Acute Leukemias Following a Diagnosis of Colorectal Cancer: Are They Therapy-Related?
Authors: Stein Eytan M. , Pareek Vipul , Kudlowitz David , Douer Dan , Tallman Martin S 
Published: October 2019

Abstract
Abstract 1453
Approximately 140,000 patients per year are diagnosed with colorectal cancer in the United States. Historically, treatment modalities have included surgery, 5-fluourouracil (5-FU) and/or radiation. Over the past ten years standard treatment has evolved and now includes platinum compounds such as Oxaliplatin, the topoisomerase I inhibitor Irinotecan, and the oral analogue of 5-FU, Capecitabine. Rectal cancer often utilizes these agents in a neoadjuvant fashion with concomitant radiation therapy, followed by surgery and postoperative chemotherapy. The incidence of therapy related acute myeloid leukemia (t-AML) has been well described after treatment for breast cancer and lymphoma and occurs most commonly in patients previously treated with alkylating agents or topoisomerase II-active agents (epipodophylotoxins or anthracyclines). However, the occurrence of acute leukemia after a diagnosis of colorectal cancer has never been systematically investigated in a large clinical database.
Using ICD-9 codes for leukemia and colorectal cancer, we identified 37 patients seen at Memorial Sloan-Kettering Cancer Center since 1970 with colon cancer, rectal cancer, or anal cancer who were subsequently diagnosed with leukemia or a myelodysplastic syndrome (MDS). Of these 37 patients, 23 had colon cancer, 13 had rectal cancer and 1 had anal cancer. Treatments for the primary malignancy included: external beam radiation alone (2), chemotherapy alone (10), chemotherapy in combination with radiation (12) and surgery alone (13). The most common leukemia was acute myeloid leukemia (20) followed by MDS (8), Pre-B cell acute lymphoblastic leukemia (ALL) (4), acute promyelocytic leukemia (APL) (3), T-ALL (1) and T- cell prolymphocytic leukemia (PLL) (1). Of the 8 patients with MDS, 4 had chronic myelomonocytic leukemia. Among patients who received chemotherapy or combined chemoradiation the most common chemotherapeutic agents were 5-Fluorouracil (19) followed by Oxaliplatin (8), intrahepatic Floxuridine (2), Irinotecan (1) and Mitomycin (1). The median time from treatment with chemotherapy and/or radiation to diagnosis of acute leukemia or MDS was 41 months (range 10 months – 135 months). The most common cytogenetic abnormalities of the patients with MDS or AML were monosomies and deletions in chromosomes 5, 7, and 12. Of the 4 patients with Pre B-ALL, 3 had t(9;22). Interestingly of the 23 patients with myeloid leukemia, 3 (13%) patients developed the APL subtype with the disease defining t(15;17). Two of these three patients had received neo-adjuvant external beam radiation and 5-FU, one received adjuvant treatment with Oxaliplatinand one was treated with surgery alone. The latency period between diagnosis or treatment of colorectal cancer and the development of APL ranged from 10 to 20 years.
Table 1. Patient Characteristics M/F 23/14 Type of Lower GI Malignancy Colon 23 Rectal 13 Anal 1 Treatment Surgery Alone 13 Radiation Alone 2 Chemo-radiation 12 Chemotherapy Alone 10 5-Fluorouracil 19 Oxaliplatin 8 Intrahepatic Floxuridine 2 Irinotecan 1 Mitomycin 1 Median Latency period (range) 41 months (10-135 months) Type of leukemia AML (non-APL) 20 APL 3 MDS 4 CMMOL 4 ALL Ph pos 3 ALL Ph neg 1 T-ALL 1 T-PLL 1
In conclusion, to our knowledge this is among the first uses of a comprehensive clinical database to investigate the occurrence of acute leukemia and MDS after the diagnosis and/or treatment of a colorectal or anal malignancy. Our finding that the most common chromosomal abnormalities seen in patients who developed MDS or AML involve chromosomes 5 and 7, similar to t-AML suggests, that some of these leukemias are therapy related. It may be that the widespread adoption of newer platinum compounds will precipitate t-AML. Future studies of larger databases of patients may help establish if the acute leukemias seen after colorectal cancer are related to prior exposure to anti-cancer therapy.

Disclosures:
Douer: Teva: Consultancy.