Busulfan Plus Cyclophosphamide vs Fludarabine as a Conditioning Regimen
Condition: Leukemia; Myelodysplastic Syndrome
MeSH terms: Leukemia; Preleukemia; Myelodysplastic Syndromes; Syndrome
Study type: Interventional
Phase: Phase 3

Summary: 
      1. At the same time of registration, patients will be randomized to one of the two
           conditioning therapy groups; Arm I (intravenous busulfan plus cyclophosphamide; BuCy) or
           Arm II (intravenous busulfan plus fludarabine; BuFlu).

        2. Randomization will be a stratified permuted-block design. 2.1The patients will be
           stratified into standard risk vs. high risk group, and related vs. unrelated donor.
           Standard risk group will be defined as follows: patients with acute leukemia in first
           remission, CML in chronic phase, and MDS (RA or RARS categories). High risk group will
           be defined as follows: patients with acute leukemia in relapse or in second or
           subsequent remission, CML in accelerated or blastic phase, and MDS (CMMoL or RAEB
           categories).

      2.2.Pre-assigned block size is 8.
    

Detailed description: 
      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.
    

Intervention name(s): BuCy vs BuFlu
Intervention type(s): Drug
Intervention description(s): Arm 1:BuCy Arm 2:BuFlu
Other intervention name(s): busulfan plus cyclophosphamide versus fludarabine
Intervention MeSH terms: Cyclophosphamide; Busulfan; Fludarabine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment