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□ CASE REPORT □

Therapy-related Leukemia with Inv(16)(p13.1q22) and Type D CBFB/MYH11 Developing after Exposure to -containing Chemoradiotherapy

Hiroki Akiyama 1, Masahide Yamamoto 1, Chizuko Sakashita 1, Yoshihiro Umezawa 1, Tetsuya Kurosu 1, Naomi Murakami 2 and Osamu Miura 1

Abstract

A 40-year-old woman developed therapy-related acute myeloid leukemia (t-AML) with inv(16)(p13.1q22) and a rare type D form of core-binding factor β-subunit gene-myosin heavy chain 11 gene (CBFB-MYH11) fusion transcript approximately 2.5 years after receiving chemoradiotherapy for uterine cervical cancer. t- AML with inv(16)(p13.1q22) and rare non-type A CBFB-MYH11 typically develops after exposure to a topoisomerase II inhibitor, with a short period of latency of one to five years. As the patient had no history of exposure to topoisomerase II inhibitors, among her previously used chemotherapeutics, the topoisomerase I inhibitor, irinotecan, was speculated to be the most plausible cause of t-AML in this case. The present case suggests that irinotecan may cause t-AML resembling that associated with topoisomerase II inhibitors.

Key words: therapy-related acute myeloid leukemia, irinotecan, CBFB-MYH11, inv(16)(p13.1q22)

(Intern Med 54: 651-655, 2015) (DOI: 10.2169/internalmedicine.54.3535)

are associated with balanced recurrent chromosomal translo- Introduction cations frequently involving MLL at 11q23, RUNX1 at 21q22 or CBFB at 16q22 and morphologically resemble the Approximately 10% of cases of acute myeloid leukemia features of de novo AML associated with these transloca- (AML) develop following exposure to and/or tions (3-5). radiation for primary malignancy (1, 2), and the disease is AML associated with the pericentric inversion of chromo- categorized as therapy-related AML (t-AML) according to some 16, inv(16)(p13.1q22), or the less frequent transloca- the WHO classification of tumors of hematopoietic and lym- tion t(16;16)(p13.1q22) represents 5-8% of all cases of phoid tissues (3). Two subsets of t-AML are generally rec- AML. This disorder characteristically exhibits an abnormal ognized based on the nature of prior treatments and the eosinophilic component in addition to monocytic and granu- characteristics of the disease. The most common type, which locytic differentiation and is thus designated as M4Eo ac- usually occurs after the exposure to alkylating agents and/or cording to the French-American-British classification (3, 6). radiation, with a latency period of 5 to 10 years, is fre- Molecularly, both inv(16)(p13.1q22) and t(16;16)(p13.1q22) quently accompanied by the unbalanced loss of genetic ma- lead to the fusion of the core-binding factor ß-subunit gene terial, often involving chromosome 5 and/or 7. This type of (CBFB) at 16q22 with the smooth muscle myosin heavy t-AML is often preceded by therapy-related myelodysplastic chain 11 gene (MYH11) at 16p13 (7). Although more than syndrome (t-MDS). The less common type, which occurs af- 10 types of CBFB-MYH11 transcripts differing in size have ter treatment with agents targeting topoisomerase II, has a been reported to date, more than 85% of fusions are type A, shorter latency period of one to five years, without the pre- with the less frequent types D and E reported in 5-10% of ceding myelodysplastic phase. The majority of these cases patients each (7-11). Similar to that observed in de novo

１Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Japan and ２Department of Clinical Laboratory, Tokyo Medical and Dental University, Japan Received for publication June 24, 2014; Accepted for publication July 27, 2014 Correspondence to Dr. Osamu Miura, [email protected]

651 Intern Med 54: 651-655, 2015 DOI: 10.2169/internalmedicine.54.3535

Figure 1. Morphological and cytogenetic analyses of bone marrow cells. A: Bone marrow smear obtained at diagnosis (Wright-Giemsa staining, ×1,000). B: A Giemsa-banded karyogram of the bone marrow cells obtained at diagnosis showing 50,XX,+8,+9,inv(16)(p13.1;q22),+21,+22. The arrow indi- cates inv(16)(p13.1;q22).

AML, inv(16)(p13.1q22) is one of the most frequently bal- blood showed an Hb level of 11.5 g/dL, platelet count of anced chromosomal translocations in patients with t-AML. 151×109/L and WBC of 4.4×109/L. One month later, after Such cases are most frequently associated with exposure to the completion of the chemotherapy, the data were as fol- topoisomerase II inhibitors and commonly involve the non- lows: Hb=10.7 g/dL, platelets=106×109/L and WBC=3.6× A types of CBFB-MYH11 (1, 10, 12-14). 109/L. Thereafter, however, both thrombocytopenia and ane- Irinotecan is an agent that targets DNA topoisomerase I mia progressed over three months. Consequently, approxi- and is currently used to treat lung, ovarian, cervical and col- mately 2.5 years after the start of the initial therapy for cer- orectal cancers worldwide (15). Because only a small num- vical cancer, the patient was referred to our department for ber of cases of t-AML developing after irinotecan therapy treatment of the thrombocytopenia. Upon admission, the pe- have been reported (16-18), the risk, as well as clinical and ripheral blood showed an Hb level of 7.6 g/dL, platelet cytogenetic features, of t-AML after exposure to topoisom- count of 16×109/L and WBC of 3.8×109/L with 2% blasts erase I inhibitors remains unknown. In this report, we de- and 52% monocytes. In addition, the bone marrow was hy- scribe a case of t-AML with type D CBFB-MYH11 that de- percellular with 29% blasts, 19.2% monoblasts/promono- veloped after exposure to irinotecan-containing chemoradio- cytes and 22% eosinophils (Fig. 1A). She was therefore di- therapy. agnosed with AML, classified morphologically as M4Eo. The leukemic cells were positive for CD13, weakly positive Case Report for CD33 and CD34 and negative for CD2. The karyotype was 46,XX,inv(16)(p13.1;q22)[12]/46,XX,del(7)(q?),inv(16) A 37-year-old woman was diagnosed with stage IIb uter- (p13.1;q22)[5]/50,XX,+8,+9,inv(16)(p13.1;q22),+21,+22[2] ine cervical cancer and received concurrent chemoradiother- (Fig. 1B), and split signals for CBFB were observed in 96% apy consisting of irinotecan, nedaplatin, and local of the cells according to an interphase FISH analysis. Fur- radiation (one cycle of irinotecan 160 mg/m2 and nedaplatin thermore, RT-PCR for CBFB-MYH11 revealed a fusion 80 mg/m2, followed by six cycles of cisplatin 70 mg/m2). product that was longer than that expected for the type A Fifteen months after starting the therapy, she developed local fusion (Fig. 2A). With approval from the Ethics Committee recurrence. Although she again received irinotecan and of Tokyo Medical and Dental University and written in- nedaplatin (three cycles of irinotecan 160 mg/m2 and formed consent from the patient, we sequenced the CBFB- nedaplatin 80 mg/m2), the cancer progressed, with bladder MYH11 RT-PCR product and found it to be identical to that invasion. Six months after recurrence, the patient was started of GenBank accession number AF249897, corresponding to on a third-line chemotherapy consisting of and the type D fusion transcript (Fig. 2B). The patient was thus (seven cycles of docetaxel 75 mg/m2 and car- diagnosed with t-AML with inv(16)(p13.1;q22); CBFB- boplatin with AUC at 5 mg/mL); however, this regimen MYH11 and treated with induction therapy comprised of failed to control the disease and she experienced persistent low-dose and due to her poor general bladder hemorrhage and abdominal pain. Although she was conditions. She subsequently failed to achieve complete re- slightly anemic, most likely due to persistent macrocytic he- mission after suffering from febrile neutropenia and severe maturia, the WBC and platelet counts generally remained hematuria with renal dysfunction during the induction ther- within the normal range during the third-line therapy. At the apy, which made her general status worse. However, she de- time of administration of the sixth cycle, the peripheral clined further intensive therapy and was treated supportively.

652 Intern Med 54: 651-655, 2015 DOI: 10.2169/internalmedicine.54.3535

Figure 2. Molecular genetic analyses of CBFB-MYH11. A: RT-PCR analysis of the CBFB/MYH11 (A) and ß-actin (B) transcripts of the bone marrow mononuclear cells derived from a normal control (1) and the patient (2). The position and length of the CBFB/MYH11 and ß-actin transcripts are indi- cated in red and black, respectively. M: molecular mass size markers. B: Sequence analysis of CBFB/ MYH11. The nucleotide sequences around the junction in addition to the deduced amino acid se- quences are shown. The number of nucleotides of CBFB and MYH11 at the fusion junction is also indicated.

In the absence of widespread metastasis of the cervical can- ally observed in the present patient. Therefore, although cer, the patient displayed a persistent fever with consequent complex karyotypic abnormalities are typically observed in multiple organ failure and died 108 days after starting the cases of t-AML caused by alkylating agents or irradiation, induction therapy for t-AML. In this case, the death was the present case should be considered to be typical of t- most likely due to leukemia or infection. AML with inv(16)(p13.1;q22), which usually develops after the administration of therapy with topoisomerase II inhibi- Discussion tors. Importantly, however, our patient had not previously re- We herein reported a case of t-AML with inv(16)(p13.1;q ceived topoisomerase II inhibitors prior to developing AML. 22) that involved the typical features of t-AML caused by With the exception of irradiation and -based agents topoisomerase II inhibitors. This type of t-AML, in contrast (nedaplatin, cisplatin and carboplatin), which act basically as to that induced by alkylating agents or irradiation, usually bifunctional alkylating agents to cause t-AML (1, 20), the develops within a relatively short period of time after expo- patient was treated with only irinotecan (total dose, 640 mg/ sure to chemotherapy or irradiation and is not preceded by m2) and docetaxel (total dose, 525 mg/m2). Irinotecan is a MDS (1-3, 5). In the present case, the patient was diagnosed semisynthetic derivative of categorized as a with AML approximately 2.5 years after the start of topoisomerase I inhibitor (15). Topoisomerase inhibitors chemoradiotherapy, not preceded by an apparent MDS phase bind to the enzyme/DNA complex at the strand cleavage and not morphologically associated with any significant dys- stage of the topoisomerase reaction, thereby interacting with plastic features. The cytogenetic and genetic features of topoisomerase I or II. Topoisomerase II inhibitors consist of AML in the present case were also typical of the type of t- intercalating agents, such as , and non- AML caused by topoisomerase II inhibitors, as this type of intercalating epipodophyllotoxins, such as . The t-AML characteristically shows balanced recurrent chromo- topoisomerase I inhibitor irinotecan is classified as a non- somal translocations, among which inv(16)(p13.1;q22) with intercalating drug (15, 21). Because the mutagenic proper- CBFB-MYH11 is one of the most frequent (1, 12, 14). It is ties of irinotecan in vitro are similar to those of topoisom- also important to note that the non-A fusion types of CBFB- erase II inhibitors, these drugs are expected to induce a MYH11, such as type D confirmed in the present case, are similar type of t-AML (21). However, as shown in Table, observed in 40-50% of patients with t-AML, although they only three cases of t-AML developing after irinotecan expo- are very rare among those with de novo AML with inv(16) sure have been previously reported (Cases #2-4), with the (p13.1;q22) (10, 11, 13), thus suggesting that the AML ob- topoisomerase II inhibitor etoposide additionally used in one served in this case was etiologically, but not simply acciden- case (Case #3) (16-18). All three patients developed t-AML tally, related to the prior . It should within three years after irinotecan exposure, without any also be noted that inv(16)(p13.1q22) is very frequently asso- documented signs of the t-MDS phase, thus resembling the ciated with additional chromosomal translocations, such as clinical course of t-AML caused by topoisomerase II inhibi- trisomies 8, 21 and 22, (10, 11, 19), which were addition- tors, although complex karyotypic abnormalities were ob-

653 Intern Med 54: 651-655, 2015 DOI: 10.2169/internalmedicine.54.3535

Table. Reported Cases of T-AML after Irinotecan or Docetaxel Exposure

Primary Latency Case Age/ Chemotherapy, Morphology tumor period Karyotype Ref. No. Sex Radiotherapy (FAB) site (months) CPT-11, NDP, CDDP, RT 32 Complex including 1 40/F Cervix M4 * CBDCA, DTX 11 inv(16)(p13;q22) LVFU 63 Complex including 2 65/F Colon CPT-11 11 M3 16 der(17)(dupq12q21) LVFU, L-OHP 8 3 64/F Ovary CPT-11, VP16 10 M5 N/A 17 4 43/M Colon CPT-11, LVFU 36 M5 Normal 18 CBDCA, DTX 40 M2 after 569/MLung Complex 22 RT 35 MDS RT 55 6 69/M Prostate VP16 18 M4 inv(16)(p13;q22) 23 CBDCA, DTX 12 The asterisk indicates the present report. CPT-11: irinotecan, NDP: nedaplatin, CDDP: cisplatin, RT: radiation therapy, CBDCA: carboplatin, DTX: docetaxel, LVFU: leucovorin + , L-OHP: , VP16: etoposide, AZP: azathioprine

served in Case #2. Hence, the present case represents the several attempts (Case #3), whereas one patient attained CR first case of t-AML with inv(16)(p13.1;q22) occurring after after the first cycle of induction therapy and remained in CR irinotecan exposure with the typical features of the type of for more than 15 months (Case #4) (16-18). The two t-AML t-AML caused by topoisomerase II inhibitors. On the other patients with a previous history of exposure to docetaxel hand, the administration of the antimicrotubule agent do- also died within approximately three months without receiv- cetaxel, which was also used in the present case, has been ing chemotherapy for t-AML (Cases #5, 6), although inv reported in association with the onset of t-AML in two (16)(p13.1;q22) was observed in Case #6 (22, 23). cases (Cases #5, 6) (22, 23). However, the patient in Case It is notable that only a few cases of t-AML following iri- #5 was also treated with the alkylating agent carboplatin in notecan exposure have been reported considering the wide addition to irradiation and presented with features resem- range of clinical use and similar mechanism of action of this bling those of t-AML caused by alkylating agents, including drug to topoisomerase II inhibitors (15, 21). This finding an antecedent t-MDS phase and complex karyotypic abnor- may be explained at least partly by the observation that pa- malities (22). Although Case #6 involved inv(16)(p13.1; tients treated with irinotecan generally exhibit a shorter q22), the patient was treated with etoposide 18 months be- overall survival than those treated with etoposide or anthra- fore developing t-AML (23). Intriguingly, four cases of t- cyclines, which are widely used to treat hematological ma- AML with inv(16)(p13.1;q22) have been reported in asso- lignancies. For instance, the overall survival of first-line ciation with the other , (13, 24). However, FOLFIRI therapy, one of the most wildly used combined except in one case, the patients were also exposed to chemotherapy regimens containing irinotecan for colorectal etoposide. Therefore, the possible leukemogenic role of cancer, is only approximately 20 months (25). However, the paclitaxel in the development of t-AML with inv(16)(p13.1; overall survival of patients treated with irinotecan is ex- q22) remains elusive, and based on the mechanism of action pected to become longer, as various novel molecular target- and details of previous case reports, we consider irinotecan ing agents are now being combined with these regi- to be the most plausible causative agent for the onset of t- mens (26). Therefore, the number of patients with t-AML AML in the present case. following exposure to irinotecan is expected to increase in Although inv(16)(p13.1;q22) is associated with a favor- the near future. Such cases should be analyzed carefully in able prognosis (3), the prognosis of t-AML with inv(16) order to determine the risk, as well as clinical and molecular (p13.1;q22) is significantly worse than that of its de novo features, of this condition. AML counterpart (4, 10). Furthermore, the current patient was unable to receive the standard AML induction therapy The authors state that they have no Conflict of Interest (COI). due to her poor condition derived from the remaining cervi- cal cancer, and she died approximately four months after re- References ceiving the diagnosis of t-AML. It is difficult to speculate regarding the prognostic implications of irinotecan exposure 1. Kayser S, Döhner K, Krauter J, et al. The impact of therapy- in patients with t-AML based on the very small number of related acute myeloid leukemia (AML) on outcome in 2853 adult cases, each with a different clinical course, reported to date patients with newly diagnosed AML. Blood 117: 2137-2145, 2011. (Table). For the record, one patient died soon after diagnosis 2. Leone G, Pagano L, Ben-Yehuda D, Voso MT. Therapy-related without receiving any therapy (Case #2) and one patient leukemia and myelodysplasia: susceptibility and incidence. Hae- died 13 months after diagnosis without attaining CR after matologica 92: 1389-1398, 2007.

654 Intern Med 54: 651-655, 2015 DOI: 10.2169/internalmedicine.54.3535

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