Ibrutinib Produces Responses in Patients With Refractory Classic Hodgkin Lymphoma


Key Points

  • Ibrutinib produced responses in two heavily pretreated patients who had received allogeneic hematopoietic cell transplantation.
  • A potential mechanism of activity is ibrutinib-mediated donor lymphocyte activation.

In a letter to The New England Journal of Medicine, Hamadani et al describe near-complete and complete responses with the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica) in two heavily pretreated patients with classic Hodgkin lymphoma.

Patient 1

The first patient was a 28-year-old women who had undergone haploidentical allogeneic hematopoietic cell transplantation after receiving eight prior therapies, including autologous hematopoietic cell transplantation and brentuximab vedotin (Adcetris). The patient developed fevers, night sweats, and weight loss at 2 months after transplantation; combined positron-emission tomography (PET) and computed tomography (CT) showed relapsed disease above and below the diaphragm, with these findings confirmed by repeat biopsy.

The patient began treatment with ibrutinib at 560 mg/d, after having received tapered tacrolimus over 4 weeks with no evidence of graft-vs-host disease. Fevers and night sweats resolved within 2 weeks after starting ibrutinib, and near-complete regression of disease was observed by PET-CT at 2 months. The response persisted for 4 months.

Patient 2

The second patient was a 38-year-old man who had undergone allogeneic hematopoietic cell transplantation after five prior therapeutic regimens, including autologous hematopoietic cell transplantation. The patient had relapsed 17 months later while receiving brentuximab vedotin maintenance, with lymphadenopathy above and below the diaphragm and symptomatic splenic lesions being observed. At relapse, the patient did not have graft-vs-host disease and was not receiving immunosuppressive therapy.

Ibrutinib at 560 mg/d was started after local radiotherapy to the spleen, with CT showing improvement in lymphadenopathy at 1 month; PET-CT showed a complete response at 4 months, and the response was ongoing > 6 months later.

Potential Mechanisms

With regard to potential mechanisms of action of ibrutinib in this setting, as discussed by the investigators, a pretreatment biopsy from patient 1 showed uniform moderate Bruton’s tyrosine kinase expression in Reed-Sternberg cells. However, Bruton’s tyrosine kinase expression is seen in only approximately 20% of patients with classic Hodgkin lymphoma.

Other potential mechanisms include ibrutinib inhibition of interleukin-2–inducible kinase in type 2 helper (Th2) T cells and potentiation of type 1 helper T-cell (Th1)-based antitumor immune responses. Plasma samples from patient 1 showed secretion of the Th1 cytokine interferon-inducible protein 10, suggesting the possibility of Th1 polarization in this patient.

The investigators noted that donor lymphocyte activation mediated by ibrutinib could be a mechanism of activity in classic Hodgkin lymphoma patients (as well as in patients with other hematologic cancers) undergoing allogeneic hematopoietic cell transplantation.

They concluded: “The activity of ibrutinib in patients with classic Hodgkin's lymphoma warrants prospective assessment.”

Mehdi Hamadani, MD, of Medical College of Wisconsin, is the corresponding author for the New England Journal of Medicine letter.

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