Thiotepa-Based Conditioning for Allogeneic Stem Cell Transplantation (allo-HSCT) in Acute Lymphoblastic Leukaemia (ALL) - a Survey from the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT)

Background
Thiotepa is an alkylating compound with an effective antineoplastic activity that was used in the past mainly for solid tumors and lymphoma, partially due to its ability to penetrate the blood-brain-barrier. Moreover, beside its myelosupressive activities, thiotepa has immunosuppressive properties making it an attractive agent to be used in the conditioning pre-transplantation.
In the current retrospective registry study, we analyzed thiotepa-based conditioning regimen for allo-HSCT in adult patients with ALL using the EBMT ALWP database.

Methods
Inclusion criteria were: adults with de novo or secondary ALL who underwent first allo-HSCT between 2000 and July 2014 with a thiotepa-based regimen. Donors were either HLA-matched siblings or matched unrelated donors. Haploidentical and cord blood transplantations were excluded as well as patients who received a previous allo-HSCT.

Results
A total of 323 patients with adult ALL were identified. Median age was 43 years (range, 18 – 76); 59% were males and 41% females. Disease status at allo-HSCT was CR1 in 48.9%, CR2 in 21.7%, CR3 in 6.2% and 23.2% of the patients had an active disease at time of transplant. Transplantation was performed from a HLA-matched sibling (49.8%) or a matched unrelated donor (51.2%). Sixty-five per cent of patients received a myeloablative and 35% a reduced-intensity conditioning regimen, respectively. Stem cell source was peripheral blood stem cells in 84% of the transplants, while 16% received bone marrow grafts.
Neutrophil engraftment (defined as >0.5x10⁹/L) was 98% with a median day of 15 (range, 2 – 41). Platelets engraftment (defined as >20x10⁹/L) was 92% with a median day of 14 (range, 7 – 98). Incidence of acute GvHD (Grade> II) was 26.6%, while chronic GvHD occurred in 35.9% at one year (24.6% with extensive disease).
With a median follow-up of 16.8 months, the non-relapse mortality was 12.4% and 25.3% at 100 days and one year, respectively. Relapse incidence at 1 year was 33.3%.The one-year leukemia-free survival and overall survival incidences were 57% and 66%.
Table 1 shows the outcome according to donor and disease status at time of allo-HSCT.
When looking for conditioning regimen more precisely, comparing thiotepa / busulfan ± melphalan (n=213) to thiotepa / other (n=110), higher relapse incidence at one year (34.9% vs 30.3%, p=0.016) and lower leukemia-free survival (38.8% vs 45.9%, p=0.0203), respectively were observed, without difference in non-relapse mortality (23.8% vs 26.3 %, n.s.) and overall-survival (59.6% vs 51.1%, p=0.109).

Conclusion
This large survey suggests that TTP-based conditioning therapy in adult ALL is feasible and effective, with main outcomes being comparable to literature published results achieved with other regimens.

Table 1

Donor

	LFS, 1 year	p-value	OS, 1 year	p-value	Relapse, 100 days	Relapse, 1 year	p-value	NRM, 100 days	NRM, 1 year	p-value
HLA- matched sibling	49%	0.0262	62%	0.0133	13.1%	31.9%	0.4641	8.7%	18.3%	0.0042
matched unrelated donor	33%		46%		15.2%	34.7%		16.2%	32.1%

 Disease status at allo-HSCT 

	LFS, 1 year	p-value	OS, 1 year	p-value	Relapse, 100 days	Relapse, 1 year	p-value	NRM, 100 days	NRM, 1 year	p-value
CR1	49%	<0.0001	68%	<0.0001	6.4%	27.5%	0.0028	7.6%	22.6%	0.1859
CR2+	33%		40%		21.5%	39%		17%	27.8%