Indications for HDT for lymphomas in the period 1987 – 2012
Figure 2 (12) – (22) provides an overview of the studies and indications for HDT for lymphomas in Norway from 1987 up until today. This type of lymphoma treatment was established at the Norwegian Radium Hospital in 1987 with three phase 2 studies for Hodgkin’s lymphoma (not published), very aggressive lymphomas (13) and relapse of aggressive lymphomas (16), respectively.
From 1996 the Norwegian Radium Hospital participated in a German phase 3 study in which patients with relapse of advanced and/or high-risk Hodgkin’s lymphoma were randomised to either HDT or standard chemotherapy without stem cell support (12). This study showed significantly better disease-free survival for the group that had received HDT (55 % compared with 34 % after three years). Corresponding treatment benefit for relapsed Hodgkin’s lymphoma was also demonstrated in a smaller, randomised study (24). These two studies are the main basis for today’s established indication for HDT for Hodgkin’s lymphoma with relapse within two years, with lack of response to primary treatment, or for other or later relapses (3, 25, 26).
In the phase 2 study that included patients with Burkitt’s lymphoma, HDT as consolidation in first remission resulted in substantially improved five-year progression-free survival – from 31 % to 71 % compared to historical controls treated with standard CHOP-based chemotherapy alone (13). The primary treatment of Burkitt’s lymphoma has gradually been greatly improved through intensive chemotherapy, so that HDT in first remission no longer provides any survival benefit (13). The treatment is therefore now recommended only for primary chemoresistance or relapse of Burkitt’s lymphoma (3, 25, 27).
For lymphoblastic lymphoma, HDT in first remission is still the alternative we recommend in Norway, based on the findings from an international, randomised multicentre study from the period 1992 – 97, in which Norwegian patients were also included. This study showed improved three-year disease-free survival with HDT compared to maintenance treatment in traditional doses (14).
HDT for diffuse large B-cell lymphoma (DLBCL) in second remission was established as the standard in Norway in 1995 (23), based on several phase 2 studies (16, 28) and one phase 3 study (29). The benefit of the treatment in first remission has also been investigated – without it being found that this results in better response rates or longer survival (15, 30). HDT is therefore not standard procedure for diffuse large B-cell lymphoma in first remission (3, 25, 27).
The above-mentioned phase 2 study of the relapsed aggressive lymphomas also included ten patients with transformed lymphomas in the period 1989 – 93 (16). From 1999 to 2004, patients with transformed lymphomas were included in a prospective phase 2 study at five Norwegian university hospitals where HDT was given in first remission (17). The results were good compared to historical controls, and when collated with data from several retrospective analyses, the study contributed to the conclusion that HDT is an option for transformed lymphomas (3, 27).
Mature T-cell lymphomas are a heterogeneous group of rare lymphomas with an aggressive clinical picture and poor prognosis (31). In the years 1990 – 2000, HDT was given to this group for chemosensitive relapse (19). From 2001 to 2007, patients with several types of mature T-cell lymphomas were included in a prospective phase 2 study led by the Nordic Lymphoma Group, where they received HDT in first remission. This study showed good results – five-year overall survival and progression-free survival of 51 % and 44 % respectively (18). The study confirmed the results of a smaller German phase 2 study (32). This regimen is now regarded as an established treatment alternative for systemic variants of mature aggressive T-cell lymphomas (3, 25, 27).
For mantle cell lymphoma (stage II-IV) the Nordic Lymphoma Group has conducted three prospective phase 2 studies with HDT in first remission (MCL1, 2 and 3). The results of MCL 1 (patients included 1996 – 2000) were disappointing and not substantially better than for historical controls treated with standard chemotherapy alone. One explanation for this was that few patients achieved good remission from induction therapy with dose-dense CHOP (maxi-CHOP) without rituximab (21). In the MCL 2 study (inclusion in the period 2000 – 06), both high dose cytarabine and rituximab were used for the induction therapy. This resulted in an increased remission rate – from 76 % in MCL 1 to 96 % in MCL 2 as well as median overall survival of more than ten years compared to the previous three years (21, 22). Based on the results of the MCL 2 study and a German randomised study (33), HDT is today considered to be the established procedure for mantle cell lymphoma in first remission (3, 25, 27).
A randomised European multicentre phase 3 study with Norwegian participation, in which patients with relapsed follicular lymphoma were included, was conducted in the period 1993 – 97. Fewer patients than desired were recruited, but there was higher progression-free survival and overall survival following HDT than after standard chemotherapy (20). HDT has since been an option for patients with recurrence of follicular lymphoma (3, 25, 27, 34).
As of today, HDT is therefore established procedure or an option for a number of clinical situations in lymphoma patients. Updated guidelines can be found on the website of the Norwegian Directorate of Health (3).