Etoposide in combination with cyclophosphamide and total body irradiation or busulfan as conditioning for marrow transplantation in adults and children

Summary:The purpose of the study was to determine the toxicities and effectiveness of a novel preparative regimen of busulfan (Bu) 14 mg/kg, etoposide 50 or 60 mg/kg, and cyclophosphamide (Cy) 120 mg/kg in non-Hodgkin's lymphoma (NHL) and to analyze results using doses based on different body weight parameters and the two different etoposide doses. Three hundred and eightytwo patients aged 16 to 72 underwent first autologous transplantation with mobilized peripheral blood progenitor cells between August 1992 and December 1998 at either of two transplant centers. Mucositis was the most common toxicity. Hepatic toxicity was the most common life-threatening toxicity; severe hepatic VOD occurred in 11 patients (2.9%). Ten patients (2.6%) died from treatment-related toxicity. The 3-year progressionfree survival (PFS) for the entire group was 46.9% (95% CI, 40.5-53.3%). Elevated LDH, resistance to chemotherapy, and intermediate/aggressive histology were significant adverse prognostic factors. For patients in sensitive first relapse PFS was 47.0% (95% CI, 37-57%). Neither etoposide dose nor body weight parameter utilized significantly affected outcome. In conclusion, the novel preparative regimen of Bu, etoposide and Cy results in a low incidence of treatment-related mortality and is effective in the treatment of patients with NHL. Bone Marrow Transplantation (2000) 25, 1243-1248. Keywords: autotransplantation; non-Hodgkin's lymphoma; busulfan High-dose chemotherapy followed by autologous transplantation of hematopoietic progenitor cells is curative in many patients with NHL who fail primary therapy. [1][2][3][4] The superiority of this approach over standard chemotherapy has been proven in patients with chemotherapy-sensitive, relapsed intermediate and high-grade NHL. 5 Autotransplantation is also commonly performed in patients with more advanced

Section: Discussionmentioning

confidence: 99%

Autotransplantation following busulfan, etoposide and cyclophosphamide in patients with non-Hodgkin's lymphoma

Copelan

Penza

Pohlman

et al. 2000

“…For many patients transplanted over this time, total body irradiation (TBI) in standard doses of 12-13.5 Gy has been used together with cyclophosphamide or etoposide (VP-16) as the preparative regimen due to its substantial anti-tumor and immunosuppressive activities. [4][5][6][7][8][9][10][11][12] Since 20-30% of patients treated with TBI-based preparative regimens die from leukemia relapse, we postulated that treatment intensity is suboptimal. The killing of leukemia cells is proportional to the radiation absorbed dose.…”

Section: Discussionmentioning

confidence: 99%

A dose escalation study of total body irradiation followed by high-dose etoposide and allogeneic blood stem cell transplantation for the treatment of advanced hematologic malignancies

Sobecks

Daugherty

Hallahan

et al. 2000

Summary:Since approximately 30% of leukemia patients relapse after allogeneic BMT using total body irradiation (TBI)-based preparative regimens, treatment intensity may be suboptimal. The killing of leukemia cells is proportional to the radiation absorbed dose. We studied the feasibility and toxicity of escalating the doses of fractionated TBI above our previous prescription of 13.5 Gy. Sixteen evaluable patients with advanced hematologic malignancies were treated with twice daily TBI using a highenergy source (18-24 MV). The first patient cohort (n = 11) received a total dose of 14.4 Gy in nine fractions, and the second cohort (n = 5) received doses escalated to 15.3 Gy. All patients received high-dose etoposide (60 mg/kg) and allogeneic stem cell transplantation following the TBI. All patients had HLA-identical sibling donors. The median times for neutrophil and platelet engraftment were 13.5 and 12 days, respectively, and did not differ between the two cohorts. All but one patient developed treatment-related grade 3 or 4 mucositis. There were three cases of grade 4 pulmonary toxicity and three cases of grade 4 hepatic toxicity among the 14.4 Gy cohort, and one case each of grade 4 pulmonary and hepatic toxicities among the 15.3 Gy cohort. In most cases comorbid conditions contributed to these toxicities. Two patients had significant GVHD of the GI tract. Six relapses occurred, five (45%) in the 14.4 Gy cohort and one (20%) in the 15.3 Gy cohort. The 100-day treatment-related mortality rates were 9% and 20% for the 14.4 Gy and 15.3 Gy cohorts, respectively, and the median survivals were 226 and 201 days, respectively. We conclude that TBI dose escalation above the previously used 13.5 Gy dose is feasible using a high-energy source and high-dose etoposide. Acute and chronic toxicities were primarily related to GVHD, infection and relapse rather than to TBI. Since 1971, bone marrow transplantation (BMT) has been increasingly used in the treatment of patients with various malignant hematologic diseases including chronic myelogenous leukemia (CML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), multiple myeloma, chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD). 1-3 Marrow ablative chemoradiotherapy and allogeneic BMT offer potential cure for patients who are not curable with conventional therapy. For many patients transplanted over this time, total body irradiation (TBI) in standard doses of 12-13.5 Gy has been used together with cyclophosphamide or etoposide (VP-16) as the preparative regimen due to its substantial anti-tumor and immunosuppressive activities. [4][5][6][7][8][9][10][11][12] Since 20-30% of patients treated with TBI-based preparative regimens die from leukemia relapse, we postulated that treatment intensity is suboptimal. The killing of leukemia cells is proportional to the radiation absorbed dose. Few patients die from direct complications of TBI. Most often, the doses of concomitant chemotherapy have been escalated or a second or third...

“…10,11,13 Dopfer et al 12 showed in a retrospective analysis that the conditioning with TBI/VP16 is superior to other conditioning regimens. A similar long-term survival was achieved with a conditioning consisting of ARA-C, melphalan and TBI.…”

Section: Conditioning Regimenmentioning

confidence: 99%

Allogeneic haematopoietic stem cell transplantation in children with acute lymphoblastic leukaemia: the BFM/IBFM/EBMT concepts

Peters

Schrauder

Schrappe

et al. 2005

Summary:Children with high risk or relapsed acute lymphoblastic leukaemia (ALL) can benefit from allogeneic haematopoietic stem cell transplantation (SCT). To reduce transplantation-associated complications, the BFM study group, the IBFM study group and the PD-WP-EBMT initiated a prospective cooperative multicentre trail for paediatric ALL patients with an indication for allogeneic stem cell transplantation. Four-digit high-resolution HLA typing for all nonsibling donors, standardised GvHD prophylaxis and therapy, uniform conditioning regimen and minimum standards for supportive care should reduce not only treatment-related mortality but also ameliorate late effects for young patients. Furthermore, the prospective evaluation aims to assess the role of haematopoietic SCT in comparison to chemotherapy to enable valuable treatment recommendations for further decisions. Bone Marrow Transplantation (2005) 35, S9-S11. doi:10.1038/sj.bmt.1704835 Keywords: acute lymphoblastic leukaemia; children; stem cell transplantation; donor; conditioning Paediatric patients with the diagnosis of high-risk acute lymphoblastic leukaemia (HR-ALL) or relapse have a prognosis clearly worse compared to all other patients with ALL.1,2 These patients require additional therapy approaches after achieving remission with multimodal chemotherapy. Allogeneic haematopoietic stem cell transplantation (SCT) shows promising results mainly due to an immunological antileukaemic control by the graftversus-leukaemia effect (GVL), but treatment-related mortality (TRM) remains a serious problem of the method. [3][4][5][6] To investigate the value of SCT, the BFM Study Group initiated a multicentre, controlled, prospective study enrolling all paediatric patients with ALL in first, second or subsequent remission with a high risk for relapse defined by cytogenetic characteristics, the response to the induction chemotherapy and the time and site of relapse, respectively.The main objectives of the study are to investigate whether SCT from a closely HLA-matched related or unrelated donor ('matched donor' -MD) is equivalent to the SCT from HLA-identical matched sibling donors (MSD), to evaluate the efficacy of SCT from HLAmismatched donors (MMD) as compared to SCT from MSD/MD and to prospectively evaluate and compare the incidence of acute and chronic GvHD after SCT (see Table 3). Indication CR1Only a particular subgroup of patients with a very high risk for relapse (see Table 1) is eligible for transplantation. In most situations, only MSD and MD are accepted as possible donors; in some patients with extremely high risk for relapse also an MMD can be recruited. CR2In relapsed ALL, patients are subdivided into risk groups according to the parameters time to relapse, site of relapse and immunophenotype. High-risk patients (early isolated or very early isolated/combined bone marrow (BM) relapse of a B-cell precursor (BCP) ALL; any BM involving relapse of a T-lineage ALL) are eligible for any allogeneic SC donor. Intermediate-risk patients (early or late combined ...