High-throughput sequencing of archival cerebrospinal fluid specimens defines B-lymphoblastic leukemia clonal composition.

Detailed characterization of the B-lymphoblastic leukemia (B-ALL) cells which invade the central nervous system (CNS) has been limited by practical challenges. To test whether the clonal composition of the cerebrospinal fluid (CSF) reflects the primary B-ALL tissue, we applied immunoglobulin (Ig) high-throughput sequencing (HTS) of archival CSF cytospin preparations from six patients with morphologically defined CNS involvement. We discovered that most CSF clones are detectable at some timepoint in the primary tissue, but that shifting clonal abundance is prevalent across tissue sites between diagnosis and relapse. Ig HTS of CSF cytospins may improve understanding of sanctuary site dissemination in B-ALL.

How I approach B-lymphoblastic lymphoma in children.

There are limited data pertaining to the prognostic features and optimal therapeutic approach for the 20%-25% of children with lymphoblastic lymphoma (LLy) who have the B-lymphoblastic subtype. Outcomes are favorable following treatment modeled after acute lymphoblastic leukemia (ALL) regimens, but prognosis is dismal after relapse, and there are no established features for predicting therapy response. Ongoing US and international trials will include the largest cohort of uniformly treated patients with B-LLy to date, providing an opportunity to define clinical and molecular predictors of relapse and to establish a standard of care for treatment to improve outcomes for this rare pediatric cancer.

Allogeneic Bone Marrow Transplant as a Cure for Refractory T-Cell Large Granular Lymphocytic Leukemia in an Adolescent.

T-cell large granular lymphocytic (T-LGL) leukemia is a rare, typically indolent neoplasm with a median age of onset above 60 years. Pathogenesis involves clonal T-cell expansion, and nearly all reported pediatric cases have been associated with concurrent autoimmune disease. Immunosuppressive therapy often mitigates sequelae, but definitive cure is not routinely achieved. Here we present an otherwise healthy 13-year-old with T-LGL leukemia refractory to all standard treatments. Our patient ultimately underwent allogeneic bone marrow transplant (BMT) and is now stable in remission 3 years post-BMT. BMT may offer a viable definitive cure for refractory T-LGL leukemia in very young patients.

Successful Bone Marrow Transplantation With Intensive Post-transplant Intrathecal Chemotherapy for CNS Relapsed AML in 2 Infants.

BACKGROUND: Infant acute myeloid leukemia is a rare but aggressive form of leukemia. OBSERVATION: We report 2 children who presented with hyperleukocytosis, subsequently diagnosed with infant acute myeloid leukemia, and both developed isolated central nervous system relapse while on chemotherapy. Both infants underwent successful bone marrow transplantation with myeloablative conditioning (thiotepa, busulfan, and cyclophosphamide) without radiation, followed by 12 empiric post-transplant lumbar punctures with intrathecal cytarabine. Both patients tolerated these therapies well, and are without infections, chronic graft-versus-host disease, or any post-transplant sequelae. CONCLUSION: Nonradiation-based conditioning followed by empiric central nervous system-directed intrathecal chemotherapy may be considered for high-risk infants with leukemia.

Myeloablative Carboplatin and Thiotepa With Autologous Stem Cell Rescue for Nonmedulloblastoma High-risk CNS Tumors in Young Children.

Malignant central nervous system (CNS) tumors in young children have a poor prognosis and pose a therapeutic challenge. We describe 11 patients with high-risk CNS tumors (6 atypical teratoid/rhabdoid tumor, 4 nonmedulloblastoma CNS embryonal tumors, and 1 glioblastoma multiforme) who received 32 consolidation cycles of myeloablative carboplatin/thiotepa followed by autologous peripheral blood stem cell rescue. All patients underwent successful stem cell harvest without significant complications. Mean time to absolute neutrophil count ≥0.5×103/µL was 10.2±1.3 days and the mean length of hospital stay was 15.7±3.0 days. There were no regimen-related deaths. Five-year event-free survival and overall survival were 45.5±15.0% and 58.4±16.3%, respectively. Tandem carboplatin/thiotepa consolidation with autologous stem cell rescue is well-tolerated in young children with nonmedulloblastoma CNS tumors.

Acute lymphoblastic leukemia clonal distribution between bone marrow and peripheral blood.

Acute lymphoblastic leukemia (ALL) is often composed of numerous subclones. Here we test whether the clonal composition of the blood is representative of the bone marrow at leukemia onset. Using ultra-deep IGH sequencing, we detected 28 clones across 16 patients; 5/28 were only in the marrow. In four patients, the most abundant clones differed between sites, including three in which the dominant medullary clones were minimally detectable in the blood. These findings demonstrate that the peripheral blood often underrepresents the genetic heterogeneity in a B-ALL and highlight the potential impact of tissue site selection on the detection of minor subclones.

A clinical perspective on immunoglobulin heavy chain clonal heterogeneity in B cell acute lymphoblastic leukemia.

B cell acute lymphoblastic leukemia (B ALL) is a genetically heterogeneous neoplasm often demonstrating extensive subclone diversity within each patient's disease. The immunoglobulin heavy chain (IGH) locus is a marker of clonal variation in B ALL due to its intrinsic role in B lymphocyte development and its diverse Vh(D)Jh rearrangement patterns. B ALL IGH evolution may contribute to limitations in minimal residual disease (MRD) monitoring methods. Evolving technologies for IGH high-throughput sequencing (HTS) have demonstrated MRD detection as sensitive as 1 cell in 1,000,000. These methods may enhance the surveillance of B ALL in the setting of extensive subclone evolution and provide opportunities for detection and intervention before the onset of relapse. However, HTS MRD methods will need to be evaluated in the context of clinical trials in order to gain further insights about the clinical relevance of such sensitive B ALL MRD detection.