Pharmacokinetic-directed high-dose busulfan combined with cyclophosphamide and etoposide results in predictable drug levels and durable long-term survival in lymphoma patients undergoing autologous stem cell transplantation

The clinical advantage of pharmacokinetic (PK)-directed-based dosing on intravenous (i.v.) versus oral busulfan-related toxicity and survival remains unclear. We performed a retrospective cohort study of sequential cohorts of patients comparing PK-directed oral and i.v. busulfan-based conditioning regimens in lymphoma patients undergoing autologous hematopoietic cell transplantation (ASCT). Patients received oral (n = 95), every 6 hours i.v. (IV16, n = 113), or once-daily i.v. (IV4, n = 86) busulfan, cyclophosphamide, and etoposide. PK-directed dosing was performed to achieve a predefined target area under the curve (AUC) of 20,000 μM-min (range: 18,400-21,600 μM-min). PK-directed dose adjustments markedly reduced the number of patients in the oral group with total AUC higher than the targeted AUC range, and reduced the variations of total AUC values in all patient groups. One hundred-day mortality was 2.1%, 3.6%, and 3.5% for oral, IV16, and IV4 cohorts, respectively. Five-year overall survival (OS) was 57% (95% confidence interval [CI] 45%-66%) and 64% (95% CI 53%-73%) for patients who received oral and i.v. busulfan, respectively. Both multivariable and instrumental variable analyses indicated the route of delivery had no significant impact on OS, whereas refractory disease and age ≥55 were significantly associated with poorer OS. In lymphoma patients undergoing ASCT, PK-directed i.v. or oral busulfan-based conditioning regimens have comparable toxicity and OS.     

Improved outcomes in intermediate- and high-risk aggressive non-Hodgkin lymphoma after autologous hematopoietic stem cell transplantation substituting intravenous for oral busulfan in a busulfan, cyclophosphamide, and etoposide preparative regimen.

Forty-nine patients with intermediate- and high-risk aggressive non-Hodgkin lymphoma underwent autologous hematopoietic stem cell transplantation (autoHSCT) using the regimen of busulfan (Bu), cyclophosphamide (Cy), and etoposide (E) that was originally developed for allogeneic HSCT. Eighteen patients treated before 1999 received Cy 2.5 g/m2 on days -3 to -2 and E 1800 mg/m2 on day -3 after oral (PO) administration of Bu 1 mg/kg every 6 hours x 4 days for a total of 16 doses beginning on day -7. After April 1999, 31 patients similar in all pretransplantation risk assessments received the same regimen except that intravenous (IV) Bu was substituted for PO Bu and pharmacokinetic-directed (PKD) dosing was attempted to achieve an area under the concentration time curve of 1000-1500 micromol/min for each dose. Nonrelapse mortality was 28% for PO Bu patients versus 3% for the IV PKD group (P = .01, chi-square test). Actuarial 5-year overall survivals were 28% for patients who received the PO Bu regimen and 58% for patients who received the IV Bu regimen (P = .010, log-rank test), and progression-free survivals were 17% and 50%, respectively (P = .008, log-rank test). After substitution of PKD IV Bu in the BuCyE regimen, we observed lower nonrelapse mortality with increased overall and progression-free survivals in patients with intermediate- and high-risk aggressive non-Hodgkin lymphoma who underwent autoHSCT.     

Veno-occlusive disease of the liver after high-dose cytoreductive therapy with busulfan and melphalan for autologous blood stem cell transplantation in multiple myeloma patients.

Veno-occlusive disease of the liver (VOD) is a potentially severe complication of high-dose cytoreductive therapy (HDT) used for stem cell transplantation (SCT). This complication is uncommon after HDT for autologous SCT (ASCT) in patients with multiple myeloma (MM). The Spanish Myeloma Group/PETHEMA conducted a study (MM2000) for patients with newly diagnosed MM consisting of induction with alternating VBMCP/VBAD chemotherapy followed by intensification with busulfan/melphalan (Bu/MEL) with a second high-dose therapy procedure in patients not achieving at least near-complete remission with the first procedure. After 2 years of the trial, a number of episodes resembling classical VOD but with a late onset were recognized. Consequently, the protocol was modified, and Bu/MEL was replaced by melphalan 200 mg/m(2) (MEL-200). Three years later, after a total of 734 patients had undergone first autologous SCT, the incidence and characteristics of VOD episodes were analyzed in the whole series. Nineteen cases of VOD (8%) were observed among the first 240 patients receiving Bu/MEL, whereas only 2 (0.4%) were observed among the 494 patients treated with MEL-200 (P < .0001). VOD manifestations in the Bu/MEL group appeared at a median of 29 days (range, 3-57 days) after ASCT. Mortality directly attributable to VOD was 2% in the Bu/MEL group and 0.2% in the MEL-200 group (P = .026). This high incidence of severe VOD probably had a multifactorial origin (busulfan followed by melphalan and previous use of BCNU). This observation should be kept in mind when designing future trials for the treatment of MM.     

Early stem cell transplantation for refractory acute leukemia after salvage therapy with high-dose etoposide and cyclophosphamide.

Primary refractory acute leukemia (AL) has a poor prognosis, although some patients can be salvaged with allogeneic stem cell transplantation (SCT). Induction of complete remission (CR) with conventional chemotherapy before SCT may improve outcome in this patient population. Between March 1991 and October 2003, 59 adults with primary refractory AL were treated with continuous-infusion etoposide (VP) 2.4 to 3.0 g/m(2) followed by cyclophosphamide (Cy) 6.0-7.2 g/m(2) intravenously over 3 to 4 days with the intention of proceeding to SCT in CR1. Forty-two patients had acute myelogenous leukemia (AML), 13 patients had acute lymphoblastic leukemia (ALL), and 4 patients had acute biphenotypic leukemia. The most frequent nonhematologic toxicities were oral mucosal, gastrointestinal, and hepatic toxicities (44%, 20%, and 15% of patients, respectively). Thirty-two (57%) of 56 evaluable patients entered CR1 with a median time to platelet and neutrophil recovery of 22 and 26 days, respectively. CR1 rates were similar in AML (54%) and ALL/acute biphenotypic leukemia (67%; P = .52), and analysis of baseline characteristics did not reveal any predictors of response to VP/Cy. Twenty-nine of 32 CR1 patients subsequently underwent SCT (24 allogeneic and 5 autologous). Estimated 5-year event-free survival (EFS) and overall survival for the entire cohort are 23% and 26%, respectively. In the allogeneic SCT group, 5-year EFS was 52% for AML patients and 14% for ALL patients (P = .04), and only male sex was predictive of a favorable outcome (P = .03). VP/Cy is able to induce CR1 in most patients with primary refractory AL with an acceptable toxicity profile. Subsequent allogeneic SCT can lead to long-term EFS in a significant proportion of patients.     

Timely reconstitution of immune competence affects clinical outcome following autologous stem cell transplantation

Abstract. The anti-tumor activity of the immune system in the setting of hematopoietic stem cell transplantation has largely been described in the context of the graft-versus-tumor effect of allogeneic stem cell transplantation. This article reviews clinical evidence suggesting the existence of an autologous graft-versus-tumor effect in the setting of host immune system recovery following autologous stem cell transplantation resulting in prolongation of survival of cancer patients.     

Ifosfamide, idarubicin, and etoposide in relapsed/refractory Hodgkin disease or non-Hodgkin lymphoma: a salvage regimen with high response rates before autologous stem cell transplantation.

To achieve long-term disease-free survival, high-dose therapy and autologous stem cell transplantation (ASCT) is the current standard approach in patients with relapsed or refractory Hodgkin disease (HD) or non-Hodgkin lymphoma (NHL). Because chemosensitivity is a significant factor in determining transplantation eligibility, it is critical to select a salvage chemotherapy regimen that has the potential to induce a high response rate with low nonhematologic toxicity. In this phase II study, 49 patients with relapsed or refractory HD (n = 22) and NHL (n = 27) with a median age of 42 years were treated with an IIVP salvage regimen consisting of ifosfamide, idarubicin, and etoposide. Twenty-seven percent of the patients had primary refractory disease, whereas 22% and 51% had early and late relapses, respectively. As analyzed by intention to treat, 16 patients (33%) achieved complete remission and 21 patients (43%) achieved a partial response, leading to an overall response rate of 76% (63% in NHL and 91% in HD). In the univariate analysis, diagnosis (HD versus NHL), remission duration before the initiation of IIVP, disease bulk, increased lactate dehydrogenase, and the presence of "B" symptoms were significant factors affecting the response achieved by the IIVP regimen. Of 37 responders, 31 (84%) underwent high-dose therapy and transplantation. The probability of 4-year overall survival (OS) and event-free survival (EFS) in this group of patients who underwent ASCT was 67.7% and 49.1%, respectively. When compared with the patients who achieved a partial response, patients who achieved complete remission with the IIVP regimen had a significantly higher probability of 4-year EFS (67.3% versus 30%; P = .016) and 4-year OS (92.3% versus 39.2%; P = .003). In patients with HD, 4-year EFS and 4-year OS were 54.9% and 70.6%, respectively, without a significant difference with respect to the survival rates obtained in patients with NHL (43.6% and 63.6%, respectively). Common side effects observed during 102 cycles of therapy were grade 3 to 4 neutropenia (62%) and thrombocytopenia (58%). The IIVP regimen is a highly effective salvage regimen for patients with relapsed or refractory HD or NHL who are candidates for ASCT. Furthermore, the degree of response to IIVP predicts the posttransplantation outcome. However, close follow-up is necessary because of a high incidence of grade 3 to 4 hematologic toxicity.     

High-dose chemotherapy plus non-cryopreserved autologous peripheral blood stem cell transplantation rescue for patients with refractory or relapsed Hodgkin disease.

A simplified schedule of high-dose chemotherapy consisting of cyclophosphamide (60 mg.kg(-1).d(-1) for 2 days), etoposide (15 mg.kg(-1).d(-1) for 2 days), and carboplatin (400 mg/m(2) per day for 2 days) plus autologous non-cryopreserved peripheral blood stem cells (PBSCs) was used for treatment of patients with relapsed (n = 25) and refractory (n = 3) Hodgkin disease. The use of such PBSCs mobilized by granulocyte colony-stimulating factor after high-dose myeloablative therapy resulted in a rapid, complete, and sustained hematopoietic recovery. The median time to achieve an absolute neutrophil count >0.5 x 10(9)/L was 13 days (range, 7-18 days). The median time to a self-sustained platelet count >20 x 10(9)/L was 15 days (range, 7-20 days). Twelve of the 28 patients (43%) were alive and without disease at a median follow-up of 16 months (range, 9-86 months) for all surviving patients. The estimated 2-year overall survival and disease-free survival for all patients were 45% and 42%, respectively. Thirteen patients died of relapse or progressive disease, 2 died of infection, and 1 was still surviving in relapse by the time of the analysis. The median time to relapse was 10 months (range, 3-28 months) from PBSC infusion. High-dose chemotherapy with short-duration chemotherapy and non-cryopreserved bone marrow is an effective and safe treatment modality for patients with relapsed or resistant Hodgkin lymphoma.     

Oral mucositis in patients with leukaemia following high-dose chemotherapy and autologous haematopoietic stem cells transplantation

Historically, oral mucositis (OM) has been identified as a symptom developing in patients undergoing irradiation due to head and neck cancers, those undergoing therapy in preparation for a stem cell transplant, or receiving special therapeutic protocols due to acute myeloid leukaemia. It results from direct toxic injury to the mucosal epithelial cells by the immunosuppressive regimen. In this article we want to describe pathogenesis, diagnostic and actual possibility of treatment of OM. The literature reports several rating scale for OM that have been used for patients undergoing cancer therapy. The most useful of them are Oral Toxicity Scale and Oral Mucositis Assessment Scale. In the prevention and treatment of OM associated with standard chemotherapy various drugs and agents acting locally and systemically are used. Many of them are still remaining in the course of research.     

Successful allogeneic stem cell transplantation with nonmyeloablative conditioning in patients with relapsed hematologic malignancy following autologous stem cell transplantation.

The use of myeloablative preparative therapy and allogeneic stem cell transplantation (alloSCT) as salvage therapy for adult patients with relapsed hematologic malignancy after autologous stem cell transplantation (autoSCT) is generally unsuccessful due to very high treatment-related mortality rates. We evaluated the outcome of HLA-matched related donor alloSCT following nonmyeloablative preparative therapy in 13 patients (median age, 38 years) with relapsed hematologic malignancies (Hodgkin's disease, n = 4; Hodgkin's disease and advanced myelodysplastic syndrome, n = 1; non-Hodgkin's lymphoma, n = 6; multiple myeloma, n = 2) after initial autoSCT. Median time from autoSCT to alloSCT was 12 months (range, 3-24 months); 6 patients had chemotherapy-refractory disease following autoSCT, 6 were in untreated relapse, and 1 had a partial response from salvage chemotherapy. Preparative therapy consisted of cyclophosphamide, 150-200 mg/kg; peritransplantation anti-thymocyte globulin; thymic irradiation (in patients who had not received previous mediastinal irradiation); and a very short course of cyclosporine as GVHD prophylaxis. All patients achieved initial mixed chimerism as defined by greater than 1% donor peripheral white blood cells. Seven patients, who had no evidence of GVHD, received prophylactic DLI beginning 5 to 6 weeks after transplantation for conversion of mixed chimerism to full donor hematopoiesis and to optimize a graft-versus-tumor effect. Six patients showed conversion to full donor chimerism and 1 lost the graft. Grade II or greater acute GVHD occurred in 9 patients. Seven patients achieved a complete response; 6 had no response. The median survival time of the 13 patients is currently 10 months (range, 3-39 months), with an overall survival probability at 2 years of 45% (95% confidence interval [CI], 19%-73%) and a disease-free survival probability at 2 years of 37.5% (95% CI, 12%-65%). Thus, this novel nonmyeloablative alloSCT strategy followed by prophylactic DLI was well tolerated and can result in durable disease-free survival among patients with advanced hematologic malignancies after a failed autoSCT. Further follow-up and evaluation of additional patients are required to conclusively establish the role of this strategy in the treatment of hematologic malignancies after an autologous transplantation.     

Immune re-education following autologous hematopoietic stem cell transplantation

The encounter with different environmental antigens during immune maturation from childhood through early adulthood could play a role in the development of autoimmune disease in individuals with a susceptible genetic background. Autologous haematopoietic stem cell transplantation (HSCT) is an experimental treatment for autoimmunity that could offer a second possibility to correct for an aberrant immune reactivity. The premise is that eradication of the existing and pathogenic immune repertoire, in combination with the reinfusion of precursor cells, could reset the immunological clock to an earlier, latent phase of disease. Re-education of the adaptive immune system would occur during the reconstitution of cells under extreme lymphopenia, in which the antigenic priming takes place with a different sequence and timing than during the previous immunological history of the individual, resulting in a different immune repertoire. In this article, we discuss different mechanisms that could contribute to the development of tolerance during immune re-education and address the role of immune renewal and the qualitative reshaping of immunological memory.     

Tandem autologous stem cell transplantation for patients with primary refractory or poor risk recurrent Hodgkin lymphoma.

Although autologous stem cell transplantation (ASCT) for patients with relapsed/refractory Hodgkin lymphoma (HL) appears to offer a survival advantage over conventional therapy, only approximately 25% to 35% of patients with primary progressive or poor-risk recurrent HL can achieve durable remission after ASCT, with disease progressive after transplant accounting for most of the treatment failures. We conducted a pilot study to evaluate the toxicities and efficacy of a tandem transplant approach in this subgroup of patients. Between April 1998 and March 2000, 46 patients were enrolled in the study. Eligibility criteria: primary progressive (n = 28) or recurrent HL (n = 18) with at least 1 of the following poor prognostic factors: first complete remission (CR) <12 months (n = 15) or extra-nodal disease (n = 4) or B symptoms at relapse (n = 4). The first cycle consisted of melphalan (150 mg/m(2)) alone. The second cycle consisted of fractionated total body irradiation (FTBI) 1200 cGy or BCNU (450 mg/m(2)) in combination with etoposide (60 mg/kg) and cyclophosphamide (100 mg/kg). Of the 46 patients, 5 (11%) did not receive the planned tandem transplants because of inadequate stem cell collection for 2 ASCT. After a median of 64 days (25-105), 41 patients received the second ASCT. With a median follow-up of 5.3 years (1.6-8.1), the 5-year estimate of overall survival, progression-free survival, and freedom from progression were 54% (95% confidence interval [CI] 40%-69%), 49% (95% CI, 34%-63%), and 55% (95%CI, 40%-70%), respectively. Our mature results from this study suggest that in patients with primary progressive or poor risk recurrent HL, this tandem ASCT program is effective and well tolerated and compares favorably with the conventional single transplant.     

Poor outcomes for IgD multiple myeloma patients following high-dose melphalan and autologous stem cell transplantation: a single center experience

Immunoglobulin (Ig) D multiple myeloma (MM) accounts for 2% of all MM cases and has been reported to be associated with poor prognosis compared with other MM subtypes. The aim of the present study was to compare the effects of high-dose melphalan treatment and autologous stem cell transplantation (ASCT) on the survival of patients with IgD MM and patients with other MM subtypes. Between November 1998 and January 2005, a total of 77 patients with MM who underwent ASCT at the Asan Medical Center were enrolled in this study. High-dose melphalan (total 200 mg/m2) was used as high-dose chemotherapy. The study population was divided into two groups based on MM subtype: those with IgD MM; and those with other MM subtypes. A total of 8 patients with IgD MM were identified, accounting for about 10% of the study population. Thirty-six patients (47%) had IgG MM, 17 patients (22%) had IgA MM, and 16 patients (20%) had free light-chain MM. The two groups were similar in baseline characteristics. The median follow-up was 17 months and the median overall survival (OS) was 39 months. In the IgD MM group, median eventfree survival (EFS) and OS were 6.9 and 12 months, respectively. In the patients with other MM subtypes, median EFS and OS were 11.5 and 55.5 months (p=0.01, p<0.01), respectively. Multivariate analysis of all patients identified IgD subtype (p=0.002) and Southwest Oncology Group (SWOG) stage 2 or greater at the time of ASCT (p=0.01) as adverse prognostic factors for survival. In this small study at a single center in Korea, patients with IgD MM had poorer outcomes after ASCT than did patients with other MM subtypes.     

Dose modification protocol using intravenous busulfan (Busulfex) and cyclophosphamide followed by autologous or allogeneic peripheral blood stem cell transplantation in patients with hematologic malignancies.

We evaluated the safety and toxicity through a 5-cohort dose-modification model of once-daily administration of IV busulfan (Bu) in combination with high-dose cyclophosphamide (Cy) as preparative therapy for stem cell transplantation. Twenty-one adult patients with hematologic malignancies were evaluated. Eleven patients underwent autologous and 10 patients underwent HLA-matched sibling allogeneic transplantation. Patients were sequentially enrolled into 5 cohorts. Cohort 1 received intravenous (IV) Bu 1.6 mg/kg every 12 hours for 2 doses and then 0.8 mg/kg every 6 hours for 12 doses; cohort 2 received IV Bu 1.6 mg/kg every 12 hours for 4 doses and then 0.8 mg/kg every 6 hours for 8 doses; cohort 3 received IV Bu 3.2 mg/kg for 1 dose and then 1.6 mg/kg every 12 hours for 2 doses and 0.8 mg/kg every 6 hours for 8 doses; cohort 4 received IV Bu 3.2 mg/kg every 24 hours for 2 doses and then 0.8 mg/kg every 6 hours for 8 doses; and cohort 5 received IV Bu 3.2 mg/kg every 24 hours for 4 doses. In all groups, Bu was administered on day -7 through day -4 and was followed at least 6 hours after the last Bu dose by Cy 60 mg/kg daily for 2 doses on days -3 and -2. Blood samples were collected for pharmacokinetic analysis on the first and last day of IV Bu administration. All patients were alive and had engrafted at day 30. Five patients developed grade 3 or 4 toxicities. Four patients developed hepatic abnormalities, and 3 exhibited evidence of veno-occlusive disease. Two of 3 patients in cohort 5 with a Bu area under the curve >6000 micromol/min developed autopsy-confirmed veno-occlusive disease. Interpatient variability in AUCs was observed in patients within and between cohorts, but no statistically significant interpatient differences were observed in Bu half-life, volume of distribution, clearance, or dose-adjusted area under the curve. Further, minimal variability in Bu pharmacokinetics was observed between the 2 evaluations performed in each patient, thus reflecting the stability of Bu disposition within individual patients. On the basis of the dosing guidelines and schedule outlined in this study, our data suggest that administration of IV Bu 3.2 mg/kg IV every 24 hours for 4 doses in combination with Cy may result in excessive toxicity.     

Autoimmune disease after autologous hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation (HSCT) is an effective treatment for refractory autoimmune diseases. The safety and long-term outcome have been also acceptable. Infectious diseases under immune suppressive state after autologous HSCT are common transplantation related complications whereas autoimmune diseases are uncommon. Organ specific autoimmune diseases, such as immune mediated thrombocytopenia and thyroid dysfunction, are the most common after autologous HSCT. Systemic autoimmune diseases can also develop after autologous HSCT in patients with hematological disorders with genetic predisposition to autoimmune diseases. Although the mechanism of autoimmunity after HSCT is not well-known, long-term follow-up is essential in patients with autoimmune diseases treated with autologous HSCT.     

Long-term outcome of myeloablative allogeneic stem cell transplantation for multiple myeloma.

Allogeneic stem cell transplantation (alloSCT) has been used in the hopes of harnessing the curative potential of the graft-versus-myeloma effect. This study examines the long-term outcomes of a large cohort of patients with myeloma who were treated with myeloablative alloSCT at a single center. Comparisons are made with those who were treated with autologous stem cell transplantation (ASCT). Between January 1989 and February 2002, 158 patients age10 years post myeloablative alloSCT, similarly there are long-term survivors post-ASCT. Myeloablative alloSCT should not be considered standard treatment, and should only be considered in the context of a clinical trial.     

Long-term follow-up after autologous hematopoietic stem cell transplantation for low-grade non-Hodgkin lymphoma.

Autologous hematopoietic stem cell transplantation (AHSCT) in low-grade non-Hodgkin lymphoma (NHL) can result in a prolonged remission, although most patients eventually relapse and die of their disease. We report long-term outcomes of AHSCT for patients with relapsed low-grade NHL. Between May 1983 and 2001, 67 patients with relapsed or refractory stage III and IV low-grade NHL received an AHSCT at the University of Minnesota at a median of 2.3 years (range, 0.4-15.2 years) after diagnosis. At transplantation, 62 patients (92%) were in complete remission (CR) (6%) or partial remission (PR) (86%); 5 (8%) had resistant disease; and 9 (14%) had transformed to a higher-grade NHL. After AHSCT, 32 (49%) of 65 evaluable patients achieved CR, and 26 (40%) achieved PR. Overall survival (OS) was 50% (95% confidence interval [CI], 38%-62%) at 4 years and 33% (95% CI, 20%-46%) at both 10 and 18 years, whereas progression-free survival (PFS) was 28% (95% CI, 17%-39%) at 4 years, 18% (95% CI, 8%-28%) at 10 years, and 14% (95% CI, 4%-25%) at 18 years. Transplant-related mortality in the first 100 days was 3% (95% CI, 0%-7%). Relapse occurred in 62% (95% CI, 48%-75%) at 4 years and 72% (95% CI, 56%-87%) at 10 years. Eleven patients (16%) developed myelodysplastic syndrome/acute myeloid leukemia 1 to 8 years after AHSCT, and 3 (5%) developed solid tumors. In multiple regression analysis, the International Prognostic Index (IPI) score at transplantation was the most significant predictor for both OS and PFS. The median OS has not been reached in patients with an IPI score of 0 or 1 at transplantation (20 of 35 survive 2 to 18 years after AHSCT), whereas it was 2.3 and 1.6 years for IPI scores of 2 and 3, respectively ( P = .002). A good response (CR/PR) to AHSCT (relative risk [RR], 0.4; 95% CI, 0.2-0.9; P = .04) and age <50 years (RR, 0.5; 95% CI, 0.2-0.8; P = .01) were also independently significant predictors of good OS and PFS. We present mature follow-up data (median follow-up, 8 years; range, 2-18 years) of patients undergoing AHSCT for relapsed low-grade NHL and demonstrate extended OS and PFS. Very long-term remissions were seen in nearly 20% of patients. AHSCT remains promising, especially for patients with sensitive relapse and lower IPI scores. Recurrent lymphoma after AHSCT remains the major problem, and prolonged survival is further tempered by a significant risk of post-transplantation second malignancies, including myelodysplastic syndrome/acute myeloid leukemia and solid tumors.     

High-dose thiotepa, etoposide and carboplatin as conditioning regimen for autologous stem cell transplantation in patients with high-risk non-Hodgkin lymphoma

High-dose chemotherapy conditioning regimens followed by autologous stem cell transplantation generally provide good results in non-Hodgkin lymphoma. We have evaluated the effects of a high-dose regimen comprising thiotepa, etoposide and carboplatin. After debulking and mobilization with high-dose cyclophosphamide or other schedules, forty-five patients at various disease stages were conditioned with thiotepa, etoposide and carboplatin prior to autologous stem cell transplantation. The overall response rate was 77.8% (30 CR, 66.7%; 5 PR, 11.1%). Ten patients (22.2%) did not respond. Two patients (4.4%) died from transplant-related complications. The mean 5-year overall survival was 71.1%: 12 patients relapsed within the first 5 years of follow-up. The overall response rate and 5-year overall survival were better for patients with an International Prognostic Index (IPI) 1 at diagnosis than for those with IPI 2 and IPI 3 (P<0.005 for all). The thiotepa, etoposide and carboplatin conditioning regimen for autologous stem cell transplantation in non-Hodgkin lymphoma has a good anti-lymphoma effect and provides encouraging results in terms of response to treatment and 5-year overall survival. Its good tolerance and acceptable toxicity suggest that it may a very useful in the management of non-Hodgkin lymphoma.     

The efficacy of high-dose melphalan with autologous peripheral blood stem cell transplantation in patients with multiple myeloma

Although high-dose therapy (HDT) with autologous hematopoietic stem cell transplantation (ASCT) is widely accepted as an effective and safe consolidation therapy for multiple myeloma (MM), few reports on its efficacy are available in Korea. We present the results of a prospective phase II study, involving 33 patients with MM treated with HDT with ASCT. The treatment consisted of 4 courses of VAD (vincristine, adriamycin, dexamethasone) induction, peripheral blood stem cell collection, and high-dose melphalan with stem cell infusion. The overall response rate was 93%, with 45% of patients having complete responses. The toxicity was predictable and tolerable. With a median follow-up of 27.6 months, the 2-year event free survival rate was 43%. At the time of writing, the median overall survival duration had not been reached with 2-year survival and projected 3-year survival rates of 81% and 74%, respectively. The overall survival was significantly better than that of the historical control patients (N=82) treated with conventional chemotherapy at our institution. The results suggest that HDT with ASCT is a valuable first or second-line treatment for patients with MM.     

Reduced-intensity allogeneic stem cell transplantation for patients whose prior autologous stem cell transplantation for hematologic malignancy failed.

Autologous hematopoietic stem cell transplantation (autoSCT) is an effective treatment for patients with various hematologic malignancies. Despite the significant improvement in the overall outcome, disease progression after transplantation remains the major cause of treatment failure. With longer follow-up, therapy-related myelodysplasia/acute myelogenous leukemia is becoming an important cause of treatment failure. The prognosis for these 2 groups of patients is very poor. Allogeneic hematopoietic stem cell transplantation (alloSCT) is a potential curative treatment for these patients. However, the outcome with conventional myeloablative alloSCT after failed autoSCT is typically poor because of high transplant-related mortality. In an attempt to reduce the treatment-related toxicity, we studied a reduced-intensity conditioning regimen followed by alloSCT for patients with progressive disease or therapy-related myelodysplasia/acute myelogenous leukemia after autoSCT. This report describes the outcomes of 28 patients with hematologic malignancies who received a reduced-intensity alloSCT after having treatment failure with a conventional autoSCT. Fourteen patients received a hematopoietic stem cell transplant from a related donor and 14 from an unrelated donor. The conditioning regimen consisted of low-dose (2 Gy) total body irradiation with or without fludarabine in 4 patients and the combination of melphalan (140 mg/m(2)) and fludarabine in 24. Cyclosporine and mycophenolate mofetil were used for posttransplantation immunosuppressive therapy, as well as graft-versus-host disease (GVHD) prophylaxis, in all patients. All patients engrafted and had >90% donor chimerism on day 100 after SCT. Currently, 13 patients (46%) are alive and disease free, 7 patients (25%) developed disease progression after alloSCT, and 8 (32%) died of nonrelapse causes. Day 100 mortality and nonrelapse mortality were 25% and 21%, respectively. With a median follow-up of 24 months for surviving patients, the 2-year probabilities of overall survival, event-free survival, and relapse rates were 56.5%, 41%, and 41.9%, respectively. Six patients (21%) developed grade III to IV acute GVHD. Among 21 evaluable patients, 15 (67%) developed chronic GVHD. We conclude that (1) reduced-intensity alloSCT is feasible and has an acceptable toxicity profile in patients who have previously received autoSCT and that (2) although follow-up was short, a durable remission may be achieved in some patients who would otherwise be expected to have a poor outcome.