Reduced-toxicity conditioning with fludarabine and treosulfan prior to allogeneic stem cell transplantation in multiple myeloma

Schmidt‐Hieber, Martin; Blau, Igor Wolfgang; Trenschel, Rudolf; Andreesen, Reinhard; Stuhler, Gernot; Einsele, Herman; Kanz, Lothar; Keilholz, Ulrich; Marinets, Olga; Beelen, Dietrich W.; Fauser, AA; Volin, Liisa; Ruutu, Tapani; Uharek, Lutz; Fietz, Thomas; Knauf, Wolfgang; Hopfenmüller, Werner; Thiel, Eckhard; Freund, Mathias; Casper, Jochen

doi:10.1038/sj.bmt.1705605

Cited by 41 publications

(41 citation statements)

References 42 publications

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“…23,[40][41][42][43]46,47,54,60 This range is comparable with non-MAC. 61,62 The lowest NRM rate has been shown in the multicenter German study in patients with ALL.…”

Section: Engraftment and Chimerismsupporting

confidence: 52%

“…23,40,43,44,46 Several studies included more homogeneous diseases, but were still based on small number of patients. 41,42,45,47 The main findings of currently available studies are summarized in Table 2.…”

Section: Regimensmentioning

confidence: 99%

“…47 These patients are often susceptible to high rates of NRM. This rate is comparable to that observed using RIC protocols, 66,67 and was significantly lower than the NRM of up to 45% observed after conventional conditioning in MM patients.…”

Section: Engraftment and Chimerismmentioning

confidence: 99%

“…Schmidt-Hieber et al 47 investigated the conditioning regimen with treosulfan and fludarabine before allo-SCT in MM patients. These patients were heavily pretreated and a majority showed disease progression before allo-SCT.…”

Section: Engraftment and Chimerismmentioning

confidence: 99%

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Treosulfan-based conditioning before hematopoietic SCT: more than a BU look-alike

Danylesko

Shimoni

Nagler

2011

Bone Marrow Transplant

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Allogeneic hematopoietic SCT is a curative treatment for a variety of hematological malignancies and genetic diseases. There is a continuous search for novel conditioning regimens that will reduce SCT-related toxicity while retaining maximal antimalignancy effect. Treosulfan (L-threitol-1,4-bis-methanesulfonate; dihydroxybusulfan) was initially used in the treatment of certain solid tumors. Preclinical studies showed that it has a myeloablative effect on committed and non-committed stem cells. It has potent immunosuppressive characteristics, more prominent than its related chemotherapy agent BU, which makes it an attractive candidate for the use in conditioning regimens before allo-SCT. It is also associated with a favorable toxicity profile with little extramedullary toxicity. The combination of fludarabine and treosulfan was explored in several studies in patients not eligible for standard myeloablative conditioning, and data are rapidly emerging. This regimen is associated with consistent engraftment. A limited non-relapse mortality (NRM) rate in the range of 9-28% was observed. This rate is promising considering the patients selected and results from low rates of organ toxicity as well as acute and chronic GVHD. The regimen was also associated with low relapse rates of 5-30% depending on disease status at SCT. Together with low NRM rate, this resulted in favorable survival in the range of 40-80%. Promising results were seen in myelodysplastic syndrome (survival 36-70%) and leukemia in remission (60-70%). Randomized prospective studies will be needed to better define the role of treosulfan-based regimens in SCT.

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“…23,[40][41][42][43]46,47,54,60 This range is comparable with non-MAC. 61,62 The lowest NRM rate has been shown in the multicenter German study in patients with ALL.…”

Section: Engraftment and Chimerismsupporting

confidence: 52%

Section: Regimensmentioning

confidence: 99%

Section: Engraftment and Chimerismmentioning

confidence: 99%

Section: Engraftment and Chimerismmentioning

confidence: 99%

See 2 more Smart Citations

Treosulfan-based conditioning before hematopoietic SCT: more than a BU look-alike

Danylesko

Shimoni

Nagler

2011

Bone Marrow Transplant

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“…Because treosulfan, which is becoming increasingly in use in multiple myeloma therapy, has shown to be active in myeloma (35,36), we also tested this promising compound in combination. In our experiments, additive (melphalan and doxorubicin) and synergistic (bortezomib and treosulfan) effects were seen when A771726 was combined with established myeloma drugs.…”

Section: Discussionmentioning

confidence: 99%

Dihydroorotate dehydrogenase inhibitor A771726 (leflunomide) induces apoptosis and diminishes proliferation of multiple myeloma cells

Baumann

Mandl-Weber

Völkl

et al. 2009

Molecular Cancer Therapeutics

103

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Multiple myeloma is still an incurable disease; therefore, new therapeutics are urgently needed. A771726 is the active metabolite of the immunosuppressive drug leflunomide, which is currently applied in the treatment of rheumatoid arthritis, BK virus nephropathy, and cytomegaly viremia. Here, we show that dihydroorotate dehydrogenase (DHODH) is commonly expressed in multiple myeloma cell lines and primary multiple myeloma cells. The DHODH inhibitor A771726 inhibits cell growth in common myeloma cell lines at clinically achievable concentrations in a time-and dose-dependent manner. Annexin V-FITC/ propidium iodide staining revealed induction of apoptosis of multiple myeloma cell lines and primary multiple myeloma cells. The 5-bromo-2 ¶-deoxyuridine cell proliferation assay showed that inhibition of cell growth was partly due to inhibition of multiple myeloma cell proliferation. A771726 induced G 1 cell cycle arrest via modulation of cyclin D2 and pRb expression. A771726 decreased phosphorylation of protein kinase B (Akt), p70S6K, and eukaryotic translation initiation factor 4E-binding protein-1 as shown by Western blotting experiments. Furthermore, we show that the stimulatory effect of conditioned medium of HS-5 bone marrow stromal cells on multiple myeloma cell growth is completely abrogated by A771726. In addition, synergism studies revealed synergistic and additive activity of A771726 together with the genotoxic agents melphalan, treosulfan, and doxorubicin as well as with dexamethasone and bortezomib. Taken together, we show that inhibition of DHODH by A771726/leflunomide is effective in multiple myeloma. Considering the favorable toxicity profile and the great clinical experience with leflunomide in rheumatoid arthritis, this drug represents a potential new candidate for targeted therapy in multiple myeloma. [Mol Cancer Ther 2009;8(2):366 -75]

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Treosulfan/fludarabine as an allogeneic hematopoietic stem cell transplant conditioning regimen for high‐risk patients

Baronciani¹,

Iori

Bartolomeo

et al. 2008

American J Hematol

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In recent years, new conditioning regimens have been explored in patients not eligible for conventional transplant with the aim to reduce transplant-related mortality. In a phase II multicentric prospective trial, we investigated the safety and feasibility of the treosulfan-fludarabine combination prior to allogeneic hematopoietic stem cell transplant in patients with various hematological malignancies not eligible for conventional regimens because of previous intensive treatment, older age, and comorbidities. Forty-six consecutive patients, median age 48 years (range 17-69), were enrolled. Sixteen of them were in complete remission, and 20 had a HSCT comorbidity index 1. Forty-four patients had regular and sustained engraftment, and 39 out of 40 evaluable patients developed complete chimerism. Nonhematological toxicity was limited. Risk of transplant-related mortality was 9% (95% CI, 2-17%) at day 1100 and plotted at 15% (95% CI, 7-22%) after 7 months. The estimated overall survival and progression-free survival with a median follow-up of 20 months were 51% and 38%, respectively. The estimated 30 months progression-free survival for patients transplanted in remission was 56%. The treosulfan-fludarabine combination is a reduced-toxicity but myeloablative regimen that can be proposed to patients not fitting criteria for conventional transplant regimens. Longer follow-up and further prospective studies are necessary to evaluate this regimen. Am. J. Hematol. 83:717-720, 2008. V

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Reduced-toxicity conditioning with fludarabine and treosulfan prior to allogeneic stem cell transplantation in multiple myeloma

Cited by 41 publications

References 42 publications

Treosulfan-based conditioning before hematopoietic SCT: more than a BU look-alike

Treosulfan-based conditioning before hematopoietic SCT: more than a BU look-alike

Dihydroorotate dehydrogenase inhibitor A771726 (leflunomide) induces apoptosis and diminishes proliferation of multiple myeloma cells

Treosulfan/fludarabine as an allogeneic hematopoietic stem cell transplant conditioning regimen for high‐risk patients

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