Allogeneic stem cell transplantation in non-Hodgkin lymphoma - benefit remains unclear in Germany

The German Institute for Quality and Efficiency in Health Care (IQWiG) has investigated whether patients suffering from non-Hodgkin lymphoma have (better) chances of recovery in case of allogeneic stem cell transplantation (SCT). In its final report, presented at the end of May 2019, the Institute concludes that it is not possible to make statements on the benefit of this high-risk treatment. There is a lack of essential studies because of the often small patient groups. For some questions, the data gap could be closed with the help of disease-specific registries.

Non-Hodgkin lymphoma (NHL) is a form of lymph node cancer. If chemotherapy and radiotherapy are insufficient, an SCT is possible. If the transferred stem cells originate from the patient himself or herself, this is referred to as autologous transplantation. Since no undesired immune reaction occurs, this variant is usually preferable. However, there are also cases, when the allogeneic option is used. This involves the transfer of stem cells from another person.

The comprehensive data collection identified 95 documents as relevant for the present benefit assessment. Of these, 32 studies (36 documents) were evaluated.

The IQWiG researchers investigated a whole range of therapeutic situations. In some cases, they compared allogeneic SCT with autologous SCT, in other cases, with palliative treatment. IQWiG also included case series for those patient groups for whom all curative treatments had already been exhausted. However, a benefit can only be derived from such studies if obvious effects are observed.

The evaluation of allogeneic stem cell treatment is complicated by the fact that the various forms of the disease are rare. Even if all types of non-Hodgkin lymphoma are considered together, there are currently only about 250 patients per year in Germany who receive allogeneic stem cell transplantation. In addition, these patients are distributed among many subgroups. For some of these extremely rare lymphomas, IQWiG therefore even evaluated international aggregated statistics from individual case reports. In the commenting procedure that followed the publication of the preliminary report, IQWiG received additional information on individual studies.

Results:

• B-cell non-Hodgkin lymphoma (B-NHL) / post-auto-SCT: the median survival rate varied from 7,2 months (Nagle 2013) to 32 months (Van Kampen 2011). However, the differences in overall survival between the patients groups that have received allo-SCT and patients groups that have not received this type of treatment were not considered dramatic. Based on this, there was no benefit of the allo-SCT observed
• B-NHL / SCT-naïve: 7 studies reported overall mortality, only 1 - treatment-associated mortality (TRM) and 3 studies - non-recurrent mortality (NRM). However, due to the very low quality of the studies results, there were no reliable proofs of better treatment outcomes identified
• T-NHL / first line / allo-SCT vs. systemic therapy: no adequate data for overall survival, TRM, NRM or health-related quality of life was available
• T-NHL / first and higher lines / allo-SCT vs. auto-SCT: basically, no studies with suitable data on overall survival could be identified. In Smith 2013, there was no significant difference in allo-SCT versus auto-SCT for the named outcome based on the results of a comprehensive review of peripheral T-cell lymphoma treatment
• T-NHL / higher line / allo-SCT vs. fateful course of the disease: the median survival rate varied from 6 months (Beitinjaneh 2015) to 66,7 months (Czajczynska 2013). Although the survival rates of allogeneic transplant patients are higher than in the comparative collective groups, it might be misleading as such difference might be caused by inequality of the patients in terms of disease status. Other patient-relevant endpoints were operationalized differently in the included fatal outcome studies for a cross-sub-divisional comparison to be possible and could not be used or were not reported in the case of hepatosplenic and NK-cell lymphoma.

Therefore, the reviewed studies either contained no useful data in terms of overall survival or showed no clear advantage of allogeneic SCT in comparison with the control treatments. There were no studies identified that would allow conclusions on the quality of life of affected patients to be made.

Overall, IQWiG consequently concludes that the benefit of allogeneic SCT is unclear. At the same time, the Institute points out the risk of a rejection reaction of the newly formed immune cells against the patient (graft-versus-host disease), which always exists with an allogeneic donor. IQWiG sees this as a hint of harm.

In the commenting procedure, discrepancies between IQWIG’s benefit assessment and clinical experience were pointed out. In particular, this concerned those patients for whom all current treatments had already been exhausted. According to the opinion of the commenting clinicians, on average, about 30% of these transplanted patients have the survival rate at least of 5 years after the procedure, whereas without it almost all decease within the first year. The Institute could not resolve this discrepancy between clinical experience and study results, even after re-examination of the data. As long as the Institute has no comparative data, at least from a disease-specific registry, there is a risk of being misled by indirect comparisons. This is because it is not possible to know whether an observed difference is actually caused by this treatment alone and not by the overall better state of health of the patients with a higher survival rate.

The full details in German can be found here.

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