Brachial plexus chloroma as a presenting feature of relapse in a child with KMT2A-rearranged acute lymphoblastic leukemia, a case report

Abstract

Approximately 30–40% of relapses in pediatric acute lymphoblastic leukemia (ALL) are extra-medullary. KMT2A gene rearrangements are common in patients with infantile ALL. Chloromas are rare tumors composed of collections of acute leukemic cells that typically involve the bone or skin. Exceptionally uncommon, chloromas invade the peripheral nervous system, a phenomenon termed “neuroleukemiosis.” We describe A 6-year-old girl with a history of pre-B ALL with CNS involvement and KMT2A rearrangement diagnosed initially at 4 months of age. During continuation therapy she developed a scalp mass that was confirmed to be a leukemic relapse. She underwent re-induction chemotherapy followed by blinatumomab with subsequent remission and proceeded to allogeneic hematopoietic cell transplant (HCT). Three years following HCT, she presented with brachial plexus palsy and was found to have a lymphoblastic chloroma invading the brachial plexus. Review of existing literature shows relapse in pediatric ALL patients presenting as brachial plexus chloroma has only been documented once before. It has long been suggested that KMT2A gene rearrangements play a role in development of chloromas in patients with AML, however it is still unclear what role KMT2A has in ALL. Here we report a rare case of ALL relapse that presented as a left arm palsy secondary to a leukemic chloroma invading the brachial plexus and aim to explore the potential role of KMT2A in the formation of ALL chloromas.

Introduction

Leukemic relapse occurring in sites other than the bone marrow is referred to as extra medullary relapse. Approximately 30–40% of relapses in pediatric acute lymphoblastic leukemia (ALL) are extra medullary.^{6, 18}Chloromas are rare tumors composed of collections of acute leukemic cells that have a propensity to invade the bone (including the orbit) and skin, but have also been reported to involve sites such as the lymph nodes, central nervous system, gastrointestinal tract, and testis.^{3, 5} Their incidence is estimated to occur in approximately three to nine percent of all acute myeloid leukemia (AML) patients, and much less frequently in those with ALL.⁴ When these tumors invade the peripheral nervous system, it is termed “neuroleukemiosis”, and this phenomenon is exceptionally uncommon.^7–11 ALL relapse in children presenting as a neuroleukemiosis has been documented a handful of times in the literature.^{2, 10, 11} Of these reports, brachial plexus chloroma as a presenting feature of ALL relapse, has only been described once before.²

KMT2A (formerly MLL) gene rearrangements are common in infantile ALL, occurring in up to 80% of patients^13,20–21. It has long been suggested that KMT2A gene rearrangements play a role in the development of chloromas in patients with AML^{12, 13, 19} However, it is still unclear what role KMT2A has in ALL, and if patients with KMT2A gene rearrangements are at increased risk for chloromas. Here we report an unusual case of ALL relapse that presented as a left arm palsy secondary to a leukemic chloroma invading the brachial plexus and aim to explore the potential role of KMT2A in this case.

Patient presentation:

We report on a caucasian female with a history of infantile pre-B cell ALL (KMT2A rearrangement). The diagnosis was originally made the patient presented with a ‘flu like illness’ and petechiae, but no overt CNS symptoms. Presenting white blood cell count was 350,000, and on diagnostic lumbar puncture CNS status was found to be CNS 2a. No chloromas were present on presentation and patient was originally treated with Children’s Oncology Group protocol AALL0631 therapy. In the continuation phase of therapy, she developed a scalp mass that was confirmed to be a leukemic relapse by morphology and flow cytometry. Bone marrow biopsy at the time of relapse demonstrated 7% lymphoblasts by flow cytometry, and CNS was clear of malignant cells. Interestingly, Fluorescent In Situ hybridization (FISH) from both the scalp lesion and bone marrow did not demonstrate KMT2A rearrangement, as was seen at diagnosis.

She underwent re-induction chemotherapy with regimen UK ALL R3 followed by blinatumomab with subsequent complete remission.⁶ She then proceeded to allogeneic hematopoietic cell transplant (HCT) using a matched unrelated donor and myeloablative conditioning (cyclophosphamide and total body irradiation). Her post-HCT course was unremarkable and she remained in a second complete remission.

Three years post-HCT at the age of six, she presented to the pediatrician with concern for weakness and decreased use of the left upper limb including loss of swing with walking and running for approximately four months. She was noted to have decreased range of motion in the affected extremity on exam and was unable to raise her left arm above her head. Initial imaging which included plain radiograph showed no acute bony joint or soft tissue abnormality. She was referred to orthopedic surgery for further evaluation where electromyography showed a lesion in the posterior cord affecting the radial and axillary nerves confirming left brachial plexopathy. At this point, her primary oncologist was contacted, and further evaluation was undertaken. The differential diagnosis was broad and included radiation induced injury, secondary malignancy (e.g. malignant peripheral nerve sheath tumor, schwannoma, or osteosarcoma), chronic graft versus host disease, unspecified autoimmune phenomenon, or an unreported injury. The patient was otherwise completely asymptomatic. A complete blood count was normal with no cellular atypia. Peripheral blood flow cytometry did not reveal an abnormal population of blasts. Magnetic resonance imaging revealed a soft tissue density extending from the left C5-C6 neural foramen to the left arm tracking along the left brachial plexus [Figures 1 & 2]. Positron emission tomography (PET) showed the brachial plexus mass to be 18F-fluorodeoxyglucose (FDG) avid. A biopsy was obtained, and flow cytometry identified a population of B lymphoblasts positive for CD19, CD34, CD38, and CD45 and negative for CD3, CD10, CD20, myeloperoxidase, TDT, and surface immunoglobulin light chains consistent with B-ALL. Karyotype obtained from the biopsy re-demonstrated t(11;19), the same translocation that was present at initial diagnosis. Lumbar puncture was obtained, and cerebrospinal fluid showed one white blood cell per microliter and cytospin positive for 20% blasts. Bone marrow was negative for any morphologic or cytogenetic evidence of leukemic infiltrate, and bone marrow minimal residual disease was <0.01% by flow cytometry.

Figure 1.

MRI T1 non-contrast image revealing brachial plexus infiltration with chloroma

Figure 2.

18F- fluorodeoxyglucose positron emission tomography scan revealing increased uptake in the left brachial plexus

The patient went on to receive CAR-T cell (tisagenlecleucel) after bridging therapy, with an unremarkable clinical course. No development of cytokine release syndrome occurred. At one and three-month post-tisagenlecleucel infusion, the patient had no evidence of disease on lumbar puncture, and PET imaging demonstrated an absence of 18F-FDG uptake. She then underwent a matched unrelated donor HCT and remains in remission at six months post-tisagenlecleucel and three months post-HCT. With physical therapy, strength and range of motion have begun to return to the affected extremity.

Discussion

Here we report a rare presentation of KMT2A rearranged ALL relapse presenting as a left arm palsy secondary to a brachial plexus chloroma. Neoplastic invasion of the CNS is a common presentation of relapse in acute leukemia. However, chloromatous infiltration into the peripheral nervous system; a phenomenon termed “neuroleukemiosis” is extremely uncommon.^7–11Neuroleukemiosis will typically present with peripheral neuropathies and/or masses, both of which were documented in our patient’s case. Our patient’s case is unique as chloromas occurring in the peripheral nerves of patients with ALL are exceedingly uncommon, and only a single additional case of brachial plexus chloroma in ALL has been reported.^2,10,11

A second interesting concept of this case was a potential association between KMT2A gene rearrangement and development of chloromas. 60–80% of infantile ALL patients harbor KMT2A rearrangements on chromosome 11q23^13,20–21. Although chloromas are rare in ALL, AML with KMT2A gene rearrangements often present with these tumors. In a review of 752 published reports of AML patients of all ages with 11q23 aberrations, 1.9% of patients were found to have chloromas. In that same review, 11 of 288 pediatric patients (3.8%) developed chloromas at some point during therapy¹². Other small studies have demonstrated greater incidences. For example, Park et el reviewed nine cases of pediatric AML with KMT2A rearrangements, three of which developed chloromas. In multiple reports, chloromas have been found on autopsy when clinicians had been previously unaware of their presence, suggesting that the overall rate of chloromas in AML with KMT2A rearrangements may in fact be underreported.¹² It is unclear what role KMT2A played in the phenotype of the patient’s relapse, particularly given the lymphoid origin.

Although rarely seen in ALL, a focal nerve palsy/neuropathy presenting acutely in a patient with previous ALL diagnosis should prompt further work up to rule out neuroleukemiosis. Early diagnosis is critical to maintain peripheral nerve function and requires a high index of suspicion.