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A 41-year-old man presented with 4 weeks of progressive dysphagia, reflux, involuntary weight loss, night sweats, dyspnea on exertion, and an enlarging left neck mass. His primary care physician initially suspected esophageal disease, but a barium swallow study showed luminal irregularities suggestive instead of external compression.
Neck and chest CT scans (see Figure 1) showed a large mass infiltrating nearly the entirety of mediastinum and involving supraclavicular fossae bilaterally (more so on the left than on the right), with extrinsic occlusion of innominate veins bilaterally, encasement of the great vessels of aortic arc, displacement of the trachea to the right, and extrinsic pressure upon the esophagus with displacement to the left — as well as a large left pleural-based nodule with partial left lung collapse. Further staging studies revealed bulky adenopathy throughout the mesentery and retroperitoneum.
A surgeon performed an excisional biopsy of a left supraclavicular node, which was consistent with T-cell lymphoblastic lymphoma: diffuse proliferation of intermediate- to large-sized lymphoid cells with irregular nuclei, dispersed chromatin, prominent nucleoli, and small amounts of cytoplasm (see Figure 2). The malignant cells expressed TdT, cytoplasmic but not surface CD3, and CD7. There was weak CD5 expression and absence of CD4, CD8, and B-cell and NK cell markers; the Ki67 proliferation index was greater than 90 percent. Because CD1a and surface CD3 were both negative, the patient's neoplasm was classified as early T-cell precursor (ETP) lymphoblastic lymphoma. Bone marrow was biopsied and did not show obvious involvement by the neoplastic process.
"Early T-cell precursor lymphoblastic lymphomas represent a small subset of high grade lymphoid neoplasms. About 85 percent of lymphoblastic lymphomas and acute lymphoblastic leukemias (ALL) are of B-cell origin, and of the 15 percent that are of T-cell origin, most are either thymic (also called cortical) or mature (also called medullary) immunologic subtypes," says Daniel DeAngelo, MD, PhD, senior clinical investigator in the Dana-Farber/Brigham and Women's Cancer Center (DF/BWCC) Adult Leukemia Program, who has a longstanding interest in ALL. "The thymic (cortical) subtype expresses surface CD3 and CD1a; the mature (medullary) subtype expresses surface CD3 but not CD1a; the ETP subtype, as in this case, expresses neither surface CD3 nor CD1a, but often expresses myeloid-associated antigens like CD33."
"Unfortunately," he adds, "the ETP lymphoblastic lymphomas are very difficult to treat successfully. There was a good paper in Nature last year (Zhang J et al, Nature 481: 157–163 (12 January 2012)) that showed this subtype of disease has a distinct gene expression and mutation profile compared to other T-ALL, including mutations activating RAS signaling. We currently treat such patients using regimens designed for ALL, but that may need to change, since they do poorly with that approach compared to patients with other T-ALL and lymphoblastic lymphomas."
"Patients with lymphoblastic lymphomas are typically treated by physicians from the leukemia team, since they are approached similarly to patients with ALL," notes David Steensma, MD, the DF/BWCC Adult Leukemia Program oncologist who cared for the patient. "When I first met this patient, I was quite worried about him, given the bulk of his disease and his disease subtype — though his young age and excellent performance status prior to diagnosis gave us some hope."
"The patient had bulky disease with impending SVC syndrome at diagnosis," he continues. "His face felt puffy and swollen, and he had edema and plethora on the first day I saw him. His local physicians had needed to place a femoral central venous catheter because the usual vessels in the neck could not be accessed. We first treated him with high-dose corticosteroids to reduce the bulk of his disease, which helped temporarily. We then treated him with an ALL combination chemotherapy regimen, which he was able to receive partly at DF/BWCC and partly in partnership with his excellent community oncologist in his hometown in Maine, Mahesh Pandey, MD."
Although the patient had a partial response to the ALL regimen, his disease quickly progressed. He was then treated with nelarabine (506U78, a prodrug for Ara-GTP) as "salvage" therapy, but without any effect.
"The patient developed pericardial tamponade, which required urgent drainage, and recurrent pleural effusions that mandated placement of a chest tube and home oxygen," explains Dr. Steensma. "After the nelarabine failed him, his performance deteriorated rapidly. He received palliative radiotherapy to the chest and neck, as well as high-dose corticosteroids, but that only helped for a few weeks. If this had been another subtype of T-cell acute lymphoblastic leukemia/lymphoma, where up to 50 percent of patients' tumors have activating mutations in Notch pathway members, he could have participated in an interesting Phase I trial with a gamma secretase (Notch pathway) inhibitor that is ongoing here at DF/BWCC — but ETP-ALL is characterized by a lack of Notch mutations."
"There are a number of newer monoclonal antibodies currently in clinical trials that may change the natural history of ALL," says Dr. DeAngelo. "At the recent American Society of Hematology annual meeting, I presented results of an early-phase study of inotuzumab ozogamicin — a humanized anti-CD22 antibody conjugated to the same calicheamycin cytotoxin as the formerly approved AML drug gemtuzumab — in patients with relapsed/refractory B-ALL whose malignant cells expressed CD22. We observed a 74-percent complete response rate, with many patients becoming minimal residual disease (MRD)-negative within just a few weeks of starting therapy — the best response we've ever seen for a single agent in this disease setting. So we've just opened a Phase III trial comparing this approach to conventional chemotherapy in patients with relapsed B-ALL."
He continues, "Blinotumomab — a member of a new class of bi-specific T-cell engagers (BiTE antibodies) that targets CD19 and CD3, and thereby recruits T-cells to the vicinity of malignant lymphoblasts — is another antibody that we've studied recently which also has striking activity in relapsed B-ALL. These antibodies are now being studied in newly diagnosed disease. It is a research priority to develop comparable antibodies for T-ALL, including ETP-ALL, where there is such unmet need."
Richard Stone, MD, director of the DF/BWCC Adult Leukemia Program, states, "Overall, patients with T-cell lymphoblastic lymphoma and leukemia do quite well with contemporary treatment approaches. But I have cared for a number of patients with ETP-ALL, including patients with the CALM-AF10 molecular rearrangement; consistent with the published literature, their outcomes have been poor, whether one uses chemotherapy regimens designed for ALL or acute myeloid leukemia." He concludes, "Based on the expression of CD33 that is often seen in this condition, I have used gemtuzumab ozogamicin in a few patients with relapsed/refractory disease, and based on the efficacy of deacetylase inhibitors in T-cell lymphomas, have used vorinostat or romidepsin — unfortunately, also without good results. We need new therapies for this subset of patients."