Trial Information

Randomized Comparison of Once-daily Intravenous Busulfan Plus Cyclophosphamide Versus Fludarabine as a Conditioning Regimen for Allogeneic Hematopoietic Cell Transplantation in Leukemia and Myelodysplastic Syndrome

1. TREATMENT PLAN

- The patients will be admitted to laminar air flow room.

- The patients will have triple lumen Hickman central venous catheter (CVC) placed.
Vancomycin 1 gm IV immediately prior to CVC placement and 1 gm q 12 hours for 3
doses. Chest X-ray should be taken after CVC placement to confirm the location of
CVC and absence of pneumothorax.

- Lumbar puncture will be done and intrathecal preservative free methotrexate 10 ㎎/㎡
(not to exceed 12 ㎎ total) will be given. Folinic acid 15 ㎎ will be given po or IV
24 hours after intrathecal methotrexate and q 6 hours for a total of 4 doses.

- Menstruating women will be given norethindrone (Norlutate) 10 ㎎ po daily.

2. The preparatory regimen is as follows:

- Conditioning therapy will start on day -7 in patients who are randomized to
receive intravenous busulfan (Busulfex®; Orphan Medical, Minnetonka, MN) plus
cyclophosphamide. Busulfex 3.2 ㎎/㎏ will be administered once daily for 4 days
(days -7 to -4) followed by cyclophosphamide 60 ㎎/㎏ in D5W 200 ㎖ i.v. over 1-2
hours on days -3 and -2. Busulfex will be diluted in normal saline 500 ㎖ and
infused over 3 hours by pump through a central venous catheter The doses of
Busulfex and cyclophosphamide will be calculated using following guideline: 1) if
actual body weight (ABW) of the patient is less or equal to ideal body weight
(IBW), ABW will be used. 2) if ABW is greater than IBW but by less than 20%, then
IBW will be used. 3) if ABW is greater than IBW by more or equal to 20 %, then the
dose will be based on; IBW + 25 % (ABW-IBW). IBW is calculated as follows: 50 ㎏ +
2.3 ㎏ (Height in inch - 60) in male, and 45.5 ㎏ +2.3 ㎏ (Height in inch -60) (1
inch= 2.54 ㎝).

- Conditioning therapy will start on day -7 in patients who are randomized to
receive Busulfex plus fludarabine (Fludara®, Schering AG, Berlin, Germany).
Busulfex 3.2 ㎎/㎏ will be administered once daily for 4 days (days -7 to -4) and
fludarabine 30 ㎎/㎡ will be infused intravenously over 30 minutes in D5W 100 ㎖ for
5 consecutive days (days -6 to -2). The dose of Busulfex will be calculated using
above-mentioned guideline (see 5.5.1). The dose of fludarabine will be calculated
using ABW.

3. GVHD prophylaxis

- All patients will receive cyclosporine 1.5 ㎎/㎏ in NS 100 ㎖ i.v. over 2-4 hours q
12 hrs (dose of cyclosporine rounded to nearest 5 ㎎) starting day -1 at 9 a.m.
Cyclosporine dose will be adjusted to provide appropriate level and according to
the change of renal function (see Appendix II).

- When the patients can tolerate oral medications, cyclosporine can be given p.o. 3
㎎/㎏ (or two times the i.v. dose) q 12 hrs.

- Cyclosporine dose will be decreased by 10 % every month starting day 60 of BMT
provided that there is no clinical evidence of GVHD.

- In addition to cyclosporine, methotrexate 15 ㎎/㎡ will be given intravenously on
day 1 and 10 ㎎/㎡ on days 3, 6, and 11. The dose of methotrexate will be decreased
or omitted according to the guideline provided in Appendix III.

- Methotrexate will not be given to patients with acute leukemia or MDS who will
receive hematopoietic cell graft from an HLA-matched sibling donor

4. Bone marrow cell infusion

- For ABO matched or minor mismatched transplantation, premedication with Avil
45.5mg I.v. push and tylenol 600 ㎎ p.o. will be given. Stem cell will be infused
over 1-2 hrs.

- For major ABO mismatched transplantation, premedication with Avil 45.5 ㎎ i.v.
push, tylenol 600 ㎎ p.o., 10 % mannitol 100 g i.v. over 4 hrs will be started 30
min before stem cell infusion, and hydrocortisone 250 ㎎ i.v. will be given
immediately before and 30 min of stem cell infusion.

5. Supportive cares.

- Dilantin 15 ㎎/㎏ (ABW) in NS 200 ㎖ i.v. over 1 hour for loading on day -8, then 200
㎎ p.o. bid through day -5. Dilantin dose should be adjusted to provide
therapeutic level.

- Allopurinol 300 ㎎/day p.o. qd day -8 to -2.

- Nystatin powder to groin, axilla, and perianal area bid from day -8 until absolute
neutrophil count (ANC) > 3,000/㎕.

- Sodium bicarbonate/saline mouthwash qid until mucositis is resolved.

- Fluconazole 100 ㎎/day p.o. qd until ANC > 3,000/㎕.

- Ciprofloxacin 500 ㎎ p.o. bid (for selective bowel decontamination) until ANC >
3,000/㎕. With the first fever spike, ciprofloxacin will be discontinued and broad
spectrum antibiotics will be begun.

- Hydration will be done with 0.9 % NS at 100 ㎖/hour while the patients are
receiving busulfan.

- IV Immunoglobulin 500 ㎎/㎏ (ABW) i.v. over 6 hours every other week starting day -7
until day 120, then every month until day 180.

- Prophylaxis against Herpes simplex virus will include acyclovir 250 ㎎/㎡ in D5W 100
㎖ i.v. q 8 hours starting at day -7. When the patient can tolerate oral
medication, acyclovir will be given 200 ㎎ p.o. tid until day 180.

- Prophylaxis against Pneumocystis carinii will include Bactrim SS 2 tablets p.o.
bid with folinic acid 7.5 ㎎ p.o. bid, 2 days weekly, starting after engraftment
through day 360.

- Amoxacillin 250 ㎎ p.o. bid starting at day 70 through day 360.

- G-CSF administration.

- Starting day 5, G-CSF 300 ㎍ in 100 ㎖ of D5W will be given i.v. over 3 hours daily
until ANC > 3,000/㎕.

- If ANC drops below 1,000/㎕, G-CSF administration will resume and continue until
ANC > 3,000/㎕.

6. In patients with acute leukemia or CML in blastic crisis, intrathecal methotrexate
administration will be resumed after the patient recovered platelet count to over
50,000/㎕. Methotrexate 10 ㎎/㎡ (not to exceed 12 ㎎ total) will be given intrathecally
once every 2 weeks for three times (total four doses including one given before
preparatory regimen). Folinic acid 15 ㎎ will be given p.o. or i.v. 24 hours after
intrathecal methotrexate and q 6 hours for a total of 4 doses.