MCVAC) Regimen Followed by Autologous Peripheral Blood Stem Cell Transplantation for High-Risk Diffuse Large B-Cell Lymphoma

Home , Ranimustine

ORIGINAL ARTICLE Safety and efﬁcacy of high-dose ranimustine, cytarabine, etoposide and CY (MCVAC) regimen followed by autologous peripheral blood stem cell transplantation for high-risk diffuse large B-cell lymphoma

J Kato1,2, T Mori1, K Yokoyama1, Y Tsukada1, T Ueda1,2, T Shimizu1 and S Okamoto1

1Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan and 2Novartis Pharma Program for Clinical Therapeutics of Hematologic Malignancy, Keio University School of Medicine, Tokyo, Japan

The efficacy of high-dose chemotherapy followed by Introduction autologous hematopoietic SCT for relapsed diffuse large B-cell lymphoma (DLBCL) has been reported, but an First-line treatment of diffuse large B-cell lymphoma optimal conditioning regimen has not been determined. (DLBCL) with CHOP or CHOP-like regimens can cure This study was conducted to evaluate the safety and B40–50% of patients with aggressive non-Hodgkin’s efficacy of the MCVAC regimen (consisting of ranimus- lymphoma. The addition of rituximab significantly im- tine (MCNU), cytarabine, etoposide and CY) followed by proved the remission rate and resulted in an improvement autologous peripheral blood stem cell transplantation in PFS and OS by 15–20% over CHOP chemotherapy (PBSCT) for patients with high-risk or relapsed DLBCL. alone.1–3 However, 20–60% of patients are refractory to A total of 40 patients with DLBCL who received the initial therapy or relapse after achieving a CR.4 Salvage MCVAC regimen followed by autologous PBSCT were chemotherapy was effective in 60–70% of patients with retrospectively evaluated. Median follow-up duration of refractory or relapsed DLBCL, but could cure no 410% of the surviving patients was 51.2 months (range, 5.4–151.2 such patients.5–9 High-dose chemotherapy followed by months). At 5-year OS and PFS were 73.7% (95% autologous hematopoietic SCT has been shown to be confidence interval (CI), 58.6–88.8) and 62.5% (95% CI, superior to salvage chemotherapy alone for patients with 46.8–78.2), respectively. Although relapse remained the chemosensitive relapsed or refractory aggressive non- most frequent cause of treatment failure, late-onset Hodgkin’s lymphoma.10–14 adverse events were observed, including two cases of BEAM, CY plus TBI (CY/TBI) and some other regimens severe pulmonary impairment, and two cases of therapy- have frequently been used as conditioning regimens related myelodysplastic syndromes (MDS)/AML. In for autologous hematopoietic SCT. However, an optimal conclusion, the MCVAC regimen would be an effective conditioning regimen which produces the least toxicity and and tolerable conditioning regimen without TBI for greatest therapeutic efficacy has not been determined.15,16 autologous PBSCT for high-risk or relapsed DLBCL. High-dose methyl 6-[3-(2-chloroethyl)-3-nitrosoureido]-6- However, late-onset pulmonary toxicity and MDS/AML deoxy-a-D-glucopyranoside (MCNU; ranimustine), cytar- should be monitored. abine, etoposide and CY (MCVAC) chemotherapy was Bone Marrow Transplantation (2011) 46, 923–928; first reported as a conditioning regimen in children, as it doi:10.1038/bmt.2010.243; published online 25 October 2010 possessed a high antitumor activity with acceptable toxicity Keywords: diffuse large B-cell lymphoma; autologous for lymphoid malignancies.17 We herein reviewed a single peripheral blood stem cell transplantation; high-dose institute experience in order to evaluate the safety and chemotherapy; MCVAC regimen; pulmonary toxicity efficacy of the MCVAC regimen with autologous peripheral blood stem transplantation (PBSCT) in adult patients with relapsed or high-risk DLBCL.

Patients and methods

Patients Patients who underwent autologous PBSCT following the Correspondence: Dr T Mori, Division of Hematology, Department of MCVAC regimen between August 1994 and April 2005 at Medicine, Keio University School of Medicine, 35 Shinanomachi, Keio University Hospital for the treatment of relapsed or Shinjuku-ku, Tokyo 160-8582, Japan. E-mail: [email protected] high-risk DLBCL were identified from our transplant Received 15 March 2010; revised 14 June 2010; accepted 12 August 2010; database, and their demographic as well as transplant data published online 25 October 2010 records were collected by chart review. Patients with disease MCVAC regimen for DLBCL J Kato et al 924 transformation from low-grade B-cell lymphomas were Results excluded. High-risk DLBCL was defined as partial or no response to initial treatment or high-intermediate/high risk Patient characteristics disease according to age-adjusted international prognostic The characteristics of 40 patients at diagnosis and index at initial diagnosis.18 Clinical staging was performed transplant are shown in Tables 1 and 2, respectively. The by computed tomography scanning of the neck, thorax, diagnosis included two patients with mediastinal DLBCL. abdomen and pelvis, BM biopsy, cerebrospinal fluid The nine patients in the first CR at transplant were at examination and other tools such as magnetic resonance high or high-intermediate risk according to age-adjusted imaging if indicated. international prognostic index at diagnosis.18 Disease was chemosensitive in 18 patients not in CR at transplant, except for 1 patient. Median time from diagnosis to MCVAC regimen, PBSCT and its toxicities transplant was 13.9 months (range, 4.2–198.4). Of the 20 The MCVAC regimen consisted of ranimustine (250 mg/m2 patients who had received radiation therapy before on day À9 and 200 mg/m2 on day À4), cytarabine (2.0 g/m2 transplant, 7 patients received involved field radiation twice daily on days À8toÀ5), etoposide (200 mg/m2 twice therapy after chemotherapy for an early-stage disease, 11 daily on days À8toÀ5) and CY (50 mg/kg on days À3 and patients received radiation therapy for bulky or residual À2) followed by unpurged PBSCT. On day 0, cryopre- disease after chemotherapy and 2 patients with mediastinal served PBSCs were rapidly thawed at 37 1C and promptly infused into the patient through a central venous catheter. Neutrophil recovery was defined as the first day of three Table 1 Patient characteristics at diagnosis (N ¼ 40) 9 consecutive days with an ANC 40.5 Â 10 /L. Platelet Median age, years (range) 49 (22–59) recovery was defined as the first of three consecutive days Sex, no. of male/no. of female 16/24 with an unsupported platelet count 420 Â 109/L. Non-hematological toxicities without nausea and hair Stage I–II 10 loss were graded according to the Common Terminology III–IV 30 Criteria for Adverse Events v3.0. B symptoms A27 Supportive care B13 All patients were managed in high-efficiency particulate air filtered-rooms. Bacterial, fungal, HSV and pneumocystis LDH pneumonitis prophylaxes were given to all patients accord- Normal 12 Elevated 25 ing to our institutional protocol. Granulocyte colony- Unknown 3 stimulating factor was given intravenously from day þ 1 until neutrophil recovery. The patients were transfused with No. of extranodal sites irradiated blood products to keep the hemoglobin level 0–1 10 9 117 above 8.0 g/100mL and the platelet count above 20 Â 10 /L. 2 or upper 13

Performance status Response criteria 0–1 26 CR was defined as the disappearance of any clinically 2–4 13 detectable signs of tumor by clinical and laboratory Unknown 1 assessment. PR was defined as 450% reduction of International prognostic index detectable tumor. No response was defined as o50% Low risk 14 reduction of detectable tumor. Progressive disease was Low-intermediate risk 7 defined as an increase in detectable tumor or the High-intermediate risk 13 appearance of any new lesion. High risk 5 Unknown 1

Statistical analysis Bulky disease OS was defined as the time from transplant until death Yes 8 No 32 because of any causes or the last follow-up. PFS was defined as the time from transplant until relapse or BM involvement progression of lymphoma, or death from any causes, or Yes 30 the last follow-up if none of these events had occurred. No 9 Unknown 1 TRM was defined as death from any causes other than lymphoma. Survival rates were estimated using the CNS involvement Kaplan–Meier method. Survival curves were compared Yes 2 applying the log-rank test. A P-value of o0.05 was No 32 considered statistically significant. Factors that were Unknown 6 potentially predictive of OS (Po0.05) and PFS (Po0.05) were entered into a multivariate analysis using the Cox Abbreviations: CNS ¼ central nervous system; LDH ¼ lactate dehydro- proportion hazards model. genase.

Bone Marrow Transplantation MCVAC regimen for DLBCL J Kato et al 925 Table 2 Patient characteristics at transplant (N ¼ 40) Table 3 Toxicities within 100 days after transplantation (N ¼ 40) Median age, years (range) 50.5 (23–61) Gradea Median time from diagnosis to transplant, 13.9 (4.2–198.4) months (range) 012345

Stage Stomatitis 0 1 8 31 0 0 CR 22 Diarrhea 1 2 18 19 0 0 1st CR 9 Liver 1 9 15 14 1 0 2nd CR 13 CNS hemorrhage 39 0 0 1 0 0 Non-CR 18 Ataxia 39 0 0 1 0 0 Cardiac 38 0 0 1 0 1 Performance status Renal 16 20 3 1 0 0 0–1 38 Cystitis 22 16 2 0 0 0 22Skin 38 0 0 2 0 0

Previous radiation therapy Infection Yes 20 Febrile neutropenia — 0 30 0 0 No 20 Sepsis — 0 4 0 0 Catheter-related bacteremia — 0 3 0 0 No. of regimens before transplant Pneumonia — 0 1 0 0 14Cellulitis — 0 1 0 0 228CMV disease — 0 1 0 1b 438 Abbreviation: CNS ¼ central nervous system. Previous rituximab therapy aGrades were determined according to the Common Terminology Criteria Yes 8 for Adverse Events v3.0. No 32 bCMV pneumonitis.

The causes of TRM included myocardial toxicity in one DLBCL received whole-lung radiation therapy. Eight of patient (day þ 14), CMV pneumonitis in one patient (day the patients had received rituximab before transplant. þ 65) and therapy-related MDS/AML in two patients (day þ 3119 and þ 830). MCVAC regimen and transplant procedures In all, 39 patients received the MCVAC regimen as Survival scheduled. One patient did not receive the second dose of Median follow-up duration of 29 patients surviving at the CY on day À2 because of progressive impaired perfor- time of the analysis was 51.2 months (range, 5.4–151.2 mance status due to severe ataxia caused by cytarabine. The months). Four patients died of the treatment-related median number of infused CD34-positive cells was complications described above, and six patients died of 4.16 Â 106/kg (range, 1.76–39.0 Â 106/kg). The median post disease progression. At 4-years, OS and PFS were 75.0% transplant days of neutrophil recovery and platelet were (95% CI, 55.8–94.2) and 60.1% (95% CI, 38.3–81.9) in 9 days (range, 8–19) and 11 days (range, 7–19), respectively. patients in CR (N ¼ 22), and 72.5% (95% CI, 49.2–95.8) and 61.1% (95% CI, 38.6–83.6) in patients in non-CR Toxicities and TRM (N ¼ 18), respectively. The differences were NS (Figure 1). Non-hematological treatment-related toxicities within the In a univariate analysis for factors affecting OS and PFS, first 100 days after transplant are shown in Table 3. only radiation therapy before transplant was significantly Prominent toxicities were stomatitis, diarrhea, liver toxicity associated with unfavorable OS (Table 4). It was also and infection. Infections included febrile neutropenia significant with a relative risk of 5.46 (95% CI, 1.2–25.5; (N ¼ 30), sepsis (N ¼ 4), catheter-related bacteremia Po0.05) by a multivariate analysis. No other factors, (N ¼ 3), pneumonia (N ¼ 1), cellulitis (N ¼ 1) and CMV including clinical stage, international prognostic index diseases (N ¼ 2). Other less common severe toxicities and lactate dehydrogenase values at diagnosis and relapse, (grades 3–5) were subdural hematoma (N ¼ 1), renal number of previous chemotherapy regimens and previous impairment (N ¼ 1), myocardial toxicity (N ¼ 1), ataxia rituximab therapy, had a significant influence on OS (N ¼ 1) and skin damage (N ¼ 2). Veno-occlusive disease of and PFS. the liver was not observed in any of the patients. Late-onset adverse events included two cases of serious restrictive pulmonary impairment due to pulmonary fibrosis diag- Discussion nosed at 61.4 and 69.2 months after transplant. One case received radiation therapy to the whole lungs before The findings of this retrospective study showed that the transplant. Two other patients developed therapy-related MCVAC regimen followed by autologous PBSCT in myelodysplastic syndrome/AML (MDS/AML), which was patients with relapsed or high-risk DLBCL was generally diagnosed at 20.3 and 94.7 months after transplant. well tolerated and yielded about a 60% or higher cure rate Early (within 100 days post transplant) and 4-year of the disease with a low TRM rate (9%). Disease status at overall TRM was 5.0% (95% confidence interval (CI), transplant has been reported to be the most important 0–11.7%) and 9.0% (95% CI, 0–19.0%), respectively. prognostic factor influencing outcome in aggressive

Bone Marrow Transplantation MCVAC regimen for DLBCL J Kato et al 926 1.0 Table 4 Univariate analysis for factors affecting OS and PFS

Category at Patients 4-year OS 4-year PFS transplant No. Proba- s.e. P-value Proba- s.e. P-value 0.8 bility bility Others Disease status CR CR 22 75.0 9.8 0.390 60.1 11.1 0.799 Non-CR 18 72.5 11.9 61.1 11.5 0.6 Performance status 0–1 38 74.8 7.9 0.608 61.4 8.2 0.751 X2 2 50.0 35.4 50.0 35.4

Probability 0.4 Gender Male 16 60.2 14.5 0.250 57.5 13.7 0.683 Female 24 81.6 8.3 62.5 9.9

0.2 Age at transplant, years o50 20 79.3 9.2 0.562 63.6 11.1 0.968 50o 20 68.7 11.9 58.2 11.4

Previous radiation therapy 0 Yes 20 57.8 12.5 0.035 45.3 12.1 0.072 02448 72 96 120 144 168 No 20 89.1 7.3 74.7 9.8 Time after transplantation (months) Previous rituximab therapy Yes 8 75.0 15.3 0.692 85.7 13.2 0.231 1.0 No 32 74.6 8.4 57.4 9.0

0.8 Early toxicities were generally tolerable, and the in- CR cidence of TRM within 100 days was limited to 5%, Others which was identical to those reported in other regimens 0.6 (3.0–14.8%).16,19–21 Late-onset adverse events, however, included therapy-related MDS/AML and severe pulmonary toxicity. Therapy-related MDS/AML has been a well-

Probability recognized complication after high-dose chemotherapy, 0.4 mainly in the setting of autologous hematopoietic SCT for non-Hodgkin’s lymphoma. Conditioning regimens, particularly those containing TBI, were initially thought 0.2 to be responsible for the development of this complication. The agents and intensity of pretransplant chemotherapy have also been reported to be major contributing factors as well as the type of conditioning regimen used for 0 transplant. In a multicenter case–control study, a higher 0 24 48 72 96 120 144 168 relative risk for developing therapy-related MDS/AML was Time after transplantation (months) observed in proportion to the total dosage and duration of pretransplant therapy with alkylating agents.22 In our Figure 1 (a)OSand(b) PFS after PBSCT in patients in CR (N ¼ 22) or study, the two patients who developed therapy-related others (N ¼ 18). MDS/AML had both received two or three lines of salvage chemotherapy and also radiation therapy before the transplant. The incidence of therapy-related MDS/AML (cumulative incidence of 3.3%) seemed identical to those of non-Hodgkin’s lymphoma.16,19 However, disease status at other studies.20,23 transplant did not have a signiﬁcant inﬂuence on survival in In two patients, severe pulmonary impairment developed the present study. Although there were a small number of 61.4 and 69.2 months after transplant. Pulmonary toxicity patients and they were evaluated in a retrospective manner, has been well recognized as a complication related to the outcomes suggest that the MCVAC regimen had the use of BCNU-containing regimens. The incidence of potential highly curative anti-lymphoma activity for not non-infectious pulmonary complications associated with only high-risk, but also relapsed DLBCL. Furthermore, BCNU-containing conditioning regimens for autologous disease was chemosensitive in 17 of 18 patients not in CR at hematopoietic SCT such as interstitial pneumonitis has transplant, which could also contribute to a high survival been reported to be 11–26% (Patti et al.,24 Mills et al.,25 rate particularly in patients not in CR. Stiff et al.,26 Alessandrino et al.27). BCNU has been

Bone Marrow Transplantation MCVAC regimen for DLBCL J Kato et al 927 implicated as one of the main causes of pulmonary toxicity, chemotherapy in patients relapsing with Hodgkin’s disease particularly in association with previous radiation therapy. after combination chemotherapy: the low probability for cure. In the present study, MCNU, which also has a potent J Clin Oncol 1992; 10: 210–218. pulmonary toxicity,17 was used instead of BCNU. In 7 Velasquez WS, McLaughlin P, Tucker S, Hagemeister FB, contrast, the pulmonary toxicity of MCNU-containing Swan F, Rodriguez MA et al. ESHAP—an effective conditioning regimens for autologous hematopoietic SCT chemotherapy regimen in refractory and relapsing lymphoma: a 4-year follow-up study. J Clin Oncol 1994; 12: 1169–1176. has not been evaluated so far. In the present study, one 8 Caballero MD, Amigo ML, Hernandez JM, Vazquez L, del patient received radiation therapy to the whole lungs Canizo C, Gonzalez M et al. Alternating mini-BEAM/ESHAP as a previous therapy, whereas the other patient did not. as salvage therapy for refractory non-Hodgkin’s lymphomas. Therefore, MCVAC without the effect of radiation therapy Ann Hematol 1997; 74: 79–82. also has the potential to cause pulmonary toxicity. An 9 Gutierrez M, Chabner BA, Pearson D, Steinberg SM, Jaffe ES, accumulation of such cases is needed to elucidate the risk Cheson BD et al. Role of a doxorubicin-containing regimen factors for the development of pulmonary toxicity after the in relapsed and resistant lymphomas: an 8-year follow-up MCVAC regimen. study of EPOCH. J Clin Oncol 2000; 18: 3633–3642. MCVAC regimen was associated with early and late 10 Bosly A, Coiffier B, Gisselbrecht C, Tilly H, Auzanneau G, et al. adverse events, which were almost identical to those Andrien F Bone marrow transplantation prolongs survival after relapse in aggressive-lymphoma patients treated reported in other regimens, such as BCNU-containing with the LNH-84 regimen. J Clin Oncol 1992; 10: 1615–1623. regimens, and considered to provide a high-survival rate in 11 Salles G, Shipp MA, Coiffier B. Chemotherapy of non- high-risk or relapsed DLBCL patients even in patients not Hodgkin’s aggressive lymphomas. Semin Hematol 1994; 31: in CR at transplant. Furthermore, as BCNU has been in 46–69. short supply, MCVAC regimen using MCNU instead of 12 Philip T, Guglielmi C, Hagenbeek A, Somers R, BCNU could be a promising high-dose regimen for high- Van der Lelie H, Bron D et al. Autologous bone marrow risk or relapsed DLBCL. We conclude that the MCVAC transplantation as compared with salvage chemotherapy in regimen would be a tolerable, effective and curative relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. conditioning regimen of autologous PBSCT for high-risk N Engl J Med 1995; 333: 1540–1545. or relapsed DLBCL. However, late-onset MDS/AML 13 Rodriguez MA, Cabanillas FC, Velasquez W, Hagemeister FB, McLaughlin P, Swan F et al. Results of a salvage and adverse effects on the lungs in long-term survivors treatment program for relapsing lymphoma: MINE consoli- can occur, and should be carefully monitored. dated with ESHAP. J Clin Oncol 1995; 13: 1734–1741. 14 Shipp MA, Abeloff MD, Antman KH, Carroll G, Hagenbeek A, Loeffler M et al. International Consensus Conference on Conflict of interest high-dose therapy with hematopoietic stem cell transplantation in aggressive non-hodgkin’s lymphomas: report of the jury. J Clin Oncol 1999; 17: 423–429. The authors decalre no conflict of interest. 15 Meehan KR, Pritchard RS, Leichter JW, Littenberg B, Welch HG. Autologous bone marrow transplantation versus chemotherapy in relapsed/refractory non-Hodgkin’s lympho- References ma: estimates of long-term survival from the recent literature. Am J Hematol 1995; 50: 116–123. 1 Sehn LH, Donaldson J, Chhanabhai M, Fitzgerald C, Gill K, 16 Salar A, Sierra J, Gandarillas M, Caballero MD, Marin J, Klasa R et al. Introduction of combined CHOP plus rituximab Lahuerta JJ et al. Autologous stem cell transplantation for therapy dramatically improved outcome of diffuse large clinically aggressive non-Hodgkin’s lymphoma: the role B-cell lymphoma in British Columbia. J Clin Oncol 2005; 23: of preparative regimens. Bone Marrow Transplant 2001; 27: 5027–5033. 405–412. 2 Feugier P, Van Hoof A, Sebban C, Solal-Celigny P, 17 Takaue Y, Watanabe T, Hoshi Y, Abe T, Matsunaga K, Saito Bouabdallah R, Ferme C et al. Long-term results of the S et al. Effectiveness of high-dose MCNU therapy and R-CHOP study in the treatment of elderly patients with diffuse hematopoietic stem cell autografts treatment of childhood large B-cell lymphoma: a study by the Groupe d’Etude des acute leukemia/lymphoma with high-risk features. Cancer Lymphomes de l’Adulte. J Clin Oncol 2005; 23: 4117–4126. 1991; 67: 1830–1837. 3 Pfreundschuh M, Trumper L, Osterborg A, Pettengell R, 18 The International Non-Hodgkin’s Lymphoma Prognostic Trneny M, Imrie K et al. CHOP-like chemotherapy plus Factors Project. A predictive model for aggressive non- rituximab versus CHOP-like chemotherapy alone in young Hodgkin’s lymphoma. N Engl J Med 1993; 329: 987–994. patients with good-prognosis diffuse large-B-cell lymphoma: a 19 Caballero MD, Perez-Simon JA, Iriondo A, Lahuerta JJ, randomised controlled trial by the MabThera International Sierra J, Marin J et al. High-dose therapy in diffuse large cell Trial (MInT) Group. Lancet Oncol 2006; 7: 379–391. lymphoma: results and prognostic factors in 452 patients 4 Fisher RI, Gaynor ER, Dahlberg S, Oken MM, Grogan TM, from the GEL-TAMO Spanish Cooperative Group. Ann Oncol Mize EM et al. Comparison of a standard regimen (CHOP) 2003; 14: 140–151. with three intensive chemotherapy regimens for advanced non- 20 Martin A, Caballero MD, Perez-Simon JA, Lopez-Holgado N, Hodgkin’s lymphoma. N Engl J Med 1993; 328: 1002–1006. Mateos MV, Canizo MC et al. Results of autologous 5 Velasquez WS, Cabanillas F, Salvador P, McLaughlin P, transplantation in lymphoma are not improved by increasing Fridrik M, Tucker S et al. Effective salvage therapy for the dose of etoposide in the BEAM regimen: a single-centre lymphoma with cisplatin in combination with high-dose sequential-cohort study. Bone Marrow Transplant 2004; 34: Ara-C and dexamethasone (DHAP). Blood 1988; 71: 117–122. 675–682. 6 Longo DL, Duffey PL, Young RC, Hubbard SM, Ihde DC, 21 Jo JC, Kang BW, Jang G, Sym SJ, Lee SS, Koo JE et al. Glatstein E et al. Conventional-dose salvage combination BEAC or BEAM high-dose chemotherapy followed by

Bone Marrow Transplantation MCVAC regimen for DLBCL J Kato et al 928 autologous stem cell transplantation in non-Hodgkin’s lym- 25 Mills W, Chopra R, McMillan A, Pearce R, Linch DC, phoma patients: comparative analysis of efﬁcacy and toxicity. Goldstone AH. BEAM chemotherapy and autologous Ann Hematol 2008; 87: 43–48. bone marrow transplantation for patients with relapsed or 22 Metayer C, Curtis RE, Vose J, Sobocinski KA, Horowitz MM, refractory non-Hodgkin’s lymphoma. J Clin Oncol 1995; 13: Bhatia S et al. Myelodysplastic syndrome and acute myeloid 588–595. leukemia after autotransplantation for lymphoma: a multi- 26 Stiff PJ, Dahlberg S, Forman SJ, McCall AR, Horning SJ, center case-control study. Blood 2003; 101: 2015–2023. Nademanee AP et al. Autologous bone marrow transplanta- 23 Howe R, Micallef IN, Inwards DJ, Ansell SM, Dewald GW, tion for patients with relapsed or refractory diffuse aggressive Dispenzieri A et al. Secondary myelodysplastic syndrome and non-Hodgkin’s lymphoma: value of augmented preparative acute myelogenous leukemia are signiﬁcant complications regimens—a Southwest Oncology Group trial. J Clin Oncol following autologous stem cell transplantation for lymphoma. 1998; 16: 48–55. Bone Marrow Transplant 2003; 32: 317–324. 27 Alessandrino EP, Bernasconi P, Colombo A, Caldera D, 24 Patti C, Majolino I, Scime R, Indovina A, Vasta S, Liberti G Martinelli G, Vitulo P et al. Pulmonary toxicity following et al. High-dose cyclophosphamide, etoposide and BCNU carmustine-based preparative regimens and autologous per- (CVB) with autologous stem cell rescue in malignant ipheral blood progenitor cell transplantation in hematological lymphomas. Eur J Haematol 1993; 51: 18–24. malignancies. Bone Marrow Transplant 2000; 25: 309–313.

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