## 2 Case Presentation
The sequencing panel showed a fusion between exon 18 of RAN-binding protein 2 (_RANB2_) on chromosome 2 (2q13) and exon 20 of ALK receptor tyrosine kinase (_ALK_) on chromosome 2 (2p23.2-2p23.1). (Figure 3) This _RANBP2::ALK_ fusion, which was presumed to retain the tyrosine kinase domain of _ALK_, was confirmed using RT-PCR and Sanger sequencing, and is consistent with the pericentric inversion of chromosome 2 noted in the initial diagnostic cytogenetic report. Figure 2: Flow cytometry showing red: leukemic blasts, green: granulocytes, blue: lymphocytes, and burgundy: debris. The blasts are positive for CD45, CD64, CD14, CD15, CD11b (partial), CD2 (partial), CD4, CD16+56 (partial, bright), and CD117 (partial) (shown here). The blasts are also positive for (not shown here) CD13, CD33, HLA-DR, CD52 (partial), CD99, CD58, CD38, and myeloperoxidase (partial). A bone marrow evaluation at the end of Induction 1 showed a minimal residual disease (MRD) positive state with 0.1% residual acute myeloid leukemia via flow cytometry. Chromosome analysis was not able to be performed at this timepoint due to a markedly hypocellular (10%) marrow, resulting in inadequate sample volume being obtained. Based on this finding, the patient was considered high risk and therefore eligible for HSCT at first remission. She began Induction 2 and was treated according to an institutional practice standard with cytarabine (100 mg/m\({}^{2}\)/dose IV every 12 h on days 1-8) and daunorubicin (50 mg/m\({}^{2}\)/dose on days 1, 3, and 5). On day 10 of Induction 2, once systemic chemotherapy was completed, crizotinib at 250 mg twice daily was started as a targeted agent against the known oncogenic activating \(ALK\) fusion. A bone marrow evaluation at the end of Induction 2 demonstrated MRD-negative remission. She then received Intensification 1 as per the institutional practice standard of high-dose cytarabine (1000 mg/m\({}^{2}\)/dose every 12 h on days 1-5) and etoposide (150 mg/m\({}^{2}\)/dose on days 1-5), again with the addition of crizotinib beginning on day 7 of the cycle. The MRD evaluation remained negative after Intensification 1. The patient tolerated the chemotherapy and crizotinib well. She experienced nausea that was managed with scheduled antiemetics; an erythematous rash of lower extremities that was likely secondary to CPX-351 and was managed with topical steroid and emollient; and episodes of febrile neutropenia during hospitalizations, but never with any bacterial or fungal organisms isolated. While on crizotinib, QTc was monitored closely and remained within the safe range to continue the medication. Following three cycles of chemotherapy, she underwent an allogeneic hematopoietic hematopoietic stem cell transplant with a 10/10 HLA-matched unrelated donor. A conditioning regimen of alemtuzumab, busulfan, and cyclophosphamide was used. Her post-transplant course was  
Figure 3: (**A**) Schematic of chromosome 2 with red lines denoting the chromosomal positions of \(ALK\) [ALK receptor tyrosine kinase] and \(RANPB2\) [RAN-binding protein 2] on chromosomes 2p23.1 and 2q13, respectively. (**B**) The \(RANBP2\):\(\mathit{ALK}\) fusion protein is predicted to maintain an intact 3\({}^{\prime}\) ALK tyrosine kinase domain (Kinase DM) by joining exon 18 of \(RANBP2\) to exon 20 of \(ALK\). The RT-PCR and Sanger sequencing confirmed the fusion breakpoint at chr2:109375004 (\(RANBP2\), NM_006267.4, exon 18) and chr2:29446394 (\(ALK\), NM_004304.4, exon 20). Domain abbreviations: MAM, meprin/A5/mu; RanBP1-like, Ran-binding protein RanBP1-like. complicated by severe shock with generalized fluid overload on day +12 in the setting of engraftment syndrome, as well as concomitant hepatic veno-occlusive disease/sinusoidal obstruction syndrome. As a result, she developed acute kidney injury that initially required continuous renal replacement therapy and then intermittent hemodialysis (last session on day +29). She was treated with 21 days of defibrotide (days +12 to +32). She engrafted on day +16 post-transplant.