The use of fludarabine and cyclophosphamide as a nonmyeloablative conditioning regimen was first reported in a pilot study, from the M.D Anderson Cancer Center, of 15 patients with chronic lymphocytic leukaemia and low grade lymphoma.r The concept was to use a fludarabine-based regimen to induce sufficient immunosuppression to allow engraftment and induction of a graft versus tumour effect. A follow-up study published in 2001 in 20 patients with indolent lymphoma demonstrated a 100% engraftment rate, a high CR rate with a cumulative incidence of grade 2-4 acute GVHD of 20% and chronic GVHD of 64%.r
In lymphoid malignancies, there is evidence for a strong graft versus tumour effect with fludarabine and cyclophosphamide, especially for indolent disorders such as follicular lymphoma and small lymphocytic lymphoma/CLL.rr
The following evidence is based on papers using total fludarabine doses of between 90 – 125 mg/m2 with total cyclophosphamide doses between 2 – 2.5 g/m2, or 120 mg/kg. Kouri et al. published their experience on 47 patients with relapsed follicular lymphoma incorporating rituximab with fludarabine and cyclophosphamide;r Auer et al. published their experience on 73 adults with relapsed/refractory lymphoid malignancies;r and Wondergem et al. published their experience on 54 patients with relapsed or refractory indolent and aggressive lymphoid malignancies.r
Fludarabine and cyclophosphamide can be used as a reduced intensity conditioning regimen in non-lymphoid malignancies.rrrr Nelson et al. published their experience on 30 AML and 20 MDS patients.r Subsequently their expanded experience in 57 AML patients was published by Khawaja et al., and outcomes were shown to be comparable with results using myeloablative conditioning with a median follow-up of 61 months.r Davies et al. published their experience on 41 AML and 15 MDS patients using fludarabine and cyclophosphamide conditioning with T-cell replete grafts, and reported low 5-year TRM of 8.9%.r
The protocol above is based on the UK study (Auer et al.r) which has the largest number of patients.
Evidence Level*
(NHRMC) |
Study |
Study Design |
Disease |
Is the conditioning regimen**
consistent with the protocol? |
Comments |
III-3 |
Khouri et al. 2008r |
Retrospective single centre (MD Anderson) |
Relapsed follicular lymphoma |
No. Similar dosing of flu/cyclo but rituximab added
|
Fludarabine 30 mg/m2, cyclophosphamide 750 mg/m2 days -5 to -3.
2 MUDS had ATG.
|
III-3 |
Nelson et al. 2010r |
Retrospective single centre (Indiana University Cancer Center, USA) |
AML/MDS |
No. Similar dosing of fludarabine. |
Fludarabine 25 mg/m2 days -5 to -1, cyclophosphamide 60 mg/kg days -7 and -6. |
III-3 |
Auer et al. 2012r |
Retrospective singe centre (St Bartholomews, London) |
Relapsed lymphoid disorders |
Yes |
No ATG. Cyclophosphamide 1 g/m2 day -3 & -2, fludarabine 25 mg/m2 days -6 to -2
|
III-3 |
Davies et al. 2013r |
Retrospective single centre (St Bartholomews, London) |
AML/MDS |
Yes |
No ATG. 2 pts had melphalan with fludarabine; 6 pts had additional idarubicin 10 mg/m2/day for 3 days. |
III-3 |
Wondergem et al. 2014r |
Retrospective single centre (VU University Medical Center, Amsterdam)
|
Relapsed /refractory indolent and aggressive malignancies
|
Similar, the only difference is that the cyclophosphamide is given for 4 doses of 500 mg/m2 for a total of 2.5 g/m2 (not 2 g/m2).
|
No ATG. Cyclophosphamide 500 mg/m2 and fludarabine 25 mg/m2 both on days -7 to -3
|
* NHMRC Evidence Hierarchy (accessed online August 2022) ** Chemotherapy ONLY
Efficacy
A summary of the evidence supporting the effect of this protocol is below:
Study |
Nos.of Patients |
Donor/Stem cell source |
NRM/TRM |
Relapse Rate |
OS (1yr/2yr) |
DFS |
Comments |
Khouri et al. 2008r |
47 |
Sib 45/MUD 2
Marrow 2/PBSC 45 |
NRM 14.9% at 2 years. |
4.3% |
OS 85% with median FU 5 yrs. |
PFS 83% with median FU 5 yrs. |
Note this study incorporated rituximab into conditioning. |
Nelson et al. 2010r |
50 |
MRD 27/MUD 23
BM 1/PBSC 49
|
NRM 32% |
Cumulative relapse 30% |
1 yr OS 58%
4 yr OS 41%
Median FU 59 mo
|
1 yr DFS 50%
4 yr DFS 37%
|
AML: 30 patients
MDS: 20 patients
56% not in remission.
|
Auer et al. 2012r |
73 |
Sib 51/MUD 19
BM 14/PBSC59
|
NRM 14% 1 year, 19% 3 years.
(5% at both 1 and 3 years for MM ) |
3 yr estimate relapse incidence
25% for follicular lymphoma.
|
3 yr 67%.
3 yr OS for indolent lymphoma 65% |
3 yr PFS 63% |
Number of patients:
Follicular lymphoma: 21
CLL: 13
Waldenstroms: 10
Myeloma: 24
|
Davies et al. 2013r |
56 |
MRD 45/ MUD 11
BM 1/ PBSC 55
|
TRM 8.9% at 5 years |
Cumulative relapse 48% |
Estimate OS 48% with median FU 60mo |
10 yr current DFS 45% |
AML pts: 41
MDS pts: 15
34% pts not in remission or untreated MDS
|
Wondergem et al. 2014r |
54 |
Sib 52/ MUD 2
BM 0/ PBSC 54 |
NRM: 11% at 1 year, 16% at 2 years. |
7% relapsed before 6 months, 13% after 6 months |
Overall: 2 yr 76%; 4 yr 67%.
Indolent lymphoma 4yr 83%, CLL 4yr 46%, aggressive B-cell lymphoma 69%
|
Overall EFS: 2 yr 70%; 4 yr 66%.
Indolent lymphoma 4yr EFS 75%, CLL 46%, aggressive lymphoma 55%. |
Number of patients:
Indolent lymphoma: 12
CLL: 13
Aggressive NHL: 13
Transformed NHL 16
|
Toxicity
A summary of the toxicities associated with this protocol are included in the table below:
Study |
Mucositis |
aGVHD
- gde 2 - 4
- gde 3/4 |
cGVHD
-total
-extensive
-limited |
Rejection |
VOD/SOS |
Lung/IPS |
Infection* |
Comment |
Kouri et al. 2008r |
NS |
11% grade 2-4 |
-60%
-36%
-24% |
2.1% |
0 |
NS |
12.7% fatal; other NS |
- |
Nelson et al. 2010r |
NS |
38% grade 2-4; 26% grade 3/4 |
-71% total
-52% extensive
|
0% |
0 |
4% |
12% fatal |
80% pts over age 50 (median age 57.5) |
Auer et al. 2012r |
NS |
-14%
-7%
|
-70%
Most extensive |
7% (4% had CLL) |
1/73 |
NS |
NS |
cGVHD significantly improved survival. |
Davies et al. 2013r |
NR |
13% grade 2-4 |
-36% extensive |
2% (late graft rejection) |
NR |
NR |
7% fatal |
- |
Wondergem et al. 2014r |
NS |
29.6% grade 2-4 |
-68%
-52%
-16% |
0 |
NS |
NS |
NS |
- |
* Infection : include neutropenic sepsis, invasive fungal infection (IFI) and viral reactivation/disease where reported