The Role of High-Dose Chemotherapy and Stem-Cell Transplantation in Patients with Multiple Myeloma: A Practice Guideline of the Cancer Care Ontario Practice Guidelines Initiative High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. Treatment of poor-risk neuroblastoma patients with high-dose chemotherapy and autologous peripheral stem cell rescue Total lymphoid irradiation-antithymocyte globulin conditioning and allogeneic transplantation for patients with myelodysplastic syndromes and myeloproliferative neoplasms. Reduced-intensity stem cell transplantation from an HLA-identical sibling donor in patients with myeloid malignancies Superiority of tandem autologous transplantation over standard therapy for previously untreated multiple myeloma. Consolidation therapy for adult acute myeloid leukemia: A systematic analysis according to evidence based medicine Comparison of autologous bone marrow transplantation and intensive chemotherapy as postremission therapy in adult acute myeloid leukemia. The Groupe Ouest Est Leucémies Aiguës Myéloblastiques (GOELAM). Autologous bone marrow transplantation as consolidation therapy in the treatment of adult patients under 60 years with acute myeloid leukaemia in first complete remission: a prospective randomized Dutch–Belgian Haemato‐Oncology Co‐operative Group (HOVON) and Swiss Group for Clinical Cancer Research  Reduced-toxicity conditioning with treosulfan, fludarabine and ATG as preparative regimen for allogeneic stem cell transplantation (alloSCT) in elderly patients with secondary acute myeloid leukemia (sAML) or myelodysplastic syndrome (MDS) Autologous stem cell transplantation after complete remission and first consolidation in acute myeloid leukemia patients aged 61-70 years: results of the prospective EORTC-GIMEMA AML-13 study. The value of augmented preparative regimens combined with an autologous bone marrow transplant for the management of relapsed or refractory Hodgkin disease: a Southwest Oncology Group phase II trial. Acute Myeloid Leukemia (AML): different treatment strategies versus a common standard arm--combined prospective analysis by the German AML Intergroup. Whole-brain radiotherapy or autologous stem-cell transplantation as consolidation strategies after high-dose methotrexate-based chemoimmunotherapy in patients with primary CNS lymphoma: results of the second randomisation of the International Extranodal Lymphoma Study Group-32 phase 2 trial. Prospective comparative study of bone marrow transplantation and postremission chemotherapy for childhood acute myelogenous leukemia. The Associazione Italiana Ematologia ed Oncologia Pediatrica Cooperative Group. An overview of the VISTA trial: newly diagnosed, untreated patients with multiple myeloma ineligible for stem cell transplantation. Granulocyte colony-stimulating factor after allogeneic bone marrow transplantation.
After more than three decades of clinical trials testing various st and ard-dose chemotherapy regimens , the disease course of patients with multiple myeloma has not changed appreciably . Conventional chemotherapy can provide effective palliation but is not curative ( 1 ) . Case series have described encouraging results in patients with myeloma undergoing allogeneic or autologous bone marrow or peripheral blood stem-cell transplantation ( 2 ) . Other studies of transplantation , including r and omized trials , have been reported in the past 6 years ( 3 , 4 ) . To facilitate decisions about treatment options , practice guidelines have been developed for use by health care providers and consumers . In Ontario , Canada , cancer treatments and policies are led by a state-funded organization , Cancer Care Ontario . To help derive treatment options , Cancer Care Ontario has developed the Program in Evidence -Based Care , which includes the Practice Guidelines Initiative . Disease Site Groups ( DSGs ) , which comprise physicians , epidemiologists , and consumers , develop guidelines through a systematic process that involves assessment of evidence , consensus , and a validation process involving practitioners from across the province . Guideline topics are chosen through a prioritization process that includes the burden of illness , availability of evidence , perceived variation in practice , the potential to affect treatment decisions , and re source utilization . The Hematology DSG noted that the use of transplantation for patients with myeloma varied among practice s across the province . Variability in practice and emerging evidence of higher quality made this a priority topic for guideline development . To approach this topic , the DSG addressed the following questions : What is optimal st and ard-dose chemotherapy for patients with myeloma ? In terms of survival , is  peripheral blood stem-cell  or  marrow transplantation better than conventional chemotherapy ? What is the relative efficacy of autologous versus allogeneic transplantation ? What specifics of the transplantation process can be recommended ? When should transplantation be performed ? Who should ( or should not ) receive a transplant ? Methods Overview of Guideline Development This guideline was developed by the Cancer Care Ontario Practice Guidelines Initiative ( CCOPGI ) using the methods of the Practice Guidelines Development Cycle ( 5 ) . Members of the CCOPGI 's Hematology DSG selected , review ed , and interpreted the evidence . This DSG comprises 25 members , including hematologists , medical and radiation oncologists , an epidemiologist , and 2 lay representatives . Several of the physician members have background training in epidemiology ; 8 hematologists regularly perform stem-cell transplantation in clinical practice . The DSG 's draft recommendations were circulated through a mailed survey to hematologists and medical or radiation oncologists in Ontario for feedback and involvement in a consensus process . Responses were used to guide the reformatting of the draft into the final guideline recommendations . The Practice Guidelines Co-ordinating Committee ( PGCC ) , which ensures consistency of guideline development across the DSGs of various tumor sites , approved the guideline . The CCOPGI has a st and ardized process to up date each guideline report ; the current guideline was up date d and review ed by the PGCC in October 2000 . Literature Search Strategy We search ed the MEDLINE , CANCERLIT , and Cochrane Library data bases for literature published from 1992 to December 1997 and subsequently up date d the search in October 1998 , June 1999 , and April 2000 . For the search es , we combined multiple myeloma ( as a Medical Subject Heading [ MeSH ] and text word ) with bone marrow transplantation ( MeSH and text word ) and drug therapy ( MeSH ) . Then , we combined these terms with the search terms for the following study design s : practice guidelines ; systematic review s or meta-analyses ; review s ; r and omized , controlled trials ; controlled clinical trials ; and comparative studies . In addition , we search ed the PubMed and Physician Data Query ( PDQ ) ( www.cancer.gov/ search / clinical _ trials/ ) data bases and review ed relevant conference proceedings ( American Society of Hematology , 1997 to 1999 , and American Society of Clinical Oncology , 1999 to 2000 ) , article bibliographies , and personal files . To address the issue of optimal chemotherapy , we performed an additional search of the same data bases using the term multiple myeloma ( MeSH ) combined with r and omized , controlled trials ( MeSH ) and the text word r and om in the title . Inclusion Criteria We selected study reports meeting one of the three following criteria : r and omized trial or meta- analysis of therapy for patients with myeloma that reported survival or quality -of-life outcomes ; nonr and omized comparative trial that addressed transplantation strategy , including a contemporaneous control group , and that reported survival or quality -of-life outcomes ; or economic evaluation that addressed transplantation strategy . Because of insufficient data on the specifics of the transplantation process and the patients who would be most likely to benefit from transplantation , we performed a second search , which identified data from noncomparative case-series studies . Data Extraction and Interpretative Summary Three members of the DSG , including an epidemiologist , determined eligibility of the articles and abstract s obtained from the literature search . The lead DSG member for this guideline extracted and summarized relevant data according to the guideline question addressed . The DSG members then review ed the summarized data and key articles . The DSG met formally three to four times annually ; at these meetings , the members method ologically assessed the articles , interpreted the data , and debated specific points in an attempt to reach a consensus . Synthesizing the Evidence Because all of the nine r and omized trials on transplantation addressed different questions , we did not statistically pool the data . DSG Consensus Process Through an iterative process that included debate at formal meetings and circulation of draft recommendations , we considered the implication s of the appraised data for each guideline question . With this process , attempts were made to reach consensus ; when this was impossible , minority opinions were recorded . Approval by each member of the DSG was required before circulation of the draft version for practitioner feedback and su bmi ssion of the final guideline to the PGCC . Practitioner Feedback To obtain practitioner feedback , we mailed a survey to 211 practitioners in Ontario ( 94 hematologists , 93 medical oncologists , and 24 radiation oncologists ) . The survey consisted of st and ardized items asking the practitioner to rate the quality of each draft guideline and to judge whether the draft recommendations should serve as a practice guideline . Written comments were invited . Follow-up reminders were sent at 2 weeks ( by postcard ) and 4 weeks ( entire package ) . After exclusion of 18 retired practitioners , 137 of 193 practitioners ( 71 % ) responded ; 90 of 137 respondents ( 66 % ) indicated that the guideline was relevant to their practice . Approval of the draft guideline was strong among these 90 practitioners : 91 % agreed or strongly agreed that the summary of the evidence was acceptable , 87 % agreed with the draft recommendations , and 81 % approved of the recommendations as a practice guideline . Thirty-nine respondents provided written comments ; these comments were , like the other responses , incorporated in the final guideline . Results Sixty-six reports met the criteria for inclusion and are categorized in Table 1 . In each section below , we describe the studies , summarize results , and describe the guideline development . Table 1 . Evidence Included in This Practice Guideline Report What Is Optimal St and ard-Dose Chemotherapy  for Patients with Multiple Myeloma ? To properly compare transplantation with conventional chemotherapy , we must define optimal conventional chemotherapy . We identified 30 r and omized trials comparing therapies in previously untreated patients . Four meta-analyses ( 6 - 9 ) evaluated these data . The Myeloma Trialists ' Collaborative Group ( 7 ) compared combination chemotherapy with melphalan plus prednisone in a meta- analysis of 27 trials . Twenty of these trials supplied individual-patient data . No difference in survival was detected . The proportional reduction in the annual odds of death was 1.5 % in favor of combination chemotherapy ( 95 % CI , 8 % to 5 % ; P > 0.2 ) , with an odds ratio ( OR ) of 0.99 ( CI , 0.93 to 1.05 ) . An earlier literature -based meta- analysis ( 6 ) of 18 trials also failed to detect a survival difference between groups ( OR , 1.04 [ CI , 0.90 to 1.19 ] ; P > 0.2 ) . Two meta-analyses evaluated interferon for multiple myeloma . An overview of 24 r and omized trials published in abstract form ( 8) demonstrated that interferon improved recurrence-free survival by 6 months and improved 3-year overall survival by 4 % . Another meta- analysis ( 9 ) measured survival by a unique measure called the mean lifetime survival . This meta- analysis found no difference in survival rate between the group receiving interferon and the group not receiving interferon ( 3.9 vs. 3.4 years , respectively ; P = 0.095 ) . Guideline Recommendation Multiagent chemotherapy or melphalan plus prednisone is appropriate therapy for a control group in a comparison of transplantation versus st and ard-dose therapy . The addition of interferon is unlikely to influence outcomes in the control group . In Terms of Survival , Is Autologous Peripheral Blood Stem-Cell or Bone Marrow Transplantation Better than Conventional Chemotherapy ? We review ed two r and omized and three nonr and omized comparisons ( Table 2 ) . Attal and colleagues ( 3 ) r and omly assigned 200 previously untreated patients younger than 65 years of age with stage II or III ( 40 ) myeloma to conventional chemotherapy or to a strategy that included autologous bone marrow transplantation . Patients were r and omly BACKGROUND High-dose therapy with supporting autologous stem-cell transplantation remains a controversial treatment for cancer . In multiple myeloma , first-line regimens incorporating high-dose therapy yield higher remission rates than do conventional-dose treatments , but evidence that this translates into improved survival is limited . METHODS In this multicenter study , the Medical Research Council Myeloma VII Trial , we r and omly assigned 407 patients with previously untreated multiple myeloma who were younger than 65 years of age to receive either st and ard conventional-dose combination chemotherapy or high-dose therapy and an autologous stem-cell transplant . RESULTS Among the 401 patients who could be evaluated , the rates of complete response were higher in the intensive-therapy group than in the st and ard-therapy group ( 44 percent vs. 8 percent , P<0.001 ) . The rates of partial response were similar ( 42 percent and 40 percent , respectively ; P=0.72 ) , and the rates of minimal response were lower in the intensive-therapy group than in the st and ard-therapy group ( 3 percent vs. 18 percent , P<0.001 ) . Intention-to-treat analysis showed a higher rate of overall survival ( P=0.04 by the log-rank test ) and progression-free survival ( P<0.001 ) in the intensive-therapy group than in the st and ard-therapy group . As compared with st and ard therapy , intensive treatment increased median survival by almost 1 year ( 54.1 months [ 95 percent confidence interval , 44.9 to 65.2 ] vs. 42.3 months [ 95 percent confidence interval , 33.1 to 51.6 ] ) . There was a trend toward a greater survival benefit in the group of patients with a poor prognosis , as defined by a high beta2-microglobulin level ( more than 8 mg per liter ) . CONCLUSIONS High-dose therapy with autologous stem-cell rescue is an effective first-line treatment for patients with multiple myeloma who are younger than 65 years of age A single institutional pilot study was conducted in which 12 poor-risk neuroblastoma ( NB ) patients were uniformly treated with multi-agent induction chemotherapy followed by myeloablative consolidation chemotherapy and unpurged peripheral blood stem cell ( PBSC ) rescue . In addition to using st and ard criteria for evaluating response to induction chemotherapy , tumor cell contamination of the peripheral blood and /or bone marrow was analyzed in seven patients by immunocytology using a panel of five anti-NB monoclonal antibodies . Seven patients had morphologic evidence of bone marrow disease at the time of diagnosis , and two additional patients had tumor cells detected in bone marrow sample s by immunocytology prior to the second cycle of chemotherapy . After three cycles of chemotherapy , two of the 12 patients continued to have evidence of bone marrow disease . Sample s from 29 PBSC harvests collected from nine patients were also analyzed for the presence of contaminating tumor cells by immunocytology . In each case , the stem cells were found to be free of tumor . Eleven of the 12 patients underwent myeloablative therapy and PBSC rescue ;  five patients remain alive without disease progression , 28 + to 53 + months from diagnosis , and six patients have developed recurrent disease . We conclude that PBSCs can be successfully harvested from children with NB , and used for hematopoietic reconstitution following myeloablative chemotherapy . However , more effective therapy for poor-risk NB patients is still urgently needed Allogeneic hematopoietic cell transplantation ( allo HCT ) is the only curative therapy for the myelodysplastic syndromes ( MDS ) and myeloproliferative neoplasms ( MPN ) , but treatment toxicity has been a barrier to its more widespread use . The nonmyeloablative regimen of total lymphoid irradiation ( TLI ) and antithymocyte globulin ( ATG ) permits the establishment of donor hematopoiesis necessary for the graft-versus-malignancy effect and is protective against acute graft-versus-host disease ( aGVHD ) , but it has minimal direct cytotoxicity against myeloid diseases . We explored the use of TLI-ATG conditioning to treat 61 patients with allo HCT for MDS ( n = 32 ) , therapy-related myeloid neoplasms ( n = 15 ) , MPN ( n = 9 ) , and chronic myelomonocytic leukemia ( n = 5 ) . The median age of all patients was 63 years ( range , 50 to 73 ) . The cumulative incidence of aGVHD grade s II to IV was 14 % ( 95 % confidence interval [ CI ] , 4 % to 23 % ) and for grade s III to IV , 4 % ( 95 % CI , 0 to 9 % ) , and it did not differ between patients who received allografts from related or unrelated donors . The cumulative incidence of nonrelapse mortality ( NRM ) at 100 days , 12 months , and 36 months was 0 % , 7 % , and 11 % . Overall survival and progression-free survival were 41 % ( 95 % CI , 29 % to 53 % ) and 35 % ( 95 % CI , 23 % to 48 % ) , respectively . The safety and tolerability of TLI-ATG , as exemplified by its low NRM , provides a foundation for further risk-adapted or prophylactic interventions to prevent disease progression Summary : The purpose of this study was to evaluate the feasibility and efficacy of allogeneic hematopoietic stem cell transplantation with a reduced-intensity regimen ( RIST ) in patients with acute myeloid leukemia ( AML ) or myelodysplastic syndrome ( MDS ) . In all , 36 patients ( median age 55 years ) underwent RIST from an HLA-matched related donor between September 1999 and December 2002 . The diagnoses included AML ( n=14 ) , leukemia evolving from MDS ( n=10 ) , and MDS ( refractory anemia with excess blasts n=6 , refractory anemia n=6 ) . The RIST regimen consisted of purine analog ( cladribine or fludarabine)/busulfan , with or without antithymocyte globulin . The regimen was well tolerated , and 34 patients achieved durable engraftment and most achieved remission after RIST . A total of 17 patients developed grade II – IV acute GVHD , and 27 developed chronic GVHD . Eight patients relapsed , and five of them received  antithymocyte globulin  ( ATG ) as part of the preparative regimen . A total of 12 patients died ( four disease progression , six transplantation-related complications , and two others ) . Estimated 1-year disease-free survival ( DFS ) in low- and high-risk groups was 85 and 64 % , respectively . We conclude that RIST can be performed safely in elderly patients with myeloid malignancies , and has therapeutic potential for those who fail conventional chemotherapy . In view of the significant association between GVHD or ATG and DFS , defined management of GVHD following RIST should become a major target of clinical research Virtually no progress has been made during more than 2 decades of clinical trials for multiple myeloma ( MM ) involving st and ard therapy ( ST ) . Recent studies suggest that dose intensification requiring hematopoietic stem cell support results in higher complete response ( CR ) rates and extended disease control .  " Total Therapy " ( TT ) consisting of noncross-resistant induction regimens , followed by a double autotransplant ( AT ) procedure , was administered to 123 untreated patients with symptomatic MM . Upon hematologic recovery , interferon ( IFN ) maintenance ( 3 million units [MU]/m2 subcutaneously thrice weekly ) was given until disease recurrence/progression . Results were compared with the outcome of untreated patients receiving ST according to Southwest Oncology Group ( SWOG ) trials . One hundred sixteen pair mates were selected from both TT and among 1,123 patients to match for the major prognostic features . TT induced CR in 40 % of all 123 patients ( intent-to-treat ) . By 12 months , 7 % had died , including 4 % from treatment-related complications . With a median follow-up of 31 months , median duration s of event-free survival ( EFS ) and overall survival ( OS ) are 49 and 62 + months , respectively . Abnormalities of chromosomes 11q and 13 were associated with inferior outcome , whereas CR within 6 months after induction was a favorable prognostic feature for both EFS and OS . In comparison to ST , TT induced higher PR rates ( 85 % v 52 % , P < .0001 ) ( CR rates not available on SWOG trials ) and extended EFS ( 49 v 22 months , P = .0001 ) and OS ( 62 + v 48 months , P = .01 ) . Compared to ST , dose intensification with double AT markedly augments tumor cytoreduction , effecting not only higher CR rates but also significantly extending EFS and OS in previously untreated patients with MM Post-remission therapy in acute myeloid leukemia ( AML ) remains problematic . It has been demonstrated that younger patients can maintain longer complete remissions ( CR ) with aggressive post-remission therapies after induction treatment : allogeneic ( allo ) , autologous ( auto ) stem cell transplantation ( SCT ) , or intensive chemotherapy ( ICC ) . The purpose of our study was to identify the most important r and omized and controlled studies comparing these three therapeutic options , in order to draw conclusions and possible suggestions for post-remission therapy of AML , according to the evidence based medicine ( EBM ) rules . We performed an exhaustive analysis of the literature , search ing either in electronic data bases or among the references of the identified articles ( h and search ing ) . We search ed the MEDLINE computer data base for reports from 1985 through January 2005 and selected for analysis the clinical trials conducted over adults affected by newly diagnosed AML aged less than 65 years . The study design had to satisfy strict method ological criteria and must consider global mortality and /or disease free survival as primary outcomes . Overall we found 7750 papers ; by using the limits “ clinical trial ” as publication type , “ all adults 19 + years ” , we were able to select 344 papers . Among these , a further selection was made , based on two main clinical queries : 1 ) is auto-SCT superior to ICC/no other therapy in improving DFS and /or OS in adult AML patients in first CR ? 2 ) is allo-SCT superior to auto-SCT/other therapeutic options in improving DFS and /or OS in adult AML patients in first CR ? Concerning the first query , a possible advantage of auto-SCT over ICC was not clearly supported by data from clinical trials ; there is no evidence that auto-SCT is superior in terms of OS to chemotherapy . Nevertheless , the reported TRM has been significantly reduced within the past years . Thus , the percentage of patients suitable for auto-SCT in CR has increased . Moreover , the scarce data concerning the comparison between auto-SCT and chemotherapy in different subsets of patients are unable to suggest a differentiated approach in patients with high-risk , st and ard-risk or low-risk AML . Data from the literature show that patients with unfavorable risk disease are more often addressed to allo-SCT and patients with low-risk disease receive more often intensive consolidation chemotherapy . Concerning the second query , interpretation of data from the main prospect i ve studies about the role of allo-SCT in previously untreated AML is not easy . The first problem is the lack of real r and omized clinical trials ; in fact , according to the reported studies , AML patients generally receive allo-SCT on the basis of donor availability ( the so called “ genetic r and omization ” ) . The second problem is the frequent absence of intention to treat analysis . Despite method ological limitations , it was possible to compare allo-SCT with auto-SCT on a donor versus no-donor analysis and within risk groups . No overall benefit of allo-grafting on survival was demonstrated by any trial . In conclusion , the EBM approach highlighted the limitations observed in the published studies concerning consolidation therapy in AML ; some suggestions , emerging from non-r and omized , as well as r and omized studies , are adequate , but not conclusive . This point , coupled with the intrinsic complexity to study AML biological heterogeneity , is probably a major obstacle to draw conclusive evidence s for consolidation therapy in AML . These observations should plan to address new r and omized studies on AML therapy ; however , due to the emergence of genetic subgroups and new drugs targeting specific abnormalities , these trials should probably be design ed directly focusing on the single entities . In this way , the cure of AML could eventually become the cure of each specific AML subset with its peculiar biological , molecular and prognostic features Three intensive consolidation strategies are currently proposed to younger adults with acute myeloid leukemia ( AML ) in first complete remission ( CR ) : allogeneic or autologous bone marrow transplantation ( BMT ) and intensive consolidation chemotherapy ( ICC ) .  Patients aged 15 to 50 years with de novo AML received an induction treatment with 7 days of cytarabine and either idarubicin or rubidazone . After achievement of a CR , patients up to the age of 40 and having an HLA-identical sibling were assigned to undergo an allogeneic BMT . All the other patients received a first course of ICC with high-dose cytarabine and the same anthracycline as for induction . They were then r and omly assigned to either receive a second course of ICC with amsacrine and etoposide or a combination of busulfan and cyclosphosphamide followed by an unpurged autologous BMT .  Of 517 eligible patients , 367 had a CR , but only 219 ( 59.5 % ) actually received the planned intensive postremission treatment ( 73 allogeneic BMT , 75 autologous BMT , and 71 ICC ) . With a median follow-up of 62 months , the 4-year disease-free survival ( DFS ) of the 367 patients in CR was 39.5 % . The 4-year overall survival ( OS ) of the 517 eligible patients was 40.5 % . In multivariate analysis , DFS and OS were influenced only by the initial white blood cell count and by the French-American-British classification . The type of postremission therapy had no significant impact on the outcome . There was no difference in the 4-year DFS and OS between 88 patients for whom an allogeneic BMT was scheduled ( respectively , 44 % and 53 % ) and 134 patients of the same age category and without an HLA-identical sibling ( respectively , 38 % and 53 % ) . Similarly , there was no difference in the outcome between autologous BMT and ICC .  The 4-year DFS was 44 % for the 86 patients r and omly assigned to autologous BMT and 40 % for the 78 patients assigned to ICC ( P = .41 ) . The 4-year OS was similar in the two groups ( 50 % v 54.5 % , P = .72 ) . The median duration of hospitalization and thrombocytopenia were longer after autologous BMT ( 39 v 32 days , P = .006 , and 109.5 v 18.5 days , P = .0001 , respectively ) . After a first course of ICC , a second course of chemotherapy is less myelotoxic than an unpurged autologous BMT but yields comparable DFS and OS rates The question as to whether autologous stem cell transplantation ( SCT ) after consolidation chemotherapy improves the probability of survival of patients with acute myeloid leukaemia ( AML ) in first remission has not been settled . Here , we present the results of a phase III study conducted in newly diagnosed adult AML patients aged < 60 years . Patients who had reached a complete remission ( CR ) after two courses of induction chemotherapy and who were not eligible for a human leucocyte antigen‐matched sibling SCT ( n = 130 ) , were r and omized after a third consolidation cycle of chemotherapy between high‐dose cytotoxic treatment and autologous bone marrow transplantation or no further treatment . No significant differences in disease‐free survival and overall survival were observed between the two treatment arms . A slightly better overall survival in the no further treatment arm was because of fewer deaths in the first CR and a significantly better overall survival after the first relapse . The results are discussed in relation to the generic problems of applying autologous transplantation and in the perspective of the limited statistical power of this and other previously published studies We investigated a dose-reduced conditioning regimen consisting of treosulfan and fludarabine followed by allogeneic stem cell transplantation ( SCT ) in 26 patients with secondary AML or MDS . Twenty patients were transplanted from matched or mismatched unrelated donors and six from HLA-identical sibling donors . The median age of the patients was 60 years ( range , 44–70 ) . None of the patients was eligible for a st and ard myeloablative preparative regimen .  No graft-failure was observed , and leukocyte and platelet engraftment were observed after a median of 16 and 17 days , respectively . Acute graft-versus-host disease ( GvHD ) grade II – IV was seen in 23 % and severe grade III GvHD in 12 % of the patients . No patients experienced grade IV acute GvHD . Chronic GvHD was noted in 36 % of the patients , which was extensive disease in 18 % . The 2-year cumulative incidence of relapse was 21 % . The relapse rate was higher in patients beyond CR1 or with intermediate two or high risk MDS ( P=0.02 ) . The treatment-related mortality at day 100 was 28 % . The 2-year estimated overall and disease-free survival was 36–34 % , respectively . No difference in survival was seen between unrelated and related SCT BACKGROUND AND OBJECTIVES The optimal post-remission treatment for elderly patients with acute myeloid leukemia ( AML ) is presently unknown . Recent studies have reported the feasibility of autologous peripheral blood stem cell transplantation ( PBSCT ) in this population . We evaluate the outcome of this post-remission approach after complete remission ( CR ) and consolidation in elderly patients included in the EORTC-GIMEMA AML-13 trial . DESIGN AND METHODS PBSCT after induction and consolidation chemotherapy was evaluated in patients aged 61 to 70 years with a WHO performance status 0 - 1 . The induction therapy was mitoxantrone , etoposide and cytarabine ( MICE ) with or without granulocyte colony-stimulating factor ( G-CSF ) during and /or after chemotherapy . The consolidation therapy consisted of non-infusion or infusional idarubicin , etposide and cytarabine ( mini-ICE ) . RESULTS Sixty-one patients were scheduled for stem cell harvest by leukapheresis after s.c . recombinant human G-CSF administration initiated after hematopoietic recovery from consolidation . Stem cells were effectively harvested from 54 patients . A median of two aphereses ( range , 1 - 5 ) were performed , result ing in a median collection of 11.7 x 10(8 ) nucleated cells/kg ( range , 2.4 - 99.8 ) containing 40.2 x 10(4 ) CFU-GM/kg ( range , 0 - 786.8 ) , and 5 x 10(6 ) CD34 + cells/kg ( range , 0.1 - 99.8 ) . For the whole group of 61 patients , the median disease-free survival ( DFS ) was 1.0 years and the 3-year DFS rate was 21 % , while the median overall survival ( OS ) was 1.4 years and the 3-year OS rate was 32 % . A total of 26 patients could not be autografed due to inadequate/no harvest ( 21 patients ) , early relapse ( 3 patients ) , or treatment refusal ( 2 patients ) . Autologous transplantation was performed in 35 patients following conditioning with the BAVC regimen . The median time for granulocyte recovery > 0.5 109 yen/L was 24 days and for platelets > 20 x10(9)/L was 23 days following transplantation . After a median follow-up of 5.0 years from transplantation , the median DFS and OS were 1.1 and 1.6 years respectively , and the 3-year rates were 28 % and 39 % respectively . Eight autografted patients were still in continuous complete remission , 22 patients had relapsed and five had died in CR . INTERPRETATION AND CONCLUSIONS Intensification of remission including autologous PBSCT is feasible in about half of harvested patients aged 61 to 70 years old , and did not improve the general outcome . This shows the limitations of autologous PBSCT and other intensive treatment modalities in elderly AML patients . Key words : acute myeloid leukemia , elderly , autologous stem cell transplantation Several single-institution pilot studies have suggested that augmented preparative regimens , including those containing total body irradiation combined with an autologous bone marrow transplantation , are superior to st and ard regimens for the treatment of relapsed or refractory Hodgkin disease . On the basis of these data , we undertook , in the cooperative group setting , a phase II trial of augmented preparative regimens for patients experiencing treatment failure with conventional chemotherapy . Eighty-one patients with either sensitive or refractory ( induction failures or chemoresistant ) relapse received etoposide ( 60 mg/kg ) , cyclophosphamide ( 100 mg/kg ) , and either total body irradiation ( 12 Gy ) or , if previously irradiated , carmustine ( 15 mg/kg ) , followed by an autologous bone marrow transplantation .  Progression-free ( PFS ) and overall ( OS ) survival were estimated , and a Cox regression model was used to assess potential prognostic variables . The 5-year PFS and OS for the 74 eligible patients treated at 20 Southwest Oncology Group centers were 41 % ( 95 % confidence interval [ CI ] , 29%-53 % ) and 54 % ( 95 % CI , 43%-65 % ) , respectively , despite a median remission after initial chemotherapy of only 6 months . The 3-year OS for those whose induction therapy failed was 72 % ( 95 % CI , 52%-93 % ) . There was 1 ( 1.4 % ) early treatment-related death , 2 late deaths due to lung toxicity , and only 1 death due to myelodysplasia . There were no differences in PFS or OS on the basis of regimen or chemosensitivity . A Cox prognostic factor analysis determined that > 2 prior regimens , relapse in a radiated field , and extranodal disease were adverse prognostic factors . Among the 46 patients who received prior radiotherapy , the 5-year OS was 38 % ( 95 % CI , 14%-61 % ) for patients with 2 or 3 adverse factors , versus 60 % ( 95 % CI , 42%-78 % ) for those with 0 factors or 1 adverse factor . Augmented preparative regimens seem promising for the treatment of relapsed or refractory Hodgkin disease , without an increase in regimen-related mortality . A poor-prognosis group was identified that should be treated with novel therapies PURPOSE Identifying true therapeutic progress in patients with acute myeloid leukemia ( AML ) requires a comparison of treatment strategies and results on the basis of uniform patient selection . To foster comparability across five clinical studies , we introduced a common st and ard arm combined with a general upfront r and omization and performed prospect i ve analyses with adjustment for differences in prognostic baseline characteristics . PATIENTS AND METHODS Whereas the studies ' own regimens differed in chemotherapies , risk adaption , and guidelines for allogeneic stem-cell transplantation , the st and ard arm contained uniform cytarabine- and anthracycline-based st and ard-dose remission induction and high-dose consolidation courses . RESULTS Of 2,995 evaluable patients aged 16 to 60 years , 290 patients were r and omly assigned to the common st and ard arm . Seventy percent of the 290 achieved complete remissions ( 62 % with complete recovery , 8 % with incomplete recovery ; 95 % CI , 65 % to 76 % ) . Five-year survival probabilities were 44.3 % ( 95 % CI , 37.7 % to 50.7 % ) for overall survival , 44.8 % ( 95 % CI , 37.0 % to 52.2 % ) for relapse-free survival , and 31.5 % ( 95 % CI , 25.7 % to 37.4 % ) for event-free survival . Neither the unadjusted survival probabilities of the Kaplan-Meier method nor their adjustment for prognostic variables in multiple Cox regression models led to statistically significant different results in the three survival end points when the outcomes of each study were compared with the st and ard arm . CONCLUSION A strictly prospect i ve comparison of different treatment strategies in patients with AML did not show clinical ly relevant outcome differences when compared through a common st and ard treatment arm . The results provide a representative basis for further therapeutic approaches BACKGROUND The International Extranodal Lymphoma Study Group-32 ( IELSG32 ) trial is an international r and omised phase 2 study that addresses two key clinical questions in the treatment of patients with newly diagnosed primary CNS lymphoma . Results of the first r and omisation have demonstrated that methotrexate , cytarabine , thiotepa , and rituximab ( called the MATRix regimen ) is the induction combination associated with significantly better outcome compared with the other induction combinations tested . Here , we report the results of the second r and omisation that addresses the efficacy of myeloablative chemotherapy supported by autologous stem-cell transplantation ( ASCT ) , as an alternative to whole-brain radiotherapy ( WBRT ) , as consolidation after high-dose-methotrexate-based chemoimmunotherapy . METHODS HIV-negative patients ( aged 18 - 70 years ) with newly diagnosed primary CNS lymphoma and an Eastern Cooperative Oncology Group performance status of 0 - 3 were r and omly assigned to receive four courses of methotrexate 3·5 g/m2 on day 1 plus cytarabine 2 g/m2 twice daily on days 2 and 3 ( group A ) ; or the same combination plus two doses of rituximab 375 mg/m2 on days -5 and 0 ( group B ) ; or the same methotrexate-cytarabine-rituximab combination plus thiotepa 30 mg/m2 on day 4 ( group C ) , with the three groups repeating treatment every 3 weeks . Patients with responsive or stable disease after induction treatment , with adequate autologous peripheral blood stem-cell collection , and without persistent iatrogenic side-effects , were eligible for the second r and omisation between WBRT ( photons of 4 - 10 MeV ; five fractions per week ; fraction size 180 cGy ; started within 4 weeks from the last induction course ; group D ) and carmustine-thiotepa conditioned ASCT ( carmustine 400 mg/m2 on day -6 , and thiotepa 5 mg/kg every 12 h on days -5 and -4 , followed by reinfusion of autologous peripheral blood stem cells ; group E ) . A permuted block r and omised design was adopted for both r and omisations , and a computer-generated r and omisation list was used within each stratum . No masking after assignment to intervention was adopted . The primary endpoint was 2-year progression-free survival , with induction group and response to induction chemotherapy as stratification parameters . Analyses were done on a modified intention-to-treat basis . This study is registered with Clinical Trials.gov , number NCT01011920 . FINDINGS Between Feb 19 , 2010 , and Aug 27 , 2014 , 227 patients were recruited from 53 centres in five countries . 219 of 227 enrolled patients were assessable . Of the 122 patients eligible for the second r and omisation , 118 patients were r and omly assigned to WBRT or ASCT  ( 59 patients per group ) and constitute the study population . WBRT and ASCT were both effective , and achieved the predetermined efficacy threshold of at least 40 progression-free survivors at 2 years among the first 52 patients in both groups D and E. There were no significant differences in 2-year progression-free survival between WBRT and ASCT : 80 % ( 95 % CI 70 - 90 ) in group D and 69 % ( 59 - 79 ) in group E ( hazard ratio 1·50 , 95 % CI 0·83 - 2·71 ; p=0·17 ) . Both consolidation therapies were well tolerated . Grade 4 non-haematological toxicity was uncommon ; as expected , haematological toxicity was more common in patients treated with ASCT than in those who received WBRT . Two toxic deaths ( infections ) were recorded , both in patients who received ASCT . INTERPRETATION WBRT and ASCT are both feasible and effective as consolidation therapies after high-dose methotrexate-based chemoimmunotherapy in patients aged 70 years or younger with primary CNS lymphoma . The risks and implication s of cognitive impairment after WBRT should be considered at the time of therapeutic decision . FUNDING Agenzia Italiana del Farmaco , Cancer Research UK , Oncosuisse , and Swiss National Science Foundation PURPOSE This study was conducted to assess the comparative values of allogeneic bone marrow transplantation ( BMT ) and autologous bone marrow transplantation ( ABMT ) with sequential postremission chemotherapy ( SPC ) in children with acute myelogenous leukemia ( AML ) in first remission . PATIENTS AND METHODS From March 1987 to March 1990 , 161 assessable patients younger than 15 years of age with newly diagnosed AML were treated uniformly with two courses of daunorubicin and st and ard-dose cytarabine . After initial consolidation with a course of daunorubicin , cytarabine , and thioguanine ( DAT ) , patients in complete remission ( CR ) were r and omized to receive either ABMT or SPC , except for those with an HLA-matched sibling who were assigned to undergo BMT . SPC consisted of three additional courses of DAT , followed by three pairs of drugs administered sequentially for a total of six cycles . RESULTS Overall , 127 of 161 patients attained CR ( 79 % ) . The estimated probabilities of survival and event-free survival ( EFS ) at 5 years for all patients were 42 % and 25 % , respectively ( median follow-up , 28 months ) . For the 127 complete responders , the 5-year probability of disease-free survival ( DFS ) was 31 % , with a cumulative risk of relapse of 64 % . For the purpose of this study , all complete responders were evaluated for analysis of disease outcome according to the intent-to-treat principle , regardless of whether they actually received the intended therapy . The 5-year DFS was 51 % for the BMT group ( n = 24 ) , significantly higher ( P = .03 ) than that observed for the other cohorts : 21 % for ABMT ( n = 35 ) , 27 % for SPC ( n = 37 ) , and 34 % for a group of 31 nonr and omized ( NR ) patients . Bone marrow relapse was the most frequent cause of postremission failure in all therapeutic subgroups , including the BMT cohort , in which no deaths attributable to the toxicity of the procedure were recorded . CONCLUSION The results of this study show that BMT is more effective than ABMT or SPC in preventing leukemia relapse and extending DFS duration in children with AML in first remission Multiple myeloma , a plasma cell neoplasm , is the second most common hematologic malignancy after non-Hodgkins lymphoma and is responsible for 2 % of cancer deaths . Melphalan and prednisone ( MP ) has been the st and ard treatment in elderly patients for many decades . The VISTA study evaluated the effect of this combination with or without the first-in-class proteasome inhibitor bortezomib in newly diagnosed myeloma patients who were not c and i date s for autologous stem cell transplantation . Altogether 682 patients were enrolled and prospect ively r and omized in this trial . All patients received nine 6-week cycles of oral melphalan ( 9 mg/m(2 ) ) and prednisone ( 60 mg/m(2 ) ) on days 1 - 4 , either alone or with bortezomib administered intravenously ( 1.3 mg/m(2 ) on days 1 , 4 , 8 , 11 , 22 , 25 , 29 and 32 during the first four cycles and on days 1 , 8 , 22 , 29 during remaining course of therapy ) . Median time to progression ( the primary end point of the trial ) was 24 months in the bortezomib-containing group compared with 16.6 months in the control group ( p < 0.001 ) . Response was evaluated in 337 patients receiving bortezomib compared with 331 patients in the control group who received MP alone ; the percentages of partial response or better was 71 vs 35 % ( p < 0.001 ) , with complete response seen in 30 vs 4 % , respectively ( p < 0.001 ) . Median response duration in both groups was 19.9 versus 13.1 months , respectively . Median overall survival has not been reached in VMP group compared with 43 months in the MP group ( p < 0.001 ) , and this benefit is maintained after long term follow-up and subsequent antimyeloma therapies . Hematological adverse events ( AEs ) were similar in both groups , although patients in the bortezomib group experienced more frequent peripheral sensory neuropathy ( including 13 % grade 3 , with less than 1 % grade 4 ) . Overall , the occurrence of grade 3 AEs was higher in patients receiving bortezomib ( 53 vs 44 % , p = 0.02 ) , but the risk of grade 4 AEs was identical ( 28 vs 27 % ) . These results confirm the superiority of MP plus bortezomib combination over MP therapy in treatment-naive patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation Hematopoietic growth factors have been shown to be effective in reducing the period of neutropenia after autologous bone marrow transplantation ( BMT ) . Initial concerns over potential aggravation of graft-versus-host disease ( GVHD ) and increase in the incidence of relapse in patients with myeloid leukemias influenced the number of studies using hematopoietic growth factors after allogeneic BMT . We report the experience with 50 patients treated at a single institution using granulocyte colony-stimulating factor ( G-CSF ) after allogeneic sibling ( n = 30 ) and matched unrelated ( n = 20 ) BMT .  The time to an absolute neutrophil count > or = 500/microL was significantly faster in patients who received G-CSF and cyclosporine and prednisone for GVHD prophylaxis when compared with historical control patients receiving the same GVHD prophylaxis ( 10 v 13 days , P < .01 ) . A similar accelerated myeloid engraftment was observed for those patients who received the addition of methotrexate for GVHD prophylaxis when compared with historical control patients receiving the same GVHD prophylaxis regimen ( 16 v 19 days , P < .05 ) . The median time to engraftment for patients receiving a matched unrelated BMT and G-CSF was 17 days ( range 13 to 26 ) . We did not observe any increase in GVHD or early mortality in the matched related sibling BMT . The incidence of acute GVHD in the matched unrelated BMT recipients was also low at 21 % ; however , 9 patients ( 45 % ) died within 100 days of the date of BMT , similar to the experience reported with granulocyte-macrophage CSF . This study confirms the efficacy of G-CSF in accelerating myeloid engraftment after allogeneic matched sibling BMT . The higher early mortality associated with patients receiving matched unrelated BMT suggests that r and omized controlled trials using G-CSF after allogeneic BMT should be performed
The Hematology DSG noted that the use of transplantation for patients with myeloma varied among practice s across the province .
In terms of survival , is  peripheral blood stem-cell  or  marrow transplantation better than conventional chemotherapy ?
What is the relative efficacy of autologous versus allogeneic transplantation ?
What specifics of the transplantation process can be recommended ?
The addition of interferon is unlikely to influence outcomes in the control group .
In Terms of Survival , Is Autologous Peripheral Blood Stem-Cell or Bone Marrow Transplantation Better than Conventional Chemotherapy ?
After more than three decades of clinical trials testing various st and ard-dose chemotherapy regimens , the disease course of patients with multiple myeloma has not changed appreciably .
Conventional chemotherapy can provide effective palliation but is not curative ( 1 ) .
Case series have described encouraging results in patients with myeloma undergoing allogeneic or autologous bone marrow or peripheral blood stem-cell transplantation ( 2 ) .
Other studies of transplantation , including r and omized trials , have been reported in the past 6 years ( 3 , 4 ) .
To facilitate decisions about treatment options , practice guidelines have been developed for use by health care providers and consumers .
In Ontario , Canada , cancer treatments and policies are led by a state-funded organization , Cancer Care Ontario .
To help derive treatment options , Cancer Care Ontario has developed the Program in Evidence -Based Care , which includes the Practice Guidelines Initiative .
To approach this topic , the DSG addressed the following questions : What is optimal st and ard-dose chemotherapy for patients with myeloma ?
When should transplantation be performed ?
Who should ( or should not ) receive a transplant ?