Ibrutinib Plus R-ICE Induces Responses in Patients With Relapsed/Refractory DLBCL

A phase I study found that adding ibrutinib to R-ICE (rituximab, ifosfamide, carboplatin, etoposide) resulted in an overall response rate of 90 percent (range = 68-99%) in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Craig S. Sauter, MD, of the Division of Hematologic Oncology, Lymphoma Service at Memorial Sloan Kettering Cancer Center in New York, and co-authors said the results were “an encouraging signal of efficacy with … [greater than] 50 percent [of patients] achieving complete remission (CR).” The study’s findings were published in Blood.

“In the post-rituximab era, approximately half [of] patients with relapsed or refractory DLBCL fail to achieve a chemosensitive response to standard salvage therapy and are thus ineligible to proceed to autologous [hematopoietic] cell transplantation (AHCT) with curative intent,” the researchers explained. Based on results from an earlier trial in which ibrutinib demonstrated single-agent activity in this setting, investigators conducted a single-center, dose-escalation study of ibrutinib plus R-ICE in transplant-eligible patients.

“[This study] confirms that ibrutinib in doses up to 840 mg daily combined with R-ICE is well tolerated, with no observed dose-limiting toxicities …”

—Craig S. Sauter, MD

The trial enrolled 21 patients (median age = 59 years; range = 19-75 years) with biopsy-confirmed CD20-positive DLBCL that relapsed after or was refractory to single-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) or similar therapies. Participants were required to have normal end-organ function, and those with HIV were eligible if they were on a stable antiretroviral regimen. Individuals were excluded if they had central nervous system involvement or serologic evidence of viral hepatitis.

Disease histology included de novo DLBCL (n=12; 57%) – both germinal center (GC; n=3; 14%) and non-GC (n=9; 43%) – primary mediastinal large B-cell lymphoma (n=4; 19%), and Richter’s transformation (n=5; 24%).

Patients received three cycles of R-ICE plus ibrutinib on days one to 21 of each cycle. Researchers used a 3+3 dosing design for ibrutinib, with patients receiving 420, 560, or 840 mg daily. All patients received growth factor support with either pegylated granulocyte-colony stimulating factor (GCSF) or daily GCSF with CD34-positive hematopoietic progenitor cell (HPC) harvest allowable after the second treatment cycle.

The researchers conducted an interim restaging evaluation with computed tomography after two cycles of therapy and full restaging after three cycles.

No patients reported dose-limiting toxicities (DLTs), so the 840 mg cohort was expanded to include 15 people. One person with non-GC DLBCL was removed from the study because of physician decision, so 20 patients were evaluable for response.

Most patients (95%) had “expected and transient grade ≥3 hematologic toxicities with recovery prior to each cycle,” the authors reported. Grade 3 events of “potential cardiovascular interest” included:

  • two sinus tachycardia events
  • two grade 3 syncopal events
  • one grade 3 hypotension

Four patients experienced febrile neutropenia and four grade 3 infections were reported (influenza, para-influenza, Clostridium difficile, and Staphylococcal catheter–associated blood stream infection).

One patient was removed from the study for asymptomatic pneumatosis coli based on interim restaging, and another patient self-discontinued because of grade 2 nausea. Both patients achieved CR after two cycles of treatment, proceeded to high-dose chemotherapy then AHCT, and remained progression-free at last follow-up.

The median number of platelet transfusions per patient over the three treatment cycles was two (range = 0-11 transfusions). Fifteen participants underwent R-ICE–primed CD34-positive HPC apheresis; of the 14 patients with collected HPCs, the median harvest was 5.5×106 CD34-positive cells/kg (range = 1.7-8.6×106 CD34-positive cells/kg). The researchers noted that the one patient who failed to collect HPCs was the only patient with HIV who received the 840 mg dose.

At a median of 14 months of follow-up (range not provided), one-year survival were:

  • event-free survival: 51% (95% CI 0.33-0.79)
  • progression-free survival (PFS): 62% (95% CI 0.43-0.90)
  • overall survival (OS): 65% (95% CI 0.46-0.93)

See TABLE for additional response outcomes. Eight of nine patients (89%; range = 52-99%) with non-GC DLBCL achieved a CR.

Of the 18 patients who achieved a response, 14 proceeded to high-dose chemotherapy and AHCT and two proceeded to allogeneic HCT. The one-year PFS and OS rates among patients who underwent transplantation are 73% (95% CI 0.51-0.99) and 82% (95% CI 0.62-0.99), respectively.

This study “confirms that ibrutinib in doses up to 840 mg daily combined with R-ICE is well tolerated, with no observed DLTs and preserved ability to mobilize HPCs,” the authors concluded. “Early signal of activity, especially in [patients with] non-GC [DLBCL], warrants further investigation in this subgroup.”

The trial is limited by its small patient population, single-center design, and lack of a comparator arm. Researchers are planning a multicenter, phase II study.

The corresponding authors report financial support from Pharmacyclics and Genentech.


Sauter CS, Matasar MJ, Schoder H, et al. A phase I study of ibrutinib in combination with R-ICE in patients with relapsed or primary refractory DLBCL. Blood. 2018 January 15. [Epub ahead of print]