Low-dose total body irradiation (TBI) and fludarabine followed by hematopoietic cell transplantation (HCT) from HLA-matched or mismatched unrelated donors and postgrafting immunosuppression with cyclosporine and mycophenolate mofetil (MMF) can induce durable complete chimerism and sustained remissions in patients with hematological diseases

Niederwieser, Dietger; Maris, Michael B.; Shizuru, Judith A.; Petersdorf, Effie W.; Hegenbart, Ute; Sandmaier, Brenda M.; Maloney, David G.; Storer, Barry E.; Lange, Thoralf; Chauncey, Thomas R.; Deininger, Michael W.; Pönisch, Wolfram; Anasetti, Claudio; Woolfrey, Ann E.; Little, Marie Térèse; Blume, Karl G.; McSweeney, Peter A.; Storb, Rainer

doi:10.1182/blood-2002-05-1340

Cited by 422 publications

(353 citation statements)

References 33 publications

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“…In our study, 54% of the patients developed aGvHD grade II-IV after a median time of 66 days following transplantation. With regard to cGvHD, results from our trial (cGvHD 56%; extensive 21% and limited 34%) and published data using CsA and MMF for NMmatched unrelated donor HSCT are also similar, 15,17,27,28 indicating the efficacy of tacrolimus and MMF in the prevention of GvHD. Despite the similar incidences of acute and cGvHD, we found that the onset of aGvHD in our patients, receiving tacrolimus and MMF, was markedly later (day þ 66), when compared with the above-mentioned trials (day þ 30) using CsA and MMF in NM-unrelated donor HSCT.…”

Section: Discussionsupporting

confidence: 57%

“…As a translation of canine preclinical studies, a combination of CsA and MMF is widely used for the prophylaxis of GvHD and graft rejection in NM allo-HSCT. 15,16 A different approach uses the combination of tacrolimus and MMF, which showed excellent early post transplant survival, while facilitating effective control of acute and cGvHD in NM-matched sibling HSCT. 18 Moreover, a combination of tacrolimus and MTX was tested in three randomized clinical trials, showing a significantly lower incidence of aGvHD as compared with the combination of CsA and MTX in both matched related and unrelated transplantations.…”

Section: Discussionmentioning

confidence: 99%

“…[9][10][11][12][13][14] Traditionally, a combination of CsA and mycophenolate mofetil (MMF) has been used as GvHD prophylaxis in the context of fludarabine/2 Gy TBI allografting, a NM regimen developed by Storb and colleagues in Seattle. 15,16,17 In 2005, Nieto et al 18 observed low rates of early-onset aGvHD in 32 patients receiving matched-sibling transplants, after conditioning with fludarabine/TBI using a combination of tacrolimus and MMF as GvHD prophylaxis. Tacrolimus was introduced in the late 1980s as an alternative to CsA for the prevention of graft rejection following solid organ transplantation.…”

Section: Introductionmentioning

confidence: 99%

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Tacrolimus and mycofenolate mofetil as GvHD prophylaxis following nonmyeloablative conditioning and unrelated hematopoietic SCT for adult patients with advanced hematologic diseases

Zohren

Schroeder

Czibere

et al. 2010

Bone Marrow Transplant

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In the current study, we evaluated a combination of tacrolimus and mycophenolate mofetil (MMF) as GvHD prophylaxis in 50 patients undergoing truly nonmyeloablative (NM; 90 mg/m 2 fludarabine, 2 Gy TBI) hematopoietic SCT (HSCT) from unrelated donors. Median patient age was 51 years (range, 25-67 years). After a median follow-up of 1123 days (range, 47-2729 days), 20 patients (40%) are alive and free from disease. The probabilities of 1-, 2-and 3-year survival were 57, 47 and 39%, respectively. Patients who achieved a remission before HSCT had a significantly better OS compared with those who had active disease (P ¼ 0.01). The incidences of grade II-IV and III-IV acute GvHD (aGvHD) were 54% (n ¼ 27) and 16% (n ¼ 8). Remarkably, using tacrolimus and MMF, the median onset of aGvHD occurred distinctly late on day þ 66 (range, 12-119 days). A total of 46 patients were evaluable for chronic GvHD (cGvHD). Out of these, 26 (56%) patients developed cGvHD, with 16 (34%) of them showing limited and 10 (21%) showing extensive disease. We conclude that the combination of tacrolimus and MMF as post transplant immunosuppression for patients receiving NM unrelated donor HSCT permits stable engraftment and effective prophylaxis for acute and cGvHD. In particular, the occurrence of severe early-onset aGvHD was attenuated.

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Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tacrolimus and mycofenolate mofetil as GvHD prophylaxis following nonmyeloablative conditioning and unrelated hematopoietic SCT for adult patients with advanced hematologic diseases

Zohren

Schroeder

Czibere

et al. 2010

Bone Marrow Transplant

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“…Additionally, there has been no study to prospectively assess whether RIST consisting of 180 mg fludarabine plus 8 mg/kg busulfan without antithymocyte globulin actually produces less significant organ toxicities and treatment-related toxicities in an older patient population. Information regarding the impact of the speed and degree of lineage-specific donor chimerism on clinical outcomes after RIST in older patients has been limited [3,8,[13][14][15][16][17]. Moreover, even studies evaluated with more homogeneous patient population, type of GvHD prophylaxis and/or tempo of withdrawal of immunosuppressive agents varied depending on transplant centers and a feasible prophylaxis regimen for acute GvHD has not been well evaluated in RIST, which is considered to require a sophisticated balance between GvHD and a graft-versus-leukemia (GvL) effect.…”

Section: Introductionmentioning

confidence: 99%

Prospective phase II trial to evaluate the complications and kinetics of chimerism induction following allogeneic hematopoietic stem cell transplantation with fludarabine and busulfan

Saito

Kami

Mori³

et al. 2007

American J Hematol

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This prospective trial assessed the safety and efficacy of allogeneic hematopoietic stem cell transplantation from a HLA-matched donor with a reduced-intensity regimen (RIST) consisting of iv fludarabine 30 mg/m 2 for 6 days and oral busulfan 4 mg/kg/day for 2 days in patients older than 50 years with hematological malignancies. Cyclosporine alone or cyclosporine with short-term methotrexate was randomized for graftversus-host disease prophylaxis. After 30 patients had been enrolled, an interim analysis was performed, and this report focuses on a precise evaluation of the toxicity profile and chimerism kinetics. Sustained engraftment in all patients, no severe regimen-related toxicity (RRT) within 20 days, and no transplantrelated mortality through Day 100 were observed. T-cell (CD3+) full-donor (over 90%) chimerism was observed in 22 of the 30 patients, while the remaining eight had mixed-donor chimerism over 77% on Day 90. Thereafter, five subsequently converted to full-donor chimerism without donor lymphocyte infusion by day 120 (n = 4) or Day 180 (n = 1). Two showed persistent mixed chimerism without relapse through Day 180. Grade III-IV acute graft-versus-host disease and extensive chronic graft-versus-host disease occurred in 10% and 73%, respectively. With a median follow-up of 1.5 years, overall survival and disease-free survival at 1 year was 83% and 62%, respectively. Seven patients hematologically relapsed overall, and five of them had myelodysplastic syndrome with poor prognostic factors. In older patients, RIST with fludarabine and busulfan was associated with acceptable toxicities and a satisfactory antileukemia effect, regardless of the early chimerism status. Am. J. Hematol. 82:873-880, 2007. V

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“…In general, patients tolerated both regimens well and survival data for this study are acceptable and well within the range of earlier reports. 3,5,[9][10][11][12][13] The regimen-related mortality at day 100 (6%) is lower than for myeloablative transplantation for similar high-risk malignancy patients, considering the older population of patients (median age 55) and the number of unrelated donor transplants (n ¼ 35) in this series. Both of these factors traditionally carry a higher mortality rate.…”

Section: Discussionmentioning

confidence: 99%

Reduced-intensity conditioning using fludarabine with either antithymocyte globulin and BU, or low-dose TBI allowing allogeneic hematopoietic SCT

Cable

Buzzeo

Schold

et al. 2009

Bone Marrow Transplant

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In a single-center study, we analyzed the outcomes of 66 patients with advanced hematological malignancies receiving two reduced-intensity conditioning regimens for allogeneic transplantation: fludarabine and low-dose TBI (flu/TBI, n ¼ 25), or fludarabine, antithymocyte globulin and BU (flu/ATG/BU, n ¼ 41). The selection criteria were based on the hypothesis that flu/TBI patients were expected to achieve autologous recovery in the event of non-engraftment. Sixty-three patients (95%) engrafted. Regimen-related mortality at day 100 and 1 year was 6 and 15%, respectively. With median follow-up of 50.4 months, survival did not differ by regimen. Multivariate analysis confirmed that the type of regimen did not affect relapse. In patients achieving full donor chimerism by day 30, those conditioned with flu/TBI showed greater overall survival (P ¼ 0.02). Engraftment failure occurred in two patients (3%), both of whom received flu/TBI. We conclude that conditioning with flu/TBI or flu/ATG/BU yields comparable survival and remission outcomes. By contrast to our hypothesis, patients receiving flu/TBI who subsequently failed engraftment did not achieve autologous recovery. Yet, rapid attainment of full donor chimerism after flu/TBI is associated with greater survival than after flu/ATG/BU. Further, larger prospective randomized studies are required to define the advantage of one regimen over the other.

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Cited by 422 publications

References 33 publications

Tacrolimus and mycofenolate mofetil as GvHD prophylaxis following nonmyeloablative conditioning and unrelated hematopoietic SCT for adult patients with advanced hematologic diseases

Tacrolimus and mycofenolate mofetil as GvHD prophylaxis following nonmyeloablative conditioning and unrelated hematopoietic SCT for adult patients with advanced hematologic diseases

Prospective phase II trial to evaluate the complications and kinetics of chimerism induction following allogeneic hematopoietic stem cell transplantation with fludarabine and busulfan

Reduced-intensity conditioning using fludarabine with either antithymocyte globulin and BU, or low-dose TBI allowing allogeneic hematopoietic SCT

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