sexes	7391 CLL patients
Hisada, et al (2001)^[5]	National Cancer Institute, Bethesda	O/E was 1.20 (95% CI 1.15-1.26)	Kaposi's sarcoma (O/E = 5.09), malignant melanoma (O/E = 3.18), cancers of the larynx (O/E = 1.72) and the lung (O/E = 1.66) Brain cancer among men (O/E = 1.91), stomach (O/E = 1.76) and bladder (O/E = 1.52) among women	16,367 patients with CLL
Kyasa, et al (2004)^[6]	University of Arkansas for Medical Sciences, Little Rock, Arkansas	16% of the CLL/SLL patients had second malignancies	21 patients had second malignancies: 19 nonlymphoid, 1 Richter's transformation, and 1 Hodgkin's disease)	132 CLL/SLL patients compared with 38,000 veterans over 11.5 years
Mauro, et al (1999)^[7]	University "La Sapienza," Rome, Italy	Second primary cancers - 8.3% in age < 55 yr and 10.7% in > 55 yr		1011 CLL patients over 10 years
Suzuki, et al (1997)^[8]	Japanese Red Cross Medical Center, Japan	Second malignancies represent 16% of all major causes of death	4 deaths from stomach cancer; 3 deaths from lung cancer; and 1 death from each liver, pancreas, and prostate cancers	75 CLL patients
Parekh, et al (1999)^[12]	Memorial Sloan-Kettering Cancer Center, New York, NY		2% had lung carcinoma (19 men and 7 women), with 38% of these having a third malignancy: melanoma, basal cell carcinoma, laryngeal carcinoma, and/or colon carcinoma	1329 patients with CLL
Schoellkopf, et al (2005)^[13]	Statens Serum Institut, Copenhagen, Denmark		Statistically significant increased RR (SIR = 1.83, 95% CI 1.55-2.15) of lung cancer; no difference in risk between women and men	9541 consecutive patients with CLL
Travis, et al (1992)^[18]	National Cancer Institute, Bethesda		O/E of 2.79 for cutaneous melanoma and 3.97 for ocular melanoma	9456 patients with CLL

CLL = chronic lymphocytic leukemia; SIR = standardized incidence ratio; RR = relative risk; O/E = observed/expected ratio; CI = confidence interval; SMR = standardized morbidity ratio; SLL = small lymphocytic lymphoma

The Impact of CLL Therapies on Immune System and Incidence of Second Cancers
CLL Therapy	Effect on Immune System	Study	Impact on Incidence of Second Cancers	Study
Purine analogs	Prolonged decrease in CD4+ (and possibly CD8+) T cells	Morra, et al (1999)^[46] Keating, et al (1998)^[47]	Increased incidence of lung cancer, but no other neoplasias in one study	Robak, et al (2004)^[17]
Alkylating agents	Unknown with chlorambucil Lymphopenia is well known to occur with cyclophosphamide use. Cyclophosphamide may also exhibit immunomodulatory activity.	N/A Multiple studies	Not increased with chlorambucil Cyclophosphamide is a known carcinogen	Callea, et al (2006)^[49] Multiple studies
Rituximab	Depletion of CD20+ B-cell pool Decreased humoral response to recall antigens Decreased memory response when administered prior to antigen exposure	Gonzales-Stawinski, et al (2001)^[52] Van der Kolk, et al (2002)^[53]	Unknown	N/A
Alemtuzumab	Prolonged depletion of T and B cells Impaired antibody-mediated immune response	Robak (2004)^[54] Lowenstein, et al (2006)^[55]	Unknown	N/A