Volunteer unrelated donor cell‐derived acute myeloid leukemia with RUNX1‐RUNX1T1

Abstract A 15‐year‐old male was diagnosed with acute myeloid leukemia with t(6;9)(p23;q34), a chimeric DEK‐NUP214 fusion gene. He underwent allogeneic bone marrow transplantation (allo‐BMT) from an unrelated volunteer donor at first molecular remission. Approximately 5 years after allo‐BMT, multiple bone marrow aspirations showed increased blasts to 63%, which were positive for myeloperoxidase, CD13, CD33, CD56, and CD34. Surprisingly, t(8;21)(q22;q22.1), a chimeric RUNX1‐RUNX1T1 (not DEK‐NUP214) fusion gene, was detected with full donor chimerism. To our best knowledge, this is the first case of a volunteer unrelated donor cell‐derived acute myeloid leukemia harboring a chimeric RUNX1‐RUNX1T1 fusion gene.

Prophylaxis for graft-versus-host disease (GVHD) included tacrolimus (TAC, 0.03 mg/kg initial dose) and short-term methotrexate. He did not have any sign of acute GVHD, but experienced chronic mild GVHD of the skin that was controlled with topical steroids. TAC was discontinued on day 165 after allo-BMT. Thereafter, the maintenance of molecular CR was confirmed by bone marrow specimens, using DEK-NUP214 chimeric gene testing (PCR), for 2 years following allo-BMT.
Of note, chimerism analysis using a short tandem repeat (STR) method on bone marrow specimens, carried out annually after allo-BMT, indicated maintenance of the donor type ( Figure 1).
During a routine examination in August 20XX (about 4.5 years after allo-BMT), however, blasts were suddenly observed on a peripheral blood smear, with a white blood cell (WBC) count of 3200/μl (blasts, 5.0%), hemoglobin level of 14.2 g/dl, and platelet count of 152,000/μl, and a detailed examination was subsequently initiated accordingly (Table 1). Multiple bone marrow aspirations showed increased blasts of up to 63%, which were positive for myeloperoxidase, CD13, CD33, CD56, and CD34. Surprisingly, chromosome banding analysis showed 46, XY, t(8;21)(q22;q22.1) [12/20], and chimeric mRNA gene analysis showed the fusion of RUNX1-RUNX1T1 in bone marrow samples. However, DEK-NUP214 and FLT3-ITD, which had been present at the time of the diagnosis of leukemia, were not detected. Finally, volunteer unrelated DCL was definitively diagnosed by multiple chimerism analysis using not only whole bone marrow samples, but also CD34-positive cells which were selected by immunomagnetic beads.
Although the patient was diagnosed as having DCL, he was asymptomatic with a small number of blasts and did not wish to receive salvage chemotherapy ( Figure 1). Therefore, he was followed up by bone marrow examination on an outpatient basis. The patient was admitted to our hospital with a cough, sputum, and fever in December 20XX. Blood tests showed a WBC count of 8300/μl (neutrophils, 62%; blasts, 15%) and a C-reactive protein level of 19.4 mg/dl. Computed tomography revealed small diffuse infiltrates in both lungs, and infiltrates in the right inferior lobe as well as enhanced bronchial shadows. The patient was hospitalized for treatment of pneumonia. The pneumonia improved after antimicrobial therapy, but blasts increased in both peripheral blood and bone marrow. Therefore, remission induction therapy for DCL (idarubicin 12 mg/m 2 on days 1-3 and cytarabine 100 mg/m 2 on days 1-7) was started from January 11, 20XX+1.
The patient developed bacteremia due to Escherichia coli during the period of bone marrow suppression, which improved with antimicrobial therapy. From February 21, 20XX+1, high-dose cytarabine therapy (cytarabine 2 g/m 2 twice daily on days 1-5) was started as a consolidation setting. Febrile neutropenia occurred, but improved after antibac-

DISCUSSION
The concept of DCL was first proposed in 1971 when Fialkow et al.
reported a case that developed between relatives following allo-BMT   Table 1).
The clinical characteristics and outcome of the five patients including our case with DCL harboring RUNX1-RUNX1T1 are summarized in  Table 3  According to an EBMT report, the prognosis of DCL is poor, with 29 of 38 patients dying at a median of 11 months (range: 0-91 months) following a DCL diagnosis [5].  is effective as consolidation therapy [15], but the usefulness of allo-HSCT in first CR has not been demonstrated. Accordingly, high-dose cytarabine therapy was given after induction therapy, and a second transplantation was not performed in the present case. Nevertheless, since the prognosis of DCL has been shown to be relatively poor, as described above, it is necessary to further accumulate clinical characteristics and outcome regarding DCL to make treatment decisions appropriately.

CONFLICT OF INTEREST
Shinsuke Iida received grants and personal fees from Celgene, grants and personal fees from Janssen, grants and personal fees from Ono, grants and personal fees from Takeda, grants and personal fees from Bristol-Myers Squibb, grants from Chugai, grants from Kyowa Kirin, grants and personal fees from Sanofi, grants from Abbvie, grants and personal fees from Daiichi Sankyo, outside the submitted work.