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Clinical Trial Results:
Allogeneic hematopoietic cell transplantation with HLA-matched donors : a phase II randomized study comparing 2 nonmyeloablative conditionings

Summary
EudraCT number	2007-002548-12
Trial protocol	BE NL
Global end of trial date	08 Jul 2016

Results information
Results version number	v1(current)
This version publication date	21 Feb 2020
First version publication date	21 Feb 2020
Other versions
Summary report(s)	medical journal article

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

TJB0702P1

ISRCTN number

US NCT number

NCT00603954

WHO universal trial number (UTN)

Sponsor organisation name

CHU de Liège

Sponsor organisation address

avenue de l'hôpital 1, Liège, Belgium, 4000

Public contact

belgian hematological society, coordinating investigator, 0032 43667201, f.baron@ulg.ac.be

Scientific contact

belgian hematological society, coordinating investigator, 0032 43667201, f.baron@ulg.ac.be

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

15 Oct 2014

Is this the analysis of the primary completion data?

Yes

Primary completion date

17 Oct 2011

Global end of trial reached?

Yes

Global end of trial date

08 Jul 2016

Was the trial ended prematurely?

Main objective of the trial

The present project aims at comparing two nonmyeloablative regimens currently used in 2 major transplant centers in the US for patients with HLA-matched related or unrelated donor: the one from the Seattle group consisting of 2 Gy total body irradiation (TBI) with fludarabine (90 mg/m²) versus the one from the Stanford group combining 8 Gy total lymphoid irradiation (TLI) with anti-thymocyte globulin (ATG). Tte primary objective is to compare the incidence of grade II-IV acute GVHD between the 2 groups.

Protection of trial subjects

Potential toxicities associated with PBSC infusions will be carefully monitored per the standard procedures.

Background therapy

After myeloablative conditioning, the association of tacrolimus + methotrexate has been associated with a lower incidence of grade II-IV acute GVHD than the association combining CSP + methotrexate . Based on these observations, we will elect to use tacrolimus instead of CSP in the 2 arms of the current study.

Evidence for comparator

Associations between GVHD and outcomes after nonmyeloablative HCT: Numerous studies have evinced a close relationship between GVHD and GVT responses after myeloablative HSCT although several observations have demonstrated GVT effects in the absence of GVHD. Thus, even though GVT reactions are thought to be mandatory for eradication of the underlying malignancy after nonmyeloablative conditioning, it has remained unclear whether clinical manifestations of GVHD are required. In order to address this question, we analyzed data from 322 patients given grafts from HLA-matched related (n=192) or unrelated (n=130) donors after 2 Gy TBI with or without fludarabine, and postgrafting immunosuppression with MMF and CSP 21. Time dependent regression Cox models were used to assess the impact of either acute or chronic GVHD on relapse, non-relapse mortality and PFS. In multivariate analyses, grades II and III-IV acute GVHD had no significant impact on the risk of relapse/progression, but were associated with an increased risk of non-relapse mortality and decreased progression-free survival (PFS). Conversely, extensive chronic GVHD was associated with a decreased risk of relapse/progression (P = 0.006), and better PFS (P= 0.003). A novel nonmyeloablative regimen combining total lymphoid irradiation (TLI) with ATG: Based on studies in a murine model, the Stanford group has developed another non-myeloablative regimen that favoured the presence of a high proportion of NK-T regulatory cells, and thus was associated with a low incidence of acute GVHD. This regimen consists of total lymphoid irradiation (TLI; 8 Gy) and ATG (Thymoglobulin, 7.5 mg/kg total dose), and postgrafting immunosuppression with MMF and CSP. First results in 37 patients indicated that this regimen was indeed associated with a low incidence of grade II-IV acute GVHD (1 of 37 patients) despite a high rate of stable engraftment, while graft-versus-tumor effects were apparently preserved. In a recent u

Actual start date of recruitment

02 Jan 2008

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Netherlands: 7

Country: Number of subjects enrolled

Belgium: 100

Worldwide total number of subjects

107

EEA total number of subjects

107

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Recruitment from January 2008 to March 2011 in the participating centers. 107 patients included, but 94 evaluable patients because screening failure (10 before transplantation and 3 excluded of analysis)

Screening details

13 patients (6 in the Flu-TBI and 7 in the TLI-ATG arm) were excluded from analysis because they did not meet the inclusion criteria at the time of the start of the conditioning (disease relapse (5), ineligible for further irradiation (3), donor refusal to give PBSC (2) HLA-mismatched donor (2), and poor PS (1))

Period 1 title

overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

TBI arm

Arm description

In the TBI arm, conditioning will consist of fludarabine 30 mg/m2 on days -4, -3 and -2 (total dose 90 mg/m2), followed by a singe dose of 2 Gy TBI administered on day 0, at a low dose-rate (≈ 7 cGy/min), before infusion of cells

Arm type

Active comparator

Investigational medicinal product name

Fludarabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

fludarabine 30 mg/m2 infused on days -4, -3 and -2 (total dose 90 mg/m2)

TLI arm

Arm description

In the TLI arm, conditioning will consist of 8 Gy TLI and ATG. TLI will be administered by linear accelerator at a dose of 80 cGy daily, starting 11 days before transplantation, until a total of 10 doses (800 cGy) has been delivered. The irradiation will consist of a supradiaphragmatic mantle field, a subdiaphragmatic field including an inverted Y and splenic ports, encompassing all major lymphoid organs, including the thymus, spleen, and lymph nodes, as used in the treatment of Hodgkin’s disease (Kaplan HS, Cancer Research 26:1268-1276, 1966). The Waldeyer ring is not included. ATG (Thymoglobulin®, Genzyme), at a dose of 1.5 mg/kg/d, will be given intravenously on days -11 through -7.

Arm type

Active comparator

Investigational medicinal product name

Thymoglobuline

Investigational medicinal product code

Other name

ATG

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

ATG (Thymoglobulin®, Genzyme) infused intravenously at a dose of 1.5 mg/kg/d on days -11 through -7 (total dose 7.5 mg/kg)

Number of subjects in period 1 ^[1]	TBI arm	TLI arm
Started	49	45
Completed	49	45

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: 13/107 included patients (6 in the Flu-TBI and 7 in the TLI-ATG arm) were excluded from analysis because they did not meet the inclusion criteria at the time of the start of the conditioning (disease relapse before the start of the conditioning (n = 5), ineligible for further irradiation (n = 3), donor refusal to give peripheral blood stem cells (PBSC) (n = 2), HLA-mismatched donor (n = 2), and poor PS precluding transplantation (n = 1)). the analysis includes data from 94 patients.

Baseline characteristics

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Reporting group title

overall trial

Reporting group description

Reporting group values	overall trial	Total
Number of subjects	94	94
Age categorical
Units: Subjects
In utero		0
Preterm newborn infants (gestational age < 37 wks)		0
Newborns (0-27 days)		0
Infants and toddlers (28 days-23 months)		0
Children (2-11 years)		0
Adolescents (12-17 years)		0
Adults (18-64 years)		0
From 65-84 years		0
85 years and over		0
Age continuous
Units: years
median (full range (min-max))	58 (32 to 73)	-
Gender categorical
Units: Subjects
Female	30	30
Male	64	64
Donor type
Units: Subjects
HLA-identical sibling	54	54
10/10 HLA-allele matched URD	40	40
CMV-serostatus (donor/patient)
the CMV serostatus of one recipient (CMV sero-positive donor) is missing; the CMV serostatus of one recipient (CMV sero-negative donor) is missing;
Units: Subjects
−/−	25	25
−/+	29	29
+/−	11	11
+/+	27	27
unknown	2	2
Disease at transplantation;
Units: Subjects
Acute myeloid leukemia	33	33
Acute lymphoblastic leukemia	5	5
Chronic lymphocytic leukemia	10	10
Myelodysplatic syndrome	17	17
Chronic myelomonocytic leukemia	5	5
Multiple myeloma	5	5
Myeloproliferative disorder	3	3
Non-Hodgkin lymphoma	15	15
Waldenström disease	1	1
Disease risk
Units: Subjects
low	27	27
standard	42	42
high	25	25

Subject analysis set title

Evaluable patient TBI arm

Subject analysis set type

Full analysis

Subject analysis set description

94 patients on 107 patients included were analysed. Thirteen patients (6 in the Flu-TBI and 7 in the TLI-ATG arm) were excluded from analysis because they did not meet the inclusion criteria at the time of the start of the conditioning (disease relapse before the start of the conditioning (n = 5), ineligible for further irradiation (n = 3), donor refusal to give peripheral blood stem cells (PBSC) (n = 2), HLA-mismatched donor (n = 2), and poor PS precluding transplantation (n = 1)).

Subject analysis set title

Evaluable patient TLI arm

Subject analysis set type

Full analysis

Subject analysis set description

13/107 patients (6/55 in the Flu-TBI and 7/52 in the TLI-ATG arm) were excluded from analysis because they did not meet the inclusion criteria at the time of the start of the conditioning (disease relapse before the start of the conditioning (n = 5), ineligible for further irradiation (n = 3), donor refusal to give peripheral blood stem cells (PBSC) (n = 2), HLA-mismatched donor (n = 2), and poor PS precluding transplantation (n = 1))

Subject analysis sets values	Evaluable patient TBI arm	Evaluable patient TLI arm
Number of subjects	49	45
Age categorical
Units: Subjects
In utero
Preterm newborn infants (gestational age < 37 wks)
Newborns (0-27 days)
Infants and toddlers (28 days-23 months)
Children (2-11 years)
Adolescents (12-17 years)
Adults (18-64 years)
From 65-84 years
85 years and over
Age continuous
Units: years
median (full range (min-max))	60 (38 to 73)	59 (32 to 71)
Gender categorical
Units: Subjects
Female	14	16
Male	35	29
Donor type
Units: Subjects
HLA-identical sibling	29	25
10/10 HLA-allele matched URD	20	20
CMV-serostatus (donor/patient)
the CMV serostatus of one recipient (CMV sero-positive donor) is missing; the CMV serostatus of one recipient (CMV sero-negative donor) is missing;
Units: Subjects
−/−	12	13
−/+	17	12
+/−	8	3
+/+	11	16
unknown	1	1
Disease at transplantation;
Units: Subjects
Acute myeloid leukemia	17	16
Acute lymphoblastic leukemia	4	1
Chronic lymphocytic leukemia	7	3
Myelodysplatic syndrome	9	8
Chronic myelomonocytic leukemia	2	3
Multiple myeloma	3	2
Myeloproliferative disorder	2	1
Non-Hodgkin lymphoma	5	10
Waldenström disease	0	1
Disease risk
Units: Subjects
low	15	12
standard	24	18
high	10	15

End points

Top of page

Reporting group title

TBI arm

Reporting group description

Reporting group title

TLI arm

Reporting group description

Subject analysis set title

Evaluable patient TBI arm

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Evaluable patient TLI arm

Subject analysis set type

Full analysis

Subject analysis set description

Primary: The 180-day incidence of grade II-IV acute GVHD

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End point title

The 180-day incidence of grade II-IV acute GVHD

End point description

The similar incidence of acute GVHD in the 2 arms was due to a lower than anticipated incidence of grade II-IV acute GVHD in the TBI arm, perhaps due to a relatively high dose of MMF used in sibling recipients, and to the relatively high targeted tacrolimus levels the first 100 days after transplantation.

End point type

Primary

End point timeframe

Incidence of grade II-IV acute GVHD at D180 after transplantation

End point values	TBI arm	TLI arm	Evaluable patient TBI arm	Evaluable patient TLI arm
Number of subjects analysed	49	45	48 ^[1]	40 ^[2]
Units: number	48	40	48	40

Attachments

Fig3 Transplant outcomes A) D180 gd2-4 aGVHD

Notes
[1] - Patients given a second allogeneic HCT were censured for GVHD analyses.
[2] - Patients given a second allogeneic HCT were censured for GVHD analyses.

Incidence of grade II-IV acute GVH

Statistical analysis description

The 180-day cumulative incidences of grade II-IV acute GVHD were 12.2% versus 8.9% in Flu-TBI and TLI ATG patients, respectively. Patients given a second allogeneic HCT were censured for GVHD analyses.

Comparison groups

Evaluable patient TBI arm v Evaluable patient TLI arm

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.508 ^[3]

Method

Multivariate Cox models

Confidence interval

Notes
[3] - The similar incidence of acute GVHD in the 2 arms

Secondary: hematopoietic (whole blood and T-cell chimerisms) engraftment and incidence of graft rejection

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End point title

hematopoietic (whole blood and T-cell chimerisms) engraftment and incidence of graft rejection

End point description

Determination of Graft failure T-cell chimerism BM chimerism ANC absolute neutrophils count (cells/µL) ALC absolute lymphocytes count (cells/µL) RBC Red blood cell count (Hemoglobin g/dL) Platelet count (g/dL) + number/timing of transfusions (plt and RBD)

End point type

Secondary

End point timeframe

1 year after transplatation

End point values	Evaluable patient TBI arm	Evaluable patient TLI arm
Number of subjects analysed	49	45
Units: number	49	45

Attachments

Fig2 Chimerism levels A) Tcell B) BM chimerism
Hematological recovery

Hematopoietic engraftment: Donor T-cell chimerism

Statistical analysis description

Donor T-cell chimerism levels were lower in the TLI ATG arm on days 180 and 365 after HCT

Comparison groups

Evaluable patient TBI arm v Evaluable patient TLI arm

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[4]

P-value

= 0.002 ^[5]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[4] - See Figure 2 chimerism levels (A)
[5] - T cell chimerism levels: P=0.09 at D100, P=0.02 at D180 and P=0.002 at D365

Graft rejection

Statistical analysis description

3 patients in the Flu-TBI arm and 4 patients in the TLI-ATG arm had graft rejection (defined as ≤ 5% donor chimerism in T cells, total white blood cells and/or total bone marrow cells).

Comparison groups

Evaluable patient TBI arm v Evaluable patient TLI arm

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Hematopoietic engraftment: marrow chimerism

Statistical analysis description

TLI-ATG patients had lower marrow chimerism levels on days 40 and 180 after allo-HCT.

Comparison groups

Evaluable patient TBI arm v Evaluable patient TLI arm

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[6]

P-value

= 0.03 ^[7]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[6] - See Figure 2 chimerism levels (B)
[7] - Bone marrow (BM) chimerism levels: P=0.03 at D40 andP=0.01 at D180

Hematologic recovery: ANC count

Statistical analysis description

In comparison to Flu-TBI patients, TLI-ATG patients had significantly lower absolute neutrophil counts on day 0

Comparison groups

Evaluable patient TBI arm v Evaluable patient TLI arm

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[8]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[8] - Day 0

Hematologic recovery: ALC count

Statistical analysis description

In comparison to Flu-TBI patients, TLI-ATG patients had significantly lower absolute lymphocyte counts from day 0 to day 42 after transplantation (Fig 1B).

Comparison groups

Evaluable patient TBI arm v Evaluable patient TLI arm

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[9]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[9] - Day 0, 7, 14, 21 < 0.001, D28= 0.01, D42= 0.04

Hematologic recovery: Hemoglobin levels

Statistical analysis description

In comparison to Flu-TBI patients, TLI-ATG patients had significantly lower hemoglobin levels on day 0 and from day 21 to day 180 after transplantation (Fig1C).

Comparison groups

Evaluable patient TBI arm v Evaluable patient TLI arm

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.006 ^[10]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[10] - P values at Day 0 =0.006, D21 < 0.001, D28 = 0.03, D42= 0.003, D60=0.01, D100=0.03, D180=0.02

Hematologic recovery: platelet levels

Statistical analysis description

In comparison to Flu-TBI patients, TLI-ATG patients had significantly lower platelet counts on days 0 and 7 after transplantation (Fig 1d)

Comparison groups

Evaluable patient TBI arm v Evaluable patient TLI arm

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[11]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[11] - Day 0 < 0.001 and Day 7< 0.001

Hematologic recovery: RBC transfusion

Statistical analysis description

Accordingly, 30 of 49 Flu-TBI patients versus 38 of 45 TLI-ATG patients were given at least 1 red blood cell transfusion the first 100 days after transplantation (P = 0.02) during that period.

Comparison groups

Evaluable patient TBI arm v Evaluable patient TLI arm

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.02

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Hematologic recovery: platelet transfusion

Statistical analysis description

Accordingly, 14 of 49 Flu-TBI patients versus 26 of 45 TLI-ATG patients were given at least 1 platelet transfusion during that period (P = 0.006).

Comparison groups

Evaluable patient TBI arm v Evaluable patient TLI arm

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.006

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Secondary: Incidence of chronic GVHD

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End point title

Incidence of chronic GVHD

End point description

In summary, in comparison to patients included in the Flu-TBI arm, patients included in the TLI-ATG arm had lower incidence of chronic GVHD. The low incidence of moderate/severe chronic GVHD in TLI-ATG patients is consistent with prior publications from the Stanford group, while the 40% incidence of chronic GVHD in Flu-TBI patients is also in agreement with observation from the Seattle consortium. Although previous studies have demonstrated a lower incidence of chronic GVHD in patients given ATG, the low incidence of chronic GVHD observed in current TLI-ATG recipients is unlikely due to ATG only, given that other studies have demonstrated that median serum active ATG levels the day of transplantation after TLI-ATG regimen are < 5 mg/L, well below the threshold associated with lower incidence of chronic in a recent study by Chawla et al. (8.12 mg/L).

End point type

Secondary

End point timeframe

2 years follow up

End point values	Evaluable patient TBI arm	Evaluable patient TLI arm
Number of subjects analysed	48 ^[12]	40 ^[13]
Units: numbers	48	40

Attachments

Fig3 Transplant outcomes B) 5yrs mod/severe cGVHD

Notes
[12] - Patients given a second allogeneic HCT were censured for GVHD analyses.
[13] - Patients given a second allogeneic HCT were censured for GVHD analyses.

Incidence of grade II-III of cGVHD

Statistical analysis description

2-year cumulative incidences of moderate/severe cGVHD were 40.8% versus 17.8% in Flu-TBI and TLI-ATG patients, respectively (P = 0.0165) (Figure 3B). Patients given a second allogeneic HCT were censured for GVHD analyses.

Comparison groups

Evaluable patient TBI arm v Evaluable patient TLI arm

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[14]

P-value

= 0.0165

Method

Multivariate Cox models

Confidence interval

Notes
[14] - In multivariate analysis, TLI-ATG conditioning (HR = 0.3, 95% confidence interval (CI): 0.1-0.8, P = 0.010), and transplantation from a HLA-identical sibling donor (HR = 0.5, 95% CI: 0.2-1.0; P = 0.0495) were associated with a lower incidence of moderate/severe cGVHD, while female donor to male recipient was associated with a higher incidence of moderate/severe cGVHD (HR 3.8, 95% CI: 1.7-8.5, P = 0.001).

Secondary: Incidences of infections

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End point title

Incidences of infections

End point description

Comparison of the number of patients who developed at least one infectious episode in the 2 groups was performed using the Fisher’s exact test.

End point type

Secondary

End point timeframe

1 year after transplantation

End point values	Evaluable patient TBI arm	Evaluable patient TLI arm
Number of subjects analysed	49	45
Units: number	49	45

Attachments

Fig3 Transplant outcomes. C) D100 CMV reactivation

Bacterial infection

Statistical analysis description

Nineteen of 49 Flu-TBI patients (39%) versus 25 of 45 TLI ATG patients (56%) had a least one episode of bacterial infection the first 100 days after transplantation (P = 0.15).

Comparison groups

Evaluable patient TBI arm v Evaluable patient TLI arm

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.15

Method

Fisher exact

Confidence interval

Fungal infection

Statistical analysis description

For fungal infections, the figures were 3 of 45 (6%) and 7 of 45 (16%), respectively (P = 0.19)

Comparison groups

Evaluable patient TBI arm v Evaluable patient TLI arm

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.19

Method

Fisher exact

Confidence interval

CMV infection

Statistical analysis description

Among CMV-seropositive patients and/or donors, the 100-day cumulative incidence of CMV reactivation was 31% in Flu-TBI patients versus 47% in TLI-ATG patients (P = 0.12;Figure 3C).

Comparison groups

Evaluable patient TBI arm v Evaluable patient TLI arm

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.12

Method

Fisher exact

Confidence interval

Secondary: Incidence of relapse (RI), nonrelapse mortality (NRM), progressionfree survival (PFS) and overall survival (OS)

Top of page

End point title

Incidence of relapse (RI), nonrelapse mortality (NRM), progressionfree survival (PFS) and overall survival (OS)

End point description

In summary, in comparison to patients included in the Flu-TBI arm, patients included in the TLI-ATG arm had higher incidence of relapse and similar OS. The TLI-ATG regimen was also associated with a higher incidence of relapse, although these results should be taken with caution given the heterogeneity of diagnoses and status at transplantation in our study. Nevertheless, supporting our data, the incidence of relapse in TLI-ATG patients in the current study (50% at 4 years) is comparable to what has been observed by the Stanford group (53% at 4-year) in a larger cohort of patients. This observation is also in accordance with prior studies that observed higher risks of relapse with lower donor T-cell chimerism and absence of chronic GVHD. This higher incidence of relapse in TLI-ATG patients translated into a trend for lower PFS, but, importantly, OS was identical in the 2 arms.

End point type

Secondary

End point timeframe

4 and 5 years follow up after transplantation

End point values	Evaluable patient TBI arm	Evaluable patient TLI arm
Number of subjects analysed	49	45
Units: number	49	45

Attachments

Fig3 Transplant outcomes. 5yrs D) RI E)PFS F)OS
Table 2 Causes of death

Incidence of relapse (RI)/progression

Statistical analysis description

Four-year cumulative incidences of relapse/progression were 22% and 50% in Flu-TBI and TLI-ATG patients, respectively (P = 0.017; Figure 3D). The difference remained statistically significant in multivariate analysis (HR = 2.3, 95% CI 1.1-4.7, P = 0.02).

Comparison groups

Evaluable patient TBI arm v Evaluable patient TLI arm

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[15]

P-value

= 0.017 ^[16]

Method

Multivariate Cox models

Parameter type

Hazard ratio (HR)

Point estimate

2.3

Confidence interval

level

95%

sides

2-sided

lower limit

1.1

upper limit

4.7

Notes
[15] - Cumulative incidence curves were used for relapse incidences (RI) with death as a competitive risk
[16] - statistically significant

Incidence of nonrelapse mortality (NMR)

Statistical analysis description

Four-year cumulative incidences of NRM were 24% and 13% in Flu-TBI and TLI-ATG patients, respectively (P = 0.5).

Comparison groups

Evaluable patient TBI arm v Evaluable patient TLI arm

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[17]

P-value

= 0.5

Method

Cumulative incidence

Confidence interval

Notes
[17] - Cumulative incidence curves with relapse as a competitive risk

Progression Free Survival (PFS)

Statistical analysis description

4-year PFS was 54% in the Flu-TBI arm, versus 37% (P = 0.12) in the TLI-ATG arm. 5-year PFS was 50% in Flu-TBI patients, versus 37% (P = 0.14) in TLI-ATG patients. Median follow-up for surviving patients of 58.5 months. (Figure 3 E-F)

Comparison groups

Evaluable patient TBI arm v Evaluable patient TLI arm

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[18]

P-value

= 0.14 ^[19]

Method

Kaplan-Meier method

Parameter type

Hazard ratio (HR)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

4.1

Notes
[18] - In multivariate analyses, there was a trend for lower PFS in patients transplanted for high-risk disease (HR = 2.0, 95% CI: 1.0-4.1, P = 0.07), while higher HCT-CI scores predicted for lower OS (HR = 1.2, 95% CI: 1.0-1.4, P = 0.02).
[19] - 4-year P=0.12 and 5-year P=0.14

Overall Survival (OS)

Statistical analysis description

4-year OS was 53% in the TBI arm, versus 54% (P = 0.9) in the TLI-ATG arm. 5-year O Swas 53% in Flu-TBI patients, versus 55% (P = 0.96) in TLI-ATG patients. Median follow-up for surviving patients of 58.5 months. Figure 3 E-F

Comparison groups

Evaluable patient TBI arm v Evaluable patient TLI arm

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[20]

P-value

= 0.96 ^[21]

Method

Kaplan-Meier method

Parameter type

Hazard ratio (HR)

Point estimate

1.2

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

1.4

Notes
[20] - In multivariate analyses, there was a trend for lower PFS in patients transplanted for high-risk disease (HR = 2.0, 95% CI: 1.0-4.1, P = 0.07), while higher HCT-CI scores predicted for lower OS (HR = 1.2, 95% CI: 1.0-1.4, P = 0.02).
[21] - 4-year P=0.9 and 5-year P=0.96

Secondary: Quality and timing of immunologic reconstitution

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End point title

Quality and timing of immunologic reconstitution

End point description

1. cytokine levels 2. T-cell chimerism levels and immune recovery 3. Lymphocyte subset reconstitutions: - CD8+ and CD4+ lymphocyte subsets - Treg and NK/T-cell recovery - B- and NK cell subset recovery 4. Thymic function (sjTREC levels)

End point type

Secondary

End point timeframe

During 3 or 4 years after the transplantation

End point values	Evaluable patient TBI arm	Evaluable patient TLI arm
Number of subjects analysed	28 ^[22]	25 ^[23]
Units: cells/microlitre
number (not applicable)	28	25

Attachments

Untitled (Filename: TJB0702-TBI Vs TLI -Publication_2015_Hannon_TBIvsTLI.pdf)
Untitled (Filename: TJB0702-TBI Vs TLI -Publication_2015_Hannon_TBIvsTLI_Suppl fig 1.pdf)
Untitled (Filename: TJB0702-TBI Vs TLI -Publication_2015_Hannon_TBIvsTLI_Suppl fig 2.pdf)
Untitled (Filename: TJB0702-TBI Vs TLI -Publication_2015_Hannon_TBIvsTLI_Suppl fig 3.pdf)

Notes
[22] - This study includes data from 53 patients (from 4 centers; out of a total cohort of 94 patients)
[23] - This study includes data from 53 patients (from 4 centers; out of a total cohort of 94 patients)

Cytokine levels: IL17

Statistical analysis description

Fig. 1B, IL7 plasma levels were higher in TLI than in TBI recipients the first 100 days after transplantation, suggesting more pronounced T-cell lymphopenia in TLI recipients, given that IL7 levels after allo-HCT depend mainly on consumption by T cells.

Comparison groups

Evaluable patient TBI arm v Evaluable patient TLI arm

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[24]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[24] - P values ranged from <0.001 to 0.5

cytokine levels: IL15, IL2, IL4, IL10

Statistical analysis description

IL15 levels were comparable between TBI and TLI recipients from preconditioning to day 28, suggesting similar CD8+ T-cell and NK cell recovery in the two groups of patients IL2 serum levels on D28 were below the threshold for detection (2.1 pg/mL) in the two groups of patients. IL4 levels were comparable in the 2 arms IL10 levels were significantly higher in TLI patients(P=0.0481), possibly suggesting a TH-2 polarization of donorT cells or a higher production of IL10 by Treg in TLI arm

Comparison groups

Evaluable patient TBI arm v Evaluable patient TLI arm

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0481 ^[25]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[25] - IL10 levels were significantly higher in TLI, suggesting a TH-2 polarization of donorT cells or a higher production of IL10 by Treg. IL4/CD4 cell ratios were significantly higher in TLI (P=0.0004). Other are comparable (Fig S1A-C Hannon et al.)

cytokine levels: IFNg & TNFa

Statistical analysis description

IFNg serum levels were similar between the two groups of patients TNFa levels were significantly higher in TLI than in TBI patients (P= 0.0493)

Comparison groups

Evaluable patient TBI arm v Evaluable patient TLI arm

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0493 ^[26]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[26] - TNFa levels were significantly higher in TLI than in TBI patients

Lymphocyte subset reconstitutions: CD8+ & CD4+

Statistical analysis description

CD8+ and CD4+ lymphocyte subsets (Hannon et al. Fig. 2): Among CD8+ T cells, TLI patients had lower percentages of naive CD8+ T cells but higher percentages of effector/effector-memory CD8+ T cells (TEM CD8+) than TBI patients. Similar observations were made for CD4+ T cells where TLI patients had dramatically lower percentages of naive CD4+ T cells but higher percentages of effector/effector-memory CD4+ T cells (TEM CD4+).

Comparison groups

Evaluable patient TBI arm v Evaluable patient TLI arm

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[27]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[27] - See figure 2 (Hannon et al.) P< 0.001 for Naive CD4+cell between TLI and TBI at D40 to D180 (Fig 2D). P< 0.05 for Naive CD8+cell between TLI and TBI at D40 (Fig 2A).

Lymphocyte subset reconstitutions: Treg and NK/T-c

Statistical analysis description

Treg and NK/T-cell recovery (Hannon et al. Fig. 3): Given the lower incidence of chronic GVHD observed in TLI patients, study of Treg recovery in our patient population was of particular interest. Median absolute Treg numbers reached the lower limit of normal values 6 months and 2 years after transplantation in TBI and TLI patients, respectively (NS), confirming the previously reported slow Treg recovery after allo-HCT

Comparison groups

Evaluable patient TBI arm v Evaluable patient TLI arm

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[28]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[28] - P < 0.001 for ration between Treg/naiveCD4+ T cell (TBI vs TLI) at day 40 and 100, P<0.05 at day 180 and 1year See Fig 3 A-F (Hannon et al.)

Lymphocyte subset reconstitutions: B- and NK cell

Statistical analysis description

B- and NK cell subset recovery: - B-cell recovery was superimposable in TBI and TLI patients. - NK cell reconstitution was similar in both arms, with faster recovery of CD56bright NK cells in comparison with CD56dim NK cells, as reported previously by other groups of investigators and particularly after HLA-haploidentical stem cell transplantation.

Comparison groups

Evaluable patient TBI arm v Evaluable patient TLI arm

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Thymic function (sjTREC levels)

Statistical analysis description

SjTREC levels were significantly higher in TBI than in TLI patients on day 100 as well as 2 and 3 years after transplantation. Indeed, although median sjTREC levels reached the lower limit of normal 2 years after transplantation in TBI patients, they remained below that limit throughout the study period in those given TLI conditioning. the sjTREC levels increased significantly from D100 to 3 yrs in patients <60yrs and not in >60yrs, reflecting an impaired thymic function in the latter group

Comparison groups

Evaluable patient TBI arm v Evaluable patient TLI arm

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.027 ^[29]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[29] - sjTREC levels increased significantly from day 100 to 1 year (P=0.027), 2 years (P=0.039), and 3 years (P =0.06) after transplantation in patients < 60 yrs at transplantation, while they did not (P values ranged from 0.11 to 0.6) >=60yrs

Adverse events

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Timeframe for reporting adverse events

5 years follow up after transplantation

Assessment type

Non-systematic

Dictionary name

CTCAE

Dictionary version

Reporting group title

TBI arm

Reporting group description

Reporting group title

TLI arm

Reporting group description

Serious adverse events	TBI arm	TLI arm
Total subjects affected by serious adverse events
subjects affected / exposed	41 / 49 (83.67%)	41 / 45 (91.11%)
number of deaths (all causes)	22	19
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Second primary malignancy
subjects affected / exposed	1 / 49 (2.04%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Vascular disorders
Thrombosis
subjects affected / exposed	1 / 49 (2.04%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Surgical and medical procedures
Surgery
Additional description: Surgery/Intervention (coronary, hip prothesis, catheter removal, endoscopy biopsy)
subjects affected / exposed	4 / 49 (8.16%)	3 / 45 (6.67%)
occurrences causally related to treatment / all	0 / 4	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
fever unknown origin
Additional description: FUO, no gem associated/identified
subjects affected / exposed	3 / 49 (6.12%)	4 / 45 (8.89%)
occurrences causally related to treatment / all	0 / 6	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Impaired quality of life
Additional description: Impaired general status, weakness
subjects affected / exposed	2 / 49 (4.08%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Immune system disorders
Acute graft versus host disease
subjects affected / exposed	15 / 49 (30.61%)	15 / 45 (33.33%)
occurrences causally related to treatment / all	0 / 15	0 / 15
deaths causally related to treatment / all	0 / 1	0 / 2
Chronic graft versus host disease
subjects affected / exposed	22 / 49 (44.90%)	13 / 45 (28.89%)
occurrences causally related to treatment / all	0 / 25	0 / 14
deaths causally related to treatment / all	0 / 2	0 / 0
Graft loss
Additional description: Graft failure
subjects affected / exposed	2 / 49 (4.08%)	5 / 45 (11.11%)
occurrences causally related to treatment / all	1 / 2	1 / 5
deaths causally related to treatment / all	0 / 1	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome
subjects affected / exposed	1 / 49 (2.04%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Dyspnoea
subjects affected / exposed	2 / 49 (4.08%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Tachycardia
subjects affected / exposed	2 / 49 (4.08%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Endocarditis
subjects affected / exposed	0 / 49 (0.00%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Epilepsy
subjects affected / exposed	1 / 49 (2.04%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
neurologic trouble
Additional description: sleeping trouble,pain, depression, encephalopathy
subjects affected / exposed	4 / 49 (8.16%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Relapse
Additional description: Relapse/progressive primary hematological disease
subjects affected / exposed	12 / 49 (24.49%)	22 / 45 (48.89%)
occurrences causally related to treatment / all	0 / 11	0 / 22
deaths causally related to treatment / all	0 / 10	0 / 13
Alveolar hemorrhage
subjects affected / exposed	1 / 49 (2.04%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Hemolytic Anaemia
subjects affected / exposed	0 / 49 (0.00%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1
hematuria
subjects affected / exposed	0 / 49 (0.00%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
febril neutropenia
subjects affected / exposed	1 / 49 (2.04%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Gastroenteritis
subjects affected / exposed	3 / 49 (6.12%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Barrett's oesophagus
subjects affected / exposed	1 / 49 (2.04%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Anorexia
Additional description: Anorexia, complains
subjects affected / exposed	1 / 49 (2.04%)	2 / 45 (4.44%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Urinary retention
subjects affected / exposed	1 / 49 (2.04%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
acute renal failure
subjects affected / exposed	0 / 49 (0.00%)	2 / 45 (4.44%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Transurethral resection
subjects affected / exposed	0 / 49 (0.00%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthritis
subjects affected / exposed	1 / 49 (2.04%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
broken ribs
subjects affected / exposed	0 / 49 (0.00%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Septic shock
subjects affected / exposed	5 / 49 (10.20%)	5 / 45 (11.11%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 5	0 / 3
Lung infection
subjects affected / exposed	7 / 49 (14.29%)	2 / 45 (4.44%)
occurrences causally related to treatment / all	0 / 11	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Viral infection
subjects affected / exposed	6 / 49 (12.24%)	4 / 45 (8.89%)
occurrences causally related to treatment / all	0 / 6	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Catheter site infection
subjects affected / exposed	2 / 49 (4.08%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	2 / 49 (4.08%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	1 / 49 (2.04%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	TBI arm	TLI arm
Total subjects affected by non serious adverse events
subjects affected / exposed	18 / 49 (36.73%)	26 / 45 (57.78%)
Infections and infestations
viral CMV reactivation
Additional description: number of first CMV reactivation
subjects affected / exposed	18 / 49 (36.73%)	21 / 45 (46.67%)
occurrences all number	18	21

More information

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Were there any global substantial amendments to the protocol? Yes

19 Jan 2015

Addition of participating centers (multicentre trial)

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

http://www.ncbi.nlm.nih.gov/pubmed/25652604
http://www.ncbi.nlm.nih.gov/pubmed/25779951

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Clinical Trial Results:
Allogeneic hematopoietic cell transplantation with HLA-matched donors : a phase II randomized study comparing 2 nonmyeloablative conditionings

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Primary: The 180-day incidence of grade II-IV acute GVHD

Primary: The 180-day incidence of grade II-IV acute GVHD

Secondary: hematopoietic (whole blood and T-cell chimerisms) engraftment and incidence of graft rejection

Secondary: hematopoietic (whole blood and T-cell chimerisms) engraftment and incidence of graft rejection

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Secondary: Incidence of relapse (RI), nonrelapse mortality (NRM), progressionfree survival (PFS) and overall survival (OS)

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Secondary: Quality and timing of immunologic reconstitution

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Clinical trials

Clinical Trial Results: Allogeneic hematopoietic cell transplantation with HLA-matched donors : a phase II randomized study comparing 2 nonmyeloablative conditionings

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Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: The 180-day incidence of grade II-IV acute GVHD

Primary: The 180-day incidence of grade II-IV acute GVHD

Secondary: hematopoietic (whole blood and T-cell chimerisms) engraftment and incidence of graft rejection

Secondary: hematopoietic (whole blood and T-cell chimerisms) engraftment and incidence of graft rejection

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Secondary: Incidence of chronic GVHD

Secondary: Incidences of infections

Secondary: Incidences of infections

Secondary: Incidence of relapse (RI), nonrelapse mortality (NRM), progressionfree survival (PFS) and overall survival (OS)

Secondary: Incidence of relapse (RI), nonrelapse mortality (NRM), progressionfree survival (PFS) and overall survival (OS)

Secondary: Quality and timing of immunologic reconstitution

Secondary: Quality and timing of immunologic reconstitution

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

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Clinical Trial Results:
Allogeneic hematopoietic cell transplantation with HLA-matched donors : a phase II randomized study comparing 2 nonmyeloablative conditionings