CD30: a new target for ALL?

CD30, also known as Ki-1 antigen, is a member of the tumor necrosis factor receptor (TNFR) family. The protein is strongly expressed on the malignant cells of classical Hodgkin lymphoma (Reed–Sternberg cells) [1], as well as on the surface of various other B-cell and T-cell lymphomas, though to a lesser extent [2,3]. A possible role of CD30 expression in lymphomatous pathogenesis remains unclear, but targeted therapy against CD30 in the form of the CD30 antibody–drug conjugate (ADC), brentuximab vedotin, has been demonstrated to be highly active in refractory classical Hodgkin lymphoma and anaplastic large cell lymphoma [4–6], and this agent is now approved for these indications by the Food and Drug Administration (FDA).

Thus far, there has been a dearth of data on CD30 expression in other hematologic malignancies, such as acute leukemias. Approximately 15 years ago, evidence for CD30 expression was reported in myeloid leukemia cell lines [7], suggesting that expression of this protein is not restricted to the lymphoid lineage. The presence of CD30 was also reported in a case of granulocytic sarcoma, by immunohistochemistry (IHC) [8]. Given the recent advent of CD30 targeted therapies, there has been growing interest to further study its prevalence. We previously performed a retrospective study of CD30 expression on primary samples of AML and myelodyspastic syndromes (MDS) by immunohistochemistry (IHC), and detected CD30 expression in approximately half of the evaluated cases. In our study, CD30 expression was associated with leukocytosis and the FLT3-ITD mutation [9]. More recently, a team from M. D. Anderson also examined a cohort of AML and MDS patient samples, but employed immunophenotyping by flow cytometry to identify CD30-positive blasts [10]. Using a cut-off of 20% expression, they considered 36% of these patients to be “positive” for CD30 expression by flow cytometry. They also reported that CD30 expression by IHC correlated with flow cytometric results [10]. Based on these pre-clinical results, there are current clinical trials testing the efficacy of using brentuximab vedotin in the treatment of CD30-positive acute myeloid leukemia (AML) either alone or in combination with traditional cytotoxic chemotherapy (ClinicalTrials.org, NCT01830777 and NCT01461538).

In the manuscript that accompanies this commentary, Zheng and colleagues from M. D. Anderson have followed up on their recent work in myeloid malignancies by assessing for the presence of CD30 expression in acute lymphoblastic leukemias (ALLs) of various subtypes and presentations [11]. They measured CD30, by use of flow cytometric immunophenotyping, in 78 consecutive cases of ALL, 44 with B-cell ALL and 34 with T-cell ALL. The authors employed an arbitrary threshold cut-off of 20%, above which CD30 expression was considered “positive.” By this criterion, 38% of T-cell ALL and 14% of B-cell ALL samples manifested CD30 expression by flow cytometric analysis. Intriguingly, they also reported increased CD30 expression in sequential samples from five patients with T-cell ALL, who were refractory to high-dose chemotherapy, concluding that this may suggest an up-regulation of CD30 after exposure to anti-leukemic cytotoxic therapy. They did not report a correlation of CD30 expression with karyotypic abnormalities, such as the BCR–ABL translocation.

These findings are intriguing, as they report for the first time the presence of CD30 expression in a sizeable proportion of cases of ALL, including both the B-cell and T-cell variants. They are also important because they may suggest a potential new target for promising antibody-based therapies in adult patients with ALL, in whom outcomes continue to be sub-optimal, despite aggressive and prolonged chemotherapeutic regimens, which are the current standard of care. Although the patient numbers are small, those patients with T-cell ALL who were refractory to previous cytotoxic treatments exhibited greater CD30 expression in serial samples, suggesting that a CD30-ADC may have a therapeutic role in those whose disease is refractory, a scenario associated with a particularly dismal prognosis. The authors do not present data on CD30 expression by IHC, which had correlated with their flow cytometric results in cases of AML. It would be interesting to demonstrate the presence and extent of CD30 expression on lymphoblasts by use of immunohistochemical techniques. In this study, a greater number of patients with T-cell ALL demonstrated CD30 expression, which is intriguing. Larger studies that evaluate the specific patient population of T-cell ALL can establish any association with karyotypic abnormalities or with the clinical progression of disease.

In summary, the data presented by Zheng et al. provide intriguing information with the potential for therapeutic impact. The possibility of novel therapies for adult ALL is a welcome development, and should be vigorously pursued. Such data can serve as groundwork for the planning of prospective clinical trials of CD30 targeted therapy for patients with T-cell and B-cell ALL and concurrent CD30 expression. Such trials would benefit from a correlative study that seeks to further identify subgroups of patients who are more likely to benefit from these targeted approaches in the future.

Potential conflict of interest:

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