A novel salvage therapy: combination lenalidomide and azacitidine for relapsed acute myeloid leukemia

Patients with acute myeloid leukemia (AML) and myelodysplasia (MDS) have limited salvage treatment options following relapse after allogeneic stem-cell transplantation (allo-SCT).¹ Most are treated with intensive chemotherapy, which is poorly tolerated and represents an area of unmet need.²

Lenalidomide (LEN) and azacitidine (AZA) have shown antitumor activity in AML; however high rates of graft-versus-host disease (GvHD) have been associated with LEN administration post-transplantation. In murine transplantation models, AZA has been shown to ameliorate GvHD. This study by Charles Craddock, from the University of Birmingham and Queen Elizabeth Hospital, UK, and colleagues, evaluated the tolerability and activity of LEN/AZA in post-transplantation relapse in AML and MDS. The VIOLA trial (ISCRCTN98163167, EudraCT 2013-002118-11) is a prospective, open-label, dose-finding, multicenter, phase I trial to determine the maximum tolerated dose (MTD) of LEN in combination with AZA.³

Study design and patient population:

The study recruited 29 patients (median age: 54 years [range, 18–73]) who had relapsed following allo-SCT for AML (n = 24) and MDS (n = 5). Patients received AZA (75mg/m² for 7 days) and escalating doses of LEN on days 10–30. Maximum tolerated dose (MTD) and dose allocation were estimated by a modified Bayesian continuous reassessment method (CRM). This allowed clinical judgements to be incorporated into calculations ensuring treatment was applicable in practice prior to implementation and guided dose escalations and de-escalations.

MTD

• Patients evaluable for MTD assessment: n = 21
• MTD (LEN dose in combination with AZA) = 25 mg daily

Safety

• Twenty treatment-related non-hematologic toxicities were observed in ≥ 10% of patients at ≥ grade 3
• Acute GvHD grade 2–4 developed in 3 patients, all of whom responded to steroid therapy
  • LEN 15 mg (n = 2): grade 2 acute skin GvHD (n = 1), grade 3 liver GvHD (n = 1)
  • LEN 25 mg (n = 1): grade 2 GvHD in lower gut
• No GvHD-related mortality was observed
• Deaths: (n = 22)
• Resistant/progressive disease: 19
• Infectious complications: 3

Efficacy

• Median follow-up: 23 months
• In patients receiving at least 3 cycles of treatment:
• Major clinical response: 47% (7/15)
  • Complete response, n = 3
  • CR with incomplete blood count recovery, n = 3
  • Partial response, n = 1
  • Median age: 52 years (28–68)
• Median overall survival in responders and non-responders: 27 months versus 10 months, P = 0.004
• Response rate of total cohort (n = 29): 24%
• Mainly limited exposure to trial therapy due to progressive disease
• CD8⁺ T cells had impaired interferon-γ/tumor necrosis factor-α production at relapse; this was not reversed by LEN/AZA administration

This study has shown LEN can be administered safely in combination with AZA, post-allograft, and that LEN/AZA combination exerts significant antileukemic activity without reversing biologic features of T-cell exhaustion. The use of LEN/AZA as a salvage therapy provides a promising novel treatment option to a patient population with few alternate options. Moving forwards, a comparative study between LEN/AZA and intensive chemotherapy is warranted. Furthermore, LEN/AZA should be considered as a maintenance therapy or pre-emptively administered to patients with evidence of MRD.