Barker et al, 2003r
Early study demonstrating feasibility of a non-myeloablative conditioning regimen in cord blood transplantation. Non-randomised with switch to Flu/Cy/TBI after 4 graft failures seen in Flu/Bu/TBI group. Engraftment rates superior in Flu/Cy/TBI group, particularly in regard to platelets, although this group received a higher nucleated cell dose. Establishes Flu/Cy/TBI as suitable RIC regimen in cord blood transplantation.
Brunstein et al, 2007r
Extension of earlier study from Minnesota group supporting the use of Flu/Cy/TBI as a non-myeloablative conditioning regimen using cord blood (in particular double unit cords) for adult patients with haematological malignancies, who lack suitable donors. Heterogeneous disease groups do not allow any specific conclusions to be drawn regarding specific disease subtypes.
Brunstein et al, 2011r
Study evaluating RIC in multiple centres with comparison between two different cell sources (dUCB v haplo). Results presented are restricted to cord blood as this protocol relates to the conditioning regimen. All patients received Flu/Cy/TBI, further extending the data with this regimen and demonstrating comparable results in multiple centres.
Brunstein et al, 2012r
Registry analysis which allows comparison between Flu/Cy/TBI and other RIC regimens in dUCB transplantation. In the context of limitations of these studies, and the fact most of the Flu/Cy/TBI recipients were from a single centre, contributes to establishing the Flu/Cy/TBI regimen as the RIC regimen of choice in cord blood transplantation, particularly as major causes of mortality in Flu/TBI/other were infection and organ failure, outcomes one tries to avoid when selecting a RIC regimen.
Bejanyan et al, 2015r
A retrospective study from the Minnesota group which observed a significant reduction in acute GVHD for patients who received higher doses of mycophenolate mofetil (1g three times daily, instead of twice daily). There was no delay in engraftment or excess infectious complications in the higher MMF dose cohort.
Evidence Level
(NHRMC)*
|
Study |
Study Design |
Disease |
Is the conditioning regimen**
consistent with the protocol?
|
Comments |
III-2 |
Barker et al, 2003r |
Prospective, non-randomised |
High risk/advanced haematological malignancy
|
yes |
Flu/BU/TBI v Flu/CY/TBI |
III-3 |
Brunstein et al, 2007r |
Single arm descriptive study |
Risk/advanced haematological malignancy
|
yes |
Flu/Cy/TBI |
III-1 |
Brunstein et al, 2011r |
Multi-centre phase 2 study |
Advanced or high risk leukaemia or lymphoma
|
yes |
|
III-2 |
Brunstein et al, 2012r |
Retrospective registry analysis |
AML and ALL |
Yes – dUCB-TCF, other dUCB |
dUCB-other (Flu/Mel/TBI 70%, Flu/Bu/TBI 20%)
|
* NHMRC Evidence Hierarchy (accessed online August 2022) ** Chemotherapy ONLY
dUCB: double umbilical cord blood; TCF: TBI, cyclophosphamide, fludarabine
Efficacy
A summary of the evidence supporting the effect of this protocol is below:
Study |
No.of Patients
|
Donor/Stem cell source |
Engraftment
ANC/Plts
|
NRM/TRM
|
Relapse Rate |
OS (1yr/2yr) |
DFS |
Comments |
Barker et al. 2003r |
Flu/Bu/TBI (21)
Flu/CY/TBI (22)
|
Single or double cord blood
transplant, > 90% 1-2 HLA
mismatched (A, B, DR)
|
Flu/BU/TBI
ANC: Primary 88%, median d26 (r12-30)
ANC: Sustained 76% (95% CI 56-96)
Platelet: (20, d180) 24% (95% CI 6-42)
Flu/CY/TBI
ANC:Primary 94%, median d9.5 (r5-28)
ANC: Sustained 94% (95% CI 84-100)
Platelet (20, d180) 80% (57-100)
|
Flu/BU/TBI
48% (95% CI 26-70)
Flu/CY/TBI
28% (95% CI 10-46)
NRM/TRM (d100)
|
NR |
OS 1 yr
39% (95% CI 23-56)
[entire group]
|
Flu/BU/TBI D100: 38% (95% CI 17-59),
1yr: 24% (95% CI 6-42)
Flu/CY/TBI
D100: 68% (95% CI 48-88),
1yr: 41% (95% CI 15-76)
|
High TRM, worse in Flu/BU/TBI group reflecting lower engraftment rates.
|
Brunstein et al. 2007r |
110 |
Single (15%) or double (85%) cord blood transplant, > 95% 1-2 HLA mismatched (A, B, DR) |
ANC: Primary 92%, median d12 (r0-32)
ANC: Sustained 85% (95% CI 77-92)
Platelet: (50, d180) 65% (95% CI 54-76), median d49 (r0-134)
|
19% (95% CI 12-26) d 180
26% (95% CI 18-34) 3y
|
31% (95% CI 21-41) 3y |
45% (95% CI 34-56) 3y |
NR |
Suggestion that recipients of double units (85%) had superior EFS and lower relapse. In recipients where age (>45) was only indication for non-myeloablative approach, 3y survival was 49% |
Brunstein et al. 2011r |
50 |
double umbilical cord blood, 94% 1-2 HLA mismatched (A, B, DR)
|
ANC: 94%, median d15 (r4-47)
Platelets: (20, d100) (95% CI 71-93), median d38 (r3-87)
Platelets: (50, d100) 59% (95% CI 44-73), median d43 (r29-323)
|
24% (95% CI 11-36) 1y |
31% (95% CI 17-44) 1y |
54% (95% CI 38-67) 1y |
46% (95% CI 31-60) 1y |
|
Brunstein et al. 2012r
|
dUCB-TCF*: 120
dUCB-other: 40
|
dUCB |
dUCB-TCF
ANC: 83% (d28) (95% CI 75-89) median d9
Platelets:(50, d180) 66% (95% CI 58-74)
dUCB-other
ANC: 83% (d28) (95% CI 69-93) median d20
Platelets: (50, d180) 58% (95% CI 42-72)
|
(2y)
dUCB-TCF
19% (95% CI 11-26)
dUCB-other
52% (95% CI 33-71)
|
(2y)
dUCB-TCF
49%, (95% CI 38-59)
dUCB-other
35%, (95% CI 19-50)
|
OS (2y)
dUCB-TCF
37%, (95% CI 28-48)
dUCB-other
19%, (95% CI 4-34)
|
(2y)
dUCB-TCF
31%, (95% CI 22-41)
dUCB-other
15%, (95% CI 2-28)
|
Overall mortality higher in dUCB-other group compared to dUCB-TCF (RR 1.08, range 1.08-2.54, p0.04). Most common causes of death in dUCB-other were infection and organ failure compared to recurrent leukaemia in dUCB-TCF |
* dUCB: double umbilical cord blood; TCF: TBI, cyclophosphamide, fludarabine
Toxicity
A summary of the toxicities associated with this protocol are included in the table below:
Study |
Mucositis |
aGVHD
- total
- gde 2-4
|
cGVHD
-total
extensive
-limited
|
Rejection |
VOD/SOS |
Lung/IPS |
Infection* |
Barker et al. 2003r |
NR |
II-IV: 44% (95% CI 28-62)
II-IV: 9% (95% CI 1-17)
|
Total (1yr)
21% (95% CI 8-34) |
Flu/BU/TBI: 4/18 (2 1°, 2 2°)
Flu/CY/TBI:
1/21 (1°)
|
NR |
NR |
NR – however infection and organ failure “predominant cause of death”
|
Brunstein et al. 2007r |
NR |
II-IV: 59% (95% CI 49-69)
III-IV: 22% (95% CI 14-30)
|
Total (1yr)
23% (95% CI 15-31)
|
7/110 (1°)
8/110 (2°)
|
NR |
NR |
cause of death in 12/110 patients |
Brunstein et al. 2011r |
4% (gd 3-4) |
II-IV: 40% (95% CI 26-54)
III-IV: 21% (95% CI 6-37)
|
Total (1yr)
25% (95% CI 12-39)
|
5/50 (1°)
1/50 (2°)
|
NR |
NR |
NR |
Brunstein et al. 2012r |
NR |
dUCB-TCF
II-IV: 50% (95% CI 41-58)
III-IV: 17% (95% CI 11-25)
DUCB-other
II-IV: 33% (95% CI 19-48)
III-IV: 18% (95% CI 8-31)
|
Total (2yr):
dUCB-TCF
34%(95% CI 25-43)
DUCB-other
36% (95% CI 22-51)
|
dUCB-TCF
9% (1°)
DUCB-other
10% (1°)
|
NR |
NR |
NR |
* Infection: includes neutropenic sepsis, invasive fungal infection (IFI) and viral reactivation/disease where reported