Brentuximab Vedotin for Refractory Anaplastic Lymphoma Kinase-Negative Anaplastic Large Cell Lymphoma in Leukemic Phase with RUNX3 Overexpression

Abstract

Anaplastic lymphoma kinase (ALK)- negative anaplastic large cell lymphoma (ALCL) is an aggressive CD30-positive non- Hodgkin lymphoma. ALK-ALCL rarely manifests with extensive bone marrow and peripheral blood involvement (known as “leukemic phase”). A 54-year-old woman was diagnosed with ALK-ALCL in leukemic phase, characterized by an extremely poor prognosis. Lymphoma cells in this case showed chromosomal translocation 1p36.1- encoded RUNX3 and overexpression of its protein. She was refractory to CHOP and salvage chemotherapy. Fortunately, she achieved complete remission with three cycles of Brentuximab vedotin (BV) and underwent umbilical cord blood transplantation. However, she died due to treatment-related mortality on day 129. The autopsy findings showed no lymphoma cells. Treatment strategy for ALK-ALCL is controversial, but the efficacy of BV in CD30-positive peripheral T-cell lymphoma not only as salvage regimens, but also in first line, has been reported in recent years. BV may be an effective option for ALK-ALCL in leukemic phase.

Super-enhancer-driven TOX2 mediates oncogenesis in Natural Killer/T Cell Lymphoma

“…RUNX3 has been implicated as a tumor suppressor or oncogene in different type of cancers [ 78 ]. We and others demonstrated that RUNX3 is oncogenic and its overexpression is correlated with poor prognosis and drug resistance in NKTL and anaplastic large cell lymphoma (ALCL) [ 17 , 79 , 80 ]. Interestingly, RUNX3 expression is also regulated by super enhancers in EBV-positive malignant B cells [ 76 ].…”

The Leukemic Phase of ALK-Negative Anaplastic Large Cell Lymphoma Is Associated with CD7 Positivity, Complex Karyotype, TP53 Deletion, and a Poor Prognosis

“…In the literature, ten cases of leukemic ALK-negative ALCL have been reported prior to the current study: eight (80%) patients had leukemic disease at initial diagnosis and two patients developed a leukemic phase five years and twenty years after initial diagnosis, respectively [ 16 , 19 ]. Most of the reported patients also had bone marrow involvement and/or thrombocytopenia [ 16 , 17 , 18 , 19 , 20 , 21 ].…”

“…Chromosomal translocations have been reported in three leukemic ALK-negative ALCL cases in the literature. One case had a translocation involving chromosome locus 1p36.1 (including RUNX3 ) and this case showed overexpression of RUNX3 [ 17 ], one case showed t(2;3)(p21;q21) [ 20 ], and one case had an inv(3)(p21q27) [ 34 ]. It is intriguing that four leukemic ALK-negative ALCL cases have harbored translocations involving 3q21-29, and it will be of interest to explore the potentially involved gene(s) on this locus.…”

“…Among the reported leukemic ALK-negative ALCL cases with follow-up data available, six of eight (75%) patients died, most within six months [ 15 , 16 , 17 , 18 , 20 , 34 ]. In the present study, the overall survival (OS) of the patients with leukemic ALK-negative ALCL was significantly shorter than that of the non-leukemic patients, confirming the poorer outcome of patients with leukemic phase ALK-negative ALCL.…”

“…The reported leukemic phase ALCL cases are almost all pediatric patients with ALK+ ALCL, which are most often associated with the morphologic features of small cell variant, t(2;5)(p23;q35), and a poorer prognosis [ 9 , 10 , 11 , 12 , 13 , 14 ]. Leukemic ALK-negative ALCL is extremely rare, with approximately ten cases reported in the literature to date, mostly as single case reports, and the patients had a poor outcome [ 15 , 16 , 17 , 18 , 19 , 20 , 21 ]. The clinicopathological features and molecular/genetic abnormalities underlying the leukemic phase of ALK-negative ALCL are largely unknown.…”