Thiotepa, busulfan, cyclophosphamide (TBC) and autologous hematopoietic transplantation: an intensive regimen for the treatment of multiple myeloma

Shimoni, Avichai; Smith, Terry L.; Aleman, Ana; Weber, Donna M.; Dimopoulos, Meletios Α.; Anderlini, Paolo; Andersson, Börje S.; Claxton, David F.; Ueno, Naoto T.; Khouri, Issa F.; Donato, M.; Körbling, Martin; Alexanian, Raymond; Champlin, Richard E.; Giralt, Sergío

doi:10.1038/sj.bmt.1703007

Cited by 36 publications

(28 citation statements)

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“…38 In a recent clinical trial evaluating the efficacy and safety of a conditioning regimen containing thiotepa, busulfan, and cyclophosphamide, the median survival of 35 months among patients with primary refractory disease was comparable to the 48 months for those with chemosensitive disease (P ¼ NS). 39 In addition, when compared to those patients in resistant relapse, those with primary resistance achieve significantly higher response rates with HDT. In a study of tandem transplants, patients with primary refractory disease had improved event-free (23 vs 14 m) and overall survival (39 vs 25 m) compared to those in resistant relapse.…”

Section: Discussionmentioning

confidence: 99%

High-dose therapy and autologous stem cell transplantation for multiple myeloma poorly responsive to initial therapy

Kumar

Lacy

Dispenzieri

et al. 2004

Bone Marrow Transplant

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Summary:Autologous stem cell transplant (SCT) improves survival in multiple myeloma (MM) and remains the standard of care for eligible patients. Nearly a third of patients with newly diagnosed MM fail initial therapy aimed at reducing tumor burden preceding SCT (primary refractory). It is unclear if an initial response is important for successful SCT. We evaluated our experience with SCT in 50 patients with primary refractory MM and compared it to 101 patients with chemosensitive disease receiving SCT. The study cohort had a median age of 56 years (range 29-72) consisting of 87 males (58%). A total of 46 patients (92%) in the refractory group and 100 (99%) in the chemosensitive group had a response to transplant (50% or greater reduction in the M-protein). In all, 10 refractory patients (20%) and 35 (35%) in the chemosensitive group achieved a CR (P ¼ 0.06). The 1-year estimated progresion-free survival from the time of transplant for the refractory group was 70% compared to 83% for the chemosensitive group (P ¼ 0.65). The lack of response to initial induction therapy does not appear to preclude a good response to SCT. We recommend that patients with primary refractory MM be offered early SCT.

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Section: Discussionmentioning

confidence: 99%

High-dose therapy and autologous stem cell transplantation for multiple myeloma poorly responsive to initial therapy

Kumar

Lacy

Dispenzieri

et al. 2004

Bone Marrow Transplant

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“…17 High-dose thiotepa is used in combination protocols with other alkylating drugs like busulfan and cyclophosphamide for patients with lymphoma or multiple myeloma. 18,19 The only way to assess the contribution of a single drug is to compare different combination regimens for efficacy and toxicity. This is a general problem in treatment situations in which combination protocols are used.…”

Section: Discussionmentioning

confidence: 99%

High-dose treosulfan in patients with relapsed or refractory high-grade lymphoma receiving tandem autologous blood stem cell transplantation

Koenigsmann

Mohren

Jentsch-Ullrich

et al. 2004

Bone Marrow Transplant

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Summary:This phase I/II study evaluated high-dose treosulfan in patients with high-grade lymphoma. In all, 21 patients (median age 51, 25-60 years) with primary refractory disease (n ¼ 3) or early (n ¼ 11) or late (n ¼ 7) relapse received DexaBEAM and one course etoposide for cytoreduction and PBPC mobilization. Subsequently, 16 patients received 30 g/m 2 treosulfan and 140 mg/m 2 melphalan, followed by autologous transplantation. Nine patients received a 2nd high-dose treatment (HDT) with 30 g/m 2 treosulfan and 750 mg/m 2 thiotepa. Recovery time to 41/nl leukocytes and 425/nl thrombocytes was 8.9 (range 8-11) and 11.9 (8-16) days after 1st and 9.6 (7-13) and 13 (9-19) days after 2nd HDT. Reversible grade 3 or 4 nonhematologic toxicities included mucositis (n ¼ 7), infection (n ¼ 7) and one episode of re-entry tachycardia. Two treatment-related deaths occurred after 2nd HDT. Since three dose-limiting toxicities occurred among nine patients receiving tandem HDT, 30 g/m 2 of treosulfan was considered MTD in this setting. Patients with late compared to early relapse or refractory disease had a higher probability of CR (6/7 vs 3/14 patients, P ¼ 0.017) and overall survival (71 vs 21%, Po0.05, 24-49 months follow-up). In conclusion, high-dose treosulfan as major therapy component induces sustained complete remissions in relapsed high-grade lymphoma with acceptable toxicity.

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“…To improve the efficacy of the HDT maneuver itself, groups have explored the use of multiple cycles of HDT (tandem transplant; refs. [6][7][8], the use of combination chemotherapy conditioning regimens using agents in addition to or replacing melphalan in HDT conditioning (9)(10)(11)(12), and the addition of radiation therapy using targeted antibodies (13,14) or external beam radiation (15). Unfortunately, none of these approaches has been shown to be superior to the use of 200 mg/m 2 of melphalan.…”

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confidence: 99%

A Phase I/II Trial Combining High-Dose Melphalan and Autologous Transplant with Bortezomib for Multiple Myeloma: A Dose- and Schedule-Finding Study

Lonial

Kaufman

Tighiouart

et al. 2010

Clinical Cancer Research

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Purpose: We did a randomized phase I/II trial designed to evaluate the safety and efficacy of combining the proteasome inhibitor bortezomib with high-dose melphalan as the conditioning for high-dose therapy and autologous transplant for myeloma.Experimental Design: Enrolled patients were limited to those who did not achieve a very good partial remission (VGPR) following one or more induction regimens, and were randomized to receive a single escalating dose of bortezomib (1.0, 1.3, or 1.6 mg/m 2 ) either 24 hours before or 24 hours after high-dose melphalan. Dose escalation was based on the escalation with overdose control (EWOC), a Bayesian statistical model. Bone marrow aspirates were collected before initiation of therapy and at the time of transplant to evaluate which sequence resulted in maximal plasma cell apoptosis, and response to transplant was assessed by the International Myeloma Working Group criteria.Results: Among 39 randomized patients, 20 received bortezomib after melphalan and 19 received bortezomib before melphalan. Toxicities and posttransplant hematopoietic recovery rates were similar between arms. The overall response rate for all patients was 87%, with 51% achieving a VGPR or better. Pharmacodynamic studies showed greater plasma cell apoptosis among patients who received bortezomib following melphalan.Conclusions: The use of bortezomib in conjunction with high-dose melphalan is safe, with data suggesting improved efficacy. A single dose of bortezomib administered after high-dose melphalan is the recommended dose and schedule for future clinical investigation. Clin Cancer Res; 16(20); 5079-86. ©2010 AACR.Multiple myeloma (MM) is a clonal plasma cell disorder characterized by lytic bone disease, renal dysfunction, abnormal hematopoietic function, and the presence of a monoclonal paraprotein in the blood and/or urine. Historical induction regimens rarely achieved major responses [very good partial remission (VGPR) or complete remission (CR)], and before the use of high-dose therapy (HDT) and autologous transplant, few therapeutic options showed significant improvements in overall survival (OS) for newly diagnosed myeloma patients (1, 2). Led first by the Intergroupe Francophone du Myelome (IFM), several groups have now shown improvements in overall response rate, progression-free survival (PFS), and OS for patients randomized to receive HDT when compared with conventional dose chemotherapy (3), rendering HDT a standard treatment approach for younger patients with newly diagnosed MM. In addition, the IFM has shown that achievement of a VGPR is a surrogate for improvement in PFS and OS (4), adding it as a new category in the revised International Myeloma Working Group response criteria (5). Despite these improvements, patients are rarely, if ever, cured of MM through the use of HDT. To improve the efficacy of the HDT maneuver itself, groups have explored the use of multiple cycles of HDT (tandem transplant; refs. 6-8), the use of combination chemotherapy conditioning regimens using agents...

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Thiotepa, busulfan, cyclophosphamide (TBC) and autologous hematopoietic transplantation: an intensive regimen for the treatment of multiple myeloma

Cited by 36 publications

References 38 publications

High-dose therapy and autologous stem cell transplantation for multiple myeloma poorly responsive to initial therapy

High-dose therapy and autologous stem cell transplantation for multiple myeloma poorly responsive to initial therapy

High-dose treosulfan in patients with relapsed or refractory high-grade lymphoma receiving tandem autologous blood stem cell transplantation

A Phase I/II Trial Combining High-Dose Melphalan and Autologous Transplant with Bortezomib for Multiple Myeloma: A Dose- and Schedule-Finding Study

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