Idiotype Immunization Following High-Dose Therapy and Autologous Stem Cell Transplantation for Non-Hodgkin Lymphoma,

The treatment of low and intermediate grade subtypes of malignant lymphoma continues to evolve. Mantle cell lymphoma (MCL) accounts for 6% of all non-Hodgkin lymphoma (NHL) and is generally considered incurable. Although high response rates can be achieved with initial chemotherapy, median survival is only 3–4 years. Intensified consolidation with high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) has been reported to improve progression free survival (PFS) but most patients eventually relapse. Indolent lymphoma accounts for 35% of all NHL and is associated with a median survival of 9 years. Like MCL, it is also generally considered to be incurable, and the PFS also appears to be improved following HDT/ASCT. With this background, we initiated a pilot study evaluating idiotype (Id) vaccination following HDT and ASCT for patients with MCL, indolent NHL and transformed NHL to evaluate the ability of Id-keyhole limpet hemocyanin (KLH) to induce immune responses when administered following HDT/ASCT, and to evaluate overall survival (OS) and PFS for patients receiving Id-KLH post-ASCT.

We enrolled patients with non-Hodgkin lymphoma between 2001–2006. Patients may have received any number of prior treatment regimens, and had adequate organ function. Tumor specific-Id was prepared from a lymph node or bone marrow biopsy, or peripheral blood sample. Patients whose lymphoma cells expressed surface Ig were then eligible to continue on the study. All patients had measurable disease after obtaining tissue for vaccine production. Following tissue collection, patients proceeded to undergo a standard cytoreductive chemotherapy regimen prior to stem cell mobilization, and HDT followed by ASCT. Vaccination was initiated at least 3 months after transplantation, and repeated for four consecutive months. This was followed by a final vaccination 2 months thereafter. 250mg GM-CSF was administered alone by daily injections for three days following each Id/KLH vaccination to enhance the immunogenicity and antitumor effects. Patients were subsequently followed for clinical and radiographic signs of relapse.

Fifteen patients were treated: 8 with MCL, 4 with follicular lymphoma, 1 with small lymphocytic lymphoma, and 2 with transformed lymphoma. Id immunizations were well tolerated with injection site reactions being the most commonly reported adverse effects. With a median follow-up of approximately 6.3 years (range 1–9), PFS and OS at 9.05 years from time of ASCT are 59% and 52%, respectively, as 8 of 15 patients are alive and are in a complete remission. The PFS and OS for patients with MCL median follow-up of up to 6.3 years from time of ASCT was 62.5% and 60%, respectively. During this follow up, no patient with MCL showed disease progression after 4 years or died after 6 years.

Early and Id-specific immune responses are seen in vaccinated patients post-ASCT as treatment for both indolent and more aggressive lymphomas. Durable clinical responses were seen with this approach, even in this heavily pre-treated population. The early appearance and durability of specific immune responses may be attributable to the administration of Id immunization during a window of immune reconstitution following HDT/ASCT. The use of HDT/ASCT provides an ideal opportunity to note effective immune responses to vaccine based on the unique Ig protein expressed by tumor cells. Our data suggests the idea that there is an immune component that can be exploited in this setting, and this strategy may extend to more aggressive lymphomas. Id vaccination in patients with MCL who undergo ASCT shows early promise of providing durable remissions and prolonged overall survival. Further investigation of the use of Id vaccination in the post-transplant setting for MCL is necessary on a larger scale to confirm these findings.

No relevant conflicts of interest to declare.