Reducedintensityconditioning (RIC) regimens have allowed performing allogeneic haemato- poietic stem cell transplantation (HSCT) in patients for whom conventional myeloablative allogeneic HSCT is associated with unacceptable risks of non-relapse-mortality. This approach relies mainly on graft-versus-tumour effects for tumour eradication. Retrospective studies have suggested that, in patients aged 40 to 60 years, RIC-HSCT was associated with a higher risk of relapse but a lower incidence of transplant-related mortality than myeloablative allogeneic HSCT, leading to similar progression-free and overall survivals. After reviewing the rationale for RIC-HSCT, this article discusses the results of RIC-HSCT in specific diseases, and proposes what could be current indications for RIC-HSCT in 2011. Finally, the article briefly presents some possible strategies aimed at increasing the anti-tumoural activity of the procedure while reducing the incidence and severity of acute graft-versus-host disease.
allo-HSCT after one or two auto-HSCTs using reduced- intensityconditioning (RIC) and an alternative donor. Therefore, we contrasted the outcomes of patients receiving cord blood (CB) allo-HSCT with those of com- parable patients receiving peripheral blood stem cells (PBSCs) during the same period of time from either 10/10 human leukocyte antigen (HLA)-matched unrelated donors (MUD) or 9/10 HLA-mismatched unrelated donors (MMUD).
Reduced-intensityconditioning regimens (RIC) were successfully introduced twenty years ago to decrease the toxicity of myeloablative allogeneic stem cell transplantation (allo-SCT). This resulted in the doubling of the number of allo-SCT performed each year, because older patients and those with comorbidities could tolerate such a procedure [1–7]. The FB2A2 regimen (fludarabine 30 mg/kg/day for 5 days, busulfan 3.2 mg/kg/d iv for 2 days, and rabbit anti-thymocyte globulin (ATG) 2.5 mg/kg/d for 2 days) was rapidly established as one of the standards of care for RIC regimen in Europe, especially in France [4–9].
Effect of Postremission Therapy before Reduced-IntensityConditioning Allogeneic Transplantation for Acute Myeloid Leukemia in First Complete Remission
Q 5 Erica D. Warlick 1 , * , Kristjan Paulson 2 , Ruta Brazauskas 3 , Xiaobo Zhong 3 , Alan M. Miller 4 , Bruce M. Camitta 5 , Biju George 6 , Bipin N. Savani 7 , Celalettin Ustun 1 , David I. Marks 8 , Edmund K. Waller 9 , Frédéric Baron 10 , César O. Freytes 11 , Gérard Socie 12 , Gorgun Akpek 13 , Harry C. Schouten 14 , Hillard M. Lazarus 15 , Edwin M. Horwitz 16 , John Koreth 17 , Jean-Yves Cahn 18 , Martin Bornhauser 19 , Matthew Seftel 2 , Mitchell S. Cairo 20 ,
Keywords: Allogeneic stem cell transplantation, Unrelated donor, Older patients, HLA matching, Acute leukemia, Toxicity, Anti-leukemic effect
The development of reducedintensityconditioning (RIC) regimens has allowed to offer allogeneic hematopoietic stem cell transplantation (allo-SCT) to adults above the age of 50 years and patients with co- morbidities [1 –8]. In acute myeloid leukemia (AML), allo-SCT performed with RIC regimen improves the leukemia-free survival (LFS) of older adults in compari- son to standard chemotherapy [9 –11] and reduces non- relapse mortality (NRM) in comparison to myeloablative conditioning (MAC) [11, 12]. RIC allo-SCT is therefore the treatment of choice for intermediate- and high-risk AML patients above 50 years having an HLA compatible donor [9 –11, 13].
that was fludarabine based in 91% of cases.
Most patients received a conditioning regimen contain- ing intravenous busulfan at a total dose of 3.2 mg/kg (n=335, 65%) and fludarabine dosed at 120 mg/m² total (91% of patients). 2-4 Thirty-three (6%) patients received a combination of melphalan at 140 mg/m² and fludarabine. Three hundred and ninety-four patients (76%) received anti-thymocyte globulin (ATG), and 101 (20%) patients received 2Gy total body irradiation (TBI). 5,6 Use of the reducedintensityconditioning (RIC) regimen was based on institution norms, physician's choice, patient's age, comorbidities, prior HSCT, and enrollment in specific clinical trials. The median CD34 + cell dose was 5.0x10 6 cells/kg (range 2-22). Median donor age was 35 years; 71% males. Graft-versus-host disease (GvHD) prophylax- is consisted of cyclosporine A (CsA) plus mycophenolate mofetil (MMF) in 47% of cases and CsA plus methotrex- ate in 20% of cases.
Reducedintensityconditioning (RIC) regimens have al- lowed performing allogeneic hematopoietic stem cell transplantation (HSCT) in patients for whom conventional myeloablative allogeneic HSCT would have been associ- ated with unacceptable risks of non-relapse mortality. This approach relies mainly on graft-versus-tumor effects for tumor eradication. Results after RIC HSCT are generally encouraging in patient with acute myeloid leukemia in complete remission, with myelodysplastic syndromes not in transformation, with indolent and chemotherapy-sensi- tive aggressive lymphoma and with chronic lymphoid leu- kemia. At the opposite, advanced aggressive diseases such as acute leukemia not in complete remission, chemother- apy-refractory high-grade lymphoma or multiple myeloma are less responsive to this therapeutic approach alone. For such diseases, previous cytoreduction by chemotherapy or autologous HSCT is generally required. Occurrence of chronic GVHD seems to correlate with a lower risk of re- lapse and better progression-free survival. However, acute GVHD is not associated with GVT effects after non- myeloablative conditioning and remains a serious compli- cation of RIC HSCT. Current research attempts at developing new methods to control it.
We have reported encouraging results of unrelated cord blood transplantation for patients with lymphoid malignan- cies. Whether those outcomes are comparable to matched unrelated donor transplants remains to be defined. We studied 645 adult patients with mature lymphoid malignancies who received an allogeneic unrelated donor trans- plant using umbilical cord blood (n=104) or mobilized peripheral blood stem cells (n=541) after a reduced-intensityconditioning regimen. Unrelated cord blood recipients had more refractory disease. Median follow-up time was 30 months. Neutrophil engraftment (81% vs. 97%, respectively; P<0.0001) and chronic graft-versus-host disease (26%
This is notably true when evaluating non-myeloablative or reduced-intensityconditioning (RIC) regimens before
allogeneic stem cell transplantation (Allo-SCT). RIC Allo-SCT has emerged in the last decade as an at- tractive modality to decrease transplant-related tox- icity. The enthusiasm for this technique has been based on heterogeneous observational studies ranging from case reports to registry cohort studies [6-14]. These studies are very heterogeneous in terms of pa- tient selection criteria and outcomes, RIC regimens and timing. For this reason, conclusions regarding the the overall body of evidence in this area are very limited . Only a few prospective controlled clinical trials have been performed in studies of myeloma. This is mostly due to practical difficulties and selection restrictions for patients affected by advanced or refractory diseases, el- derly patients, or patients with comorbidities for whom * Correspondence: email@example.com
BACKGROUND: Fludarabine plus busulfan (FB) and fludarabine plus melphalan (FM) are 2 widely used reduced-intensityconditioning (RIC) regimens for allogeneic hematopoietic stem cell transplantation (allo-SCT). METHODS: The current survey compared transplan- tation outcomes for a cohort of 394 acute myeloid leukemia (AML) patients given bone marrow or peripheral blood stem cells from human leukocyte antigen–identical siblings after FB (n 5 218) or FM (n 5 176). Patients given manipulated grafts and those given T- cell–depleting agents (anti-thymocyte globulins or alemtuzumab) were not included. RESULTS: At the time of transplantation, 266 patients (68%) were experiencing their first complete remission (CR), 69 (18%) were experiencing a later CR, and 59 (15%) had advanced disease. The incidences of acute and chronic graft-versus-host disease were similar in the 2 groups of patients. The 2-year relapse incidence (RI), nonrelapse mortality (NRM) rate, leukemia-free survival (LFS) rate, and overall survival (OS) rate were 31% 6 3%, 18% 6 3%, 51% 6 4%, and 54% 6 4%, respectively, for FB patients and 20% 6 3% (P 5.007), 20% 6 3% (P 5.4), 60% 6 4% (P 5.08), and 62% 6 4% (P 5.2), respectively, for FM patients. Among FB patients given intravenous busulfan (n 5 81), the 2-year RI, NRM, LFS, and OS rates were 26% 6 5% (P 5.43 vs FM patients), 25% 6 6% (P 5.18), 49% 6 7% (P 5.07), and 54% 6 7% (P 5.13), respec- tively. In multivariate analyses, FM was associated with a lower RI (hazard ratio [HR], 0.5; P 5.01) and a trend toward higher NRM (HR, 1.6; P 5.1) with similar LFS (HR, 0.8; P 5.2) and OS (HR, 0.9; P 5.6). CONCLUSIONS: These results suggest that although FM pro- vides better AML control than FB as an RIC regimen for allo-SCT, the 2 regimens provide similar survival. Multicenter randomized studies are needed to confirm these findings. Cancer 2014;000:000-000. V C 2014 American Cancer Society.
Supporting this hypothesis, Bolan et al. 26 found that donor
RBC chimerism (defined as the initial detection of donor RBCs in
peripheral blood) was markedly delayed following nonmyelo- ablative (n ¼ 14) versus myeloablative (n ¼ 12) conditioning (median, 114 versus 40 days; Po0.0001) in patients with major ABO incompatibility with their donor. Further, four out of 14 nonmyeloablative versus zero out of 12 myeloablative reci- pients experienced pure red cell aplasia (P ¼ 0.10). Interestingly, donor RBC chimerism closely correlated with decreasing host anti-donor HA levels. The latter disappeared more slowly after nonmyeloablative than after myeloablative conditioning (median, 83 versus 44 days; P ¼ 0.03). In addition, CSP disconti- nuation induced potent graft-versus-plasma cell effects, and allowed resolution of pure red cell aplasia in all four patients. The existence of a graft-versus-plasma cell effect was further supported by the observation that severe acute GVHD was associated with a rapid decrease in anti-donor HA titers in two patients, in agreement with a previous study by Mielcarek et al. 27 showing faster decrease in anti-donor HA in patients developing acute GVHD than in those without acute GVHD, after myeloablative conditioning. However, a recent study described the persistence of significant percentages of recipient- derived plasma cells in patients with pure red cell aplasia after nonmyeloablative conditioning, despite full donor T-cell and granulocyte chimerisms. 28 This suggests that host-derived plasma cells might be less susceptible than host-derived T cells or myeloid cells to donor-derived alloreactive T cells. 29
Sloand and coworkers described results in 12 patients (median age 43 years) given G-PBMC from HLA-iden- tical siblings after conditioning with cyclophosphamide (120 mg/kg) and ﬂ udarabine (125 mg/m 2 ). 48 Postgrafting immunosuppression consisted of CSP with or without MMF. Seven patients were in ﬁ rst chronic phase and 5 in second chronic phase at HCT. No patient died of non- relapse causes. Six patients developed grade II–IV acute GVHD, and chronic GVHD was seen in 6 patients. All 7 patients transplanted in ﬁ rst chronic phase achieved stable molecular remissions: 2 with no posttransplant intervention; 3 after DLI, imatinib, and interferon; and 2 after subsequent myeloablative HCT. Four of 5 patients transplanted in second chronic phase died in blast cri- sis and 1 survived in molecular remission. Th e authors speculated that the poor disease control might have been due to the high leukemic burden in these patients.
NONMYELOABLATIVE OR REDUCED-INTENSITY REGIMENS
Many of the reduced-intensityconditioning regimens do not meet criteria of nonmyeloablative conditioning as first proposed by Champlin et al., which include (i) no eradication of host hematopoiesis, (ii) prompt hematologic revovery (<4 weeks) without transplant, and (iii) presence of mixed chimerism upon engraftment (18,19). Most reduced-intensityconditioning regimens com- bine modest dose of highly immunosuppressive purine analogs (fludarabine, cladribine, or pentostatin) given to overcome host-versus-graft reactions, with reasonably high-dose of alkylating agents, usually busulfan or melphalan, given to supplement the GVT effects in the task of tumor eradication. Conversely, nonmyeloablative conditioning regimens usually combine two highly immuno- suppressive agents together (low-dose TBI, fludarabine, or cyclophosphamide) to overcome host-versus-graft reactions to allow engraftment and tumor eradi- cation via GVT effects (16,20). Although the division of what constitutes a nonmyeloablative versus reduced-intensityconditioning regimen is somewhat arbitrary, the distinction might be important, given that nonmyeloablative con- ditioning has been associated with a lower degree of donor engraftment, decreased risk of nonrelapse mortality, and perhaps higher risk of relapse in comparison with reduced-intensity regimens (21).
“standard” myeloablative conditioning (MAC) and reduced-intensityconditioning (RIC) or nonmyeloablative (NMA) based on the expected duration of the pancyto- penia (irreversible, prolonged, minimal) and on the requirement for stem cell support (essential, required, optional) [ 2 – 4 ]. Since these criteria are rather vague, the European Society for Blood and Marrow Transplantation (EBMT) [ 5 ] and the Center for International Blood and Marrow Transplant Research (CIBMTR) [ 6 ] proposed in 2009 operational de ﬁnitions for stratiﬁcation of transplant conditioning as MAC or RIC based on the total dose of the alkylating agents and/or total body irradiation (TBI) used. Brie ﬂy, RIC usually includes a purine analog and an alkylating agent or TBI at a dose which is generally reduced by at least ≥30% of the classical MAC regimens [ 7 , 8 ]. The RIC/MAC classi ﬁcation model has served as a reliable clinical tool offering safer transplantation in older and un ﬁt patients and is widely referenced in the scientiﬁc literature, but has never been updated or more precisely * Alexandros Spyridonidis
Haplo-identical hematopoietic stem cell transplantation (haplo-SCT) is an attractive transplant procedure since it provides a possibility of transplantation to almost all patients needing an allogeneic SCT. Historical approaches of haplo-SCT performed with unmanipulated bone marrow stem cell grafts, standard myeloablative conditioning, and graft-versus-host disease (GVHD) prophylaxis were associ- ated with high risks of graft rejection and severe GVHD due to uncontrolled bi-directional recipient and donor allo- reactivity [1–4]. Although the development of T cell de- pleted haplo-SCT has allowed to control the risk of severe GVHD, the poor T cell immune reconstitution observed in these patients is associated with a high incidence of life- threatening infections [5–10]. In the last decade, several strategies of T cell replete bone marrow (BM) or peripheral blood (PB) haplo-SCT have been developed with both reducedintensity (RIC) and fully intensive myeloablative conditioning (MAC) regimens and variable GVHD prophy- laxis strategies [11–26]. While some groups have used a combination of anti-thymocyte globulin (ATG) with im- munosuppressive agents with or without monoclonal anti- bodies such as rituximab and basiluximab [11–16], others have adopted the Baltimore’s strategy [17–26] of in vivo T cell depletion by the administration of high doses of cyclo- phosphamide (Cy) on days 3 and 4 post-SCT (PT-Cy). These approaches have improved immune reconstitu- tion and reduced non-relapse mortality (NRM) of haplo-SCT [20, 27–29]. In single center experiences, these new haplo-SCT platforms allow similar transplant outcomes than allo-SCT performed with HLA-matched donors [30–37]. However, the optimal conditioning regimen for haplo-SCT in acute leukemia remains a question of debate.
questionnaire-based research. The present study of borrowing is based on the analysis of free- speech corpora from four Slavic minority languages spoken in Austria, Germany, Greece, and Italy. The analysis of the data, totalling 34,000 word tokens, shows that speakers from Italy produced significantly more borrowings and noun borrowings than speakers from the other three countries. A Random Forests analysis identifies ‘language’ as the main predictor for the ratio of both borrowings and noun borrowings, indicating the existence of borrowing patterns that individual speakers conform to. Finally, we suggest that the patterns of borrowing that prevail in the communities under study relate to the intensity of contact in the past, and to the presence or absence of literary traditions for the minority languages.
This paper examines the operational and regulation aspects of Reduced Crew Operations. An im- pact analysis of the applicable US Federal Aviation Regulations, particularly Part 117 Flight and Duty Limitations and Rest Requirements: Flight Crew Members, and Part 121 Operating Require- ments: Domestic, Flag, and Supplemental Operations is presented. This paper provides a summary of the research into RCO concept of operations, including research jointly conducted by NASA and Rockwell Collins. Based on the regulation impacts and the studies, this paper identifies the present operational, procedural, and technical challenges that must be addressed to safely implement Re- duced Crew Operations.
As an illustration, we make here a digression towards automata. Let A be the minimal (deterministic) automaton which recognizes L ∗ , we note L ∗ = L(A). Let B be the same automaton in its B¨ uchi version, L ω is recognized by B and we note L ω = Lω(B). So, we intend to apply the reduction to L which is already minimal whenever it is not reduced. How does a reduction step operate on a deterministic B¨ uchi automaton ? It suppresses a recognition state from one cycle. To do this, it induces a dilation of others as shown in Figure 1.
From these data, we find that there is no difference between the discounted
games and high-intensity intermittent exercise in the performance test. 6. Discussion
From the results of the tests performed, we realize that there is no significant difference between the reduced games and high-intensity intermittent exercise in the development of aerobic capacity (VO2max and VMA) in football. These results confirm the results achieved in the same field. Indeed, some authors Dellal (2008); Mallo and Navarro (2008), Rampinini (2006), Robineau and Lacroix (2009) had noted that the reduced games allowed many developing aerobic capacity of soccer players, as many studies such as those Balsom (1999); Hill-Haas (2007) or Impellizzerri (2006) confirmed our results.