Secondary Malignancies in Chronic Lymphocytic Leukemia: A Single Centre Retrospective Analysis of 514 Cases
Authors: Reda Gianluigi , Fattizzo Bruno , Cassin Ramona , Orofino Nicola , Flospergher Elena , Iurlo Alessandra , Barcellini Wilma , Cortelezzi Agostino 
Published: November 2019

Abstract
Background: chronic lymphocytic leukemia (CLL) is characterized by progressive immunodeficiency with high prevalence of infections, autoimmune phenomena and secondary malignancies. The immune deregulation may be due to the disease itself or it may be a consequence of the treatment performed. Despite the use of highly effective chemo-immunotherapy, CLL remains incurable nowadays, even if the availability of new drugs is improving life expectancy.
Aims: to evaluate the incidence of second cancers in CLL patients, and to investigate their relationship with disease features and therapy lines.
Methods: 514 CLL patients diagnosed and followed from 1983 until 2014 at our Institution were retrospectively evaluated. Secondary cancers were categorized according to the originating organ or tissue; skin cancers were divided into melanoma and non-melanoma. History of neoplasia preceding CLL diagnosis was also registered.
Results: clinical, hematological and biological characteristics at CLL diagnosis are listed in Table 1. During the follow up 88 patients (17%) developed secondary cancers, with a mean time from diagnosis to secondary neoplasia of 9 years.
Considering tumor site, we observed 9 hematological malignancies, 9 lung, 5 breast, 19 uro-genital tract (5 kidney, 10 prostate, 4 bladder, 2 uterus, and 2 ovarian), 15 gastro-enteric tract (12 colon, 2 gastric and 1 tongue), 4 pancreas, 3 melanoma and 15 skin cancers other than melanoma.
No significant differences were observed according to age, gender, Rai/Binet stage and hematologic parameters in patients with or without secondary tumors (Table 1).
Considering prognostic features, no association was found with 13q deletion, chromosome 12 trisomy, VHIG mutational status, or with ZAP-70 and CD-38 positivity. On the contrary, the development of second cancers was associated with the presence of chromosome 17p (8% with secondary neoplasia versus 6% without, p=0.05) and 11q deletions (13% versus 9%, p=0.08).
Medical history was positive for malignancies in 70 patients (13%): 2 hematological malignancies, 3 airways (2 lower and 1 upper), 3 breast, 6 uro-genital tract (3 bladder, 3 prostate, 2 uterus and 1 ovarian), 3 gastro-enteric tract, 3 skin cancers other than melanoma, and 3 melanoma.
As regards treatment, 46/88 (52.3%) and 219/426 (51.4%) patients with or without secondary cancers, underwent at least one therapy line.
Eighty-six patients were treated with fludarabine containing regimens, of whom 11 developed a secondary cancer; 180 patients received chlorambucil and 34 developed a secondary tumor. Among 65 patients who underwent alemtuzumab treatment, 10 were later diagnosed with a second cancer.
During the follow up, 121 patients died, 18 with secondary malignancy.
Of note, 41 patients died from CLL progression, 2 from thrombotic events, 11 from infections and 8 from secondary malignancy.
Conclusions: secondary malignancies are not infrequent in patients with CLL and their occurrence is not clearly related to biologic markers or to the treatment performed. A careful clinical follow up, encompassing sex and age adjusted tumors screening, is advisable for an early diagnosis and appropriate treatment of secondary malignancies in CLL.
Table 1. clinical and laboratory features of 514 CLL patients with or without secondary malignancies. Data are expressed as median (range) or absolute number (%). Secondary malignancies Yes (N=88) No (N=426) Age years 64 (39-80) 63 (31-90) Gender M/F 57/31 250/176 Follow-up years 12 (0-30) 12 (1-25) Rai/Binet<C/III> C/III 85 (97) 3 (3) 401 (94) 25 (6) WBC x10e3/mmc 18.74 (3.6-138) 17.3 (3-384) ALC x10e3/mmc 12.63 (1.8-91.8) 11.9 (1.4-381) Hb g/dL 14 (9-17) 14 (8-18) PLT x10e3/mmc 198 (77-608) 184 (58-472) LDH U/L 325 (144-838) 334 (142-795) Beta2microglobulin mg/L 2 (1-23) 2 (0-10) FISH*Del11qDel13qDel17p+12 6 (13) 19 (40) 4 (8) 6 (13) 23 (9) 101 (40) 15 (6) 38 (15) VHIG unmutated** 15 (42) 80 (39) ZAP-70 positive*** 14 (39) 73 (36) CD-38 positive**** 15 (42) 76 (37) *Tested in 48 and 252 patients respectively. **Tested in 36 and 205 patients respectively. ***Tested in 33 and 182 patients respectively. ****Tested in 56 and 291 patients respectively.

Disclosures
No relevant conflicts of interest to declare.