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Professor of Medicine
Department of Medicine
Harvard Medical School
Chief of the Division of Leukemia
Department of Medical Oncology
Division of Hematologic Malignancies
Dana‐Farber Cancer Institute
Daniel J. DeAngelo, MD, PhD, has disclosed that he has received consulting fees from Amgen, Autolus Therapeutics, Celgene, Forty Seven, Incyte, Jazz, Novartis, Pfizer, Shire, and Takeda and funds for research support from AbbVie, GlycoMimetics, and Novartis.
In this commentary, I describe my current approach to diagnosis and initial workup for patients with acute lymphoblastic leukemia (ALL). Although the diagnosis of ALL can be made using blood or bone marrow, it is typical to perform a bone marrow examination in any patient who has peripheral blasts and/or cytopenia. The bone marrow examination should include flow cytometric analysis in order to determine the blast immunophenotype and assessment of an expanded array of antigens including CD19 and CD22 specifically, because there are FDA-approved immunotherapies for patients with ALL such as blinatumomab and inotuzumab ozogamicin that target these 2 antigens, respectively.
Cytogenetic Karyotyping and Molecular Diagnostics
In addition to flow cytometric analysis, standard cytogenetic karyotyping and molecular diagnostics should be performed in all patients with ALL for risk stratification. Molecular assessments of importance include PCR for the BCR‑ABL1 transcript that indicates Philadelphia chromosome (Ph)–positive disease, and next-generation sequencing (NGS) for molecular abnormalities such as TP53 mutations or IKZF1 deletions. This screening is important because patients are often triaged between Ph-positive and Ph-negative diseases. In our center, we try to get an assessment of BCR-ABL1 transcript or cytogenetics by FISH within 2 days of diagnosis to determine if a tyrosine kinase inhibitor, such as imatinib or dasatinib, should be included in the initial induction regimen.
In addition, there is a new entity that we refer to as Ph-like signature, which has a gene expression profile similar to that of Ph-positive disease that results in a large panoply of activated tyrosine kinases. There are now several platforms available to identify Ph-like disease. Although testing for Ph-like signature should ideally be performed at initial diagnosis, it is particularly important for patients with relapsed/refractory disease, as it can help guide subsequent treatments.
Assessment of Cerebrospinal Fluid and Extramedullary Disease
The initial workup should also include assessment of cerebrospinal fluid (CSF) for central nervous system (CNS) involvement. In pediatric patients, this is often performed prior to initiation of chemotherapy. In adult patients, however, CSF testing is often deferred until clearance of the peripheral blasts. Although there is no true consensus on when CNS involvement should be assessed in adult patients, earlier sampling is likely better because patients can present with asymptomatic CNS disease. I recommend following the treatment protocol for pediatric-inspired regimens, in which an early lumbar puncture and risk stratification are performed.
Another important consideration in the diagnostic workup for patients with T-cell ALL is to assess for extramedullary disease such as a mediastinal mass, which is present in approximately two thirds of patients with T-cell ALL. Therefore, routine imaging such as a chest x-ray or CT scans should be performed. In patients with widespread lymphadenopathy, a PET/CT scan is often employed. If patients have evidence of extramedullary disease such as lymphadenopathy, splenomegaly, or a mediastinal mass, they need to be followed closely.
Assessment of Measurable Residual Disease
Finally, once a patient has been treated with induction therapy and is being assessed for response, it is of utmost importance to assess measurable residual disease (MRD). Most assays that assess MRD including flow cytometry, PCR, and NGS are able to detect 1 malignant cell out of 10,000 cells, and this must be incorporated into the treatment response assessment of all patients with ALL. For patients with Ph‑positive disease, molecular testing should also be included in the assessment of MRD. Moreover, baseline MRD characterization of leukemic clone to facilitate subsequent MRD analysis can be considered at the time of initial diagnosis.
What are your questions and thoughts on the initial diagnosis and workup of ALL? I encourage you to answer the polling question and share your thoughts in the comments box below.
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