Table 1.

Fludarabine in conditioning improves engraftment

Table 1a. Fludarabine Containing Regimen Experience: AD-HCT Outcomes Similar to MSD-HCT
	Reference	n=	AlloHCT Details	% Neutrophil Engraftment (Median)	GVHD (Grade III/IV Acute, Chronic)	Overall survival
MSD-HCT	Shimada 2012 [37] Japan 2001–2011	2	Indication: BMF Conditioning: FLU 150 mg/m2, CY 40 mg/kg Donor graft: MSD unmanipulated BM GVHD prophylaxis: ATG + MTX + CsA	100% (d+16)	0%, 0%	100% (median follow-up 72 months)
	Benajiba 2015 [38] France 2004–2013	20	Indication: BMF Conditioning: FLU 90 mg/m2, CY 40 mg/kg Donor graft: MSD unmanipulated (16 BM, 4 UCB) GVHD prophylaxis: CsA + MMF (+ATG in 6)	100% (d+17)	15%, 25%	2 yr OS 95%
AD-HCT	Chaudhury 2008 [39] Memorial-Sloan Kettering 1999–2005	18	Indication: 8 BMF, 4 MDS, 6 AML Conditioning: FLU 150 mg/m2, CY 40 mg/kg, TBI 450 cGy Donor graft: 8 mMRD, 3 MUD, 7 mMUD GCSF mobilized CD34+ selected (3 BM, 15 PBSC) GVHD prophylaxis: ATG (D-5 to −2) + tacrolimus	100% (d+10)	6%, 6%	5 yr OS 72.2% (5 yr DFS 66.6%)
	Bonfim 2012 [40] Brazil 2002–2011	33	Indication: all BMF Conditioning: FLU 125 mg/m2 + CY 60 mg/kg Donor graft: 29 MUD, 4 mMUD unmanipulated BM GVHD prophylaxis: ATG + CsA + MTX	97%	39% (Gr II–IV), 42%	3 yr OS: 79% <10 yrs age: 94% MUD BMT: 86%
	Shimada 2012 [37] Japan 2001–2011	6	Indiction: 5 BMF, 1 MDS Conditioning: FLU 120–180 mg/m2, CY 40 mg/kg + TBI/TLI 400–450 cGy (URD) OR TBI/TLI 200 cGy (mmRD) Donor graft: 1 MRD (maternal), 1 mMRD, 4 MUD unmanipulated BM GVHD prophylaxis: ATG + MTX + CNI	100% (d+16)	0%, 0%	100% (median follow-up 72 months)
	Chao 2015 [41] Germany 2006–2014	17	Indication: 12 BMF, 5 MDS Conditioning: FLU 180 mg/m2, BU 2 mg/kg, CY 40 mg/kg Donor graft: 1 mMRD PBSC, 8 MUD (7 BM, 1 PBSC), 8 mMUD (5 BM, 3 PBSC), mismatched grafts CD34+ selected with addback of 1 x 106 CD3+/kg GVHD prophylaxis: CAMPATH (15) or ATG (2) + CsA	100% (d+12)	0%, 0%	2 yr OS 88%

Table 1b. Fludarabine vs. non-Fludarabine Containing Regimen Experience
Reference	n=	AlloHCT Details	Neutrophil Engraftment (FLU vs. non-FLU)	Overall survival (FLU vs. non-FLU)	Other factors influencing OS in multivariate analysis
Locatelli 2007 [42] Italian Registry (AIEOP) 1989–2005	64	Indication: BMF Donor graft: 31 MSD-HCT, 33 AD-HCT Conditioning regimen: FLU (total 120 mg/m2), n=25 Non-FLU, n=39	94% vs. 94% Multivariate analysis: No impact of FLU on engraftment (values not reported)	8 yr OS: 86% vs. 59% (LR p=0.04) Multivariate analysis: FLU associated with decreased mortality (RR 0.16, p=0.05)	Increased mortality: Donor type URD (RR 7.65, p=0.03)
Wagner 2007 [35] CIBMTR 1990–2003	98	Indication: 75 BMF, 14 MDS, 7 AML, 2 unknown Donor graft: AD-HCT Conditioning regimen: FLU (dose not described), n=46 Non-FLU, n=52	89% vs. 69% (LR p=0.02) Multivariate analysis: DEB mosaicism with lower engraftment in non-FLU regimen (OR 0.09, p=0.004)	3 yr OS: 52% vs.13% (p<0.001)	Increased mortality: >20 pRBC transfusions prior to HCT (RR 2.49, p=0.004) CMV seropositivity: D+/R+ (RR 4.52, p<0.001)
Gluckman 2007 [43] EBMT 1994–2005	93	Indication: 81 BMF, 8 MDS, 4 Acute leukemia Donor graft: AD-HCT (UCBT) Conditioning regimen: FLU (dose not described), n=57 Non-FLU containing, n=36	72% vs. 42% (LR p=0.02) Multivariate analysis: FLU associated with improved engraftment (HR 1.86, p=0.05)	3 yr OS: 50% vs.25% (LR p=0.01) Multivariate analysis: FLU associated with increased OS (HR 1.79, p=0.04)	Increased survival: Recipient CMV seronegative (HR 2.82, p<0.001) TNC infused >/= 4.9 x 107/kg (HR 1.75, p=0.05)
Stepensky 2011 [44] 3 centers: Israel x2, Russia 1993–2007	41	Indication: 35 BMF, 3 MDS, 3 AML Donor graft: 26 MSD-HCT, 15 AD-HCT Conditioning regimen: FLU (150–180 mg/m2), n=24 Non-FLU, n=17	92% vs.100% (LR p=0.005)	9 yr OS: 83% vs. 35% (LR p=0.02)	No multivariate analysis completed
Peffault de Latour 2013 [36] EBMT 1972–2010	795	Indication: 737 BMF, 58 MDS/AML Donor graft: 471 MSD, 324 MUD Conditioning regimen: FLU (dose not described), n=233 Non-FLU, n=492	Overall 92% Multivariate analysis: FLU associated with decreased graft failure (HR 0.31, p=0.013)	5 yr OS: Overall 65% Multivariate analysis: FLU associated with decreased mortality (HR 0.40, p<0.001)	Increased mortality: Age >10 yrs 20–50 yrs (HR 1.92, p=0.003) CMV serology D−/R+ (HR 2.11, p=0.001) D+/R+ (HR 1.68, p=0.16) Time from dx to HCT >12 mon (HR 1.55, p=0.005) Indication: MDS/AML (HR 2.10, p=0.0002) Irradiation exposure >5 yrs post-HCT (HR 5.29, p=0.011) Chronic GVHD (HR 3.10, p<0.001) 2ry malignancy (HR 23, p<0.001)
MacMillan 2015 [45] Univ of Minnesota 1995–2012	130	Indication: 120 BMF/early MDS, 10 late MDS Donor graft: AD-HCT Conditioning regimen: FLU (140 mg/m2), n=107 Non-FLU, n=23	96% vs. 60% (LR p<0.01) Multivariate analysis: FLU + TBI associated with improved engraftment (450 cGy: RR 2.6, p<0.01; 300 cGy: RR 2.9, p<0.01)	5 yr OS: Overall 58% Multivariate analysis: FLU + TBI associated with decreased mortality (450 cGy: RR 0.3, p<0.01; 300 cGy: RR 0.1, p<0.01)	Increased mortality: Age >10 yrs 10–17 yrs (RR 2.2, p=0.33) ≥18 yrs (RR 2.7, p=0.01) Pre-HCT opportunistic infection (RR 3.5, p<0.01) Recipient CMV seropositivity (RR 2.3, p=0.02)

AD-HCT, alternative donor hematopoietic cell transplant; MSD, matched sibling donor; alloHCT, allogeneic hematopoietic cell transplant; GVHD, graft-versus-host disease; BMF, bone marrow failure; FLU, fludarabine; CY, cyclophosphamide; BM, bone marrow; ATG, anti-thymocyte globulin; MTX, methotrexate; CsA, cyclosporine A; UCB, umbilical cord blood; MMF, mycophenylate mofetil; OS, overall survival; MDS, myelodysplastic disorder; AML, acute myeloid leukemia; TBI, total body irradiation; mMRD, mismatched related donor; mMUD mismatched unrelated donor; GCSF, granulocyte colony stimulating factor; PBSC, peripheral blood stem cell; DFS, disease free survival; MUD, matched unrelated donor; TLI, total lymphoid irradiation; URD, unrelated donor; CNI, calcineurin inhibitor; BU, busulfan; LR, log rank; RR, relative risk; OR, odds ratio; pRBC, packed red blood cell; HR, hazard ratio; TNC, total nucleated cell; NS, non-significant