400 cGy in 2 split fractions will be administered per Department of RadiationOncology SOPs.

On day 0 the cells will be infused per cell source specific institutional guidelines

ATG will be administered IV every 24 hours beginning on day -8 for all patients.

Dosing will be model-based using Bayesian methodology13,14,15. Total doses and total number of doses (1-4 doses) will be determined based on absolute lymphocyte count and weight.

Fludarabine will be administered IV over 1 hour every 24 hours on day -5 to day - 2. The daily dose of fludarabine will be determined by model-based dosing utilizing Bayesian methodology with a cumulative area under the curve (cAUC) of 20 mg*hr/L (range 18-22 mg*hr/L).

Busulfan dosing and administration and therapeutic drug monitoring (TDM) per institutional guidelines. Initial busulfan dosing will be determined by model-based dosing utilizing Bayesian methods with a cumulative area under the curve (cAUC) of 75 mg*hr/L.

Cyclophosphamide will be administered at a dose of 14.5 mg/kg over 2 hours IV daily on days -6 and -5. Cyclophosphamide dosing is calculated based on actual body weight (ABW).

For Arm D - Cyclophosphamide 50 mg/kg IV will be administered over 2 hours on days +3 and

+4. Cyclophosphamide dosing for post-transplant is calculated based on ideal body weight (IBW) unless patient weighs less than IBW, in which case actual body weight (ABW) will be used.

Patients on Arm A and Arm D will receive sirolimus; beginning on day -3 and continuing until day +180 for patients on Arm A or beginning on day +5 and continuing until 1 year post transplant for patients on Arm D.

Patients on Arm B and Arm C will receive tacrolimus, beginning on day -3 and continuing until day +180. Tacrolimus dosing and monitoring will be per institutional guidelines.

MMF will begin on day -3 (Arm A, B & C) or day +5 (Arm D). Patients treated on adult service will receive 15 mg/kg (max 1500 mg/dose) given every 12 hours, rounded to nearest 250 mg. Patients on pediatric service will receive 15 mg/kg (max 1000 mg/dose) given every 8 hours. MMF dosing will be monitored and altered as clinically appropriate based on institutional guidelines. MMF will be stopped at day +30 (Arms A, B & C) or day +35 (Arm D) or 7 days after engraftment, whichever day is later, if no acute GVHD.

Plerixafor will beused to significantly increase stem cell yields on a second collection day compared to donors who continued mobilization on G-CSF only.

Chronic Graft versus Host Disease (GvHD) Free at 2 years post HCT.

Failure Free Survival 2 years post HCT.