Fludarabine and melphalan (FluMel) reduced intensity conditioning (RIC) haematopoietic stem cell transplantation (HSCT) was initially described by the MD Anderson group, with a 2001 paper by Giralt et al.r The MD Anderson group demonstrated good engraftment and response rates balanced against tolerable toxicities in a cohort with a mixed range of haematological malignancies. The efficacy of FluMel HSCT has subsequently been demonstrated across a wide range of malignant and non-malignant haematological conditions. Key studies demonstrating the efficacy and toxicities of this regimen are tabulated below, after a brief overarching summary of evidence by disease group.
Acute myeloid leukaemia and high-risk myelodysplasia
Large registry studies support the long-term efficacy of FluMel RIC allograft in the acute myeloid leukaemia/myelodysplasia (AML/MDS) cohort. An EBMT registry study comparing FluMel to fludarabine and busulfan (FluBu) RIC allograft reported 2-year non-relapse mortality (NRM), overall survival (OS) and disease-free survival (DFS) of 20%, 62% and 60%, respectively, in the FluMel arm at a median follow-up of 3.5 years, with better disease control, higher treatment-related mortality (TRM) and comparable survival outcomes to FluBu conditioningr. An ABMTRR review with a median follow-up of 3.4 years reported a 1 year NRM, 3 year OS and DFS of 22%, 57% and 51% in patients with myeloid malignancies, 88% of whom had AML/MDS.r This study found NRM, OS and DFS outcomes in AML appeared better in those in complete remission 1 (CR1), human leukocyte antigen (HLA)-identical sibling transplants, cytomegalovirus (CMV) negative, and in the presence of chronic graft versus host disease (cGVHD). The optimal melphalan dose is unclear, with these registry studies including doses varying from 120-150 mg/m2 without comparison between dosing groups. Two studies comparing FluMel 140 and 180 demonstrated no clear survival benefit and higher non-lethal toxicity of the FluMel 180 regimen.rr One study comparing FluMel 100 and 140 found no difference in survival outcomes with the lower melphalan doser; another comparing FluMel 100 to FluMel 140/180 found similar survival outcomes if transplanted in CR, but due to low numbers, could not compare outcomes in active disease.r
Myelofibrosis
There is good evidence for the efficacy of FluMel RIC allograft in treatment of myelofibrosis (MF). A multicentre retrospective review comparing long-term transplant outcomes between FluBu and FluMel RIC allograft for MF found 7yr progression-free survival (PFS) and OS of 52% in the FluMel arm, with lower relapse rates (4% vs. 35.7%, p=0.008) and a trend to higher NRM (43% vs 31%, p=0.068) in the FluMel group, with no significant difference in OS outcomes between groups (52% vs 59%, p=0.08)r. A phase II prospective clinical trial investigated FluMel RIC allograft for MF comparing related to unrelated donor transplants and found superior engraftment and survival outcomes in patients undergoing transplants from related donors.r At a median of 25 months follow-up, they reported graft failure, NRM, OS and PFS rates of 6%, 22%, 75% and 71% in patients with related donors, compared with 36%, 59%, 32% and 32% in patients with unrelated donors. This suggests the potential to improve survival outcomes with patient/donor selection in this disease cohort.
Acute lymphoblastic leukaemia
FluMel RIC allograft appears to be a feasible conditioning regimen for acute lymphoblastic leukaemia (ALL), though evidence supporting its use limited. The largest study in this cohort is a retrospective review by Eom and colleagues, comparing 60 patients undergoing FluMel RIC allograft to 120 patients undergoing cyclophosphamide and total body irradiation (CyTBI) myeloablative conditioning (MAC) allograft. r Patients undergoing FluMel RIC allograft were significantly older (46 versus 33yrs, p < 0.001), patient characteristics were otherwise similar. At a median follow-up of 67 months, FluMel RIC and CyTBI MAC allograft had similar 5yr NRM (21% vs 24%, p=0.54) and OS (54% vs 58%, p=0.18); however a higher relapse rate was seen in the FluMel group (34% vs 26%), with a trend to lower DFS (51% vs 55%, p=0.07). Higher relapse risk was only seen in the subgroup of Philadelphia chromosome-positive patients undergoing FluMel RIC allograft.
Non-Hodgkin lymphoma
An early study by Rodriguez et al. found that, in a mixed cohort of patients with non-Hodgkin lymphoma (NHL) of different subtypes, FluMel RIC allograft appears to have comparable survival outcomes to TBI or busulfan and cyclophosphamide (BuCy) based MAC allograftr. Despite significantly higher relapse rates in the FluMel RIC group (28% vs 13%, p=0.05), survival did not differ significantly between groups, with 1yr TRM 28% vs 33% (p=0.40), 2yr OS 53% vs 52% (p=0.99), and 2yr PFS 40% vs 46% (p=0.46), respectively.
A subsequent ABMTRR registry study by Bryant et al. found FluMel RIC allograft appears to yield similar transplant outcomes for both lymphoid and myeloid malignancies when compared as disease groups.r A wide range of malignancies were compared (see table), with NHL accounting for 58% of patients within the lymphoid group and AML accounting for 71% of patients in the myeloid group. 3yr OS of 59% vs 57% (p=0.5) and 3yr DFS of 48% vs 51% (p=0.8) were reported in the lymphoid and myeloid groups, respectively, with lower rates of CR achieved in lymphoid malignancies (75% vs 90%, p=0.001).r
FluMel RIC allograft outcomes appear to vary by NHL subtype, with more aggressive disease subtypes having poorer outcomes. Sub-analysis of the ABMTRR study demonstrated a trend toward poorer 3yr OS in patients with diffuse large B-cell lymphoma (DLBCL) compared with chronic lymphocytic leukaemia (CLL)/follicular lymphoma (FL) (33% vs 64%, p=0.06). A multicentre retrospective review reported similar survival outcomes in a cohort of 48 patients with DLBCL undergoing FluMel RIC allograft with alemtuzumab, with 4yr NRM, OS and PFS of 32%, 47% and 48%, respectively.r Chemosensitive patients had significantly better 4yr OS than chemo-refractory patients (54% vs 12%, p=0.016).
Pinana and colleagues investigated FluMel RIC allograft for a cohort of 37 patients with FL, finding 4yr NRM, OS and DFS of 37%, 57% and 55%, respectively.r A trend toward improved OS was seen in patients in CR at transplant, compared with those with PR or PD (71%, 48% and 29%, p=0.09). Approximately one-third of this cohort received melphalan dosing of 80 mg/m2, though outcomes were not compared to the alternative 140 mg/m2 dose. A subsequent study by Ono et al. of 19 patients with FL undergoing RIC allograft with FluMel 140 mg/m2 conditioning reported 5yr TRM, OS and PFS of 15.8%, 84.2% and 84.2%, with no cases of disease progression at 75 months follow-up.r
Studies reporting outcomes of FluMel RIC allograft for mantle cell lymphoma (MCL) is less clear, with evidence limited to small retrospective reviews. A study by Cruz et al. of 21 patients with MCL undergoing FluMel RIC allograft found high engraftment rates, low 4yr NRM of 19.5%, and high 5yr OS and PFS of 80%. r
Evidence for FluMel RIC allograft in T-cell lymphomas (TCL) is similarly limited. A small study of 27 patients with mature TCL’s by Delioukina and colleagues showed high neutrophil engraftment rates, with 2yr NRM, OS and PFS of 22%, 55% and 47%, respectively.r A trend to poorer outcomes was seen in cutaneous TCL compared with other histologies, with a 2-year OS of 45% vs 62% (p=0.38) and NRM of 27% versus 19% (p=NR).
Hodgkin lymphoma
Early retrospective reviews of transplant outcomes in Hodgkin lymphoma (HL) patients undergoing FluMel RIC yielded 2 yr OS in the range of 48-64% and PFS 27-32%.rrr A study of 67 patients with HL undergoing FluMel RIC allograft by Peggs et al. investigated the impact of GVH prophylaxis on outcomes.r The authors reported superior outcomes with alemtuzumab/ciclosporin compared with methotrexate/ciclosporin GVHD prophylaxis, with lower GVHD rates in the alemtuzumab group (29 vs. 42.9%, p=0.0034), and a corresponding trend to improved 4yr OS (39% vs 62%, p=0.0724) and 4yr PFS (25% vs 39%, p=0.0586). Chemosensitivity appears to predict transplant outcomes, with several studies reporting superior survival in HL patients with chemosensitive compared with chemo-refractory disease.rr A 2014 study by Chen et al. suggested that pre-treatment with potent agents such as brentuximab vedotin (BV) may result in better pre-transplant disease control/fitness and superior transplant outcomes.r The authors compared 21 contemporary BV-exposed patients to a historical cohort of 23 BV-naïve patients undergoing FluMel RIC allograft; there were no other significant demographic differences between groups. Higher pre-transplant CR rates (28.6% vs 4.3%, p=0.04) and lower haematopoietic stem cell transplantation - comorbidity index (HSCT-CI) (median 0 vs 2, p<0.01) were seen in the BV-exposed group, with superior transplant outcomes including lower rates of grade II-IV GVH (23.8% vs 47.8%, p=0.06) and higher PFS (59.3% vs 26.1%, p=0.03).
Multiple myeloma
Early studies investigating FluMel RIC allograft for multiple myeloma (MM) demonstrated high TRM/relapse and low survival, with two long-term follow-up studies finding 7yr OS and PFS of 25-34% and 20-26%, respectively.rrPatient/donor selection may improve transplant outcomes, with better survival seen in the subgroup of patients with good response to pre-transplant treatmentrr, early in disease courser and with HLA and gender-matched donors.rr Discouragingly, a study investigating long-term outcomes up to 10 years post FluMel RIC allograft for MM did not identify a plateau in late relapses, suggesting that the GVT effect may be inadequate for long-term disease control in this cohort.r Survival outcomes do not appear to be improved by variations in conditioning and GVHD prophylaxis regimens. A study by Bashir et al. of 50 MM patients undergoing FluMel RIC allograft investigated the impact of 100 mg/m2 versus 140 mg/m2 melphalan dosing on transplant outcome, finding no significant difference in OS (63% vs 45%, p=0.38) and PFS (41% vs 24%, p=0.12)r Kroger et al. compared outcomes of alemtuzumab versus ATG GVHD prophylaxis in 73 MM patients undergoing FluMel RIC, finding a trend to lower grade II-IV aGVHD rates in the alemtuzumab group (24% vs 47%, p=0.06), but higher relapse rates (HR 2.37, p=0.05), and no difference in 2yr OS (45% vs 54%, p=0.5) or 2yr PFS (36% vs 30%, p=0.5).r
Evidence Level (NHMRC) |
Study |
Study Design |
Disease |
Is the conditioning regimen consistent with the protocol?
|
Comments |
AML/MDS |
|
|
|
|
|
III-3 |
Baron et al.r |
Retrospective study |
AML |
Yes |
Survey design study |
III-3 |
Bryant et al.r |
Multicentre, retrospective study |
Myeloid and lymphoid malignancies |
Yes |
Dosing within the following ranges included:
Fludarabine 25-30 mg/m2
Melphalan 120-160 mg/m2
|
MF |
|
|
|
|
|
III-3 |
Robin et al.r |
Multicentre, retrospective study |
MF |
No |
Fludarabine 90 mg/m2
Melphalan 140 mg/m2
|
III-2 |
Rondelli et al.r |
Phase II prospective study |
MF |
No |
Fludarabine 30 mg/m2 (Day-6 to Day-2)
Melphalan 70 mg/m2 (Day-2 to Day-1)
|
ALL |
|
|
|
|
|
III-3 |
Eom et al.r |
Retrospective study |
ALL |
No |
Fludarabine 150 mg/m2
Melphalan 140 mg/m2
|
NHL |
|
|
|
|
|
III-3 |
Rodriguez et al.r |
Single centre, retrospective study |
NHL |
Yes |
- |
III-3 |
Thomson et al.r |
Multicentre, retrospective study |
NHL (DLBCL) |
No |
Addition of alemtuzumab to conditioning regimen. |
III-1 |
Pinana et al.r |
Phase II prospective study |
NHL (FL) |
No |
Dosing within the following ranges administered:
Fludarabine 125-130 mg/m2
Melphalan 80-140 mg/m2
|
HL |
|
|
|
|
|
III-3 |
Alvarez et al.r |
Multicentre, retrospective study |
HL |
No |
Fludarabine 30 mg/m2 for 5 days
Melphalan 140 mg/m2 for 2 days
|
III-3 |
Anderlini et al.r |
Single centre, retrospective study |
HL |
No |
Fludarabine 25 mg/m2 daily for 5 days (Day -6 to Day-2) or 33 mg/m2 daily for 4 days (Day -5 to Day -2)
Melphalan 70 mg/m2 daily for 2 days (Day -3 and Day-2) |
III-2 |
Chen et al.r |
Single centre, retrospective study |
HL |
No |
Melphalan 140 mg/m2 given over 1 day only |
MM |
|
|
|
|
|
III-3 |
Sahebi et al.r |
Single centre, retrospective study |
MM |
No |
Melphalan 140 mg/m2 given over 1 day only |
III-3 |
Shimoni et al.r |
Multicentre, retrospective study |
MM |
No |
Dosing within the following ranges administered:
Fludarabine 90 - 150 mg/m2
Melphalan 100 -150 mg/m2
|
III-3 |
Kroger et al.r |
Phase II prospective study |
MM |
No |
Fludarabine 30 mg/m2 (Day -6 to Day -4)
Melphalan 140 mg/m2 (Day -3)
|
Efficacy
Study |
No.of patients |
Donor/stem cell source |
NRM/TRM |
Relapse Rate |
OS |
DFS/PFS |
Comments |
AML/MDS |
|
|
|
|
|
|
|
Baron et al.r |
394
|
|
2 yrs NRM
FluMel 20%
FluBu 18%
p=0.40
|
|
2 yr OS
FluMel 62%
FluBu 54%
p=0.20
|
2 yr DFS
FluMel 60%
FluBu 51%
p=0.08
|
|
Bryant et al.r |
344
Myeloid malignancy n=234
(AML:166, MDS:40, MF:8, CML:15, Other:2)
Lymphoid malignancy n=110
(CLL:31, HL:12, FL:30, DLBCL:11, TCL:8, Other:18)
|
|
TRM 14% at day 100
TRM 22% at 1 yr
(NS difference in TRM between lymphoid/myeloid)
|
15% at 1 yr
28% at 2 yrs
20% at 3 yrs
(NS difference in relapse rate between myeloid and lymphoid malignancies)
|
3 yr OS
Myeloid 57%
Lymphoid 59%
p=0.5
(NS difference in OS between myeloid and lymphoid malignancies)
|
3 yr DFS
Myeloid 51%
Lymphoid 48%
p=0.8
(NS difference in DFS between myeloid and lymphoid malignancies)
|
|
MF |
|
|
|
|
|
|
|
Robin et al.r |
160 |
|
7 yr NRM
FluMel 43%
FluBu 31%
p=0.068
|
|
7 yr OS
FluMel 52%
FluBu 59%
p=0.08
|
|
|
Rondelli et al.r |
66 |
|
NRM at 25 months
Patients with related donors: 22%
Patients with unrelated donors: 59%
|
|
OS at 25 months
Patients with related donors: 75%
Patients with unrelated donors: 32%
|
PFS at 25 months
Patients with related donors: 71%
Patients with unrelated donors: 32%
|
|
ALL |
|
|
|
|
|
|
|
Eom et al.r |
180 |
|
5 yr NRM
FluMel 21.2%
CyTBI 24.3%
p=0.54
|
5 yr relapse risk
FluMel 34.2%
CyTBI 26.4%
p=0.019
|
5 yr OS
FluMel 54%
CyTBI 58%
p=0.18
|
5 yr DFS
FluMel 50.8%
CyTBI 54.9%
p=0.07
|
|
NHL |
|
|
|
|
|
|
|
Rodriguez et al.r |
88 |
|
1 yr TRM
TBI-based/BuCy 33%
FluMel 28%
p=0.40
|
2 yr relapse rate
TBI-based/BuCy 13%
FluMel 28%
|
2 yr OS
TBI-based/BuCy 52%
FluMel 53%
p=0.99
|
2 yr PFS
TBI-based/BuCy 46%
FluMel 40%
p=0.46
|
|
Thomson et al.r |
48 |
|
4 yr NRM 32% |
4 yr relapse risk 33%
(occurring at median of 4 months)
|
4 yr OS
47% overall
54% if chemo sensitive
12% if chemo refractory
p=0.016
|
4 yr PFS 48% overall |
|
Pinana et al.r |
37 |
|
4 yr NRM 37% |
Relapse in 8% of patients at median 122 days |
4 yr OS 57% overall
|
4 yr DFS 55% overall |
|
HL |
|
|
|
|
|
|
|
Alvarez et al.r |
40 |
|
TRM 12% at day 100
TRM 25% at 1 yr
|
|
2 yr OS 48% |
2 yr PFS 32% |
|
Anderlini et al.r |
58 |
|
TRM 7% at day 100
TRM 15% at 2 yrs
|
|
2 yr OS 64% |
2 yr PFS 32% |
|
Chen et al.r |
24 |
|
NRM 4.2% at day 100
NRM 13.1% at 1 yr
NRM 13.1% at 2 yrs
|
2 yr relapse 63% at median 181 days till progression. |
1 yr OS 75%
2 yr OS 60%
|
1 yr PFS 50%
2 yr PFS 27%
|
|
MM |
|
|
|
|
|
|
|
Sahebi et al.r |
60 |
|
NRM 10% at 1 yr
NRM 12% at 7 yrs
|
7 yr relapse rate 67% |
7 yr OS 42% |
7 yr PFS 31% |
|
Shimoni et al.r |
50 |
|
NRM 26% at 5 yrs
(cumulative rate)
|
|
7 yr OS 34%, with median survival 2.3yrs. |
7 yr PFS 26%. PFS poorer if SD/PD at SCT, no cGVHD, female donor to male recipient, no CR achieved post SCT, and transplant >5yrs post diagnosis of MM. If none of these present, 7 yr PFS was 47% |
|
Kroger et al.r |
49 |
|
NRM 25% at 1 yr |
1 yr relapse incidence 17%
3 yr relapse incidence 55%
(18 deaths due to progression)
|
5 yr OS 26% |
5 yr PFS 20% |
|
NS = not significant
Toxicity
A summary of the toxicities associated with this protocol from the two largest studies 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 |
AML/MDS |
|
|
|
|
|
|
|
|
Baron et al.r |
- |
Grade II: FluBu 14%, FluMel 16%
Grade III: FluBu 5%, FluMel 7%
Grade IV: FluBu 4%, FluMel 3%
|
cGVHD at 2yrs
FluBu 54% vs FluMel 48%
p=0.15
|
1.3% FluBu (n=3)
0% FluMel
|
- |
- |
- |
- |
Bryant et al.r |
- |
Grade II-IV
Lymphoid 47%
Myeloid 39%
Cumulative incidence of aGVHD total: 41%
|
cGVHD 70% at day 100 (in n=256 evaluable)
Cumulative incidence of extensive cGVHD total: 34%
|
- |
- |
- |
- |
- |
aGVHD = acute graft versus host disease; cGVHD = chronic graft versus host disease; VOD = veno-occlusive disease; SOS = sinusoidal obstruction syndrome; IPS = idiopathic pneumonia syndrome