Tandem high-dose chemotherapy followed by autologous transplantation in patients with locally advanced or metastatic sarcoma. High-dose chemotherapy and autologous peripheral blood stem cell transplantation in adult patients with high-risk or advanced Ewing and soft tissue sarcoma. Up-front tandem high-dose chemotherapy compared with standard chemotherapy with doxorubicin and paclitaxel in metastatic breast cancer: results of a randomized trial. High-dose therapy followed by autologous purged stem cell transplantation and doxorubicin-based chemotherapy in patients with advanced follicular lymphoma: a randomized multicenter study by the GOELAMS with final results after a median follow-up of 9 years. Dose intensity of chemotherapy in patients with relapsed Hodgkin's lymphoma. Successive double high-dose chemotherapy with peripheral blood stem cell rescue collected during a single leukapheresis round in patients with high-risk pediatric solid tumors: a pilot study in a single center. Early autologous stem-cell transplantation versus conventional chemotherapy as front-line therapy in high-risk, aggressive non-Hodgkin's lymphoma: an Italian multicenter randomized trial. Better outcome of adult acute lymphoblastic leukemia after early genoidentical allogeneic bone marrow transplantation (BMT) than after late high-dose therapy and autologous BMT: a GOELAMS trial. Standard chemotherapy with interferon compared with CHOP followed by high-dose therapy with autologous stem cell transplantation in untreated patients with advanced follicular lymphoma: the GELF-94 randomized study from the Groupe d'Etude des Lymphomes de l'Adulte (GELA). Autologous stem cell transplantation for high-risk Ewing's sarcoma and other pediatric solid tumors. Prospective, randomized study of single compared with double autologous stem-cell transplantation for multiple myeloma: Bologna 96 clinical study.
Patients with locally advanced or metastatic/recurrent soft tissue and Ewing's sarcoma (EWS) have few treatment options. The purpose of our phase II study was to assess the feasibility, safety and efficacy of tandem high-dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT) in such patients.
                Thirteen patients were enrolled onto this study. The first cycle of HDCT consisted of doxorubicin (150 mg/m(2)) and ifosfamide (14 g/m(2)) mixed with mesna (14 g/m(2)), while the second cycle consisted of melphalan (150 mg/m(2)) and cisplatin (200 mg/m(2)).
                Eleven out of 13 patients were able to complete both cycles of HDCT. No treatment-related mortality occurred and grade 3 or 4 toxicity was clinically tolerable. The 5-year progression-free survival (PFS) and overall survival (OS) for all patients was 23% (confidence interval, CI: 0-46%) and 31% (CI: 14-70%), respectively. Out of the four patients still alive, two had EWS and measurable disease at the time of ASCT and achieved a complete remission, remaining progression free 126 and 155 months after ASCT.
                Our study demonstrates the feasibility and safety of tandem HDCT in patients with high-risk or metastatic/recurrent sarcoma, with some patients achieving long-term PFS and OS. Despite the availability of combined-modality treatment for Ewing sarcoma (ES) and soft tissue sarcomas (STS), results from independent groups still indicate a poor prognosis for high-risk and metastasized patients. The benefit of high-dose chemotherapy (HDCT) with autologous peripheral blood stem cell transplantation (ASCT) as compared to standard treatment is not defined.
                Here, we report of HDCT in 35 consecutive adult patients with poor-risk ES or rhabdomyosarcoma (n = 11) and STS (n = 24) undergoing ASCT between July 1992 and March 2003. At a median follow-up of 100.6 months after ASCT, 11 patients are alive, with nine in sustained complete remission (CR) and each one in partial remission (PR) and stable disease. Median overall survival (OS) from ASCT was 17.1 months. Response to pretreatment, Karnofsky index > 80%, R (0) resection and first-line ASCT were associated with long-term OS (p < 0.05).
                These data indicate that (1) patients achieving a CR or PR following induction, with preserved performance status and R (0) resection may benefit from ASCT and (2) that this can be an useful therapeutic modality in a subset of patients, in some achieving remarkable responses. The role of high-dose chemotherapy (HDCT) in metastatic breast cancer remains controversial. Trials with late intensification HDCT have failed to show an advantage in overall survival. This study was initiated to compare up-front tandem HDCT and standard combination therapy in patients with metastatic breast cancer.
                Patients without prior chemotherapy for metastatic disease were randomly assigned to standard combination therapy with doxorubicin and paclitaxel (AT) or double HDCT with cyclophosphamide, mitoxantrone, and etoposide followed by peripheral-blood stem-cell transplantation. HDCT was repeated after 6 weeks. Patients were stratified by menopausal and hormone-receptor status. The primary objective was to compare complete response (CR) rates.
                A total of 93 patients were enrolled onto the trial. Intent-to-treat CR rates for patients randomized to HDCT and AT were 12.5% and 11.1%, respectively (P = .84). Objective response rates were 66.7% for patients in the high-dose group and 64.4% for patients in the AT arm (P = .82). In an intent-to-treat analysis, there were no significant differences between the two treatments in median time to progression (HDCT, 11.1 months; AT, 10.6 months; P = .67), duration of response (HDCT, 13.9 months; AT, 14.3 months; P = .98), and overall survival (HDCT, 26.9 months; AT, 23.4 months; P = .60). HDCT was associated with significantly more myelosuppression, infection, diarrhea, stomatitis, and nausea and vomiting, whereas patients treated with AT developed more neurotoxicity.
                This trial failed to show a benefit for up-front tandem HDCT compared with standard combination therapy. HDCT was associated with more acute adverse effects. Autologous stem cell transplantation (ASCT) as first-line therapy for follicular lymphoma (FL) remains controversial. The multicenter study randomized 172 patients with untreated FL for either immunochemotherapy or high-dose therapy (HDT) followed by purged ASCT. Conditioning was performed with total body irradiation (TBI) and cyclophosphamide. The 9-year overall survival (OS) was similar in the HDT and conventional chemotherapy groups (76% and 80%, respectively). The 9-year progression-free survival (PFS) was higher in the ASCT than the chemotherapy group (64% vs 39%; P = .004). A PFS plateau was observed in the HDT group after 7 years. On multivariate analysis, OS and PFS were independently affected by the per-formance status score, the number of nodal areas involved, and the treatment group. Secondary malignancies were more frequent in the HDT than in the chemotherapy group (6 secondary myelodysplastic syndrome/acute myeloid leukemia and 6 second solid tumor cancers vs 1 acute myeloid leukemia, P = .01). The occurrence of a PFS plateau suggests that a subgroup of patients might have their FL cured by ASCT. However, the increased rate of secondary malignancies may discourage the use of purged ASCT in combination with TBI as first-line treatment for FL. This trial has been registered with ClinicalTrials.gov under identifier NCT00696735. High-dose chemotherapy (HDCT) followed by autologous stem-cell transplantation (PBSCT) has become the standard treatment for patients with relapsed Hodgkin's lymphoma (HL). The intensity of treatment needed is unclear. This European intergroup study evaluated the impact of sequential high-dose chemotherapy (SHDCT) before myeloablative therapy.
                Patients with histologically confirmed, relapsed HL were treated with two cycles of dexamethasone, cytarabine, and cisplatin, and those without disease progression were randomly assigned. In the standard arm (A), patients received myeloablative therapy with carmustine, BEAM (carmustine, etoposide, cytarabine, and melphalan) followed by PBSCT. Patients in the experimental arm (B) also received sequential cyclophosphamide, methotrexate, and etoposide in high-doses before BEAM. Freedom from treatment failure (FFTF) was the primary end point. Remission rates, overall survival (OS), and toxicity of treatment were secondary end points.
                From a total of 284 patients included, 241 responding patients were randomly assigned after two cycles of dexamethasone, cytarabine, and cisplatinum. Patients treated in arm B had longer treatment duration and experienced more toxicity and protocol violations (P < .05). Mortality was similar in both arms (20% and 18%). With a median observation time of 42 months, there was no significant difference in terms of FFTF (P = .56) and OS (P = .82) between arms. FFTF at 3 years was 62% (95% CI, 56% to 68%) and OS was 80% (95% CI, 75% to 85%). Patients with stage IV, early relapse, multiple relapse, anemia, or B symptoms had a higher risk of recurrence (P < .001).
                Compared with conventional high-dose chemotherapy, additional SHDCT is associated with more adverse effects and does not improve the prognosis of patients with relapsed HL. In total, 18 of 26 double high-dose chemotherapies (HDCT) in pediatric solid tumors were rescued with peripheral blood stem cells collected during a single leukapheresis round (single-harvest group, SHG). In the remaining eight HDCT, additional leukapheresis were necessary after the first HDCT (HDCT1) to rescue the second HDCT (HDCT2) (double-harvest group, DHG). Stem cell collection after HDCT1 was inefficient and delayed in patients who had received prior chemotherapy before HDCT1. The interval between HDCT1 and HDCT2 was shorter in SHG than in DHG (median 62.5 days vs 178.5 days, P-value=0.002). Hematologic recovery in HDCT2 was delayed compared to HDCT1. However, there was no difference in hematologic recovery between SHG and DHG. A high rate of treatment-related mortality (TRM) was recorded during HDCT2, but there was no evidence that the shorter interval caused a higher rate of TRM (P-value=0.454). The probability of disease-free survival at 2 years after HDCT2 in the SHG and DHG were 66.7 and 25.0%, respectively (P-value=0.031). Therefore, to administer the second HDCT earlier in double HDCT, and thus to improve the survival of patients with high-risk solid tumors, the single-harvest approach is recommended rather than the double-harvest approach. To evaluate the role of early intensification with high-dose therapy (HDT) and autologous stem-cell transplantation (ASCT) as front-line chemotherapy for patients with high-risk, histologically aggressive non-Hodgkin's lymphoma (NHL).
                We planned a multicenter, randomized trial to compare a conventional chemotherapy regimen of methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B; arm A) with an abbreviated regimen of MACOP-B (8 weeks) followed by HDT and ASCT (arm B) for intermediate-high-risk/high-risk patients (according to the age-adjusted International Prognostic Index). From September 1994 to April 1998, 150 patients with aggressive lymphoma were enrolled onto the trial. Seventy-five patients were randomly assigned to arm A and 75 patients were randomly assigned to arm B. In both arms, involved-field radiation therapy (36 Gy) was delivered to the site of bulky disease.
                The rate of complete response was 68% in arm A and 76% in arm B (P = not significant [NS]). Three toxic deaths (4%) occurred in arm B and one (1%) occurred in arm A (P = NS). In arm B, 30 patients (40%) did not undergo HDT and ASCT. According to the intention-to-treat analysis at a median follow-up of 24 months, 5-year overall survival probability in arms A and B was 65% and 64% (P =.95), 5-year progression-free survival was 49% and 61% (P =.21), and 5-year relapse-free survival was 65% and 77% (P =.22), respectively.
                Abbreviated chemotherapy followed by intensification with HDT-ASCT is not superior to conventional chemotherapy in patients with high-risk, aggressive NHL. Additional randomized trials will clarify whether HDT-ASCT as front-line therapy after a complete course of conventional chemotherapy improves survival in this group of patients. Various transplantation strategies have been designed to improve the poor prognosis of adult (ages 15 to 60 years) acute lymphoblastic leukemia (ALL). The GOELAL02 trial evaluated the impact of early allogeneic bone marrow transplantation (alloBMT) or delayed unpurged autologous stem cell transplantation (ASCT) for patients who had no human leukocyte antigen (HLA)-matched sibling donor or who were older than 50 years. Inclusion criteria included at least one of the following: age older than 35 years; non-T-ALL; leukocytosis greater than 30 x 10(9)/L; t(9;22), t(4;11), or t(1; 19); or failure to achieve complete remission (CR) after one induction course. Among 198 patients, the median age was 33 years. The CR rate was 80% with vincristine, idarubicine, L-asparaginase, and randomized intravenous injection or oral steroids (P = nonsignificant [ns]). AlloBMT was performed after 2 consolidation courses while ASCT was delayed after 1 additional reinduction. Intensified conditioning regimen before transplantation included etoposide, cyclophosphamide, and total body irradiation (TBI). Median follow-up was 5.1 years. The median overall survival (OS) was 29 months, with a 6-year OS of 41%. On an intent-to-treat analysis for patients younger than 50 years, alloBMT significantly improved the 6-year OS (75% versus 40% after ASCT; P = .0027). Randomized interferon-alpha maintenance had no effect on relapse or survival after ASCT. In conclusion, the outcome of adult ALL is better after early alloBMT than after delayed ASCT. The purpose of this study is to compare our standard chemotherapy regimen (CHVP [cyclophosphamide, doxorubicin, teniposide, and prednisone]) plus interferon with 4 courses of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by high-dose therapy with autologous stem cell transplantation (ASCT) in treatment-naive patients with advanced follicular lymphoma. Four hundred one patients were included from July 1994 to March 2001: 209 received 12 cycles of CHVP plus interferon alpha for 18 months (CHVP-I arm) and 192 received 4 cycles of CHOP followed by high-dose therapy (HDT) with total body irradiation and ASCT (CHOP-HDT arm). Overall response rates were similar in both groups (79% and 78% after induction chemotherapy, respectively). One hundred thirty-one of the 150 patients eligible for HDT underwent transplantation (87%). Intent-to-treat analysis after a median follow-up of 7.5 years showed that there was no difference between the 2 arms for overall survival (P = .53) or event-free survival (P = .11). Patients with a complete response at the end of the induction therapy had a statistically longer event-free survival and overall survival (P = .02 and < .001, respectively). After long-term follow-up, our study showed that there was no statistically significant benefit in favor of first-line high-dose therapy in patients with follicular lymphoma. High-dose therapy should be reserved for relapsing patients. The prognosis for many pediatric and young adult patients with solid tumors that have metastasized at the time of diagnosis or have relapsed after therapy remains very poor. The steep dose-response curve of many of these tumors to alkylating agents makes myeloablative chemotherapy followed by autologous stem cell transplantation (ASCT) an attractive potential therapy. The role of ASCT for these high-risk patients is yet to be conclusively determined. We have transplanted 36 patients on two consecutive protocols with a variety of histological diagnoses. Overall survival (OS) was 63% (95% CI: 47-79%) at 1 year and 33% (95% CI: 16-50%) at 3 years. Patients with a diagnosis of Ewing's sarcoma (ES) or desmoplastic small round cell tumor (DSRCT) had significantly better survival than those with other diagnoses with estimated 3-year OS of 54% (95% CI: 29-79%) for this group of patients (P = 0.03). There were two transplant-related deaths both attributable to hepatic veno-occlusive disease. Median follow-up among survivors is 3.5 years (range: 0.6-7.9 years). These data justify continued investigation of ASCT as a consolidation therapy in patients with metastatic or relapsed ES and DSRCT. We performed a prospective, randomized study of single (arm A) versus double (arm B) autologous stem-cell transplantation (ASCT) for younger patients with newly diagnosed multiple myeloma (MM).
                A total of 321 patients were enrolled onto the study and were randomly assigned to receive either a single course of high-dose melphalan at 200 mg/m2 (arm A) or melphalan at 200 mg/m2 followed, after 3 to 6 months, by melphalan at 120 mg/m2 and busulfan at 12 mg/kilogram (arm B).
                As compared with assignment to the single-transplantation group (n = 163 patients), random assignment to receive double ASCT (n = 158 patients) significantly increased the probability to attain at least a near complete response (nCR; 33% v 47%, respectively; P = .008), prolonged relapse-free survival (RFS) duration of 18 months (median, 24 v 42 months, respectively; P < .001), and significantly extended event-free survival (EFS; median, 23 v 35 months, respectively; P = .001). Administration of a second transplantation and of novel agents for treating sequential relapses in up to 50% of patients randomly assigned to receive a single ASCT likely contributed to prolong the survival duration of the whole group, whose 7-year rate (46%) was similar to that of the double-transplantation group (43%; P = .90). Transplantation-related mortality was 3% in arm A and 4% in arm B (P = .70).
                In comparison with a single ASCT as up-front therapy for newly diagnosed MM, double ASCT effected superior CR or nCR rate, RFS, and EFS, but failed to significantly prolong overall survival. Benefits offered by double ASCT were particularly evident among patients who failed at least nCR after one autotransplantation.
The currently available evidence suggests a PFS benefit for patients with relapsed or refractory HL after first-line therapy, who are treated with HDCT followed by ASCT compared to patients treated with conventional chemotherapy. In addition, data showes a positive trend regarding OS, but more trials are needed to detect a significant effect.
Intensifying the HDCT regime before HDCT followed by ASCT did not show a difference as compared to HDCT followed by ASCT, but was associated with increased adverse events.