Table 1.
BMT platform and supportive care measures.
| Day | Drug/Intervention | Adult Dosing | Pediatric Dosing |
| Prior to day −11 | Busulfan test dose | 0.8 mg/kg IV to calculate AUC& | 0.8 mg/kg IV to calculate AUC* |
| Day −11 and day −7 | Pentostatin | 4 mg/m2/day IV | |
| Days −11 through −8 | Cyclophosphamide | 3 mg/kg/day orally or IV, dosage cap of 200 mg/day | |
| Days −7 through −4 | Cyclophosphamide | If ALC on day −7 > 100 cells/μL, escalation to 5 mg/kg/day orally$; dosage cap of 400 mg/day | |
| Days −3 and −2 | Busulfan | Pharmacokinetically-dosed, with targeted daily systemic exposure of 4600 uMol-min based on test dose AUC; default dose of 3.2 mg/kg/day if test dose cannot be performed | |
| Day −1 | Day of rest | ||
| Day 0 | Fresh infusion of T-cell replete marrow | Target dose 4.5 × 108 TNC/kg recipient IBW | |
| Days +3 and +4 | Cyclophosphamide@ | 50 mg/kg/day IV% | |
| Mesna | 50 mg/kg/day IV% | ||
| Day +5 | Sirolimus loading dose$ | 6 mg orally | 3 mg/m2 orally#; maximum initial dose 6 mg |
| Days +5 through +35 | MMF | 15 mg/kg orally or IV three times daily; maximum 1000 mg/dose | |
| Starting day +6, continued through day+180 then stopped without taper^ | Sirolimus maintenance dose$ | 2 mg orally goal trough of 5–12 ng/mL | 1 mg/m2 orally#; maximum initial dose 2 mg; goal trough of 5–12 ng/mL |
| Day | Supportive Care Measure | Adult Dosing | Pediatric Dosing |
| Prior to day −11 | Leuprolide for ovarian suppression | Menstruating females | |
| Prior to day −11 | Ivermectin, if from area with endemic Strongyloides | 200 mcg/kg orally daily for 2 consecutive days | |
| −11 through −1 | PJP prophylaxis: trimethoprim-sulfamethoxazole or alternative | ||
| −4 through −1 | Clonazepam for seizure prophylaxis | 0.5 mg orally twice daily | < 10 years old or < 30 kg: 0.005–0.015 mg/kg/dose twice daily, rounded to tablet sizes |
| −4 through −1 | Levetiracetam for seizure prophylaxis | 500 mg orally twice daily | 10 mg/kg orally or IV twice daily, maximum dose 500 mg |
| −11 through +100 | Ursodiol for hepatic protection | < 90 kg: 300 mg orally twice daily ≥ 90 kg: 300 mg each morning and 600 mg each evening, orally |
< 40 kg: 300 mg orally twice daily |
| −11 through +100 or longer | Antifungal prophylaxis | Agent chosen as indicated and tolerated by organ function and drug interactions; end of therapy often chosen to coincide with cessation of sirolimus given drug interactions | |
| −11 through +100 | Weekly whole blood monitoring by quantitative PCR for CMV, EBV, adenovirus, and HHV6; pre-emptive treatment strategy used for CMV (letermovir not approved yet during study period for prophylaxis) | ||
| −11 through +2 years | HSV/VZV prophylaxis: acyclovir | 800 mg orally twice daily | 20 mg/kg orally twice daily, maximum dose 800 mg |
| Upon count recovery through +1 year | PJP prophylaxis: trimethoprim-sulfamethoxazole or alternative | ||
| 0 until PJP prophylaxis resumed | Twice weekly whole blood qualitative PCR for Toxoplasmosis in seropositive individuals | ||
| 0 through ANC recovery | Antibacterial prophylaxis: levofloxacin, or alternative as appropriate | ||
| 0 through +5 | Avoidance of corticosteroids; hydrocortisone permitted for adrenal insufficiency | ||
| +2 through +5 | Normal saline for uroprotection | 90 mL/m2/hr IV | |
| +5 until ANC ≥ 1000/μL for 3 days | Filgrastim | 5 mcg/kg/day SQ or IV | |
| Post-engraftment, as indicated | Immunoglobulin replacement | ||
| +180 onward | Post-BMT immunizations | ||
Abbreviations: IV, intravenous; AUC, area under the curve; ALC, absolute lymphocyte count; IBW, ideal body weight; MMF, mycophenolate mofetil; PJP, Pneumocystis jiroveci pneumonia; PCR, polymerase chain reaction; CMV, cytomegalovirus; EBV, Epstein-Barr virus; HHV6, human herpesvirus 6; HSV, herpes simplex virus; VZV, varicella zoster virus; ANC, absolute neutrophil count; BMT, bone marrow transplantation
Post-transplantation cyclophosphamide infusion on day +3 began 60–72 hours after graft infused (72 hours preferred)
For recipients older than age 16 years, busulfan test dose was based on ideal body weight (IBW) or actual body weight (ABW), whichever is lower, unless recipient was > 120% of IBW, in which case adjusted ideal body weight (IBW+ 25% of difference between IBW and ABW) was used.
For children age 4–16 years, busulfan test dose was based on ABW. Only one patient, P14, could not undergo busulfan pharmacokinetics.
All patients received this dose increase.
Dosed according to IBW, unless recipient weighed less than IBW, in which case ABW was used
Based on ABW
Sirolimus could be stopped sooner for toxicities or mixed chimerism, either with or without an alternative agent depending on the clinical situation
Sirolimus loading and maintenance doses individualized as necessary based on each patient’s concomitant medications and potential drug interactions, particularly the use of azoles, where co-administration was not considered contraindicated, but required significant sirolimus dose reductions.