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Institute for Quality and Efficiency in Health Care: Executive Summaries [Internet]. Cologne, Germany: Institute for Quality and Efficiency in Health Care (IQWiG); 2005-.

Institute for Quality and Efficiency in Health Care: Executive Summaries [Internet].

Unrelated donor allogeneic stem cell transplantation for Hodgkin’s lymphoma1

Executive summary of final report N05-03F, Version 1.1

Created: April 4, 2011.

Research question

The aim of this investigation was the benefit assessment of different types of allogeneic SCT with an unrelated donor in adult patients with HL compared with:

in each case withregard to patient-relevant outcomes.

In addition, this investigation aimed to compare different types of allogeneic SCT with each other in adult patients with HL with regard to patient-relevant outcomes:

  • allogeneic SCT with related versus unrelated donors
  • unrelated donor allogeneic SCT with prior myeloablative conditioning versus reduced-intensity conditioning

Methods

The target population of the studies to be assessed comprised adult patients with HL. Only those studies were included in which the proportion of adult patients with HL was over 80% or in which subgroup analyses had been performed for this patient group.

The investigation included the following endpoints that enabled an assessment of patient-relevant outcomes: survival time (overall survival), disease-free survival or a comparable endpoint, relevant therapy-related complications, health-related quality of life, and / or other parameters of quality of life (e.g. fatigue), as well as psychosocial aspects.

The literature search for relevant published studies was performed in the following bibliographic databases: EMBASE, MEDLINE, PubMed, as well as the Cochrane Central Register of Controlled Trials (Clinical Trials). The last search was performed in April 2010. In addition, from the time-point of the last search to June 2010, a supplementary search was conducted in the databases MEDLINE and EMBASE by means of the auto-alert function.

Furthermore, we screened reference lists of relevant secondary publications (systematic and narrative reviews,2 HTA reports, meta-analyses), publicly accessible study registries, as well as abstract volumes and websites of international conferences. Professional societies and study groups were asked to provide information on ongoing or completed, but still unpublishedstudies.

Besides randomized controlled trials (RCTs), the following study types were also included in the benefit assessment if a sufficient number of studies with a higher evidence level and / or quality was not available for the comparison of interest: prospective comparative studies with allocation to treatment groups on the basis of donor availability (so-called “genetically-randomized studies), prospective non-randomized studies with a comparator group, and retrospective comparative studies. Registry analyses comparing 2 treatment options with each other were also considered. If no separate presentation of related and unrelated donors was available within these studies, the authors were asked to provide differentiated information. In addition, non-comparative studies were included in the benefit assessment, as long as a minimum number of 10 patients had been included in the indication to be evaluated.

The risk of bias was assessed for each study included in the benefit assessment. The results of the patient-relevant outcomes reported in the studies were described in a comparative manner in the report. Meta-analyses were not performed, due to the heterogeneity between studies and within the presentation of results.

Results

A total of 30 studies fulfilled the inclusion criteria defined; 8 thereof could be included in the benefit assessment.

Only 5 studies were available for a direct comparison of allogeneic SCT with related versus unrelated donors. None of these studies was an RCT. In addition, 2 registry analyses (without a comparative presentation of results) and one prospective non-comparative study were included in the benefit assessment. The other research questions of the report could not be answered as no studies on them were identified.

In the 8 studies included, 454 patients underwent allogeneic SCT. Of these patients, 245 patients received a transplant from an unrelated donor (6 studies) and a further 60 received umbilical cord blood from an unrelated donor. In contrast, 121 patients received a transplant from a related donor. A further 28 patients received a transplant from a haplo-identical donor.

All patients in the studies included underwent intensive pre-therapy and, with a few exceptions, received a reduced-intensity conditioning regimen. The patient populations, as well as the treatment protocols applied, were only comparable to a limited extent.

Of the 5 studies with comparative presentations of treatment groups, only one study had an aim directly targeted towards the relevant comparison for the investigation of the partial research question “allogeneic SCT with related versus unrelated donors”. The other 4 studies primarily had other aims, but provided relevant post-hoc comparisons. The risk of bias was classified as high in the 5 studies. Due to their study design, the risk of bias in the 3 non-comparative studies was also assessed as high.

In the following text, results of studies with haplo-identical donors and unrelated umbilical cord blood donors are presented separately.

Data on overall survival were available for all 4 comparative studies with unrelated donors. However, statistically significant differences were not noted between treatment groups. A consistent tendency in favour of a donor type was not observed. The same applied to progression-free survival, which was reported in all studies. Only in one study was the difference between treatment groups statistically significant in favour of allogeneic SCT with an unrelated donor. Nor did the results on therapy-associated mortality or non-relapse mortality, which were reported in 3 studies, provide a uniform picture. In one study, the difference between treatment groups was not statistically significant, while in the second study a statistically significant difference was shown for patients with related donors. In the third study, a tendency was shown in favour of patients with unrelated donors.

In 3 of the 4 comparative studies with unrelated donors, data on acute and chronic GvHD (graft-versus-host disease) were reported. The frequency of acute GvHD (grade II–IV) varied greatly between the patient populations in the studies included. The frequency of chronic GvHD also varied. However, the definition of this endpoint was not unambiguous in all studies, which is why a direct comparison between studies was not possible. For both acute and chronic GvHD, a statistically significant difference in favour of the group of patients who received a transplant from a related donor was shown in only one study. In other studies no consistent tendency in favour of a donor type could be identified.

Umbilical cord blood donors

In the study with patients receiving umbilical cord blood from unrelated donors, no statistically significant differences between treatment groups were shown with regard to overall and progression-free survival. Data on transplant-associated mortality or non-relapse mortality were not reported in the study. For acute GvHD, at 70% the rates in both patient populations lay above those in the studies described above. The rates for both acute and extensive chronic GvHD were not statistically significantly different between treatment groups. Detailed data on infections in patients with HL were only available in this study. Bacterial infections were most frequent, followed by viral and fungal infections. No statistically significant differences between treatment groups were shown.

Haplo-identical donors

The overall survival of patients in the only study with haplo-identical donors was not statistically significantly different from that of the populations with related or unrelated donors included in this study. In contrast, compared with these two populations, a statistically significant difference was shown for progression-free survival in favour of haplo-identical donors. Regarding the rate of non-relapse mortality, in this study, very similar rates were shown in patients with haplo-identical donors and those with unrelated donors. In contrast, the rate in the group with related donors was statistically significantly increased. The acuteGvHD rates were comparable in all treatment groups. In the group of patients with haplo-identical donors, chronic GvHD rates were not statistically significantly lower.

Non-comparative studies

In the non-comparative study with unrelated donors, a tendency towards poorer results was shown for most endpoints versus the comparative studies. In the 2 non-comparative studies with umbilical cord blood transplants, regarding overall survival, results were comparable to those of the only comparative study that used umbilical cord blood from unrelated donors. In contrast, the estimates for progression-free survival were slightly lower.

No useable data could be extracted from the 8 included studies with regard to further serious therapy-related complications, secondary neoplasms, or quality of life and psychosocial aspects.

In summary, only isolated statistically significant differences could be found between patient populations with related and those with unrelated donors. The results should also be considered in the context of the small populations and the high risk of bias in the studies. An indication of an additional benefit or harm from unrelated donor SCT compared to related donor SCT cannot therefore be inferred from the studies available. Nor can equivalence be inferred from the results presented in this report, as specific methods are required to investigate equivalence or non-inferiority hypotheses.

Conclusion

In patients with HL, no direct comparative studies were identified for the comparison of unrelated donor allogeneic SCT versus autologous transplantation or cytostatic therapy without stem cell support. In principle, therefore, the question remains unanswered as to the benefit and harm from unrelated donor allogeneic SCT versus these therapy alternatives.

In contrast, a few studies could be identified for the comparison between unrelated donor allogeneic SCT and transplantation with a related donor. From these studies, neither proof nor an indication of an additional benefit or harm could be inferred for unrelated donor allogeneic SCT versus transplantation with a related donor. However, no equivalence can be inferred from the results presented in this report.

Further need for research is particularly evident in the analyses of studies on allogeneic SCT in HL. Studies not analysed according to donor types show that in patients with relapsed or treatment-resistant HL, allogeneic SCT with reduced-intensity conditioning substantially improves overall survival compared to chemo- and / or radiotherapy alone. These studies could not be included in the benefit assessment due to the fact that the analysis did not distinguish between donor type. In view of the question as to the relevance of donor type, treatment arms of such studies on allogeneic SCT should in future be analysed separately for patients with related donors and those with unrelated ones. Studies on allogeneic SCT with reduced-intensity conditioning versus autologous transplantation in (multiple) relapsed or therapy-resistant patients were not identified, so that it is unclear whether the survival advantage observed also applies to this comparison.

All studies reviewed for this report included (multiple) relapsed or therapy-resistant patients who had undergone intensive pre-therapy and in most cases had already received an autologous transplantation. Taking into account the results of the studies described above, it therefore seems justified, due to a lack of therapy alternatives, to offer these patients a potentially curative therapy in the form of allogeneic SCT, including unrelated donor SCT. However, the condition for this is that the patient’s medical status is sufficiently stable to undergo the strain of treatment and that he or she is informed about the uncertain evidence base.

Keywords: Hodgkin’s lymphoma, lymphoma, stem cell transplantation, allogeneic stem cell transplantation, autologous stem cell transplantation, chemotherapy, systematic review

Footnotes

2

As only few systematic reviews exist on the research question in this report, detailed narrative reviews were also considered.

Footnotes

1

Translation of the executive summary of the final report “Allogene Stammzelltransplantation mit nicht verwandtem Spender bei der Indikation Hodgkin-Lymphom” (Version 1.0 of 02.08.2010 and Erratum of 04.04.2011). Please note: This translation is provided as a service by IQWiG to English-language readers. However, solely the German original text is absolutely authoritative and legally binding.

Publishing details

Publisher:

Institute for Quality and Efficiency in Health Care

Topic:

Unrelated donor allogeneic stem cell transplantation for Hodgkin’slymphoma

Contracting agency:

Federal Joint Committee

Commission awarded on:

15.03.2005

Internal Commission No.:

N05-03F

Publisher’s address:

Institute for Quality and Efficiency in Health Care

Im Mediapark 8

50670 Cologne

Germany

Tel.: +49 -221/35685-0

Fax: +49-221/35685-1

ed.giwqi@ethcireb

www.iqwig.de

The Institute for Quality and Efficiency in Health Care (IQWiG) was commissioned by the Federal Joint Committee (G-BA) to perform a benefit assessment of allogeneic stem cell transplantation (SCT) with an unrelated donor in adult patients with Hodgkin’s lymphoma (HL).

© IQWiG (Institute for Quality and Efficiency in Health Care)

PMID: 23101103

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