Non-myeloablative stem cell transplantation (NST): chimerism testing as guidance for immune-therapeutic manipulations

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Allo-SCT with reduced-intensity conditioning (RIC) results in lower non-relapse mortality (NRM), but higher relapse rate than myeloablative conditioning (MAC) in AML/myelodysplastic syndromes (MDS). Novel regimens with intensive anti-leukemic activity, but with limited toxicity will be of benefit. In all, 85 patients with AML/MDS, not eligible for MAC, were given fludarabine-treosulfan conditioning (FT). Outcomes were compared with those in patients given fludarabine-BU RIC (FB2, n ¼ 106) or reduced-toxicity (RTC) conditioning (FB4, fludarabine and myeloablative BU dose, n ¼ 85). The 5-year NRM was 29%, 20% and 18% after FT, FB2 and FB4, respectively (P ¼ NS). Multivariate analysis (MVA) identified comorbidity score (HCT-CI) 42 and advanced disease as adverse factors with no independent impact of regimen. The 5-year relapse rate was 36%, 47% and 40%, respectively (P ¼ 0.17). MVA identified advanced disease as the major adverse factor, while FT had significantly lower relapse rate (hazard ratio 0.6, P ¼ 0.03). The 5-year survival (OS) was 37% with advanced disease. HCT-CI 42 and age X50 were found as adverse factors. The 5-year OS was 46%, 44% and 50% after FT, FB2 and FB4 in early-intermediate-stage disease (P ¼ NS) and 33%, 9% and 28% in advanced disease, respectively (P ¼ 0.02). FT is an RTC regimen with intensive anti-leukemia effect in MAC non-eligible patients.

Section: Evaluation Of Responsementioning

confidence: 99%

Allo-SCT for AML and MDS with treosulfan compared with BU-based regimens: reduced toxicity vs reduced intensity

Shimoni

Shem‐Tov

Volchek

et al. 2012

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“…49 Early achievement of complete chimerism may be important for rapid induction of graft-vs-malignancy effect and limiting of early relapse. 50 Toxicity and GVHD Table 1 outlines the major toxicities of treosulfan compared with BU. BU concentrates in the liver, lung, brain and kidneys 23 and complications include VOD, 23 interstitial pneumonia, hemorrhagic cystitis, permanent alopecia, convulsions and mucositis.…”

Section: Engraftment and Chimerismmentioning

confidence: 99%

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

Danylesko

Shimoni

Nagler

2011

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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.

“…[1][2][3] They are also applied preemptively for mixed hematopoietic chimerism after non-myeloablative or T-cell-depleted (TCD) conditioning. [4][5][6][7] However, the benefit from DLI is hampered by the risk of inducing GHVD in 40-60% of recipients. 2,8 Previous studies have shown that the removal of CD8-positive T cells from DLI might reduce the risk of GVHD, while preserving beneficial DLI effects.…”

Section: Introductionmentioning

confidence: 99%

Donor CD4 T cells convert mixed to full donor T-cell chimerism and replenish the CD52-positive T-cell pool after alemtuzumab-based T-cell-depleted allo-transplantation

Meyer

Wagner

Konur

et al. 2009

Donor lymphocyte infusions (DLI) are used to resolve mixed T-cell chimerism (TCC) after allo-SCT despite a substantial risk of GVHD. We analyzed the impact of prophylactic CD8-depleted (CD8 depl ) DLI in 20 recipients of anti-CD52 alemtuzumab in vivo T-cell-depleted allografts with declining donor TCC after day þ 60. A total of 13 patients received CD8 depl DLI and 7 patients did not. All but one of the DLI patients converted to complete donor T-cell chimeras, whereas only one non-DLI patient converted spontaneously. DLI induced transient acute GVHD in five and extensive chronic GVHD in two patients. These data suggest the use of CD8 depl DLI as an effective treatment for mixed TCC, particularly in patients at high risk for GVHD. We also observed that the majority of reconstituting donor-derived T cells after alemtuzumab conditioning were CD52-negative. CD8 depl DLI significantly increased the proportion of CD52-positive CD4 T cells, whereby their beneficial effect on reconstituting the post-transplant T-cell repertoire was shown.