Stanford and City of Hope (COH) groups first evaluated a conditioning regimen consisting of fractionated TBI to a total dose 1320 cGy in 11 fractions on day -7 to day -4 administered erect and with lung shielding together with IV etoposide at 60 mg/kg administered over 4 hours on day -3.r This group subsequently demonstrated considerable activity of this regimen in patients with advanced acute leukaemia in a randomised prospective SWOG trial versus Bu/Cy conditioning.r A German study using the same regimen reported 64% disease-free survival (DFS) at 18 months in 17 high-risk patients (10 were not in remission at transplantation).r In less advanced disease, these groups reported cumulative probabilities of disease-free survival (DFS) and relapse at 3 years of 61% and 12%, respectively, for 61 patients with acute myeloid leukaemia (AML) and 64% and 12%, respectively, for 34 patients with acute lymphoblastic leukaemia (ALL).r Given these initial results the Medical Research Council UKALL12/Eastern Cooperative Oncology Group study adopted this conditioning regimen as standard in 1993.r
Marks et al., reported a registry based comparison of the outcome of 500 adult and paediatric patients with ALL in first complete remission (CR1) or second complete remission (CR2) who received either Cy-TBI or etoposide-TBI prior to a HLA matched sibling transplant. Cyclophosphamide doses ranged from 100 to 130 mg/kg, and etoposide doses ranged from 40 to 60 mg/kg. 217 patients received Cy-TBI less than 13 Gy, 81 patients received Cy-TBI greater than or equal to 13 Gy, 53 patients received etoposide-TBI less than 13 Gy, and 151 received etoposide-TBI greater than or equal to 13 Gy. COH provided data as a single institution for 75 patients who received etoposide-TBI greater than or equal to 13 Gy as their conditioning regimen. The median follow-up of survivors was 67 months (range, 8-156 months).Transplant-related mortality (TRM) did not differ by conditioning regimen but was significantly associated with age greater than or equal to 20, and receiving peripheral blood stem cells versus bone marrow.r
Philadelphia-positive (Ph+) ALL
Laport et al., reviewed the 20 year Stanford and COH experience of etoposide and TBI regimen in Ph+ ALL. 67 patients received etoposide and TBI, 11 patients received etoposide/cyclophosphamide/TBI and 1 patient received etoposide/Bu/TBI. All patients received an HLA-matched sibling allograft. 62% CR1, 38% greater than CR1. 10 yr overall survival (OS) for CR1 54% and greater than CR1, 29% (p=0.01) with no increase in relapse between the groups (28% vs. 41%, p=0.28) but a substantial increase in TRM for the greater than CR1 group (31% vs 54%, p=0.03). Multivariate analysis of outcomes for overall survival (OS) and event-free survival (EFS) are presented below.r
Table - multivariate analysis of risk factorsr
© Blood 2008
Philadelphia-negative (Ph-) ALL
On behalf of the Acute Leukaemia Working Party of the European Society for Blood and Marrow Transplantation, Czyz et al. reviewed the outcomes of Ph- ALL patients who received etoposide/TBI (n=152) in comparison with cyclophosphamide/TBI (n=1346) between 2000 and 2015.r All patients underwent their first alloSCT in CR1 (79%) or CR2 (21%) from sibling (46%) or unrelated donors (54%). Stem cell source was peripheral blood in 62%. The median TBI dose was 12Gy. Patients who received etoposide/TBI were younger (median age 28 years vs 30 years, P = 0.037), were more frequently in CR1 (87% vs 78%, P = 0.014) and underwent alloSCT more recently (median year of alloSCT 2009 vs 2007, P = 0.014). The study group did not differ with respect to other characteristics.
At 5 years, patients who received etoposide/TBI had lower relapse rates (17% vs 30%, P =0.007), increased rate of leukaemia-free survival (60% vs 50%, P = 0.04) and improved graft versus host disease (GVHD)-relapse-free survival (43% vs 33%, P =0.04). There was no difference in OS, acute or chronic GVHD.
Evidence Level (NHMRC) |
Study |
Study Design |
Disease |
Is the conditioning regimen* consistent with the protocol? |
Comments |
II |
Blume et al.1993r |
Phase III |
AML or ALL (with induction failure, in second complete remission or beyond)
Chronic myeloid leukaemia (CML) (in accelerated phase or blast crisis)
|
Yes. However, in the trial an electron boost of 4Gy was given to the testes on day -7 and 3Gy twice daily to the chest on days -5 and -4. |
|
III-2 |
Blume et al. 1987r |
Phase I/II |
Acute leukaemia and other haematological malignancies (refractory anaemia, chronic myeloid leukaemia, chronic myelomonocytic leukaemia, Hodgkin's lymphoma, myelofibrosis) |
Yes. However, in the trial an electron boost of 4Gy was given to the testes on day -7 and 3Gy twice daily to the chest on days -5 and -4. |
|
III-3 |
Schmitz et al.1988r |
Phase I/II |
Acute leukaemia, chronic myeloid leukaemia and refractory anaemia. |
No. TBI administered at a dose of 11-12Gy. |
|
III-3 |
Snyder et al.1993r |
Phase I/II |
Acute leukaemia (AML, ALL, biphenotypic leukaemia and undifferentiated leukaemia) in first complete remission |
Yes. However, in the trial an electron boost of 4Gy was given to the testes on day -7 and 3Gy twice daily to the chest on days -5 and -4. |
|
III-3 |
Marks et al. 2006r |
Retrospective |
Acute lymphoblastic leukaemia in first or second complete remission |
Partially. TBI administered between 12 to 13Gy and ≥13 to 14.5Gy. No data on TBI administration between different centres. |
|
III-3 |
Laport et al. 2008r |
Retrospective |
Philadelphia positive acute lymphoblastic leukaemia |
Partially. 15% of patients received cyclophosphamide or busulphan, in addition to etoposide-TBI; and electron boost of 4Gy was given to the testes on day -7 and 3Gy twice daily to the chest on days -5 and -4. |
Only 22% of patients were on a tyrosine-kinase inhibitor. 62% of patients were in first complete remission. |
III-3 |
Czyz et al. 2018r |
Retrospective |
Philadelphia negative ALL |
Partially, noting median dose of TBI was 12Gy. |
|
*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 |
Blume et al.1993r |
Total: 61
25 patients (ALL) - 8 "good risk" and 17 "poor risk"
37 patients (AML or CML)
|
Bone marrow source, all HLA-matched siblings |
31% for all patients
|
43.7% for all patients |
26% (all patients), but 52.4% in “good risk” patients and 12.5% in “poor risk” patients. |
25.5% |
Numbers too small to compare effectiveness of treatment in different leukaemias. |
Blume et al.1987r |
Total: 47
33 acute leukaemia
14 other haematological malignancies
|
Sibling 46 patients
Syngeneic 1 patient
|
27.7% overall
7/20 (35%) for acute non-ALL leukaemia patients
4/12 (30.8%) for ALL patients
2/14 (13.3%) for non-leukaemia patients
|
32% for patients with acute leukaemia |
44.7% |
43% for patients with acute leukaemia |
|
Schmitz et al.1988r |
Total: 38
35 acute leukaemia, 2 CML and 1 refractory anaemia
|
Bone marrow source, all HLA-matched siblings except 1 patient (mismatched)
|
67% for all ALL and ANLL patients
65% for ALL patients
|
17.2% (ALL and ANLL patients only)
|
61% (ALL and ANLL patients only)
|
51.1% in patients with fully HLA matched sibling donors
|
|
Snyder et al.1993r |
Total: 99
61 AML, 34 ALL, 3 biphenotypic and 1 acute undifferentiated leukaemia
|
Bone marrow source, all HLA-matched siblings
|
28.3% (all patients)
|
12% (ALL patients only, 3-years)
|
65% (ALL patients only, median 28 months follow up)
|
64% (ALL patients, 3-years)
|
88% of ALL patients had 1 or more high risk features
|
Marks et al.2006r |
Total: 204
53 patients etoposide and TBI <13Gy and 151 patients etoposide and TBI ≥13Gy
|
95% bone marrow source, all HLA-matched siblings
|
For patients in CR1, approximately 30% (etoposide/TBI <13Gy) and approximately 10% (etoposide/TBI ≥13Gy) at 5 years.
For patients in CR2, approximately 20% at 5 years (either dose of TBI).
|
For patients in CR1, approximately 20% at 5 years (either dose of TBI).
For patients in CR2, approximately 30% at 5 years (either dose of TBI).
|
For patients in CR1, approximately 65% at 5 years (either dose of TBI).
For patients in CR2, approximately 50% at 5 years (either dose of TBI).
|
For patients in CR1, approximately 60% at 5 years (either dose of TBI).
For patients in CR2, approximately 50% at 5 years (either dose of TBI)
|
|
Laport et al.2008r |
Total: 79
Ph+ ALL
|
54% bone marrow, all HLA-matched siblings |
All patients, 35% with majority of events occurring within 3 years of transplant.
NRM significantly lower in patients in CR1 (31%) versus not in CR1 (54%).
|
For patients in CR1, 42% at 10 years.
For patients not in CR1, 34% at 10 years.
|
For patients in CR1, 54% at 10 years.
For patients not in CR1, 29% at 10 years.
|
For patients in CR1, 48% at 10 years.
For patients not in CR1, 26% at 10 years
|
|
Czyz et al.2018r |
Total: 152
Ph- ALL
|
69% peripheral blood stem cell source, 48% HLA-matched siblings |
20% at 5 years |
17% at 5 years |
62% at 5 years |
60% at 5 years |
41% had in-vivo T-cell depletion |
Toxicity
A summary of the toxicities associated with this protocol are included in the table below:
Study |
Mucositis |
aGVHD |
cGVHD |
Rejection |
VOD/SOS |
Lung/IPS |
Infection* |
Blume et al.1993r |
Not reported |
Grade 2-4: 18% |
27% |
None |
None |
12.7% had fatal pneumonia |
7.3% had fatal sepsis |
Blume et al.1987r |
20 patients (42.6%) |
Grade 2-4: 41% |
3 patients (6.5%) developed chronic GVHD |
4.3%
(2 patients) |
None |
27.7% fatal; n=2 developed COPD |
87.2% developed clinical sepsis – fatality NS |
Schmitz et al.1988r |
38 patients (100%) |
Grade 2-4: 65%
Grade 3-4: 24% |
54% |
8.8%
(3 patients) |
Not reported |
21.2% had pulmonary complication, of which 18% CMV pneumonitis and 3 had idiopathic pneumonitis) |
78% had sepsis, 7.9% had fatal sepsis. |
Snyder et al.1993r |
Not reported |
Grade 2-4: 16%
|
48% |
None |
2% died from veno-occlusive disease (all patients)
|
5% had fatal pneumonia |
2% died from invasive fungal infection |
Marks et al.2006r |
Not reported |
Not reported |
Not reported |
0.5%
(1 patient, which was fatal) |
Not described
|
For ALL in first complete remission, 30% in Vp-TBI <13Gy and 37% in Vp-TBI≥13Gy
For ALL in second complete remission, 6% in Vp-TBI <13Gy and 15% in Vp-TBI≥13Gy |
10% had fatal sepsis (21 patients) |
Laport et al.2008r |
Not reported |
49% in all patients
Grade 2-4: 35%
|
26 in 68 patients assessed (38%); extensive in 9 patients (13%) |
Not reported |
Not reported
|
10% had fatal cardiopulmonary complications (8 patients) |
12.6% had fatal sepsis (10 patients) |
Czyz et al.2018r |
Not reported |
Grade 2-4: 39%
Grade 3-4: 17% |
47%, extensive in 18% |
0.7% |
Not reported |
Not reported |
Not reported |
*Infection: include neutropenic sepsis, invasive fungal infection (IFI) and viral reactivation/disease where reported.