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白血病分子分型骨髓移植(英文版)(可編輯)

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1、白血病--分子分型骨髓移植(英文版) AML acute myeloid leukemia ATG antithymocyte globulin BMT CTN Blood and Marrow Transplant Clinical Trials Network CR complete remission MDACC University of Texas M D Anderson Cancer Center This is an incomplete list of the ongoing cooperative group or

2、 consortia efforts to evaluate new methods to prevent GVHD The Blood and Marrow Transplant Clinical Trials Network BMT CTN is currently performing a trial in recipients of matched sibling donor transplantations comparing tacrolimus with either methotrexate or sirolimus for GVHD prophylaxis In addi

3、tion we have just completed BMT CTN 0303 which is a T-cell depletion trial In addition a consortium from JohnsHopkins University the University of Texas M D Anderson Cancer Center and the Fred Hutchinson Cancer Research Center is conducting prospective trials of the use of posttransplantation cyclop

4、hosphamide to deplete alloreactive Tcells in patients undergoing bone marrow transplantations from matched sibling and matched unrelated donors I think this is a very interesting approach in these patients many of whom do not develop acute or chronic GVHD and do not require long-term immunosuppressi

5、on Finally approaches including use of polyclonal and monoclonal antibodies are in early-stage investigation ALL acute lymphoblastic leukemia AML acute myeloid leukemia CR1 first complete remission T-cell depletion is an old concept that is considered to be associated with a lot of problems Howe

6、ver it is interesting that centers that have focused on T-cell depletion have had very good outcomes in patients with AML who underwent transplantation in first or second remission Data from the University of Perugia Memorial Sloan-Kettering Cancer Center the Dana-Farber Cancer Institute and other g

7、roups have demonstrated very favorable outcomes for patients transplanted earlier in the course of disease AML acute myeloid leukemia ATG antithymocyte globulin BMT CTN Blood and Marrow Transplant Clinical Trials Network CR complete remission G-CSF granulocyte colony stimulating factor GVHD graf

8、t vs host disease PB peripheral blood TBI total body irradiation In 2003 the multicenter BMT CTN0303 trial for patients with AML in first or second remission with matched sibling donors was developed The protocol originally allowed patients as old as 60years of age but was subsequently amended to

9、allow patients as old as 65years of age These patients received a conditioning regimen of hyperfractionated total body radiation chemotherapy and ATG underwent T-cell depletion using CD34 selection and were not given any pharmacologic GVHD prophylaxis following transplantation BMT CTN Blood and Ma

10、rrow Transplant Clinical Trials Network CR1 first complete remission CR2 second complete remission KPS Karnofsky performance score This trial was completed in late December 2008 and 44 patients underwent transplantation Of note more than one third of the patients on this trial were at very high ris

11、k for relapse based on their karyotype or molecular profile The data are very encouraging showing very good disease-free survival with low risk of both acute and chronic GVHD and low risk of relapse I think this is an approach that merits further consideration in a prospective trial using not only m

12、atched sibling donors but also matched unrelated donors AML acute myeloid leukemia CALGB Cancer and Leukemia Group B CBF core-binding factor In the last couple of slides I would like to consider the other major area for risk stratification age Traditionally allogeneic transplantation for patients

13、 60years of age or older has not been considered a good treatment option A CALGB study of more than 600patients who were risk stratified based on cytogenetics demonstrated the dismal outcome for patients with AML who were 60years of age or older Very little progress has been made in improving surviv

14、al in this group of patients during the last 30years and we had to start afresh to think of anything that might lead to improvements in survival in these patients AML acute myeloid leukemia CALGB Cancer and Leukemia Group B CR1 first complete remission DFS disease-free survival RIC reduced-inten

15、sity conditioning The advent of reduced-intensity conditioning regimens for older patients and those with significant comorbidities allowed us to design a prospective trial in 2003 that investigated reduced-intensity conditioning in patients older than 60 years of age who are able to achieve a remi

16、ssion To develop the statistical basis for the trial the best risk group of patients in the CALGB trials was first considered Of the more than 600patients who were 75years of age or younger and had received at least 1 course of consolidation treatment per protocol approximately 276were able to achi

17、eve first remission Even in this group of best or selected patients the 3-year disease-free survival was only 17 At the same time studies were published suggesting that reduced-intensity conditioning for allogeneic transplantation was feasible in older patients However virtually all the published s

18、tudies were retrospective highly heterogeneous and lacked a standardized approach It was therefore reasonable to conduct a prospective trial in this specific patient population AML acute myeloid leukemia ANC absolute neutrophil count CALGB Cancer and Leukemia Group B CR1 first complete remission

19、G-CSF granulocyte colony stimulating factor PBSC peripheral blood stem cell SQ subcutaneously This shows the initial trial design of CALGB 100103 Fludarabinebusulfan as the conditioning regimen was chosen on the scant amount of data available in 2003 The data suggested that it was relatively well t

20、olerated without a lot of extramedullary toxicity The patients received fludarabinebusulfan conditioning matched sibling donors only were allowed when the trial was opened and all patients received tacrolimus and minimethotrexate GVHD prophylaxis CALGB Cancer and Leukemia Group B DFS disease-free

21、 survival The primary endpoint of CALGB 100103 was 2-year disease-free survival Our aim was to double the survival from 20 to 40 It was initially calculated that this would require 36patients and enrollment would be completed in 3 years CALGB Cancer and Leukemia Group B The trial was activated i

22、n January 2004 and even though there is always a ramp up period for trials to get activated by the end of 2005 only 6 patients had been enrollednot the estimated 18 patients At this point we had to decide whether we wanted to move forward or not with the trial ATG antithymocyte globulin BMT CTN Bl

23、ood and Marrow Transplant Clinical Trials Network CALGB Cancer and Leukemia Group B DFS disease-free survival DLI donor lymphocyte infusion SWOG Southwest Oncology Group It was discouraging that the SWOG trial in this patient population looking at transplantation had just been closed due to poor ac

24、crual However a protocol team was formed with the BMT CTN to determine how to improve accrual Given the data that suggested that patients could do as well and potentially even better with matched unrelated donors as with matched sibling donors it was considered reasonable to amend the protocol to in

25、clude matched unrelated donors At the time ATG was included because of the concern of increased incidence of GVHD At the same time the 2-year disease-free survival goal was revised to 35 from 40 which increased the target accrual to 61 BMT CTN Blood and Marrow Transplant Clinical Trials Network C

26、ALGB Cancer and Leukemia Group B This trial reopened in June 2006 55of the 68patients were enrolled in 2007 and 2008 and accrual was completed in late December 2008 The trial has just been reactivated to increase the number of unrelated donors The CALGB 100103 trial experience serves as an example

27、of what can be done when people work together to try to address an important question where patient numbers may otherwise be limiting ATG antithymocyte globulin AZA azacytidine CALGB Cancer and Leukemia Group B COH City of Hope EBMT European Blood and Marrow Transplantation Group ECOG Eastern Coop

28、erative Oncology Group FluTBI fludarabinetotal body irradiation Std standard TLI total lymphoid irradiation Many other groups are interested in this question of allogeneic transplantation to improve outcomes in older patients The EBMT is about to open a randomized trial Stanford the University of T

29、exas M DAnderson Cancer Center and the Swedish Cancer Foundation are also performing trials and the Cancer and Leukemia Group B and Eastern Cooperative Oncology Group also are about to open prospective trials to try to improve outcomes for patients in this very high–risk group older than 60 years o

30、f age with AML in first remission AML acute myeloid leukemia CR1 first complete remission In conclusion allogeneic transplantation remains a vital therapy for younger patients with AML in first remission at high risk for relapse Who exactly should be recommended for transplantation in first remis

31、sion and what allografts are suitable in this setting remain in flux and are questions to be answered by prospective trials Patients in first remission and 60years of age or older in my opinion should only undergo transplantation on clinical trials Because single centers cannot address this question

32、 adequately cooperative groups and consortia must work together to get prospective AML-focused trials completed Lastly there is no standard allogeneic transplantation approach because everything we do can and should be improved Thank you very much for your time and listening That concludes our pres

33、entation If you wish to earn CME credit for this activity please close the window and click the Test tab in the CME module underneath and go ahead and take the test AML acute myeloid leukemia This presentation focuses on the use of new and forthcoming data for risk stratification of patients with

34、 acute myeloid leukemia AML and how these are applied in making treatment decisions for these patients AML acute myeloid leukemia Currently excluding the approximately 20 to 30 of good-risk patients 40 to 90 of younger patients with AML achieving remission are ultimately destined to relapse All

35、but a select subset of older AML patients will die due to relapsed or refractory disease Clearly there is a lot of room for improvement of outcomes AML acute myeloid leukemia CR complete remission MDS myelodysplastic syndromes MRD minimal residual disease WBC white blood cell count Several patient

36、- and disease-related variables have recently been identified which impact significantly on the patients likelihood of achieving or sustaining a remission These variables can be useful for assigning prognosis AML acute myeloid leukemia CR complete remission FISH fluorescence in situ hybridization

37、MRD minimal residual disease WBC white blood cell count However despite the fact that we have much more information about the molecular heterogeneity of AML at the present time age and cytogenetic or molecular risk profile remain the most important and most useful tools we have for risk-stratifying

38、 patients with AML and for determining the appropriate treatments Currently gene expression profiles micro-RNA expression and even gene sequencing are more useful for understanding the molecular pathogenesis of AML rather than for making treatment decisions AML acute myeloid leukemia That AML is

39、 a heterogeneous disease or group of diseases is not a new concept as illustrated in this slide However greater understanding of the cytogenetic and molecular risk groups in AML have allowed us to unveil novel targets for inhibiting leukemogenesis and also for assigning the most appropriate therapie

40、s in these patients AML acute myeloid leukemia In a landmark study the CancerandLeukemiaGroupB was able to assign younger patients with AML to 3 general cytogenetic categories The largest proportion of patients fall into the intermediate-risk group but there are also patients with favorable-risk

41、 cytogenetics who have a low risk of relapse as well as a group of patients with very adverse–risk cytogenetics who have a very high risk for treatment-related mortality and relapse Traditionally these cytogenetic categories have been used to assign a treatment strategy in patients with AML younger

42、than 60years of age AML acute myeloid leukemia BMT bone marrow transplantation CI confidence interval ECOG Eastern Cooperative Oncology Group SWOG Southwestern Oncology Group Intergroup studies in the UnitedStates and in Europe designed more than 15years ago typically would assign patients with A

43、ML who were younger than 45or 55 years of age and who had matched sibling donors to allogeneic transplantation following myeloablative conditioning Data from the SWOGECOG trial published nearly a decade ago demonstrated the significant benefit in patients with adverse-risk cytogenetics of allogeneic

44、 transplantation compared with autologous transplantation or conventional chemotherapy AML acute myeloid leukemia BMT bone marrow transplantation CR complete remission EORTC European Organization for Research and Treatment of Cancer GIMEMA Gruppo Italiano Malattie Ematologiche dellAdulto These da

45、ta were also confirmed in the EORTC GIMEMA study of patients 45years of age and younger Those patients who had a matched sibling donor underwent myeloablative bone marrow transplantation and had a significantly better overall survival compared with patients with adverse cytogenetics treated with con

46、ventional chemotherapy AML acute myeloid leukemia CR1 first complete remission I think most people would agree that an allogeneic transplantation is an appropriate consolidation for a patient in first remission at least up to the age of 55 or 60years There are some questions about the use of unre

47、lated donors in this setting and whether a myeloablative or a less intensive conditioning regimen is appropriate especially for older patients AML acute myeloid leukemia CR1 first complete remission By contrast I think that in general there is no role for allogeneic transplantation in patients w

48、ith favorable-risk cytogenetics in first remission AML acute myeloid leukemia CR1 first complete remission In patients with intermediate-risk cytogenetics there is no such general agreement Recent large meta-analyses have suggested either a progression-free survival or an overall survival advanta

49、ge with allogeneic transplantation in patients with intermediate-risk cytogenetics However we have yet to adequately understand which of these patients benefit and which patients may do better with more conventional approaches AML acute myeloid leukemia Approximately 45 of patients with AML are c

50、ytogenetically normal and are included in the intermediate-risk cytogenetics category However more than 80 of these patients harbor either genetic mutations or changes in the expression level of hematopoietic genes that influence leukemogenesis as well as response to treatment AML acute myeloid l

51、eukemia ITD internal tandem duplication PTD partial tandem duplications TKD tyrosine kinase domain There is a great deal of heterogeneity and this is an incomplete list of the genetic mutations that have been shown to affect either the likelihood of achieving remission or of sustaining remission Th

52、e class I mutations such as the FLT3-ITD or TKD mutation affect cellular proliferation However class II mutations that affect cellular differentiation like CEBP alpha may impart a favorable prognosis in these otherwise cytogenetically normal patients Approximately 60 of patients also have a mutation

53、 in the NPM1 gene and those patients in which this occurs in the absence of a FLT3-ITD mutation have a favorable prognosis and may not benefit from allogeneic transplantation in first remission AML acute myeloid leukemia In addition recent studies have suggested that the expression levels of var

54、ious hematopoietic genes including BAALC ERG and MN1 and levels of the micro-RNA miR-181 affect prognosis The German AML Study Group demonstrated that high expression levels of BAALC ERG and MN1 in patients with otherwise cytogenetically normal AML have an unfavorable impact on overall survival

55、There are some data to suggest that patients with high BAALC expression levels benefit from allogeneic transplantation at remission although this finding needs to be confirmed with more data However the influence of the expression level of these genes on overall survival has also been confirmed by t

56、he CancerandLeukemiaGroupB as well as other AML study groups abnl abnormal AML acute myeloid leukemia del deletion inv inversion ITD internal tandem repeat t translocation These data were used recently by an international group of leukemia experts to compile a schema for risk-stratifying AML based

57、 on a cytogenetic or molecular risk profile This table presents the newer risk stratification of patients which may also be useful for treatment assignment Patients with the intermediate-I intermediate-II and adverse risk are reasonable candidates to consider for allogeneic transplantation in first

58、remission whereas those in the favorable group may not necessarily benefit from an allogeneic transplantation unless they relapse or are refractory to primary therapy AML acute myeloid leukemia BMT bone marrow transplantation ITD internal tandem duplication A retrospective analysis from the Germa

59、n-Austrian AML Study Group investigated the influence of genetic aberrations on overall survival following myeloablative allogeneic transplantation using a matched sibling donor Allogeneic transplantation is not associated with an improvement in survival in patients who have the NPM1 mutation withou

60、t a concomitant FLT3-ITD top graph However patients with other mutations including the FLT3-ITD or with the triple wild-type genotype may benefit from allogeneic transplantation with a matched related donor in first remission bottom graph These are retrospective data that suggest that there are

61、patients who we can consider for allogeneic transplantation in first remission In this study approximately 45 of the patients with cytogenetically normal AML had a favorable mutation and would not necessarily benefit from allogeneic transplantation whereas approximately 55 of these patients had a l

62、ess favorable mutation conferring potential advantage with allogeneic transplantation In other words approximately one half of the cytogenetically normal patients would be considered candidates for allogeneic transplantation When combined with the 12 to 14 of patients with de novo AML who have an ad

63、verse-risk cytogenetics approximately one third to 40 of all patients with AML in first remission would be good candidates in my opinion for prospective trials evaluating allogeneic transplantation in first remission AML acute myeloid leukemia CI confidence interval SCT stem cell transplantation

64、 A recent large meta-analysis has suggested an overall survival advantage for allogeneic transplantation in patients with intermediate- and poor-risk cytogenetics red arrows Therefore I think it is reasonable to consider particularly on prospective trials transplantation in the intermediate-risk g

65、roup of patients with AML who have cytogenetic abnormalities AML acute myeloid leukemia CR1 first complete remission HCT hematopoietic cell transplantation Allogeneic hematopoietic cell therapy is the single most effective therapy currently available for the prevention of relapse which is the goa

66、l in AML therapy However there are risks associated with allogeneic transplantation such that many treating physicians remain reluctant to recommend it in first remission unless mortality could be substantially lowered AML acute myeloid leukemia ITD internal tandem duplication Currently cytogenetic or molecular risk profile of patients younger than 60 years of age forms the basis of treatment decisions There is little disagreement in how to treat patients with the adverse-risk karyotype Treatm

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