High-dose cyclophosphamide, carmustine, and etoposide followed by autologous peripheral stem cell transplantation for patients with relapsed Hodgkin's disease.

Between February 1986 and March 1990, 56 patients with relapsed Hodgkin's disease treated with high-dose cyclophosphamide, carmustine, and etoposide (CBV) received an autologous peripheral stem cell transplantation (PSCT) rather than an autologous bone marrow transplantation (ABMT) because each patient had a marrow abnormality, either hypocellularity or tumor involvement. At least 6.5 x 10(8) [corrected] mononuclear cells/kg patient weight were collected from the peripheral blood of each patient, cyropreserved, and returned intravenously following CBV administration. Three patients had an early death 2, 22, and 25 days after PSCT. The actuarial event-free survival for these 56 patients at 3 years was 37% and was at least as good as that reported for relapsed Hodgkin's disease patients treated with CBV and ABMT. The 30 patients who had no marrow metastases at the time of PSC harvesting had an actuarial event-free survival of 47%, while those 26 patients with marrow metastases had a significantly different actuarial event-free survival of 27% (P = .02). CBV and PSCT for patients with relapsed Hodgkin's diseases who have marrow hypocellularity in traditional harvest sites or histopathologic evidence of BM metastases can result in long-term event-free survival.     

High-dose cyclophosphamide, carmustine, and etoposide and autologous bone marrow transplantation for relapsed Hodgkin's disease

Thirty patients with relapsed Hodgkin's disease were treated with high-dose cyclophosphamide, carmustine, and etoposide (CBV) and autologous bone marrow transplantation. The median age of the patients was 28 years, and 18 were male. More than half had extranodal sites of relapse and constitutional symptoms. Most had been heavily pretreated with multiple salvage chemotherapy regimens and radiotherapy. At the time of transplantation, 23 patients were having progressive disease despite salvage chemotherapy. High-dose CBV chemotherapy induced complete responses in 15 patients and partial responses in 10 patients. Eleven patients are still in complete remission, 1 of whom has had an unmaintained remission for more than 44 months. Toxicity was moderate; all patients had severe myelosuppression requiring supportive therapy, and 1 patient failed to reconstitute her bone marrow. High-dose CBV chemotherapy and autologous bone marrow rescue proved to be effective as salvage therapy for a select group of heavily pretreated patients with relapsed Hodgkin's disease.     

Autologous stem cell transplantation followed by consolidation chemotherapy for relapsed or refractory Hodgkin's lymphoma

Relapse remains a major cause of treatment failure after autotransplantation (auto-PBSCT) for Hodgkin's disease (HD). The administration of non-crossresistant therapies during the post-transplant period may delay or prevent relapse. We prospectively studied the role of consolidation chemotherapy (CC) after auto-PBSCT in 37 patients with relapsed or refractory HD. Patients received high-dose gemcitabine-BCNU-melphalan and auto-PBSCT followed by involved-field radiation and up to four cycles of the DCEP-G regimen, which consisted of dexamethasone, cyclophosphamide, etoposide, cisplatin, gemcitabine given at 3 and 9 months post transplant alternating with a second regimen (DPP) of dexamethasone, cisplatin, paclitaxel at 6 and 12 months post transplant. The probabilities of event-free survival (EFS) and overall survival (OS) at 2.5 years were 59% (95% CI=42-76%) and 86% (95% CI=71-99%), respectively. In all, 17 patients received 54 courses of CC and 15 were surviving event free (2.5 years, EFS=87%). There were no treatment-related deaths during or after the CC phase. Post-transplant CC is feasible and well tolerated. The impact of this approach on EFS should be evaluated in a larger, randomized study.     

Cytoreduction and stem cell mobilization with a regimen of paclitaxel, etoposide and cyclophosphamide followed by autologous transplantation using a preparative regimen of busulfan, etoposide and cyclophosphamide for patients with advanced lymphoma

Forty-one patients with advanced Hodgkin's disease or intermediate or high-grade lymphoma, after having received standard salvage chemotherapy, were treated with a nonablative high-dose regimen of paclitaxel, etoposide and cyclophosphamide (D-TEC) to optimally cytoreduce their disease and simultaneously mobilize peripheral blood stem cells. This regimen produced a response rate of 78% (35% complete and 43.2% partial response) and mobilized sufficient peripheral blood stem cells in 94% of the patients. Thirty-two of these patients then underwent autologous progenitor cell transplantation after ablative conditioning with busulfan, etoposide and cyclophosphamide. Actuarial overall survival at 61 months was 71.9% with an event-free survival (EFS) of 65.6%. Median EFS was 24.4 months. EFS of patients responsive to salvage chemotherapy was 75% at 61 months, compared to 33.3% at 51.4 months in patients resistant to salvage chemotherapy. EFS of patients with disease sensitive to D-TEC was 75% at 61 months compared to 0% at 13.1 months in patients resistant to D-TEC. In a multivariate analysis, the only significant parameter for transplant outcome was sensitivity to D-TEC (p = 0.016), but not sensitivity to standard salvage chemotherapy. Aggressive cytoreduction may permit even those patients who are resistant to standard salvage chemotherapy to become successful transplant candidates.     

Safety and feasibility of high-dose ranimustine (MCNU), carboplatin, etoposide, and cyclophosphamide (MCVC) therapy followed by autologous stem cell transplantation for malignant lymphoma

High-dose chemotherapy followed by autologous stem cell transplantation (auto-SCT) is widely used as a salvage therapy in the treatment of refractory malignant lymphoma. To investigate the safety and feasibility of a high-dose MCNU, carboplatin, etoposide and cyclophosphamide (MCVC) regimen, we conducted a prospective multicenter trial. Thirty patients with relapsed/refractory/poor-risk non-Hodgkin lymphoma (NHL n?=?27) or Hodgkin lymphoma (HD n?=?3) were uniformly treated with an MCVC regimen and underwent auto-SCT. The median follow-up duration of the surviving patients was 67?months (56?C133?months). The major toxicities were anorexia (94?%), diarrhea (80?%), nausea (79?%), febrile neutropenia (70?%), alopecia (67?%) and mucositis (60?%). Three patients developed severe left ventricular dysfunction, and two patients developed severe sinusoidal obstructive syndrome (SOS). Of these patients, two died without disease progression. Treatment-related mortality was 6.6?%. Late-onset adverse events including two cases of cytomegalovirus pneumonia and one of interstitial pneumonia were observed. In DLBCL (n?=?13) and transformed FL (n?=?2) patients, OS and EFS at 3?years were 72 and 46?%, respectively. These results suggest that the MCVC regimen followed by auto-SCT is a feasible and tolerable therapy for relapsed/refractory malignant lymphoma. However, cardiac toxicity due to high-dose cyclophosphamide and development of SOS can occur and should be carefully monitored. Further follow-up is needed to evaluate the long-term efficacy and safety of this regimen.     

Treatment of refractory lymphoma with high dose cytarabine, cyclophosphamide and either TBI or VP-16 followed by autologous bone marrow transplantation

This study was designed to test the efficacy and toxicity of combining high-dose cytarabine (3 g/m2 every 12 h x 8 doses day -7 to day -4, total dose 24 g/m2), methyl prednisolone (0.5 mg/kg every 4 h day -7 to day -1), and cyclophosphamide (CY) (60 mg/kg day -3 and day -2) with either total body irradiation (TBI) (900 cGy in a single fraction on day -1) or VP-16 (600 mg/m2/days -7, -5, and -3) in patients not eligible for TBI secondary to prior radiotherapy. We treated 14 patients (eight male, six female) with either non-Hodgkin's lymphoma (n = 5) or Hodgkin's disease (n = 9). All patients had failed prior conventional chemotherapy (median two regimens range 1-5). Five patients were treated with TBI and nine with VP-16. There were eight complete remissions, two partial remissions, four were inevaluable for response due to early death. Overall survival is 21% (3/14) and relapse-free survival is 7% (1/14) with the sole disease-free survivor now 40 months from transplant. Very significantly, among patients receiving TBI, there were no survivors (median survival 24 days, range 17-330 days) and 4/5 had pulmonary complications. Median DLCO in these four patients was 61% (range 50-67) prior to transplant and none had an infectious etiology established by bronchoalveolar lavage. Median time to an absolute granulocyte count of 500 x 10(6)/l was 16 days (range 10-37 days) and to a platelet count of 20 x 10(9)/l was 12 days (range 7-22 days). In conclusion, the addition of high-dose cytarabine (24 g/m2) to CY and single-dose TBI or VP-16, while being very active, produced excessive pulmonary toxicity in this group of patients with lymphoma.     

Outpatient autologous hematopoietic stem cell transplantation for patients with relapsed follicular lymphoma

Autologous stem cell transplantation (ASCT) has emerged as a viable option for the treatment of relapsed follicular non-Hodgkin’s lymphoma. We report on the outpatient experience of 60 patients who underwent ASCT for this condition. The median age was 51 years (30–65). Pre-transplantation conditioning regimens consisted of either etoposide/melphalan/TBI, CBV or BEAM. Patients participated in this transplant program for a median of 20.5 days (14–78), and 58.4% of the total program days were spent in the outpatient setting. Six patients were well enough to be treated solely as outpatients. Ninety percent of patients required at least one inpatient admission (median 7 days), and 70% of first inpatient transfers occurred within the first week following transplant and always before day +12. There were no predictors for prolonged inpatient stays. Febrile neutropenia and gastrointestinal toxicity were the main reasons for inpatient transfers. No outpatient required an urgent admission to the ICU or died in the outpatient setting. The treatment-related mortality at days 30 and 100 was 0 and 1.7%, respectively. The overall and progression-free survivals at 5 years were 65.7 and 56.1%, respectively. Outpatient ASCT with total body irradiation is feasible, safe, and effective for patients with relapsed follicular lymphoma.     

High-dose cyclophosphamide,BCNU, and VP-16 (CBV) conditioning before allogeneic stem cell transplantation for patients with non-Hodgkin's lymphoma

Allogeneic stem cell transplantation (SCT) has been shown to be a curative therapy for some patients with non-Hodgkin's lymphoma (NHL). Total-body irradiation and high-dose cyclophosphamide combinations are the most established conditioning regimens used in this setting. We examined the efficacy and toxicity of cyclophosphamide, BCNU, and VP-16 (CBV) as a suitable chemotherapy-only regimen for NHL patients. In total, 18 patients, median age 42 years, with NHL were treated with CBV followed by allotransplant. Patients had received a median of two prior chemotherapy regimens. Median times to neutrophil and platelet recovery were 19 and 15 days, respectively. Interstitial pneumonitis occurred in one patient. There have been four relapses after a median follow-up of 39 months. Overall, there were four deaths, one because of relapse. The 2-year estimates of relapse-free and overall survival are 56 and 76%, respectively. CBV is a safe and an effective alternative to TBI-containing regimens before allogeneic SCT for NHL.     

Clinical outcome of allogeneic hematopoietic stem cell transplantation with FLAG sequential busulfan/cyclophosphamide conditioning regimen for refractory/relapsed acute myeloid leukemia

正Objective To investigate the therapeutic effects of allogeneic hematopoietic stem cell transplantation (alloHSCT) with FLAG sequential busulfan/cyclophosphamide (Bu/Cy) conditioning regimen for refractory/relapsed acute myeloid leukemia.Methods From February2012 to June 2017, 21 patients with refractory/relapsed acute myeloid leukemia underwent allo-HSCT with FLAG     

Allogeneic or autologous stem cell transplantation (SCT) for relapsed and refractory Hodgkin's disease and non-Hodgkin's lymphoma: a single-centre experience

PURPOSE OF THE STUDY: The aim of the study was to evaluate which patient might benefit most from allogeneic stem cell transplantation (SCT) in the treatment of relapsed and/or refractory lymphoma. PATIENTS AND METHODS: Thirty-eight consecutive lymphoma patients receiving either autologous (n = 24) or allogeneic (n = 14) stem cell grafts at our institution from 1986 to 1998 were retrospectively analysed regarding overall survival (OS), disease-free survival (DFS), transplant-related mortality (TRM), and relapse incidence (RI). Uni- and multivariate analyses were performed to identify patient characteristics predictive for outcome after SCT. RESULTS: The probabilities of OS, DFS, TRM, and relapse were 57%, 51%, 29%, and 30% following autologous and 43%, 43%, 29%, and 38% following allogeneic SCT. Disease status (sensitive versus refractory) and the time interval between diagnosis and SCT were the most powerful predictive parameters for OS and TRM, whereas elevated serum LDH levels were signifcant in determining relapse. CONCLUSIONS: In patients with elevated serum LDH levels and bone marrow involvement at the time of transplantation allogeneic was superior to autologous SCT and resulted in better outcome due to a lower relapse incidence strongly suggesting the existence of a graft-versus-lymphoma effect.     

The role of hematopoietic stem cell transplantation for relapsed and refractory Hodgkin lymphoma

The optimal treatment strategy with the use of hematopoietic stem cell transplantation (HSCT) for relapsed and refractory Hodgkin lymphoma (HL) remains unclear. We performed a retrospective analysis using registry data from the Japanese Society for Hematopoietic Cell Transplantation. Adult patients with HL who underwent a first autologous or a first allogeneic HSCT between 2002 and 2009 were included. Patients who underwent HSCT in first complete remission (CR) were excluded. Autologous and allogeneic HSCT were performed in 298 and 122 patients, respectively. For autologous HSCT, overall survival at 3 years (3yOS) was 70%, and sex, age, disease status, and performance status (PS) at HSCT were prognostic factors. OS was favorable even in patients who underwent autologous HSCT in disease status other than CR. For allogeneic HSCT, 3yOS was 43%, and sex and PS at HSCT were prognostic factors. Disease status at HSCT, previous autologous HSCT, and conditioning intensity did not affect OS. Moreover, graft‐versus‐host disease did not affect progression‐free survival or relapse/progression rate. A first allogeneic HSCT without a previous autologous HSCT was performed in 40 patients. 3yOS was 45%, and was significantly inferior to that in patients who underwent their first autologous HSCT. This result was retained after the correction by the different patient characteristics according to the type of HSCT. In conclusion, autologous HSCT is effective in prolonging survival in patients with relapsed and refractory HL. Allogeneic HSCT might be beneficial even to relapsed HL after autologous HSCT, although establishing the role of allogeneic HSCT remains a challenge. Am. J. Hematol. 90:132–138, 2015. © 2014 Wiley Periodicals, Inc.     

Successful peripheral blood stem cell mobilization with etoposide (VP-16) in patients with relapsed or resistant lymphoma who failed cyclophosphamide mobilization.

High-dose chemotherapy (HDCT) followed by autologous blood stem cell transplantation is considered the treatment of choice for patients with relapsed or resistant aggressive non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD). However, several authors report failure of standard mobilization regimens in 29% to 56% of these patients making the completion of HDCT impossible and as a result, negatively influencing long-term outcome. Thus, effective new regimens for patients failing initial mobilization are needed. Here we report the results of using etoposide as a mobilizing agent in 16 patients with primary resistant or relapsed malignant lymphoma who had failed prior mobilization of peripheral blood stem cells (PBSC) with cyclophosphamide (4 g/m2) followed by G-CSF. The use of etoposide 500 mg/m2 (days 1-4) + G-CSF resulted in the successful collection of adequate numbers of PBSC with a median harvest of 3.6 x 10(6)/kg (range 2.2-12.6) CD34+ cells in all 16 patients. In 7/16 (44%) patients, the target yield of at least 2.0 x 10(6) CD34+ cells was harvested by a single apheresis and the maximum number of separations for all patients was two. No excessive toxicities appeared, allowing all patients to proceed to myeloablative chemotherapy. In addition, median peak values of circulating CD34+ cells were significantly higher after etoposide as compared to cyclophosphamide (49.2/microl vs 4.7/microl; P = 0.0004). These results indicate that etoposide + G-CSF is a highly effective mobilization regimen in patients who have failed cyclophosphamide mobilization.     

Regimen-related toxicity and non-relapse mortality with high-dose cyclophosphamide, carmustine (BCNU) and etoposide (VP16-213) (CBV) and CBV plus cisplatin (CBVP) followed by autologous stem cell transplantation in patients with Hodgkin's disease.

This analysis compares the regimen-related toxicity (RRT) and overall non-relapse mortality (NRM) in Hodgkin's disease patients conditioned with either CBV (cyclophosphamide, BCNU (carmustine), and VP16-213 (etoposide)) (26 patients) or CBVP (CBV + cisplatin) (68 patients) followed by autologous stem cell transplantation (ASCT). CBVP included a continuous infusion rather than intermittent doses of etoposide, a lower BCNU dose and the addition of cisplatin. RRT and NRM were determined for each regimen and compared; risk factors for each were examined by multivariate analysis. Grade IV (fatal) RRT occurred in five patients (pulmonary in two, cardiac in two, and central nervous system in one). Eighteen patients experienced grade II-III pulmonary RRT, consistent with BCNU damage in 15. Prior nitrosourea exposure was the main risk factor for pulmonary RRT. Grade II mucosal and hepatic RRT occurred less often after CBVP vs CBV (P = 0.031 and 0.0003, respectively). In addition, three other early and eight late non-relapse deaths were seen. Median follow-up of the entire group is 5.1 (range 2.8-10.2) years. The probability of overall NRM was 26% (95% confidence interval (CI) 13-50%) with CBV vs 23% (95% CI 12-41%) with CBVP (P = 0.40). The progression-free survival and relapse rates were similar. Although the rates of fatal RRT, pulmonary RRT and overall NRM were similar with CBV or CBVP, CBVP produced less mucosal and liver RRT with a comparable antitumor effect. As many autografted patients are cured, future efforts should include measures to decrease NRM.     

High-dose infusional ifosfamide,etoposide plus methylprednisolone followed by dexamethasone,high-dose ara-C and cisplatinum and autologous stem cell transplantation for refractory or relapsed aggressive non-Hodgkin's lymphoma

BACKGROUND AND OBJECTIVES: A salvage program including infusional high-dose ifosfamide plus etoposide (IFOVM) was evaluated in patients with refractory or relapsed aggressive non-Hodgkin's lymphoma. DESIGN AND METHODS: Forty-six patients were included. IFOVM consisted of ifosfamide (10 g/m2 as a 72-hour continuous infusion), etoposide (900 mg/m2) and methylprednisolone; responding patients underwent two cycles of DHAP and subsequently an autologous peripheral blood stem cell transplantation (APBSCT) with BEAM as the conditioning regimen. RESULTS: All but one patient showed tumor regression following IFOVM. Myelosuppression was brief but 26 patients developed neutropenic fever. All but two patients proceeded to DHAP. Overall response rate to IFOVM/DHAP was 59% (29% CR and 30% PR). Refractory patients had a significantly lower response rate than relapsed patients (39% vs. 85% p=0.002). All refractory patients with intermediate-high or high IPI progressed during IFOVM/DHAP. Twenty-seven patients proceeded to APBSCT. Two-year overall survival of patients with low or low-intermediate IPI was 47% [95% CI 25-69%], which was significantly better than that obtained in patients with intermediate-high or high IPI (11% [95% CI 0-22%] p=0.0001). INTERPRETATION AND CONCLUSIONS: This sequential regimen of IFOVM, followed by DHAP and consolidated with BEAM is active in relapsed or refractory patients with low or low-intermediate IPI aggressive lymphoma. However, it has little activity in those patients with intermediate or high IPI, especially in refractory lymphomas.     

High-dose mitoxantrone and etoposide conditioning in autologous bone marrow transplantation for relapsed Hodgkin's disease.

We administered high-dose mitoxantrone in combination with etoposide to 6 patients with relapsed Hodgkin's disease as the conditioning regimen for autologous bone marrow transplantation. This regimen was well tolerated and no significant cardiotoxicity was observed. Responses of the Hodgkin's disease to this therapy were favourable but short-lived. Serial measurements of the serum levels of mitoxantrone suggested an open 3-compartment model of drug distribution. The rapid early phase of drug distribution was followed by an intermediate phase and a slow terminal drug-elimination phase. However, mitoxantrone was still detected in the serum of all patients 7 days after the last dose of mitoxantrone and on the day of bone marrow re-infusion. The clinical significance of such findings is unclear but they may suggest a need for the use of other anthracycline-related cytotoxic agents for the conditioning in autologous bone marrow transplantation.     

Ifosfamide, etoposide, cytarabine, and dexamethasone as salvage treatment followed by high-dose cyclophosphamide, melphalan, and etoposide with autologous peripheral blood stem cell transplantation for relapsed or refractory lymphomas

High-dose chemotherapy (HD-CT) with autologous stem cell transplantation is considered to be the treatment of choice for relapsed high-grade non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (HL) patients, but the optimal treatment has not yet been defined. We evaluated a salvage treatment regimen consisting of conventional cycles with ifosfamide, etoposide, cytarabine, and dexamethasone (IVAD) followed by two cycles of HD-CT consisting of cyclophosphamide, melphalan, and etoposide (CMV) with autologous stem cell support in patients with relapsed or refractory NHL (n = 59) and HL (n = 16). Response to IVAD was complete remission (CR) in 16 patients (21%), partial remission (PR) in 39 patients (52%), stable disease (SD) in 18 patients (24%), and progressive disease (PD) in two patients (2.7%). Of 70 patients treated with HD-CT, 41 patients (59%) showed a CR, 20 patients a PR (29%), eight patients a SD (11%), and one patient a PD (1.4%). The 5-yr overall survival for the entire group of patients was 29%, and for patients with NHL and HL 25%, and 38%, respectively. The respective event-free survival probabilities at 5 yr were 22%, 16%, and 31%. Seven treatment-related deaths due to septicemia (three), cardiac arrhythmia (one), pneumonia (one), pneumonitis (one), and toxic epidermal necrolysis (one) were observed. In multivariate analysis, an International Prognostic Index of > or = 2 and resistant disease to first-line chemotherapy were poor independent prognostic factors for the subgroup of patients with NHL. In conclusion, these results indicate that IVAD/CMV is feasible as a salvage therapy for lymphoma patients. This treatment is currently evaluated with the addition of rituximab.     

Myelofibrosis with myeloid metaplasia in a patient with relapsed Hodgkin's lymphoma who underwent autologous hematopoietic stem cell transplantation

Second malignancies after autologous haematopoietic stem-cell transplantation (AHSCT) are well-known long-term complications.

We present a case of a 24-year-old male with relapsed Hodgkin lymphoma (HL) with no involvement of his bone marrow who underwent AHSCT. Four years later he developed mild anaemia and a computed tomography showed an enlarged spleen. As his anaemia worsened, a bone marrow was performed. There was no evidence of HL but intense reticular and collagen fibrosis with hypocellularity was detected. Cytogenetic studies could not obtain cells in metaphase in two occasions. PCR for V617F JAK2 mutation was positive. Until now, with 7 years of follow up from his diagnosis of myelofibrosis with myeloid metaplasia (MMM) he did not require specific treatment besides from red cell transfusions when anaemia worsened during a pneumocistis carinii infection.

We present this case, because MMM is a infrequent second neoplasm after AHSCT. Revising the literature we could not find any case like this reported previously.     

Busulfan,cyclophosphamide, and etoposide as conditioning for autologous stem cell transplantation in multiple myeloma

Autologous stem cell transplantation (ASCT) has enabled the use of high-dose alkylating agents either as a single agent or in combination with other cytotoxic agents and/or total body irradiation (TBI) for the treatment of multiple myeloma. Despite improved complete remission rates, relapse and regimen-related toxicities remain challenging. In an effort to increase event-free survival and decrease the high incidence of regimen-related toxicity, we have studied the use of etoposide in combination with reduced-dose busulfan and cyclophosphamide as a conditioning regimen for ASCT in a group of 26 patients with advanced multiple myeloma. Median follow-up for the group was 30 months. There was no early treatment-related mortality. The main toxicity was mucositis. Otherwise, there was 1 case of reversible, clinically diagnosed hepatic veno-occlusive disease. Post-engraftment, 10 patients (38%) achieved CR, 15 (58%) patients achieved PR or SD, and 1 patient developed progressive disease (4%). Five patients in PR and 1 with progressive disease before transplant attained a CR post-transplant. The median times for event-free survival and overall survival after transplantation were 24 and 43 months, respectively. In conclusion, conditioning with busulfan, cyclophosphamide, and etoposide followed by ASCT is a safe regimen with comparable effectiveness to other previously used preparative regimens, thus providing another approach of non-TBI containing high-dose chemotherapy for patients with multiple myeloma.