Poor prognosis of B‐cell acute lymphoblastic leukemia with TCF/PBX1 fusion gene and ovarian involvement at diagnosis: Two case reports and review of the literature

To the Editor: Translocation t(1;19)(q23;p13) is a well-known recurrent genetic abnormality in pediatric B-cell acute lymphoblastic leukemia (B-ALL) that creates the TCF3/PBX1 fusion gene and accounts for 3–5% of all cases.1 Studies from the Pediatric Oncology Group showed that the subgroup of children with pre-B-cell ALL and t(1;19) had a poorer response to treatment in comparison to other patients not carrying the translocation.2 The implementation of early-dose-intensified induction in the ALL-Berlin-Frankfurt-Münster trial was highly effective in improving the prognosis of children with TCF3/PBX1.3,4 Similar data were also reported by other groups, confirming that outcome is favorable when chemotherapy is adapted to the risk group.5 Translocation t(1;19) has also been described in a few patients with B-cell lymphoblastic lymphoma (B-LBL). 6 We describe two pediatric patients with TCF3/PBX1 positive BALL, unusually showing abdominal mass and ovarian enlargement at diagnosis, who experienced refractory/early relapse disease and failed second-line treatment. The first patient was a 12-year-old girl, admitted to another hospital for abdominal pain; chest X ray and ultrasound examination revealed bilateral pleural effusions and abdominal masses with left ovarian enlargement. The bone marrow aspirate revealed 50% leukemic blasts, while cerebrospinal fluid (CSF) analysis was normal. The TCF3/PBX1 transcript was identified by fluorescence in situ hybridization. The bone marrow aspirate, evaluated after a 4drug induction chemotherapy (including vincristine, daunorubicin, Lasparaginase, anddexamethasone) showedpersistenceof blasts (42%). Residual abdominal mass was surgically removed, and a subsequent course of chemotherapy (high-dose cytarabine, mitoxantrone) was administered. The patient was then referred to our unit. Flow cytometry analysis revealed 80% leukemic blasts in the bone marrow. CSF analysis revealed the presence of leukemic cells, and two parenchymal masses were described at magnetic resonance imaging: intradural spinal mass lesions at D11 and extradural frontal-parietal mass. Due to an intracranial hemorrhage following Rickham placement, it was decided to administer anti-CD22 immunotherapy (inotuzumab) instead of chemotherapy treatment. The bonemarrowevaluation after two doses of inotuzumab showed the persistence of blasts which were CD22(80%). A third-line treatment was administered (steroids and vincristine), but clinical conditions worsened rapidly until death due to disease progression. The second patient was a 5-year-old girl admitted to a local hospital for abdominal pain. Abdominal ultrasound showed ileus intussusception and right ovarian enlargement. Surgery was necessary to treat the intussusception, and ovary biopsy demonstrated infiltration by atypical cells. Bone marrow aspirate showed infiltration (66%) of pre-B leukemic cells and fusion gene screening revealed TCF3/PBX1. CSFwas normal. ALL induction chemotherapy was started (Studio Osservazionale LLA 2017 with vincristine, daunorubicin, PEG-L-asp, prednisolone, cyclophosphamide, cytarabine, 6-mercaptopurine, and intrathecal methotrexate). 7 Molecular assessment of minimal residual disease by polymerase chain reaction using two markers after induction (treatment day 33) and consolidation (day 78) therapy showed M1 neg, M2 neg and M1 neg, M2 positive <1 × 10–4, respectively. Chemotherapy was interrupted during delayed intensification therapy for febrile neutropenia; the bone marrow aspirate, performed for persistent aplasia and increased level of lactate dehydrogenase (16,742 U/L), revealed a full-blown relapse. The second-line treatment (IntReALLHR 2010)8 was administered for only 3 weeks due to a systemic infection sustained by Pseudomonas aeruginosa. A subsequent extramedullary relapse was documented by computed tomography scan (soft tissues of the submandibular region) 9 months after the diagnosis. Unfortunately, the patient was refractory to two consecutive immunotherapy treatment (inotuzumab followed by blinatumomab) and died of disease progression. Pre-BALL and pre-B LBL aremorphologically indistinguishable conditions; genetic and cell biological differences have not been fully clarified, and bone marrow aspiration is crucial for their discrimination: a diagnosis of pre-B ALL is performed when the percentage of blasts is higher than 25%, while pre-B LBL is diagnosed when manifesting as a tumor mass with minimal or absent marrow involvement. While the prognosis of newly diagnosed patients with t(1;19)(q23;p13) is similar to that of the general population of childrenwith B-ALL, their outcome after the occurrence of relapse is dismal.9 By contrast, few reports described TCF3/PBX1 positive B-LBL and the prognosis is unclear. Kubota-Tanaka et al. reported seven patients with TCF3/PBX1 B-LBL.6 Bone lesions were reported in three patients, and bone marrow minimal disseminated disease was described in all three cases that were evaluated. Three out of these seven patients experienced early relapse. The two patients described in the current report had TCF3/PBX1 BALL with ovarian involvement, and both experienced early relapse and