Second Case of Leukaemia after Gene Therapy in France Interferes With Continuation of a Clinical Study Involving the Use of Retroviral Vectors in Germany

On Friday, 20th December 2002, Dr. Alain Fischer, Hôpital Necker des Enfants Malades, Paris, informed the Paul-Ehrlich-Institut on the diagnosis of a leukaemia-like disease in a second patient treated by gene therapy. In agreement with the Commission of Somatic Gene Therapy (Kommission Somatische Gentherapie (KSG)) of the Scientific Council of the German Medical Association, the Paul-Ehrlich-Institut informed the principal clinical investigators of clinical studies using live retrovirally modified cells in Germany within a day. After the first case of leukaemia in France, the continuation of the clinical studies was considered possible for three out of 16 notified clinical studies in Germany involving the use of retroviral vectors (see Joint Press Release issued by the Paul-Ehrlich-Institut and the German Medical Association of 22nd November 2002). Until the second case of leukaemia has been further clarified, the KSG and the Paul-Ehrlich-Institut will keep on clinical hold the CGD study (a congenital immune deficiency disease called Chronic Granulomatous Disease, see "Background Information"). Similar to the study in France, the CGD study uses retrovirally modified blood stem cells the risk of which is tentatively, and until further information will be obtained, estimated to be higher than that of other retrovirally modified cells. The continuation of two studies for the treatment of 'Graft-versus-Host Disease' (GvHD) by lymphocytes using a drug-inducible cell-killing (suicide) gene will be recommended shortly on condition that the appropriate patient information leaflet is again modified (to include a mention of the second case of leukaemia) (see "GvHD treatment by 'suicide gene' transfer and administration of Ganciclovir" in "Background Information"). The clinical hold of all other clinical studies in Germany using live retrovirally modified cells will be maintained. Some of these studies have already been completed.

Applications for two new studies using modified lymphocytes in HIV infected individuals and modified (synovial) cells from joints in patients suffering from rheumatoid arthritis have been submitted. The recommendations of the KSG and the decisions of the Paul-Ehrlich-Institut on those two studies and the above-mentioned CGD study will be discussed in February.

According to Prof. Klaus Cichutek, Vice President of the Paul-Ehrlich-Institut and chairman of the KSG, "the news about the second case of leukaemia in France marks a major setback for gene therapy involving the use of retrovirally modified blood stem cells". As he stated, a final assessment of the frequency of the occurrence of leukaemia following in vivo transfer of retrovirally modified blood stem cells could not currently be made. However, as he explained, with the exception of the two cases of leukaemia in France, no further cases of cancer had been reported or become publicly known, which had been suspected to have been caused by the use of particular vectors or cells. According to one of the possible, although currently unproved explanations, the leukaemias diagnosed during the SCID-X1 study could be induced by the use of retroviral gene transfer in blood stem cells in conjunction with other cell-growth promoting conditions. These other conditions may include the therapeutic gene used as an important critical factor. From that point of view, these cases would have to be investigated very thoroughly to gain certainty on whether stem cell gene therapy used in other life-threatening diseases would bear the same risk.

The Paul-Ehrlich-Institut and the KSG had been informed on a case of a patient in France developing a leukaemia-like disease after treatment with gene therapy for the first time in September 2002. In this French study, children suffering from the congenital immune deficiency disease SCID-X1 (type X1 of the "Severe Combined Immunodeficiency Disease") were treated with autologous (patient's own), modified blood stem cells. In this congenital disease, the normal functionality of the blood stem cells is restored by retroviral transfer of the intact form (allele) of the defective gene underlying the disease. The study has been on hold up until the present day. Following this case of leukaemia, the KSG last had discussed a possible continuation of the affected clinical studies involving gene therapy in Germany with the Paul-Ehrlich-Institut on the basis of the above results in November 2002.

Prof. Dr. Klaus Cichutek
Vice President of the Paul-Ehrlich-Institut
Chairman of the "Commission for Somatic Gene Therapy" (Kommission Somatische Gentherapie (KSG))

Background Information:

Since the clinical hold of all 16 studies involving the use of live retrovirally modified cells, three modifications of protocols (amendments) and one new application for the continuation of a study as well as one new application for a new study (application at the KSG and/or submission pursuant to Section 40 German Drug Law (AMG) at the Paul-Ehrlich-Institut) have been submitted in Germany.

1. Gene therapy of a monogenic hereditary disorder:

For the treatment of the life-threatening hereditary disorder (CGD) "Chronic Granulomatous Disease"), autologous blood stem cells are transplanted, the gene defect of which was corrected by retroviral transfer of a functionally intact gene. This serves to alleviate, or even cure, the congenital immune deficiency.

Status:1 registered study; on hold;

A modification of the protocol is available and is to be discussed again.

2. GvHD-treatment by 'suicide gene' transfer and administration of Ganciclovir:

Suppression of graft-versus-host disease during the treatment of leukaemia by transplantation of donor (allogeneic) blood stem cells and lymphocytes. The transfer of allogeneic donor lymphocytes is a conventional tumour therapy which, after prior chemotherapy and stem cell transplantation, leads to a suppression of leukaemia (donor-versus-leukaemia effect). However, a strong immunological reaction (Graft-versus-Host Disease; GvHD) caused by the transplanted lymphocytes can occur and may cause possibly life-threatening complications. If allogeneic donor lymphocytes are used into which a drug-inducible cell-killing gene ("suicide gene"; thymidin kinase gene of the Herpes simplex virus) was transferred by a retroviral vector, these cells can be killed in vivo by administration of the specific drug Ganciclovir in the event of a severe GvHD. This treatment therefore helps to avoid life-threatening complications.

Status: 4 registered studies; on hold,two of these studies will be two studies are recommended for continuation with restrictions (modifications of the protocols).

3. HIV-gene therapy:

The transfer of lymphocytes which harbour an HIV inhibiting gene serves to suppress HIV replication in vivo.

Status: 1 registered study withdrawn after clinical hold;

1 revised new application, submitted and to be discussed according to the regular procedure.

4. Local gene therapy of rheumatoid arthritis:

(Synovial) cells are removed from the joints affected by arthritis. After retroviral transfer of a gene (IRAP, "interleukin receptor antagonist"), the product of which can block factors contributing to the inflammation of the joint (cytokines), the modified cells are re-transferred to the joint. During subsequent surgical removal of the joint, which has so far been unavoidable in this patient group, the cells are removed again. .

Status: 1 registered study, on hold;

new application for the continuation of this study submitted; to be discussed according to the regular procedure.

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