Recent interest has focused on the use of mobilised peripheral blood stem cells for transplantation and several centres have investigated methodologies of T cell depletion in vitro. A small number of patients have received T depleted PBSC and it appears that haemopoietic reconstitution is particularly rapid. This may be an effective way to overcome problems of slow engraftment or graft rejection. Pre-emptive administration of donor lymphocytes is proposed when there is molecular evidence for leukaemic relapse.
To date the best results have been obtained with either of two protocols:
In both the transplant complications have been very low (less than 10% combined risk of graft failure or severe GvHD) and leukaemia-free survival has been good (approx 60% at 2 years for patients with acute leukaemia transplanted in first remission). These results are significantly better than with depletion of donor T cells alone.
There were significant variations in the rate of engraftment between different centres. Analysis is complicated by confounding differences in protocol, but the most important factors predicting slow engraftment seem to be low cell dose and the use of single dose, rather than fractionated radiation (but timing of radiation might be important).
This has become the largest application of CAMPATH1 antibodies. Children have largely been treated according to Protocol 02 (CAMPATH1G in vivo with CAMPATH1M ex vivo) and this has proved to be successful with good control of GvHD and graft rejection and satisfactory leukaemia-free survival (Bristol). So far there are few published data with which to compare the results.
Some adults have been treated on the same protocol (mainly with acute leukaemia), but others (mainly with CML) have received just CAMPATH1G in vivo both before and after the transplant (Protocol 06). The donor marrow has not been manipulated but conventional GvHD prophylaxis of CyA and MTX has been given. This also appears to give improved control of chronic GvHD, although it is by no means eliminated. Relapse of CML does occur, but not as frequently as with T depleted transplants in matched siblings. Pre- emptive treatment by donor lymphocyte infusions has often been effective.
A randomised trial to compare CAMPATH1H in vivo against conventional GvH prophylaxis was initiated by the Hammersmith team but hardly any patients were recruited, partly because of lack of interest by other centres and partly because of patient preference for T cell depletion. This trial has now been abandoned.
Several groups have studied in vitro T cell depletion of mobilised peripheral blood leukocytes, comparing CAMPATH1M, CAMPATH1G and CAMPATH1H. They all appear to work as well as with bone marrow. A few clinical studies have started and the initial results are encouraging. Engraftment is particularly rapid with the large cell doses available from PBSC.
Supplies of CAMPATH1M are now very limited. Future production is still uncertain. Despite the success of this antibody for in vitro T cell depletion, we feel it is important to develop protocols using the IgG antibodies which have a better prospect of being made more widely available.
CAMPATH1G or CAMPATH1H in vivo pre- and post-transplant (Protocol 06) is recommended with a suggested dose of 10 mg daily for 10 days from day -5 to day +4. Post-transplant CyA is recommended. We are interested to compare the effectiveness of CAMPATH1G and CAMPATH1H and would like the opportunity to monitor serum antibody levels in some of these patients.
Any centre planning to use T-depleted PBSC should first carry out a program of in vitro development to establish the methodology. CAMPATH1H ”in the bag• would be the preferred method. All centres carrying out PBSC studies are requested to send a report to the TAC for collation and distribution so that we can jointly agree on one or two consensus protocols. Antibodies will not be supplied for continued ad hoc studies.
Protocol guidelines will be drawn up by the Oxford team following discussion with principal investigators. Copies will be available on request. Variations from the protocol guidelines will be strongly discouraged but should always require prior discussion and approval by the coordinating investigators (GH & HW).
It is essential that all protocols are properly approved by local ethical committees and, if required, by the national regulatory authority. The coordinating investigator (GH) can provide supporting data and answer questions which may arise. Clinical investigators are responsible for arranging any insurance or indemnity which may be necessary. UK investigators must apply to the Medicines Control Agency for a Doctor‘s and Dentist‘s Exemption Certificate in respect of any clinical trial which they propose; this includes all of the applications of CAMPATH1 antibodies described above. Similar requirements may be in place in other countries.
We do not recommend or support the use of CAMPATH1 antibodies for treatment of GvHD. Anecdotal results to date have been very poor. Short-term benefit has been claimed in some cases, but the majority of patients have succumbed to infection or recurrence of GvHD. Supplies of antibody are too limited to embark on any studies in this situation at present.
We find it very hard to support other ad hoc requests for CAMPATH1 antibodies, either from new centres who require it for just a few patients or from established centres who have a special case. These requests are difficult to handle because they diminish the amount of antibody available for protocol studies and lead us into many difficulties relating to legal liabilities etc.
Converted to HTML by Steve Cobbold (19th August 1996)
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