α-Interferon with very-low-dose donor lymphocyte infusion for hematologic or cytogenetic relapse of chronic myeloid leukemia induces rapid and durable complete remissions and is associated with acceptable graft-versus-host disease

Abstract

Donor lymphocyte infusion (DLI) results in complete cytogenetic remission (CCR) of relapsed chronic-phase chronic myeloid leukemia (CML-CP) after allogeneic stem cell transplantation (SCT) in up to 80% of patients. The main complication of DLI is graft-versus-host disease (GVHD). Decreasing the dose of DLI is associated with less GVHD but also with a longer interval between treatment and CCR. We postulated that combining alpha-interferon (alpha-IFN) with DLI would enable us to decrease the dose of DLI, thereby limiting GVHD, and at the same time to decrease the interval between DLI and CCR for patients with either a hematologic or cytogenetic relapse. For molecular relapses, we hypothesized that because of a lower tumor load, very low doses of DLI without alpha-IFN could be an effective treatment. Two groups of CML-CP patients treated with DLI at a very low dose of 0.5 to 1.0 x 10(7) mononuclear cells per kilogram, containing 2 to 6 x 10(6) CD3+ T cells per kilogram, were analyzed: 13 patients with a cytogenetic or a hematologic relapse after allogeneic SCT (group A) were treated with additional alpha-IFN therapy at a dose of 3 x 10(6) U 5 d/wk, and 8 patients with a molecular relapse were treated without alpha-IFN (group B). Twelve patients from group A reached a CCR. The median interval between DLI and CCR was 7 weeks (range, 5-18 weeks) for group A. All patients with a CCR reached complete donor chimerism at a median of 10 weeks after DLI (range, 6-121 weeks). Eleven patients reached molecular remission at a median of 15 weeks after DLI (range, 8-34 weeks). In group B, all patients reached a molecular remission at a median of 14 weeks (range, 12-29 weeks). Five patients from group A developed acute GVHD grade II to IV and extensive chronic GVHD. In group B, 1 patient developed acute GVHD grade II to IV and subsequently developed extensive chronic GVHD. With a median follow-up of 62 months, 10 patients in group A are alive and in continuous CCR. One patient had a molecular relapse, for which she successfully received additional DLI; another patient reached molecular remission only after 5 doses of DLI. Two patients from group A died of a gram-negative sepsis, and 1 died of an acute myocardial infection. In group B, all patients are alive and in molecular remission with a median follow-up of 20 months. One patient's disease progressed but was successfully treated with DLI plus alpha-IFN. In conclusion, very-low-dose DLI in combination with alpha-IFN as treatment for cytogenetic or hematologic relapses of CML-CP after allogeneic SCT reduced the interval to obtain a CCR with acceptable GVHD when compared with the literature. Patients with a CCR also reached complete donor chimerism and complete molecular remissions. For patients with a molecular relapse, very-low-dose DLI alone is sufficient to induce molecular remissions in most patients and is associated with limited GVHD.

Long-term follow-up of myeloablative allogeneic stem cell transplantation using Campath ‘in the bag’ as T-cell depletion: the Leiden experience

“…Sex-matched donor/patient combinations, chimerism was determined on post-Ficoll bone marrow using a STR-PCR based protocol. 20 Complete donor chimerism was defined as 100% donor chimerism at 3 months after alloSCT. Toxicity was graded according to the World Health Organization toxicity scale.…”

Donor leukocyte infusions to treat hematologic malignancy relapse following allo-SCT in a pediatric population

“…Newer strategies under development include infusions of activated DLI 12 or low-dose DLI augmented with biological agents such as interferon-a. 13 Alternatively, strategies directed at preventing relapse in the first place may be efficacious. For example, post transplant imatinib appeared beneficial at reducing the relapse rate in Philadelphia-chromosome positive ALL patients with detectable minimal residual disease.…”

Intentional donor lymphocyte-induced limited acute graft-versus-host disease is essential for long-term survival of relapsed acute myeloid leukemia after allogeneic stem cell transplantation

“…18,31 Previously, we demonstrated that treatment of patients with low-dose interferon-α could shorten the interval between the DLI and onset of the immune response. 23 Therefore, interferon-α was implemented in our strategy to boost the immune response by activating rapid and efficient antigen-presentation. 23,[32][33][34] In contrast to treatment of chronic myeloid leukemia, we used relatively high doses of DLI to induce a rapid immune response with high amplitude, although we anticipated that this would occur at the cost of GvHD.…”

“…21,22 If no acute GvHD was observed within 3 weeks after DLI, the immune response was further stimulated by treatment with interferon-α. 23 We hypothesized that the combination of efficient cytoreduction by re-induction therapy for initial disease control, with DLI administered in rapid succession under circumstances favoring the development of an early and profound immune response may be essential to eradicate relapsed leukemia, but likely at the cost of GvHD. …”