Double-Conditioning Regimens Consisting of Thiotepa, Melphalan and Busulfan with Stem Cell Rescue for the Treatment of Pediatric Solid Tumors

Home , Pirarubicin, Thiotepa

Bone Marrow Transplantation, (1998) 22, 7–12  1998 Stockton Press All rights reserved 0268–3369/98 $12.00 http://www.stockton-press.co.uk/bmt Double-conditioning regimens consisting of thiotepa, melphalan and busulfan with stem cell rescue for the treatment of pediatric solid tumors

J Hara1, Y Osugi1, H Ohta1, Y Matsuda1, K Nakanishi1, K Takai1, H Fujisaki1, S Tokimasa1, M Fukuzawa2, A Okada2 and S Okada1

Departments of 1Pediatrics and 2Pediatric Surgery, Osaka University School of Medicine, Osaka, Japan

Summary: High-dose chemotherapy (HDC) requiring autologous stem cell rescue has been increasingly utilized to treat a variety Major dose-limiting factors of high-dose thiotepa of pediatric solid tumors. However, an appropriate precon- (TEPA) and melphalan are life-threatening mucositis ditioning regimen is unidentified and the contribution of and neurotoxicity. To administer a maximum dose of HDC to survival rate improvement is still not established. these drugs safely and to obtain a maximum anti-cancer In previous reports, etoposide and carboplatin in addition effect, a double-conditioning regimen with a single to an alkylating agent have been frequently used as key grafting, two cycles of administration of a combination drugs in preconditioning regimens.1 However, tumor cells of TEPA (300–600 mg/m2) plus melphalan (70– are supposedly at least partially resistant to these drugs, 150 mg/m2) with a 1-week interval was attempted in 20 since they were repeatedly used in previous chemotherapy patients with pediatric advanced or chemotherapy- at standard doses before HDC. In contrast, alkylating agents resistant solid tumors (seven rhabdomyosarcoma, four such as thiotepa (TEPA), melphalan and busulfan (Bu) are hepatoblastoma, three neuroblastoma and four other not used in chemotherapy administered prior to HDC and malignancy). Combinations of TEPA plus are therefore expected to retain considerable anti-tumor melphalan/busulfan (Bu) (8–10 mg/kg) and TEPA plus activity. Alkylating agents have several suitable character- Bu were given to four and two patients with brain istics for HDC including: (1) a logarithmic cytotoxic tumors, respectively. In an additional two patients, activity in proportion to the doses; (2) less cross resistance; three cycles of drug administration were performed. and (3) no specific adverse effects other than myelosuppres- According to the results of the dose-escalating study, the sion and mucositis.2 In addition, the ratios of maximum maximum tolerable doses of TEPA and melphalan for amounts of TEPA and Bu for HDC with stem cell rescue children aged 2 years old or older were 1000 mg/m2 and in conventional chemotherapy are much higher (five- and 280 mg/m2, respectively. Mucositis was dose-limiting. 20-fold) than other agents including etoposide and car- Renal toxicity was also dose-limiting in young children boplatin.3 Nevertheless, combinations of these drugs were (Ͻ2 years old). There were two treatment-related anticipated to cause severe mucositis and neurotoxicity.4–7 deaths (7%) (fungal pneumonia and renal tubular Therefore, to administer a maximum dose of these drugs acidosis). Among 13 patients who received high-dose safely, a double-conditioning regimen (two cycles of drug chemotherapy during CR, 10 are alive with no evidence combinations with a 1-week interval) was attempted in 26 of disease (15–59 months, median: 35 months) and in children with pediatric solid tumors. In two patients, three 13 evaluable patients without CR, six are alive without cycles were given. regrowth of the disease (14–59 months, median: 39 months). Thus, these novel conditioning regimens allowed us to increase the dose intensity to nearly the Patients and methods maximum for each drug and seemed to reduce adverse effects compared to previously reported regimens with Patients (Table 1) these drugs. With regard to the effect on outcome, the results of this study seem to be encouraging, but a Between January 1993 and February 1997, 28 consecutive further study on a larger number of patients is patients with poor prognosis solid tumors aged 1 to 19 required. years (median age: 3 years) underwent HDC with stem cell Keywords: high-dose chemotherapy; thiotepa; mel- transplantation after several courses of chemotherapy. The phalan; busulfan; stem cell patients had advanced disease, disease resistant to chemotherapy, relapsed disease, or brain tumors. All patients received HDC after several courses of chemotherapy containing cisplatin, cyclophosphamide and vincristine. Ifosfa- Correspondence: J Hara at his present address: Department of Pediatrics, mide, dactinomycin, etoposide, carboplatin and pirarubicin Suita City Hospital, 2-13-20, Katayamacho, Suita, Osaka, 564 Japan were also administered in some patients. Twelve and nine Received 4 October 1997; accepted 14 February 1998 patients received autologous bone marrow and peripheral Double-conditioning regimens J Hara et al 8 Table 1 Patient characteristics and outcome

Patient Age Diagnosis Stage Pre-HDC Time to Status Response Post Outcome Site of Present No. (year) Surgery/LRT HDC at HDC to HDC HDC relapse status (months) therapy

1 14 GCT (AFP) 1st rel (brain, −/− 8 no CR CR — RRD (2 mo) dead (2 mo) cord) (PD) 2 9 GCT (HCG) II (brain) +/+ 8 CR — — NED alive (34 mo+) 3 8 GCT (HCG) II (brain) +/+ 7 CR — — NED alive (37 mo+) 4 9 GCT (HCG) II (brain) +(partial)/+ 6 CR — — NED alive (47 mo+) 5 3 Medulloblastoma 1st rel (brain, −/− 4 no CR PR — REL (4 mo) L,BM dead (5 mo) BM) (PD) 6 1 Neuroblastoma II (brain) +(partial)/− 10 no CR MR Local SD (14 mo+) alive radiation 7a 6 GCT (AFP) 4th rel −/− 5 CR — — NED alive (54 mo+) 8 19 GCT (HCG) III −/− 6 CR — — NED alive (36 mo+) 9 3 Hepatoblastoma 3rd rel −/− 4 no CR PR – REL (3 mo) L dead (5 mo) (PD) 10 2 Hepatoblastoma II +/− 12 no CR CR — NED alive (50 mo+) 11 1 Hepatoblastoma III +/− 6 no CR CR — NED alive (19 mo+) 12 1 Hepatoblastoma III +/− 7 no CR CR — NED alive (34 mo+) 13 3 Neuroblastoma IV (bone, BM)b −/− 6 CR — — REL (8 mo) L dead (13 mo) 14 2 Neuroblastoma IV (bone, BM)b −/− 5 no CR MR Surgery NED alive (45 mo+) 15 2 Neuroblastoma IV (bone, BM)b −/− 4 no CR MR Surgery NED alive (59 mo+) 16 1 RMS (alveolar) III −/+ 8 no CR NE — RRD (1 mo) dead (1 mo) 17 18 RMS (alveolar) IV +/− 6 CR — — REL (4 mo) lung dead (6 mo) 18 1 RMS (alveolar) IV +/+ 6 CR — — NED alive (32 mo+) 19 15 RMS (embryonal) 1st rel +/− 8 CR — — NED alive (21 mo+) 20a 7 RMS (embryonal) 3rd rel (brain) +/+ 5 CR — — NED alive (32 mo+) 21 3 RMS (embryonal) III +(partial)/+ 7 CR — — NED alive (15 mo+) 22 3 RMS (embryonal) IV +(partial)/+ 7 CR — — REL (3 mo) L dead (6 mo) 23 12 PNET 1st rel −/− 5 no CR MR — REL (2 mo) L, lung dead (3 mo) (PD) 24 2 PNET IV −/− 5 CR — — NED alive (59 mo+) 25 5 Ewing sarcoma III −/− 3 no CR NR Chemo- REL (12 mo) L alive therapy (25 mo+) 26 3 Pulmonary blastoma III +(partial)/− 6 no CR CR — REL (5 mo) brain dead (8 mo) 27 16 multicentric OS IV −/− 9 no CR PR — REL (1 mo) L dead (4 mo) (PD) 28 5 MRT III −/− 5 no CR PR — REL (1 mo) L, dead (7 mo) (PD) pleura

GCT, germ cell tumor (HCG or AFP producing); RMS, rhabdomyosarcoma; PNET, peripheral neuroectodermal tumor; OS, osteosarcoma; MRT, malignant rhabdoid tumor; REL, relapse; BM, bone marrow; CR, complete response; PD, progressive disease; PR, partial response; MR, minor response; NR, no response; NE, not estimated; NED, no evidence of disease; RRD, regimen-related death; L, local. aPatients who had received HDC previously. bThese patients had extensive bone and bone marrow involvement. The N-myc gene was ampliﬁed (10 times) in patient 14.

stem cells (PSC), respectively. Six patients received stem eral CD34+ cells from an HLA-mismatched donor (father) cells from both bone marrow and peripheral blood. In the were used as stem cells as previously described elsewhere.8 remaining patient (patient 5), because HLA-matched Patient characteristics and clinical stages are shown in related or unrelated donors were available and neither was Table 1. Patients 7 and 20 received HDC consisting of an autologous stem cell source, positively selected periph- TEPA and melphalan (single cycle administration) and mel- Double-conditioning regimens J Hara et al 9 phalan, etoposide and carboplatin, respectively, prior to the was administered as a 1-h infusion. Patients received Bu fourth and third relapse. HDC was performed during CR 1–1.25 mg/kg orally every 6 h each day. Phenobarbital was or no CR in 13 and 15 patients, respectively. orally administered for the prophylaxis of convulsions induced by Bu. In patients 20 and 22, after one cycle of drug administration, convulsions and Candida albicans Bone marrow and PSC harvest sepsis occurred on days −10 and −7, respectively. There- Bone marrow was used as the sole stem cell source before fore, TEPA was eliminated from the second cycle of HDC 1994. No contamination of the stem cell inoculums with in patient 20 and the second cycle was stopped in patient tumor cells was morphologically conﬁrmed. Thereafter, 22. after the second or third course of chemotherapy, PSCs After 2 days rest, stem cells were infused on day 0. A mobilized with G-CSF were harvested and frozen until use. minimum of 2.2 × 106/kg peripheral CD34+ cells or In the case of shortage of CD34+ cells for hematopoietic 2.4 × 107/kg mononuclear bone marrow cells were used. reconstitution (Ͻ2.0 × 106/kg), bone marrow was harvested When the number of peripheral CD34+ cells obtained was and infused together with PSCs. less than 2 × 106/kg, bone marrow cells were also infused.

Conditioning regimen and stem cell infusion (Tables 2 Supportive care and 3) All patients were isolated, treated in laminar air flow, and Nineteen patients received two tandem cycles of HDC con- received total parenteral nutrition and nonabsorbable anti- sisting of TEPA and melphalan. A combination of TEPA biotics. Administration of 5 ␮g/kg of G-CSF (lenograstim) (150–300 mg/m2) and melphalan (35–75 mg/m2) was was started on day 1. administered on days −11, −10, −4 and −3. Doses of drugs were gradually escalated as noted in Table 3. After June 1996, the dose was reduced in patients younger than 2 years Definitions of tumor response old (patients 6 and 11) because of the high frequency of CR was defined as the disappearance of all evidence of renal toxicity. In two patients, because of inadequate disease, which included return to normal levels of serum responses to two cycles of drug administration, a third cycle tumor markers. For the patients with neuroblastoma, BM of TEPA was added after a 1-week interval, ie TEPA samples were obtained from both iliac bones for the deter- (250 mg/m2) and melphalan (75 mg/m2) was administered mination of CR. PR was defined as a greater than 50% on days −18, −17, −11 −10 and 250 mg/m2 of TEPA was decrease in all measurable tumor lesions. Minor response added on days −4 and −3. Three patients received TEPA (MR) was defined as a decrease of between 25% to 50% (250 or 300 mg/m2) and Bu (4 or 5 mg/kg) on days −11 in all tumor lesions. No response (NR) was defined as no and −10, and TEPA (250 or 300 mg/m2) and melphalan significant change in any tumor lesions, and progressive (75 mg/m2) on days −4 and −3. Two patients received a disease (PD) was defined as the appearance of new lesion(s) combination of TEPA (250 or 300 mg/m2) and Bu (4 or or a greater than 25% increase in pre-existing lesion(s). 5 mg/kg) on days −11, −10, −4 and −3. TEPA was given Duration of response was not included in the response in two equally divided doses on each day and infused over definition. Response duration and survival were measured 2 h. After June 1995 TEPA was administered as a 24-h from the date of stem cell infusion to the date of continuous infusion to minimize organ toxicity. Melphalan progression and the date of death, respectively.

Table 2 Preconditioning regimens Results Day −18 −17 −11 −10 −4 −3 −2 −10 Toxicity and hematopoietic reconstitution Thiotepa 150–300 mg/m2 ¼¼¼¼ Melphalan 35–75 mg/m2 ¼¼¼¼ The median duration of granulocytopenia (Ͻ0.5 × 109/l) n = 20a was 14 days (range 9–33 days). The duration of granulocy- 2 ¼¼¼¼¼¼ Thiotepa 250 mg/m topenia depended on the stem cell source. The duration was Melphalan 75 mg/m2 ¼¼¼¼ n = 2 shortest after PSCT (9–20 days; median 11 days) and 6 Thiotepa 250 or 300 mg/m2 ¼¼¼¼ days shorter than after BMT (10–33 days; median, 17 Melphalan 75 mg/m2 ¼¼ days). Although the cell number was insufﬁcient for hema- Busulfan 4 or 5 mg/kg ¼¼ topoietic reconstitution, the addition of a small number of n = 4b Thiotepa 250 or 300 mg/m2 ¼¼¼¼ PSCs to BM cells shortened the period of granulocytopenia Busulfan 4 or 5 mg/kg ¼¼¼¼ (10–25 days; median, 13.5 days). The median duration of n = 2 thrombocytopenia (Ͻ20 × 109/l) was 33 days (4–252 days). The duration was shorter after PSCT (14–126 days; median, Thiotepa in two divided doses (2 h i.v. each) or c.i.v. (24 h); melphalan, 23 days) than after transplantation of BM or BM and PSCs i.v. (1 h); busulfan, in four divided doses (p.o.). (14–252 days; median, 39 days). The addition of a small aIn one patient, the second cycle was sustained because of Candida sepsis which occurred after the 1st cycle. number of PSCs to BM cells did not shorten the period bIn one patient, the 2nd administration of TEPA was sustained because of thrombocytopenia. of convulsion which occurred after the 1st cycle. The major toxicity observed was on the mucosa of the Double-conditioning regimens J Hara et al 10 Table 3 Preconditioning regimens and regimen-related toxicity

Patient Age TEPA Melphalan BU Stem cell Infused cell dose Days to Days to PLTC Toxicity grade (WHO grade) No. (year) mg/m2 mg/m2 mg/kg source ANC Ͼ20 × 109/l Ͼ × 9 PB CD34+ BM MNC0.5 10 /l GI Renal CNS Others (×106/kg) (×107/kg) tract

22 3 500b 140b — PB 4.4 — 10 44 1 0 0 Sepsisg 25 5 600 300 — PB 10.5 — 11 15 2 0 0 11a 1 800 140 — PB 2.5 — 14 19 0 0 0 6a 1 800 180 — BM — 18.0 14 4 0 0 0 7 6 800 200 — BM — 8.5 20 39 0 0 0 24 2 800 200 — BM — 10.1 21 40 1 0 0 10 2 800 280 — BM — 5.7 14 31 1 0 0 12a 1 800 280 — BM — 9.0 10 23 1 2 (HUS) 1 TMA 16a 1 800 280 — BM — 3.5 17 — 1 3 (RTA)f 0 18a 1 800 280 — BM — 2.4 23 76 1 1 0 21 3 800 280 — PB 32.0 — 9 14 0 0 0 23 12 800 280 — BM+PB 0.5 10.0 25 45 1 0 0 26 3 800 280 — PB 2.8 — 14 14 1 0 0 9 3 1000 280 — BM — 5.8 21 24 1 0 0 13 3 1000 280 — BM — 4.7 33 97 1 0 0 14 2 1000 280 — BM — 11.0 14 33 1 0 0 15 2 1000 300 — BM — 13.0 29 57 4 (HEM) 0 0 Heart 17 18 1000 300 — BM+PB 0.6 12.0 10 56 1 0 0 failure 19 15 1000 300 — BM+PB 0.7 7.5 18 252 4 (HEM) 3 (HUS) 1 TMA 8 19 1200 300 — PB 0.17e —1035300 27 16 1500c 300 — PB 3.3 — 20 126 3 0 0 28 5 1500c 300 — PB 32.7 — 11 60 3 0 0 2 9 1000 150 8 BM+PB 56.0d 4.0 14 14 0 0 0 3 8 1200 150 8 BM+PB 0.58d 2.5 10 12 2 0 0 20 7 600b 150 10 BM+PB 1.1d 4.2 13 62 1 2 (HUS) 1g TMA 1 14 1200 150 10 PB 2.2 — 11 19 3 0 1 Fungal 4 9 1000 — 16 BM — 6.2 13 19 0 0 0 pneumoniaf 5 3 1200 — 20 PB 4.3 — 11 27 0 0 0

aDrug dose was reduced to 75% of indicated doses. b2nd cycles were suspended. cIn three cycles. dTotal MNCs. eCFU-GM. fFatal toxicity. gComplication occurred before stem cell transplantation. HEM, hematochezia; HUS, hemolytic uremic syndrome; RTA, renal tubular acidosis; TMA, thrombotic microangiopathy.

digestive tract. The incidence of severe mucositis (grade 2 ment-related deaths among the 28 patients (7%) (fungal or higher) was high in patients who received three alkylat- pneumonia and RTA). ing agents (two of four) and patients who had both 1000 mg/m2 of TEPA and 300 mg/m2 of melphalan or Response to HDC greater (five of six). Two (patients 15 and 19) of these seven patients developed severe lower gastrointestinal tract Responses to HDC are summarized in Table 1. Among 13 mucositis. Renal toxicity was another concern and was patients who received HDC during CR, 10 patients are alive observed in five patients in spite of normal renal function with no evidence of disease (15–59 months, median: 35). before HDC. There were three life-threatening renal toxi- The remaining three patients (two group IV RMS and one cities of which one was acute renal tubular acidosis (RTA) stage IV NB), relapsed 3 to 8 months after HDC. In one leading to sudden death on day 31 (patient 16) and two of these patients (patient 22), the second HDC cycle was required temporary dialysis (patients 12 and 19). Three of not given because of sepsis following the first cycle. Dis- five renal toxicities were hemolytic uremic syndrome ease recurrence was observed at the original tumor site in (HUS) resulting from thrombotic microangiopathy (TMA), two patients. The remaining patient developed a tumor in and two of these were associated with transient reversible the lung. disturbance of consciousness. All three patients with TMA In 14 evaluable patients who underwent HDC while not showed erythrocyte fragmentation, hemolytic anemia and in CR, complete and partial (PR) responses were obtained sudden decrease in platelet counts. Because all three young in five and four patients after HDC. The remaining four and children (Ͻ2 years) who had received 800 mg/m2 of TEPA one patients showed minor (MR) and no (NR) responses, and 280 mg/m2 of melphalan suffered renal toxicities, the respectively. Among the five patients in CR after HDC, doses of these drugs were reduced in the following two 1- three with HB had no measurable tumor, but persistent year-old patients (patients 6 and 11). There were two treat- elevation of the serum AFP level had been documented Double-conditioning regimens J Hara et al 11 before HDC. They remain in continuous CR (CCR) to date. quencies of life-threatening mucositis and veno-occlusive In the remaining two patients, brain metastasis appeared in disease (VOD) increased even with the lower dose of one patient with pulmonary blastoma 5 months post-trans- TEPA.13,18–20 However, patients who received TEPA and plant and the other (patient 1) died of regimen-related toxi- substantial doses of melphalan and/or Bu with a double- city (RRT). Four patients in PR showed regrowth of tumor conditioning regimen developed mucositis and CNS com- at the primary site after a short duration with stable disease. plications less often and VOD was not observed. Among four patients in MR, the primary tumor was surgi- The outcome of patients depended strongly on the status cally resected in two patients with NB (patients 14 and 15) of the disease before HDC. While only three of 13 patients, and a small number of residual viable tumor cells was who had been in CR at HDC, relapsed after HDC, seven found in tumors from both patients. Thereafter, both of 13 evaluable patients, who had been unable to obtain patients are relapse-free to date (45 and 59 months). One CR before HDC, relapsed after a short duration with stable patient with brain NB received local irradiation after HDC, disease. However, the finding that five patients not in CR and regrowth of the tumor has not been observed to date. at HDC (three with HB and two with NB) and two patients The remaining patient in MR and the patients with NR who had relapsed after the first HDC during prior relapses showed disease progression. Altogether, in 13 evaluable were in CCR was encouraging. Indeed, three of four patients who underwent HDC not in CR, six are alive with- patients with HB achieved CR and had durable responses. out relapse or regrowth of the diseases (14–59 months, This preconditioning regimen seems to have had potent median: 39). activity against HB and a further study is warranted. Two patients with NB were in CCR (45 and 59 months) after resection of the primary tumors indicating that HDC eradi- Discussion cated micrometastasis, although HDC was unable to eradicate tumor cells completely. The contribution of HDC to the survival improvement of Because of high penetration of the blood–brain barrier pediatric patients with a variety of tumors is still not estab- with TEPA and Bu, these drugs have been used in various lished. In this study, we attempted to establish an effective types of brain tumor in phase II studies with limited preconditioning regimen and selected three alkylating efficiency.4,14,19 We used the double-conditioning regimen agents, TEPA, melphalan and Bu for this purpose, which including TEPA and Bu with or without melphalan in seven have documented anti-cancer activity in a variety of solid patients with brain tumors (three with HCG-secreting tumors.4–7,9–14 In our experience, a preparative regimen con- GCT, one with AFP-secreting GCT, two with medullo- sisting of 800 mg/m2 of TEPA, 140 mg/m2 of melphalan blastoma/NB and one with metastatic RMS). All three and 16 mg/kg of Bu was safe and tolerable, but severe patients with HCG-secreting GCT and one with RMS were mucositis was observed and anti-cancer activity was unsat- in CCR (32–47 months) and one with AFP-secreting GCT isfactory. Therefore, to administer a maximum dose of who received HDC with progressive disease died of RRT these drugs safely and to obtain a maximum anti-cancer after achieving CR. One with brain NB who had been effect, a double-conditioning regimen with two cycles of a resistant to chemotherapy obtained a PR and was in CCR. combination of drugs with a 1-week interval, was designed. These patients in CCR received involved field irradiation According to the results obtained from this study, with the before or after HDC and had a good performance status combination of TEPA and melphalan, the maximum toler- without sequelae caused by HDC or radiotherapy. Taken able doses were 1000 mg/m2 and 280 mg/m2, respectively, together, a combination of TEPA and Bu, with or without and mucositis was dose-limiting. In patients with brain melphalan, seems to be effective on at least intracranial tumors, Bu was administered together with TEPA with or GCT. without melphalan. Although the number of patients stud- Although several studies with high-dose melphalan ied was small and no conclusion can be drawn, coadminis- showed some usefulness for chemotherapy-resistant Ewing tration of three drugs seemed to cause severe mucositis sarcoma and RMS,14,21,22 the contribution of HDC to the more frequently. The distinctive toxicity of this regimen improvement of disease-free survival has not been proved. was renal in young children (Ͻ2 years). All three patients A recent report of a meta-analysis of HDC mainly con- younger than 2 years old who received 800 mg/m2 of TEPA sisting of melphalan, etoposide and carboplatin for 36 and 280 mg/m2 of melphalan evidenced renal toxicity patients with RMS from a German and Austrian group including RTA and HUS (TMA).15 Patient 20 with HUS failed to show the advantage of HDC.23 In our study, of was receiving the second HDC after the third relapse. Thus, six evaluable patients with RMS, four were alive and dis- high sensitivity of vascular endothelium to these drugs ease-free (range 15–32 months). However, because of the and/or immaturity of renal function leading to high serum short follow-up period and the small number of patients, level of drugs seems to have resulted in this serious no conclusions can be drawn. toxicity. This study showed that the double-conditioning regimens In comparison with previous studies on HDC with TEPA enabled us to safely coadminister TEPA, melphalan and/or reported by others,6,7,16,17 the frequency of severe mucositis Bu at nearly maximum doses in the previously known was lower. In a phase I study of TEPA, 20 and 15% of single-agent setting and these appeared associated with less patients with 1005–1215 mg/m2 of TEPA exhibited severe toxicity than single cycle regimens of drug administration. (fatal) gastrointestinal toxicity and CNS complications, The major toxicity was mucositis. With regard to the anti- respectively.6 When other drugs including etoposide, cancer effect, these regimens resulted in a good response BCNU and carboplatin and/or TBI were added, the fre- in advanced pediatric malignancies, especially in patients Double-conditioning regimens J Hara et al 12 with minimal disease. 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