Research question:

This investigation comprises the following 4 research questions:

1) benefit assessment of allogeneic stem cell transplantation in adult patients with aggressive B-cell non-Hodgkin lymphoma (not including primary central nervous system [CNS] lymphomas) who did not respond to treatment with high-dose chemotherapy and autologous stem cell transplantation or have had a relapse in comparison with another treatment without curative intent (fateful course of disease) (“B-NHL/post-auto-SCT”)

2) benefit assessment of allogeneic stem cell transplantation in adult patients with aggressive B-cell non-Hodgkin lymphoma (not including primary CNS lymphomas) who did not respond to treatment without stem cell transplantation or have had a relapse in comparison with high-dose chemotherapy and autologous stem cell transplantation (“B-NHL/SCT-naïve”)

3) benefit assessment of allogeneic stem cell transplantation in the first-line therapy of adult patients with T-cell non-Hodgkin lymphoma (except cutaneous T-cell lymphomas) requiring systemic drug therapy in comparison with treatment with systemic drug therapy alone or in combination with high-dose chemotherapy and autologous stem cell transplantation (“T-NHL/first line”) and

4) benefit assessment of allogeneic stem cell transplantation in adult patients with T-cell non-Hodgkin lymphoma (not including cutaneous T-cell lymphomas) with progression or relapse following systemic therapy in comparison with another treatment without curative intent (fateful course of disease) (“T-NHL/higher line”)

each with regard to patient-relevant outcomes.

Conclusion:

This benefit assessment is based on a total of 32 analysed studies on 4 research questions, which investigated allogeneic stem cell transplantation in patients with B-NHL or T-NHL at different points in the course of treatment as well as 11 studies documenting the fateful course. The searches yielded only studies with lower evidence levels. On the basis of such studies, conclusions on benefit were possible only in case of dramatic effects. Studies that would have permitted drawing conclusions on the patients’ quality of life were not found for any of the comparisons. The evidence base does not reveal whether allogeneic stem cell transplantation is associated with benefits. The occurrence of graft-versus-host-disease, a specific adverse effect following allogeneic stem cell transplantation, resulted in a hint of harm of allogeneic stem cell transplantation for all research questions.

Research question 1 (B-NHL/post-auto-SCT): For the comparison of allogeneic stem cell transplantation with fateful course in patients with progressive or relapsed B-NHL following autologous stem cell transplantation, only non-comparative studies were found, from which only the outcomes of overall survival and graft-versus-host disease were considered. Studies with usable data were found on B-NHL overall as well as on the subentities of diffuse large B-cell lymphoma and mantle-cell lymphoma. For the outcome of overall survival, no benefit or harm of allogeneic stem cell transplantation was found, either across all subgroups or for the considered subentities.

Research question 2 (B-NHL/SCT-naïve): For the comparison of allogeneic versus autologous stem cell transplantation in B-NHL, retrospective comparative cohort studies were found on the subentities of diffuse large B-cell lymphoma, follicular lymphoma grade 3, transformed lymphoma, and mantle-cell lymphoma. For these subentities, there is no hint of greater benefit or harm of allo-SCT with regard to the outcome of overall survival. With regard to the outcomes of treatment-related or non-relapse mortality, there is no hint of greater benefit or harm of allogeneic stem cell transplantation in diffuse large B-cell lymphoma. No related data were available for the other considered subentities. The outcome of disease-free survival was unusable as a patient-relevant outcome due to the operationalization used in the studies; consequently, a conclusion regarding benefit or harm was not possible. For the outcome of adverse events, only fatal adverse events were reported. This did not result in a hint of benefit or harm of allogeneic stem cell transplantation.

Research question 3 (T-NHL/first line/allo-SCT versus systemic therapy): For the comparison of allogeneic stem cell transplantation with systemic drug therapy in treatment-naïve T-NHL, 1 comparative study was found on the histological subtype of precursor T-cell lymphoblastic lymphoma. This study did not supply any usable data for the benefit assessment on mortality or morbidity outcomes. For the outcome of adverse events, only fatal adverse events were reported. This did not result in a hint of benefit or harm of allogeneic stem cell transplantation.

Research questions 3 + 4 (T-NHL/first and higher line/allo-SCT versus auto-SCT):

1) Research question 3 (T-NHL/first line): For the comparison between allogeneic and autologous stem cell transplantation in treatment-naïve T-NHL, 1 retrospective comparative cohort study on T-NHL overall was found. This study did not supply any usable data. Furthermore, the final results of 1 prematurely terminated RCT on this question are intended to be published by the authors in mid-2019.

2) Research questions 3+4 (T-NHL/first and higher line): For the comparison of allogeneic and autologous stem cell transplantation in T-NHL, 3 further retrospective comparative cohort studies on T-NHL overall and 1 retrospective comparative cohort study on the subentity of natural killer cell lymphoma were found; their populations received heterogeneous prior therapy and was therefore not unequivocally assignable to either research question 3 or 4. However, usable data were available only for T-NHL overall. This resulted in no hint of greater benefit or harm of the intervention to be assessed with regard to the outcome of overall survival. For the outcome of adverse events, only fatal adverse events were reported. This did not result in a hint of benefit or harm of allogeneic stem cell transplantation. No further outcomes were suitable for use in the benefit assessment.

3) Research question 4 (T-NHL/higher line): For the comparison of allogeneic and autologous stem cell transplantation in higher-line therapy of T-NHL, 1 retrospective comparative cohort study on T-NHL overall was found. This study did not supply any usable data.

Research question 4 (T-NHL/higher line/allo-SCT versus fateful course): For the comparison of allogeneic stem cell transplantation with fateful course in patients with T-NHL and progression following systemic therapy, only non-comparative studies were found, from which only the outcomes of overall survival and graft-versus-host disease were considered. In addition to studies presenting T-NHL across subentities, studies on the subentities of hepatosplenic lymphoma and natural killer cell lymphoma were found. No hint of benefit or harm of allogeneic stem cell transplantation with regard to overall survival was found for T-NHL overall or for either of the presented subentities.

For the time being, allogeneic stem cell transplantation is always associated with the risk of graft-versus-host disease. The benefit of allogeneic stem cell transplantation in B-NHL and T-NHL, in contrast, is generally unclear due to a lack of reliable studies.

To obtain reliable data for future use, all patients with NHL should be registered in a disease-specific registry from the date of diagnosis.

Publisher

Institute for Quality and Efficiency in Health Care

Topic

Allogeneic stem cell transplantation in aggressive B-cell non-Hodgkin lymphoma and in T-cell non-Hodgkin lymphoma

Commissioning agency

Federal Joint Committee

Commission awarded on

16 March 2019

Internal Commission No.

N17-02

Address of publisher

This report was prepared in collaboration with external experts.

The responsibility for the contents of the report lies solely with IQWiG.

According to §139b (3) No. 2 of Social Code Book (SGB) V, Statutory Health Insurance, external experts who are involved in the Institute’s research commissions must disclose “all connections to interest groups and contract organizations, particularly in the pharmaceutical and medical devices industries, including details on the type and amount of any remuneration received”. The Institute received the completed Form for disclosure of potential conflicts of interest from each external expert. The information provided was reviewed by a Committee of the Institute specifically established to assess conflicts of interests. The information on conflicts of interest provided by the external experts and external reviewers is presented in Chapter A8 of the full report. No conflicts of interest were detected that could endanger professional independence with regard to the work on the present commission.

External experts

• Birgit Burkhardt, University Hospital, Münster, Germany
• Renate Heinz, Vienna, Austria
• Dawid Pieper, Institute for Research in Operative Medicine, Witten/Herdecke, Germany,
• Barbara Prediger, Institute for Research in Operative Medicine, Witten/Herdecke, Germany

IQWiG thanks the external experts for their collaboration in the project.

IQWiG employees

• Daniela Rüttgers
• Elke Hausner
• Tatj ana Hermanns
• Katharina Hirsch
• Anne Rummer
• Britta Runkel
• Stefan Sauerland
• Fueloep Scheibler
• Wiebke Sieben
• Andrea Steinzen