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Haematological Malignancies
Table 1: Summary of Selected Reported of this study suggest that profound transcranial Doppler (TCD) should
Series of Allogeneic Stem Cell Transplantation
be avoided.
in Multiple Myeloma
As a result of the experience of full-intensity alloSCT, investigators
Functional Imaging Allogeneic Stem Cell Transplantation
explored the use of RIC alloSCT in MM to reduce TRM and to permit
Conditioning Regimen n CR (%) TRM (%) EFS OS Ref.
the application of alloSCT to older patients. Several studies have
Cyclophosphamide/TBI 39 47.2 31.5 13.3 (5y) 28.1 (5y) 17
shown that this approach is feasible, with a significant reduction in
Melphalan/TBI 78 54.7 35.3 36.2 (5y) 44.1 (5y) 17
Bu/Cyclo/TBI 15 53.3 17 31 (6y) 77 (6y) 53
TRM (see Table 1). By definition, in the absence of intensive
Cyclo/TBI (± idarubicin) 53 19 34 Med. 18m Med. 25m 18
chemo-radiotherapy, RIC alloSCT is to a large extent dependent on
Mel/TBI 72 38 22 31.4 (10y) 39.9 (10y) 36
allogeneic GvM effects.
19
A number of phase II studies have reported
Reduced-intensity Conditioning Allogeneic Stem Cell Transplantation
similar findings.
20–22
In these studies, the presence of chronic GvHD
Conditioning Regimen n CR (%) TRM (%) EFS OS Ref.
was associated with the achievement of CR and improved overall
Flu/Bu/ATG 41 24 17 41 (2y) 62 (2y) 20
survival (OS)/PFS.
Flu/TBI
200Gy
52 27 17 29.4 (1.5y) 41 (1.5y) 22
ASCTbarb2rightFlu/TBI
200Gy
16 62 16 36 (3y) 62 (3y) 24 Two prospective ‘biologically randomised’ studies of RIC alloSCT have
ASCTbarb2rightFlu/Bu 46 33 11 – 57 (2y) 4
been published. IFM-99-03/04 enrolled patients with poor-risk disease
ASCTbarb2rightFlu/Mel/ATG 17 73 18 56 (2y) 74 (2y) 54
as defined by the presence of del13 by FISH along with elevated
ASCTbarb2rightTBI
200Gy
54 57 7 55 (2y) 78 (2y) 19
β
2
-microglobulin (>3mg/l).
23
Those without a sibling donor received
ASCTbarb2rightFlu/Bu/ATG 65 62.2 10.9 Med. 32m Med. 35m 23
tandem ASCT, whereas those with a sibling donor received a
ASCTbarb2rightFlu/Mel/TBI2
200Gy
45 64 36 13 (3y) 36 (3y) 55
sequential ASCT/RIC alloSCT, the latter conditioning utilising
(Non-relapse/ref.) 12 – – 80 (3y) 80 (3y)
antithymocyte globulin (ATG) (Genzyme). This study showed no
CR = complete relapse; TRM = treatment-related mortality; EFS = event-free survival;
OS = overall survival; Cyclo = cyclophosphamide; ASCT = planned tandem autologous stem
benefit in terms of OS/event-free survival (EFS) and no patients in
cell transplant (ASCT) followed by an alloSCT; Flu = fludarabine; TBI200Gy = single fraction
either arm achieved durable EFS. Bruno et al. reported on a group of
total body irradiation; Bu = intravenous busulphan; ATG = antithymocyte globulin;
Mel = high-dose melphalan; med. = median; m = month; y = year.
unselected patients who were biologically randomised in a similar
fashion to tandem ASCT or a sequential ASCT/RIC alloSCT.
24
The RIC
deletion17p by fluorescence in situ hybridisation (FISH) being alloSCT arm demonstrated significantly superior OS/EFS. While no
associated with adverse outcome.
11–13,14
prospective trials have compared full-intensity with RIC alloSCT in this
setting, an EBMT analysis has shown similar OS with both approaches.
Following the first alloSCT for MM in the early 1980s, a retrospective As might be expected, RIC alloSCT had a lower TRM but a higher
analysis of the European Group for Blood and Marrow Transplantation relapse rate and lower PFS.
25
(EBMT) registry data with a median follow-up of 6.5 years reported
that myeloablative alloSCT achieved an overall survival of 40% but Generally speaking, outcomes with matched unrelated donor (MUD)
was associated with a high TRM.
15
A subsequent comparison of alloSCT have improved with time and in many settings have
patient cohorts transplanted in 1983–1993 and 1994–1998 showed become equivalent to matched sibling transplantation. However,
that TRM decreased from 46 to 30%
4
due to better patient selection, retrospective studies in myeloma have shown a significantly higher
particularly transplantation earlier in the course of the disease. TRM than sibling alloSCT,
26
and myeloablative MUD alloSCT is not
Subsequently, there were several reports from single centres currently recommended and should be carried out only in the context
indicating that with stringent patient selection, better results could be of prospective clinical trials. However, the role of RIC MUD alloSCT
obtained (see Table 1). Two prospective, randomised studies have remains to be defined. Encouraging results have been reported for
included a biological randomisation to alloSCT. In the US Intergroup TRM of approximately 20–21% at two and three years.
27,28
Clearly,
S9321 study, patients were randomised to autologous SCT, further prospective trials are warranted in order to better define the
chemotherapy or Cy/total body irradiation (TBI) ablative alloSCT if a role of RIC MUD alloSCT for patients with myeloma.
matched sibling was identified. The alloSCT arm was closed early as a
result of high TRM (53%). However, a subsequent analysis with No prospective trials have compared functional imaging (FI) with RIC
seven-year follow-up showed identical survival at 39% with slightly alloSCT in MM, and the type of RIC regimen and the therapy previously
superior progression-free survival (PFS) in the alloSCT arm (22 versus administered may matter. However, an EBMT analysis has shown
15%). There was also evidence of a plateau on the survival curve of similar OS with both approaches, although the RIC alloSCT group had
the alloSCT arm.
16
Similar results were obtained from a retrospective a lower TRM but a higher relapse rate and thus lower PFS.
25
This may
British Society of Blood and Marrow Transplantation (BSBMT) study of reflect the heterogeneity of the patient populations, and further
139 patients <55 years of age, which showed superiority for adaptation of RIC alloSCT may be required to maximise the antitumour
melphalan/TBI over cyclophosphamide/TBI conditioning in both TRM effect in association with the well-established reduced TRM. In
and relapse rates.
17
In an attempt to reduce TRM and the high patients >40 years of age or in those deemed unfit for an FI alloSCT,
incidence of GvHD, patients <55 years of age entered into the RIC alloSCT has been shown to reduce TRM. By definition, as FI
Haemato-Oncology Co-operative Group (HOVON) 24 MM study who conditioning is not given, RIC transplants are largely dependent on the
had an HLA-matched sibling received a Cy/TBI T-cell depleted (TCD) adoptive immunotherapeutic effect of GvM. As such, a ‘tandem’
alloSCT.
18
Patients without a donor were randomised to receive a sequential strategy has been developed to generate a minimal tumour
Cy/TBI autologous stem cell transplant (ASCT) or no further burden pre-RIC alloSCT using high-dose melphalan-conditioned ASCT.
chemotherapy. Despite TCD, the TRM remained high at 34%, and there A number of phase II studies have reported the feasibility and efficacy
was a high relapse rate, with only three out of 53 alloSCT recipients in of such a strategy, especially in association with limited chronic
complete relapse (CR) at a median follow-up of 38 months. The results GvHD.
20,21,25,29
Bruno and colleagues reported on a biologically
62 EUROPEAN HAEMATOLOGY
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