Malignancies Occurring during Therapy with Tyrosine Kinase Inhibitors (TKI) for Chronic Myeloid Leukemia (CML) and Other Hematologic Malignancies.
Authors: Verma Dushyant , Kantarjian Hagop M. , Rios Mary Beth , O’Brien Susan , Ault Pat , Burton Elizabeth M. , Estrov Zeev , Borthakur Gautam , Verstovsek Srdan , Garcia-Manero Guillermo , Ravandi Farhad , Cortes Jorge 
Published: April 2020

Background: Success of tyrosine kinase inhibitors (TKIs) (imatinib, dasatinib, nilotinib, bosutinib) in chronic myeloid leukemia (CML) has given patients (pts) hope for a long disease free survival, and with increased survival, may be some late effects of TKI treatment in the form of development of another malignancy. One prior report suggested an unexpected increased incidence of cancers among pts treated with imatinib after failure to interferon (Roy et al, Leukemia 2005).

Aims: To investigate the frequency and characteristics of 2nd malignancies (other than AML, ALL or MDS) among pts with CML or other hematologic malignancies treated with TKI.

Methods: We analyzed the records of 1647 pts treated with TKIs at our institution: 384 in chronic phase treated with imatinib after interferon failure, 338 treated with imatinib in advanced phases, 312 treated with imatinib as initial therapy, 422 treated with 2nd generation TKI after imatinib failure, and 109 treated with 2nd generation TKI as frontline therapy.

Results: A total of 67 (4.07%) pts (47 male, 20 female) developed a 2nd cancer. Their median age was 67 (range 31–85) years; the median follow-up after CML diagnosis was 94 (range 13–480) months (mo), and median time from start of TKI to development of another cancer was 38 (range 2–95) mo. These included 31/67(46%) pts who received imatinib as 1st line therapy for median 39.5 (range 16–88) mo, 5 pts who received 2nd generation TKI after imatinib failure (4 dasatinib, 1 bosutinib) for a median 10 (range 3–22) mo, and 1 pt received nilotinib as frontline therapy for 3 mo before diagnosis of 2nd cancer. The accompanying table summarizes the findings. The most common cancer was non-melanoma skin cancer representing 31% of all cancers. Excluding these, the 2nd cancers were seen in 2.8% of all pts treated. The skin cancers and melanomas were scattered and not localized to any particular anatomical site. Prostate cancer patients had median age 69 (range 43–83) years and imatinib treatment of median 38 (range 18–74) mo, for a cumulative incidence of 1.18% among male pts. Two patients with CLL were diagnosed on flow cytometry after loosing their hematologic response while still maintaining complete cytogenetic response (CCyR) on imatinib. After median follow up of 22 (range 1–95) mo from diagnosis of 2nd cancer, 12 (18%) pts have died (none from 2nd cancer). 49 pts continue on therapy with TKI after the diagnosis of 2nd cancer with 15 in complete molecular response (CMR), 25 with complete cytogenetic response (CCyR), 4 with partial cytogenetic response (PCyR), 5 having only complete hematologic response (CHR). All the frontline imatinib patients who are alive with a second cancer are in CCyR except one who is having CHR only

Type of second cancer No. of patients (n=67) Skin Cancer (BCC+SCC) 21 (11+10) Melanoma 7 Prostate cancer 11 GU cancer (Ovarian+Uterine) 2 (1+1) GU cancer (Urinary bladder+Kidney) 4 (1+3) GI cancer (Colon+Gastric+Esophageal) 6 (3+2+1) GI cancer (Hepatobiliary) 1 Lung cancer 1 Thyroid cancer (Papillary+Follicular) 2 (1+1) Thymoma 1 Lymphoma (large B-cell) 1 CLL 2 MPD 1 Breast cancer (relapse+new) 4 (2+2) Head & neck cancer 2 Cancer of Unknown Primary 1

BCC: basal cell carcinoma, SCC: squamous cell carcinoma, GU: genito-urinary, GI: gastro-intestinal, CLL: chronic lymphocytic leukemia, MPD: myeloproliferative disorder

Conclusion: Second cancers occur in a small percentage of pts receiving therapy with TKI for hematologic malignancies, mostly CML. These results need to be analyzed in the context of the underlying lifetime risk of developing cancer in the general population and in cancer survivors. There is no evidence at the moment to suggest that exposure to TKI is carcinogenic.