: 6 2 2 bu sulf an, thiotepa, m elph alan 3 =A b s t r a c t = B u s u lf an, th i o te p a, an d m e lp h al an a s a c on dit i on in g re g im e n f o r allo g e n e ic b o n e m arro w t ran s p l an t ati o n in p atie n t s w ith ac u te m y e lo g e n o u s le u k e m i a Soo- Jeong P ark, M.D., Woo- Sung Min, M.D., Hee - Je Kim, M.D., Eun - Joung P ark, M.D., Ki- Seong Eom, M.D., Hyeon - Seok Eom, M.D., Chang - Ki Min, M.D., Dong - Wook Kim, M.D., Jong - Wook Lee, M.D., Jong - Yul Jin, M.D., Chi- Wha Han, M.D. and Chun - Choo Kim, M.D. Catholic H ematop oietic Stem Cell T ransp lantation Center, The Catholic University, Seoul, K orea B ackg round : The purpose of this study was to evaluate the toxicity and efficacy of high- dose chemotherapy with busulfan, thiotepa and melphalan (BTM) as a myeloablative regimen in allogeneic bone marrow transplantation (allo- BMT ) for patients with acute myelogenous leukemia (AML). Meth ods : T wenty-seven patients with AML were enrolled; Sixteen patients had standard risk (SR) diseases (first complete remission () and de novo AML) and eleven patients had high risk (HR) diseases (second, or subsequent remission, secondary AML, relapsed, or refractory AML, marrow with persisting extramedullary manifestation (chloroma), or hypoplastic acute leukemia). The conditioning regimen included busulfan 4 mg/ kg/ day for a total dose of 2 mg/ kg; thiotepa 25 mg/ m 2 / day for a total dose of 5 mg/ m 2 ; and melphalan 5 mg/ m 2 / day for a total dose of mg/ m 2. Cyclosporine A and short- course methotrexate were used for graft- versus- host disease (GVHD) prophylaxis. Re s ult s : The median time to recovery a granulocyte count of.5 x 9 / L was 4 days (range 25 days) and platelet transfusion independence was 3 days (range 2 49 days). The major regimen-related toxicities were gastrointestinal-related symptoms including oral mucositis, nausea, vomiting, and diarrhea. All patients experienced oral mucositis ( grade ) and the patients with oral mucositis of equal and greater than grade 3 were 44% in SR and 45% in HR. The toxicities : 2 5 3 : 2 7 :, 6 665, (43- ) E -mail: hellenpark @hanmail.net. - 56 -
Soo- Jeong Park, et al : Busulfan, thiotepa, and melphalan as a conditioning regimen for allogeneic bone marrow transplantation in patients with acute myelogenous leukemia associated with lung, skin, heart and brain were minimal. Three (%) patients had severe or fatal veno-occlusive disease (VOD). There were five treatment-related death (9%) (hepatic VOD with multiorgan failure (n=3), pneumonia and ARDS (n=2)) within the first days after allo- BMT. T here was not a significant difference between SR and HR group (p =.7). The incidence of acute GVHD equal or greater than grade II was less than %. The actual survival at 2 year was 7.4%(95% confidence interval (CI), 54.7% 86.%)(SR; 8.3% (95% CI; 63.4 99.%) vs HR; 54.6% (95% CI; 28.7 8.4%), p =.54). After a median follow- up of 63 days, 8 of 27 (67%, 355 62 days) patients are alive without evidence of disease. Three of the 27 patients relapsed (SR; % vs HR; 55.6% (95% CI; 9.6 7.3%), p =.4). Conclus ion : The BTM regimen followed by allo- BMT is associated with acceptable toxicity and appears to have significant activity in patients with AML. It should be used with caution in patients with prior hepatopathy or refractory state who have an increased risk of severe VOD. Busulfan, thiotepa, and melphalan is an effective and alternative myeloablative regimen for patients with AML. (Korean J Med 6:56-6, 2) Key Words : Bone Marrow Transplantation; Transplantation, Homologous; Leukemia, Myelocytic, Acute; Busulfan; T hiotepa; Melphalan ). 2 ) 3 ) 5%., 5-25% 4, 5 ), 2 5-75% 5, 6 ).. cyclophosphamide (total body irradiation, T BI) 7, 8 ), busulfan cyclophosphamide 9 ).... T hiotepa (N,N ',N '' triethylenethiophosphoramide) P45 tepa 2 ),,, 3, 4 ). 5-25%,., FHC (Fred Hutchinson Cancer Research Center) busulfan, melphalan, thiotepa 3, 2 5 ), 3 ). 3 7 ), 3 2.,, busulfan, thiotepa melphalan 3,,, - 57 -
: 6 2 486 2 T able. Patient characteristics No. of patients Median age in years (range) No. of patients (male/ female) Standard risk 3( 39) 6/ High risk 35(4 48) 7/ 4 Disease status at BMT 2 Refractory Hypoplastic acute leukemia Persistent extramedullary disease 3 5 2 Prior chemotherapy No. of cycles (range) 2(2 3) 3( 5) FAB classification Hypoplastic leukemia M M M3 M5 M6 M7 2ndary AML 4 2 2 4 2 4 4 Abbreviations: ; complete remission, FAB; French-American-British classification, AML; acute myelogenous leukemia.. 997 6 999 3 3 27 (T able ). 3 HLA- (HLA- matched sibling donor),,.,, HLA, 3,,. (standard risk group), 2,, 2 (secondary acute leukemia) (high risk group). 3:4, 3 (4-48 ). - 58 -
: busulfan, thiotepa, melphalan 3 2. busulfan, mg/ kg 6 4 3 (D- 8, - 7, - 6) ( 2 mg/ kg), thiotepa 25 mg/m 2 / day 2 (D-5, -4), melphalan 5 mg/ m 2 / day 2 (D- 3, - 2). cyclosporine A methotrexate. 8 ). 3. 2. 7 ( 2, 5 ) - (> kg) G- CSF g/ kg/ day 3 G- CSF 2 (D). 4. 9 ) 2 ) Seattle group, NCI 2). Jones (veno- occlusive disease, VOD) 22 ) (idiopathic interstitial pneumonitis). 2, 6, 2, 24. RFLP (restriction fragment length polymorphism),, FISH (fluorescence in situ hybridization). 5. 58 (7,62 ) ( ; 54 (24,35 ), ; 365 (7,62 )). 63 (355,62 ).,,, - Kaplan- Meier, log- rank. proportion confidence interval (CI) binorr distribution...48 x 8 / kg (.88 2.65 x 8 / kg). 2 kg, 3 G- CSF / kg. 2.66 x 8 / kg (.88 6. x 8 / kg). 5 kg, 3 G- CSF / kg. 2. ) (n=) 28 4 (87.5%). 2 24,..5 x 9 / L 4 ( 25 ), 3 2 x 9 / L 3 (2 49 ). 28 RFLP. 2) (n=) 28 9 (8.8%). 2-59 -
Korean Journal of Medicine : Vol. 6, No. 2, 2 T able 2. Conditioning reg imen - related tox icities Standard Risk mucositis nausea vomiting diarrhea skin fever * bilirubin neurosensory High Risk mucositis nausea vomiting diarrhea skin fever * bilirubin neurosensory * unknown origin fever Number/ total number of patients (%) Grade of toxicity I II III IV 4/ (25%) 5/ (3%) 7/ (44%) / (63%) 5/ (3%) / (6%) 2/ (3%) 8/ (5%) 4/ (25%) 2/ (3%) 6/ (38%) 6/ (38%) 4/ (25%) 5/ (94%) / (6%) 4/ (25%) 5/ (3%) 7/ (44%) / (69%) 2/ (3%) / (6%) 2/ (3%) / (%) 2/ (8%) 4/ (36%) 3/ (27%) 2/ (8%) 5/ (46%) 3/ (27%) 2/ (8%) / (9%) 5/ (46%) 3/ (27%) 3/ (27%) 3/ (27%) 6/ (55%) 2/ (8%) / (%) 3/ (27%) 2/ (8%) 6/ (55%) 8/ (73%) / (9%) 2/ (8%) / (%) 7 35. 5,..5 x 9 / L 5 ( 2 ), 3 2 x 9 / L 3 (5 36 ). 28 RFLP. 3. (T able 2)., 3 44%, 45% 3. 3 6%, 27%, 3 3% 27%, 3 25% 8%., 3. 5 (3%), 2 7 (44%), 2 (8%) 6 (55%). 3 2 (3%, vs 8%),. 2, (thrombotic thrombocytopenic purpura, T T P). 4. (6%), 2 (8%), 3 - -
Soo- Jeong Park, et al : Busulfan, thiotepa, and melphalan as a conditioning regimen for allogeneic bone marrow transplantation in patients with acute myelogenous leukemia T able 3. A cute and chronic GV HD Standard Risk Group(n=) High Risk Group(n=) agvhd cgvhd agvhd cgvhd grade I II III IV limited ext. I II III IV limited ext. skin oral gut liver lung eye sal.gl *. 3(9%) 2(3%) 2(3%) (6%) (6%) 3(9%) (6%) (6%) (6%) (6%) 2(8%) (9%) 2(8%) (9%) Abbreviations: GVHD; graft- versus- host disease, agvhd; acute GVHD, cgvhd; chronic GVHD, *; salivary gland, ; extensive GVHD 2(8%) (9%) (9%) (9%) T able 4. Patients ' outcome Patient No. 2 3 4 5 6 7 8 9 2 3 4 5 7 8 9 2 2 22 23 24 25 26 27 Sex/ Age (years) F/ 3 F/ 34 M/ 34 M/ 32 M/ 23 F/ 3 F/ 39 M/ 32 F/ 27 M/ 22 F/ 25 F/ 29 M/ 34 F/ 27 F/ 37 F/ M/ 48 M/ 3 F/ 36 M/ 4 F/ 4 F/ 7 M/ 22 M/ 35 M/ 25 M/ 35 F/ 36 AML subtype M M M M M3 M3 M5a M6 M6 M7 hypoplastic M M M M 2ndary AML Previous chemotherapy x3 x4 x5 x3 x3 x4 x3 x Pre- BMT * disease status PD 2 PD 2 2 PD PD PD - B/ PD- E - B/ PD- E PD Cell dose MNC x 8 / kg.7.33.48.26 2.9 2.48.5.96.4 2.65.42 2.4.88.36.97.4 6..9 4.83.88 2. 5.5.9.6. 4.9. ANC recovery (days) 4 3 2 2 25 2 2 2 4 5 8 2 7 3 5 PLT recovery (days) 26 24 2 23 9 49 35 38 3 5 27 35 35 32 5 27 not cover 3 3 3 36 32 Outcome T RM * * T RM T RM * * relapse relapse T RM T RM * * relapse Present status alive, 887 days alive, 832 days alive, 58 days dead, 26 days alive, 436 days alive, 355 days alive, 22 days alive, 5 days alive, 35 days alive, 572 days dead, 24 days alive, 365 days alive, 473 days alive, 832 days dead, 29 days alive, 59 days dead, 96 days alive, 62 days dead, 7 days alive, 944 days dead, 63 days dead, 87 days dead, 4 days alive, 63 days alive, 365 days dead, 35 days alive, 985 days Abbreviations: ; standard risk group, 7 27; high risk group, AML; Acute Myelogeneous leukemia, *; Bone marrow transplantation, ; Mononuclear cell, ; Absolute neutrophil count, ; Platelet, ; Complete remission, ; Acute GVHD(gr aft versus host disease), ; Expansion BM, **; VOD associated T RM, ; Pneumonia & ARDS, ; Persistent Disease, ; after chemotherapy and allo- PBSCT, ; Bone m arrow but persistent extramedullary chloroma. (, ) - -
: 6 2 486 2. 2 5,. 5. (T able 3)..., table 3. 6. 63 (355,62 ) 3 (8.7%) (T able 4, Figure- A)., probability of relpase (SR; % vs HR; 55.6% (95% CI; 9.6 7.3%), p =.4, Figure - B). 22, 8, 425., 2. 7. 27 (actual survival at 2 year) 7.4% (95% confidence interval (CI), 54.7% 86.%) (Figure 2- A). 8.3% (95% CI; 63.4 99.%) 54.6% (95% CI; 28.7 8.4%) (p =.54) (Figure 2- B). 3 Fig ure. Actuarial estimate of relapse following allogeneic bone marrow transplantation for AML; A, total patients; B, standard risk group (bottom solid line), vs. high risk group (top dashed line). T here was observed a significant difference between standard and high risk group (p <.5). Fig ure 2. Kaplan- Meier probability of overall survival.;a, total; B, standard risk (top solid line) vs. high risk (bottom dashed line) group. No significant difference (p =.54) is observed between standard and high risk group in overall survival. - 2 -
: busulfan, thiotepa, melphalan 3 (33%), 3 (33%), 2 (22%), (2%). 9 4 ( 7 35 ),. (treatment related mortality) (p =.7). 3 (8.8%), (33.3%), (33.3%), (33.3%). 6 (54.5%), (.7%), 2 (33.3%), 2 (33.3%), (.7%).. cyclophosphamide 7, 8 ), busulfan 9 - ). 2-3.. busulfan, thiotepa, melphalan 3 5, )., 3. 3 7, 23-25). 3 3,,,, 3. 3. 5, 6).,,. (p =.4) (p =.54). 3, 3 45% (, 44%;, 45%).. busulfan 3. thiotepa. 3 E - 3 -
Korean Journal of Medicine : Vol. 6, No. 2, 2, ursodeoxycholic acid, pentoxifylline low molecular weight heparin ( U/kg/ day).. 5 3 3. 3, 3. 3. 3. 3 busulfan. : busulfan, thiotepa, melphalan 3,,. : 997 6 999 3 busulfan, thiotepa, melphalan 3 27., 3 4. : 28.. 3 44%, 45%.,,. 33% 3. 2. 7.4% (95% CI; 54.7% 86.%), 8.4% (95% CI; 63.4 99.%) 54.6% (95% CI; 28.7 8.4%) (p =.54). 8.7%., 3 (SR; % vs HR; 55.6%(95% CI; 9.6 7.3%), p =.4).. : 3. 8.4%, 54.6% 3. R E F E R E N C E S ) Thomas ED. Karnofsky M emorial Lecture. M arrow transp lantation for malignant diseases. J Clin Oncol :57-53, 983-4 -
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: 6 2 486 2 7),,,,,,,,,.. 34:288-296, 999 8),,,,,,,,,,,,,,,,.. 28:38-35, 996 9) Glucksberg H, Storb R, Fefer A, Buckner CD, Nerman PE, Clift RA, Lerner KG, Thomas ED. Clinical manif estation of graft versus host disease in human recip ients of marrow f rom HLA - matched sibling donor. T ransp lant 8:295-34, 974 2) Shulman MH, Sullivan KM, Weiden PL, Mcdonald GB, Striker GE, Sale GE, Hanckman R, T soi MS, Storb R, Thomas ED. Chronic graf t versus host syndrome in man: A long term clinicopathologic study of 2 Seattle patients. A m J M ed 6:24-27, 98 2) NCI: Common T oxicity Criteria. Bethesda, MD, National Cancer Institue, Division of Cancer T reatment, 988 22) Jones RJ, Lee KS, Beschorner WE, Vogel VG, Grochow LB, Braine HG, Vogelsang GB, Sensenbrenner LL, Santos GW, Saral R. Venoocclusive disease of the liver f ollowing bone marrow transp lantation. T ransp lant 44:778-783, 987 23),,,,,,,. Busulfan, Melphalan, T hiotepa(bumt ) T BI bi- alkylator. 29:874-885, 997 24) Weaver CH, Bensinger WI, Appelbaum FR, Lilleby K, Sandmaier B, Brunvand M, Rowley S, Petersdorf S, Rivkin S, Gooley T, Weiden P, Zuckerman N, Montgomery P, Trueblood K, Klarnet J, Buckner CD. Phase I study of high- dose busulfan, m elphalan, and thiotepa with autologous stem cell supp ort in patients with refractory malignancies. B one M arrow T ransp lant 4:84-89, 994 25) Moormeier JA, Williams SF, Kaminer LS, Garner M, Bitran JD. H igh- dose tri-alkylator chemotherapy with autologous stem cell rescue in patients with ref ractory malignancies. J N atl Cancer Inst 82:29-34, 99-6 -