Stem Cell Transplantation In First Remission Research Articles

Allogeneic Transplantation in First Remission Improves Outcome in Secondary Acute Myeloid Leukemia

Allogeneic stem cell transplantation (SCT) is widely used as post-remission treatment in younger patients with poor or intermediate risk AML. Transplant decisions are mainly based on cytogenetic and molecular risk group, age, comorbidity and on the availability of a suitable donor. Secondary AML, including therapy-related AML (t-AML) and AML after an antecedent hematological disorder (AHD-AML), constitutes more than one fourth of the AML cases and is a predictor of a poor outcome. However, the extent to which SCT improves outcome of this patient group is poorly studied.In this study, we set out to investigate the role of SCT for the survival of secondary AML patients within the population-based Swedish Adult Acute Leukemia Registry. In total, 5881 patients with AML diagnosed during the period 1997 – 2013 were included in the study. Of these, 4233 (72%) were de novo AML, 1098 (19%) AHD-AML and 550 (9%) t-AML. The median age at diagnosis was 70 in de novo AML, 73 in AHD-AML and 70 in t-AML. The gender distribution was equal in de novo AML (51% males). In AHD-AML, there was a male predominance of 57% whereas in t-AML, there was a female predominance of 56%. The proportion of patients who underwent SCT in first remission (CR1) was 10% in de novo AML, 5% in AHD-AML and 8% in t-AML (de novo vs AHD-AML p < 0.001, de novo vs t-AML p = 0.068, AHD-AML vs t-AML p = 0.081; Fisher’s exact test). In patients aged 65 or below, the proportion of SCT in CR1 was 24%, 21% and 20%, respectively. The median age of SCT patients was 48 (range 17 – 71) in de novo AML, 57 (27 – 76) in AHD-AML and 49.5 (18 – 68) in t-AML. In de novo AML, the distribution of genetic risk groups among SCT patients was 3% low risk, 55% intermediate risk and 42% high risk. Corresponding figures for AHD-AML was 0%, 34% and 66% and for t-AML 5%, 45% and 50% respectively (de novo vs AHD-AML p = 0.004, de novo vs t-AML p = 0.299, AHD-AML vs t-AML p = 0.124; Fisher’s exact test).The estimated median survival after the date of SCT in CR1 was 15 months in AHD-AML and 22 months in t-AML but not reached in de novo AML (95% lower confidence limit 107 months). Among patients <65 years who had been in CR for 3 months (genetic low risk excluded), those with secondary AML had a greater benefit from consolidation with SCT than those with de novo AML (Figure 1). The projected 7-year survival in de novo AML was 60% with SCT and 44% with conventional post remission therapy (CPRT) as compared to 46% and 21%, respectively, in secondary AML. The survival hazard with SCT was 0.45 in secondary AML (95% CI 0.28-0.72) as compared to 0.66 in de novo AML (CI 0.53 – 0.82), by multivariable Cox regression adjusting for type of secondary AML, age, sex, and cytogenetic risk group. To refine the analysis correcting for major confounding factors, a matched pair analysis was performed in patients with CR longer than 3 months. Matching criteria were type of secondary AML (AHD or t-AML), cytogenetic risk group and age (+/- 3 years). Remission of the patient with CPRT was at least as long as the time between CR1 and transplantation for the matched patient undergoing SCT. The projected 7-year survival rate was 43% in the SCT and 8% in the CPRT group (p = 0.01; log-rank test, Figure 2) further indicating a benefit for SCT as post remission therapy in secondary AML. We conclude that SCT improves survival in patients with secondary AML. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Peripheral T-cell lymphomas in a large US multicenter cohort: prognostication in the modern era including impact of frontline therapy

Optimal frontline therapy for peripheral T-cell lymphoma (PTCL) in the modern era remains unclear. We examined patient characteristics, treatment, and outcomes among 341 newly diagnosed PTCL patients from 2000 to 2011. Outcome was compared with a matched cohort of diffuse large B-cell lymphoma (DLBCL) patients, and prognostic factors were assessed using univariate and multivariate analyses. PTCL subtypes included PTCL, not otherwise specified (PTCL-NOS) (31%), anaplastic large T-cell lymphoma (ALCL) (26%), angioimmunoblastic T-cell lymphoma (23%), NK/T-cell lymphoma (7%), acute T-cell leukemia/lymphoma (6%), and other (7%). Median age was 62 years (range 18-95 years), and 74% had stage III-IV disease. Twenty-three (7%) patients received only palliative care whereas 318 received chemotherapy: CHOP-like regimens (70%), hyperCVAD/MA (6%), or other (18%). Thirty-three patients (10%) underwent stem-cell transplantation (SCT) in first remission. The overall response rate was 73% (61% complete); 24% had primary refractory disease. With 39-month median follow-up, 3-year progression-free survival (PFS) and overall survival (OS) were 32% and 52%. PFS and OS for PTCL patients were significantly inferior to matched patients with DLBCL. On multivariate analysis, stage I-II disease was the only significant pretreatment prognostic factor [PFS: hazard ratio (HR) 0.54, 95% confidence interval (CI) 0.34-0.85, P = 0.007; OS: HR 0.42, 95% CI 0.22-0.78, P = 0.006]. ALK positivity in ALCL was prognostic on univariate analysis, but lost significance on multivariate analysis. The most dominant prognostic factor was response to initial therapy (complete response versus other), including adjustment for stage and SCT [PFS: HR 0.19, 95% CI 0.14-0.28, P < 0.0001; OS: HR 0.26, 95% CI 0.17-0.40, P < 0.0001]. No overall survival difference was observed based on choice of upfront regimen or SCT in first remission. This analysis identifies early-stage disease and initial treatment response as dominant prognostic factors in PTCL. No clear benefit was observed for patients undergoing consolidative SCT. Novel therapeutic approaches for PTCL are critically needed.

Consolidative autologous hematopoietic stem-cell transplantation in first remission for non-Hodgkin lymphoma: current indications and future perspective.

The non-Hodgkin lymphomas (NHLs) are a heterogeneous group of diseases with variable clinical outcomes. Autologous hematopoietic stem-cell transplantation (ASCT) as frontline, consolidative therapy has been evaluated based upon histological subtype of NHL. In this review, we summarize the major clinical trials guiding the use of frontline ASCT in NHL. With the constantly changing landscape of upfront therapy and multiple promising novel agents, the ability to conduct randomized trials to evaluate the benefit of consolidative ASCT is not only challenging but may be considered by some an inept utilization of resources. Our recommendation for consolidative ASCT is based on analyzing the current available data.

Expanding Clinical Trial Networks in Pediatric Acute Lymphoblastic Leukemia

Expanding Clinical Trial Networks in Pediatric Acute Lymphoblastic Leukemia

Impact Of Induction Regimen and Consolidative Stem Cell Transplantation In Patients With Double Hit Lymphoma (DHL): A Large Multicenter Retrospective Analysis

▪ BackgroundDHL are high-grade B-cell lymphomas (BCL) characterized by dual gene rearrangements (RA) of MYC and either BCL2 or BCL6. Outcomes are typically dismal, particularly when treated with R-CHOP, as compared to those observed in patients (pts) with similar histologies without dual RA. Few reports have evaluated the use of intensive induction regimens, with or without consolidative stem cell transplantation (SCT). We sought to evaluate the role of intensive induction as well as SCT, and to investigate predictors of outcome in DHL. MethodsThis study was an IRB-approved retrospective analysis across 15 centers. Cases were diagnosed between 2000-2012 as aggressive BCL harboring RA, by FISH, of MYC along with RA of BCL2 and/or BCL6. Pts were treated with either R-CHOP, or one of the following intensified regimens: R-HyperCVAD, R-EPOCH, R-CODOX-M/IVAC, R-ICE. Survival was estimated using Kaplan Meier method, and comparisons made with log rank test. Multivariable analysis (MVA) was performed using the Cox proportional hazard regression. ResultsOne hundred six pts were analyzed. Median age at diagnosis was 60; 59% were male. The majority had DHL characterized by RA of MYC and BCL2 (77%); the remainder showed RA of MYC and BCL6 (10%), or all three (12%). History of indolent lymphoma was present in 29 pts (27%). The most common histology was DLBCL in 56 pts (53%), followed by BCL unclassifiable (BCLU) in 45 (42%), and Burkitt-like in 5 (5%). Thirty six pts (33%) received R-CHOP, 33 (31%) R-EPOCH, and 28 (36%) R-Hyper-CVAD or CODOX-M/IVAC. Fourteen pts (13%) were consolidated with SCT (n=1 allo and n=13 auto SCT); all were treated with intensive induction. Three additional pts underwent SCT in partial remission or progressive disease following R-CHOP induction. The median PFS and OS for the entire cohort were 8.8 mo and 12 mo, respectively (Table 1); of the 24 pts (23%) alive and without progression, median follow-up was 19 mo. R-EPOCH was superior in achieving complete response (CR) compared with R-CHOP (P 0.01), and trended towards significance compared with pts receiving other intensive induction (P 0.07). Additionally, primary refractory disease, observed in 37 pts (34.5%), occurred less frequently in pts receiving R-EPOCH compared to R-CHOP (P .005) or other intensive regimens (P 0.03); induction regimen did not impact OS in patients not receiving SCT (P 0.7; Fig 1). SCT in first remission was associated with improved OS (P 0.02), and PFS (P 0.006) compared with induction alone. However, among pts achieving CR, SCT was not associated with improved OS compared with observation (P 0.22; Fig 2). Pts with prior history of indolent NHL did not fare worse than those with de novo DHL (P 0.5). No difference in OS was observed based on histology (P 0.2). The following factors were evaluated in MVA: prior indolent lymphoma, histological subtype, IPI>/=3, primary refractory disease, type of induction (R-CHOP vs intensified), and consolidative SCT. Only primary refractory disease (P<0.0001) predicted for inferior OS. Consolidative SCT did not improve OS on MVA (P 0.13).TreatmentN^CR1 Achieved (%)Primary Refectory Disease (%)PFS (mo)OS (mo)Entire Cohort*10657 (53.7)37 (34.9)8.812R-CHOP3316 (48.8)15 (45.5)7.712R-CHOP w/ SCT30 (0)2 (66.6)8.813.1R-EPOCH2819 (67.8)5 (17.9)9.211.6R-EPOCH w/ CR1 SCT55 (100)0 (0)1212R-Hyper CVAD155 (33.3)8 (53.3)811R-Hyper CVAD w/ CR1 SCT66 (100)0 (0)22.621R-CODOX-M/IVAC62 (33.3)4 (66.6)46.4R-CODOX-M/IVAC w/ CR1SCT11 (100)0 (0)15.415.4 [Display omitted] [Display omitted] ConclusionsIn this analysis of DHL, primary refractory disease was the primary predictor of OS. Pts achieving CR did not appear to benefit from consolidative SCT, though our analysis was limited by the fact that pts receiving SCT are often highly selected (for chemosensitivity, age, comorbidities) and in this study, by the low number of pts receiving SCT. R-EPOCH was associated with a decreased rate of primary refractory disease compared to other regimens, and increased rate of CR compared to R-CHOP, but the lack of clear survival benefit suggests that relapsed disease offsets early benefit. Our analysis confirms the generally poor outcomes for pts with DHL, though a subset with chemosensitive disease has an improved prognosis, likely due to favorable disease biology. Further investigation on the role of SCT and of novel agents is needed for this high-risk population.^Three patients untreated, one received multiple regimens Disclosures:Off Label Use: Brentuximab Vedotin is approved for relapsed, refractory Hodgkin Lymphoma in patients who have already had a transplant or are ineligible for one, or for patients with relapsed, refractory anaplastic large cell lymphoma. Patients treated on clinical trials or off label will be included in this presentation. Petrich:Genetech: Consultancy, Honoraria. Fenske:Seattle Genetics : Consultancy, Honoraria. Smith:Seattle Genetics, Inc.: Research Funding; Spectrum: Consultancy; Cephalon: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; GlaxoSmith Kline: Speakers Bureau. Evens:Seattle Genetics: Consultancy, Honoraria; Millennium: Consultancy, Honoraria, Research Funding; Ziopharm, Inc: Research Funding; Celgene: Consultancy, Honoraria.

Clofarabine Combined with Busulfan Provides Excellent Disease Control in Adult Patients with Acute Lymphoblastic Leukemia Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

We investigated the safety and early disease control data for i.v. busulfan (Bu) in combination with clofarabine (Clo) in patients with acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplantation (SCT). Fifty-one patients (median age, 36 years; range, 20-64 years) received a matched sibling (n = 24), syngeneic (n = 2), or matched unrelated donor transplant (n = 25) for acute lymphoblastic leukemia in first complete remission (n = 30), second complete remission (n = 13), or active disease (n = 8). More than one-half of the patients had a high-risk cytogenetic profile, as defined by the presence of t(9;22) (n = 17), t(4;11) (n = 3), or complex cytogenetics (n = 7). Clo 40 mg/m(2) was given once daily, with each dose followed by pharmacokinetically dosed Bu infused over 3 hours daily for 4 days, followed by hematopoietic SCT 2 days later. The Bu dose was based on drug clearance, as determined by the patient's response to a 32-mg/m(2) Bu test dose given 48 hours before the high-dose regimen. The target daily area under the receiver-operating characteristic curve was 5500 μM/min for patients age <60 years and 4000 μM/min for those age ≥60 years. The regimen was well tolerated, with a 100-day nonrelapse mortality rate of 6%. With a median follow-up of 14 months among surviving patients (range, 6-28 months), the 1-year overall survival, disease-free survival, and nonrelapse mortality rates were 67% (95% confidence interval [CI], 55%-83%), 54% (95% CI, 41%-71%), and 32% (95% CI, 16%-45%), respectively. For patients undergoing SCT in first remission, these respective rates were 74%, 64%, and 25%. Our data indicate that the combination of Clo and Bu provides effective disease control while maintaining a favorable safety profile.

Improved outcome for young adult patients with ALL

The success achieved in the management of children with acute lymphoblastic leukemia has now been extended to older adolescents and young adults, as demonstrated recently by Nachman and coauthors. The effectiveness of treatment with an intense multiagent chemotherapy protocol renders the use of allogeneic hematopoietic stem-cell transplantation in first remission questionable, and calls for careful evaluation of the use of this chemotherapy in this patient population.

Successful Subtype Oriented Treatment Strategies in Adult T-All; Results of 744 Patients Treated in Three Consecutive GMALL Studies.

Abstract 324 Introduction and classification:This is the largest adult T-ALL cohort treated according to immunologic subtypes. All patients were immunophenotyped in one central lab (Berlin). T-ALL (cyCD3+, CD7+) were subclassified into early T-ALL (sCD3-, CD1a-), thymic T-ALL (sCD3-/+, CD1a+) and mature T-ALL (sCD3+, CD1a-). T-ALL constitutes in 3 consecutive GMALL-studies 24% of ALL patients. Patients and methods:A total of 744 T-ALL pts (15 to 55 yrs) were accrued in 102 hospitals in the GMALL studies 05/93, 06/99 and 07/2003. In GMALL 05/93 239 adult T-ALL patients, were treated according to a multi-agent chemoprotocol. Stem cell transplantation (SCT) was not recommended in CR1. In GMALL studies 06/99 and 07/03 505 T-ALL pts received intensified chemotherapy; particularly with introduction of PEG-asparaginase in induction as well as HDMTX/PEG-Asp consolidation cycles. Based on study 05/93 results, SCT from sibling (Sib) as well as matched unrelated (MUD) donor in CR1 was recommended for all patients with early T-ALL, mature T-ALL and for high-risk (HR) pts with thymic T-ALL (defined as late CR, complex karyotype or MRD positivity (MRD+)). Results:T-ALL subtype distribution in the total cohort of 744 adult T-ALL was early-T 23% (N=170), thymic-T 56% (N=420), mature-T 21% (N=154), without any differences between the studies. GMALL Study 05/93: The overall CR rate was 86% (early-T 72%, thymic-T 93%, mature-T 84%. The lower CR rate in early T-ALL was mainly due to early death (19%). The overall CCR rate was 47% (early-T 45%, thymic-T 54%, mature-T 30%). The overall survival rate at 10 yrs for all pts was 47% (early-T 47%, thymic-T 55%, mature-T 25%). GMALL Study 06/99 and 07/03:Of the 505 patients, 87% achieved CR (early-T 84%, thymic-T 92%, mature-T 77%). PR/Failure was higher in early-T (13%) and mature-T (17%) compared to thymic-T (5%). Early death was 4% and equally distributed. 267 pts (64%) received chemotherapy only and the majority were 229 pts (86%) with thymic T-ALL, not considered for SCT in CR1. The CCR rate was 61%. The few early (n = 15) and mature (n = 23) T-ALL pts, which could not have a transplant in CR1, are a negative selection (e.g. early relapse, comorbidity, no donor) and their CCR rate was 33% and 22% respectively. This was due to a high relapse rate in early T-ALL (60%) and mature-T (74%) compared to 33% in thymic-T. Overall survival rate at 8 yrs for thymic T-ALL with chemotherapy was 68%, for the 77 adolescent pts (15 to 25 yrs) even 76%. Stem cell transplantation:153 T-ALL pts in studies 06/99 and 07/03 received a SCT in first remission. SCT realisation rate in early T-ALL was 84%, in mature-T 68%. Overall CCR rate was 58% (early-T 47%, HR thymic-T 79%, mature-T 61%). Relapse rate after SCT was in early-T 33% and in mature-T 22%. The overall TRM rate was 18% despite more than half MUD SCT, without any TRM difference between the immunological subtypes. Overall survival rate after SCT in CR1 at 8 yrs was 53%, early-T 44%, thymic-T 67%, mature-T 59%. SCT modalit:49% received alloSib, 55% alloMUD and 20% auto-SCT. Overall CCR rate after alloSib for the total cohort was 65% (early-T 60%, thymic-T 73% and mature-T 69%); for alloMUD total 55% (early-T 45%, thymic-T 77%, mature-T 61%) and for the small cohort of 20 pts with auto-SCT CCR was 35%. Conclusion:The strategy in three consecutive GMALL studies to stratify and treat adult T-ALL pts according to the immunologic T-subtypes was successful. Overall survival at 5 yrs could be improved to 56% from 44%. There was a particular improvement for mature T-ALL (49% vs. 30%) and early-T (40% vs. 33%). This was mainly due to a high realisation rate of SCT in early T-ALL and mature T-ALL and the substantial better results of SCT. Results of alloMUD SCT were comparable to alloSib SCT. The small cohort of HR thymic T-ALL pts also had a benefit from SCT. The excellent outcome of SR thymic T-ALL (∼ 50% of all T-ALL) with the OS of 68% and 76% in adolescents due to intensified chemo, partic. PEG-Asp, does not suggest SCT in CR1. Several molecular markers, such as ERG, BAALC, WT1, had in a retrospective analysis some prognostic relevance in this pt cohort. The new GMALL study generation will however focus in thymic T-ALL on early evaluation of MRD to decide for SCT (MRD+) or not (MRD-) whereas early/mature T-ALL remain allocated to high risk groups with SCT in CR1.Supported by Deutsche Krebshilfe 702657Ho2 and BMBF 01GI9971/8 Disclosures:No relevant conflicts of interest to declare.

Young Adults With Acute Lymphoblastic Leukemia Have an Excellent Outcome With Chemotherapy Alone and Benefit From Intensive Postinduction Treatment: A Report From the Children's Oncology Group

Patients 16 to 21 years of age with acute lymphoblastic leukemia (ALL) have an inferior outcome compared with younger children, leading some medical oncologists to advocate allogeneic stem-cell transplantation in first remission for these patients. We examined outcome for young adults with ALL enrolled onto the Children's Cancer Group (CCG) 1961 study between 1996 and 2002. CCG 1961 entered patients with ALL 1 to 21 years of age with initial WBC count > or = 50,000/microL and/or age > or = 10 years. Randomly assigned therapies evaluated the impact of postinduction treatment intensification on outcome. We examined outcome and prognostic factors for 262 young adults with ALL. Five-year event-free and overall survival rates for young adult patients are 71.5% (SE, 3.6%) and 77.5% (SE, 3.3%), respectively. Rapid responder patients (< 25% bone marrow blasts on day 7) randomly assigned to augmented therapy had 5-year event-free survival of 81.8% (SE, 7%), as compared with 66.8% (SE, 6.7%) for patients receiving standard therapy (P = .07). One versus two interim maintenance and delayed intensification courses had no significant impact on event-free survival. WBC count more than 50,000/microL was an adverse prognostic factor. Young adult patients with ALL showing a rapid response to induction chemotherapy benefit from early intensive postinduction therapy but do not benefit from a second interim maintenance and delayed intensification phase. Given the excellent outcome with this chemotherapy, there seems to be no role for the routine use of allogeneic stem-cell transplantation in first remission for young adults with ALL.

Allogeneic Stem Cell Transplantation in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a heterogeneous disorder with subtypes that differ considerably in morphology and in their underlying chromosomal and molecular aberrations, which, in turn, determine their prognosis. The establishment of the indications for allogeneic stem cell transplantation (SCT) therefore requires individualized risk stratification based on a combination of multiple diagnostic methods, including cytogenetic and molecular genetic studies, and immunophenotyping, as well as the sensitivity of the disease to chemotherapy. This article surveys the current strategies for establishing the indications for SCT in AML on the basis of a selective review of the relevant literature in the Medline database. In patients with a high risk constellation-e.g., chromosome 7 anomalies, complex aberrations, or FLT3-length mutations-there is an indication for SCT in first remission. The balanced translocations t(15;17) and t(8;21), and the inversion inv(16) are prognostically favorable and are thus not considered an indication for SCT in first remission. The establishment of indications for stem cell transplantation also depends on the residual leukemic cell burden (minimal residual disease, MRD) as determined by the quantitative polymerase chain reaction or by flow cytometry, as well as an insufficient response to induction chemotherapy. Reduced-dose conditioning, a new technique that lessens acute toxicity, has been found to be associated with a 30% to over 50% two-year survival rate when used in the treatment of chemotherapeutically unresponsive or relapsing AML. The indications for allogeneic SCT in AML should be further refined by more investigation in large studies.

Identical Outcome After Autologous or Allogeneic Genoidentical Hematopoietic Stem-Cell Transplantation in First Remission of Acute Myelocytic Leukemia Carrying Inversion 16 or t(8;21): A Retrospective Study From the European Cooperative Group for Blood and Marrow Transplantation

Patients with acute myelocytic leukemia carrying inversion 16 (inv16) or t(8;21) have a better initial response to high-dose cytarabine than patients without these chromosomal abnormalities. They presently do not undergo transplantation in first remission (CR1), but there is concern about late relapses. From 1990 to 2004, 325 adult patients received transplantations in CR1 (159 patients with inv16 and 166 patients with t(8;21), including 35 and 60 patients, respectively, with additional chromosomal abnormalities). Genoidentical allografts were performed in 64 patients with inv16 and 81 patients with t(8;21), and autografts were performed in 95 patients with inv16 and 85 patients with t(8;21). In patients with inv16, after allogeneic and autologous transplantation, the 5-year leukemia-free survival (LFS) rates were 59% and 66% (P = .5), the relapse incidence (RI) rates were 27% and 32% (P = .45), and the transplantation-related mortality (TRM) rates were 14% and 2% (P = .003), respectively. Female patients had a lower RI and a higher LFS. Additional chromosomal abnormalities, compared with no additional abnormalities, were associated with lower RI rate (12% v 34%, respectively; P = .01) and higher 5-year LFS rate (78% v 59%, respectively; P = .04). In patients with t(8;21), after allogeneic and autologous transplantation, the 5-year LFS rates were 60% and 66% (P = .69), the RI rates were 15% and 28% (P = .03), and the TRM rates were 24% and 6% (P = .003), respectively. Younger age and a lower WBC count at diagnosis were associated with a lower TRM and a better LFS. The TRM was lower and the RI was higher in patients with autologous transplantations versus allogeneic transplantations. Both autologous and allogeneic transplantation resulted in similar outcomes.

Outcome after Relapse of Childhood Acute Myeloid Leukemia: The St. Jude Experience.

We reviewed the records of 408 patients who were less than 21 years old at the time of diagnosis of acute myeloid leukemia (excluding patients with Down syndrome or acute promyelocytic leukemia) treated on five consecutive institution protocols from 1980–2002 to investigate prognostic factors for attainment of second complete remission (CR2) and overall survival (OS) after first relapse. Of the 320 (78%) patients who achieved CR, 158 patients suffered hematologic relapses at a median of 11.9 months (range, 2.9–119.9 months) from the time of diagnosis. Forty-one patients relapsed on therapy and 117 relapsed after the completion of all planned therapy. For patients who relapsed off therapy, 38 were diagnosed with relapse because of symptoms suggestive of recurrent leukemia and 78 were diagnosed at the time of a routine follow up (information not available for one patient). After relapse, 20 patients received palliative care, 82 received chemotherapy alone, 36 received chemotherapy followed by hematopoietic stem cell transplant (SCT), and 20 proceeded directly to SCT. Eighty-five (54%) patients attained CR2. In univariate analyses, factors associated with the achievement of CR2 include initial therapy (chemotherapy alone, 56%; autologous SCT, 71%; allogeneic SCT, 20%; p=0.008) and time from the diagnosis of AML to relapse (≤ 1 year, 44%; > 1 year, 65%; p=0.010). Logistic regression analysis demonstrated that patients with male gender (odds ratio [OR], 2.46; 95% confidence interval [CI], 1.14–5.28; p=0.021) and greater time from diagnosis to relapse (OR, 1.05; CI, 1.01–1.09; p=0.016) were more likely to achieve CR2, whereas patients with M7 morphology (OR, 0.11; CI, 0.01–1.04; p=0.054) and allogeneic SCT in first remission (OR, 0.17; CI, 0.03–0.85; p=0.031) were less likely to achieve CR2. At the time of last follow up, 19 patients were alive, 115 died of progressive disease, and 24 died of regimen-related toxicity. The 2-year OS estimate ± SE for the entire cohort of 158 patients was 15.8% ± 2.8%. For patients who relapsed off therapy, there was no significant difference in outcome between those whose relapse was diagnosed at the time of a routine follow up and those diagnosed because of symptoms. Cox proportional-hazards regression modeling indicated that M7 morphology (hazard ratio [HR], 3.06; CI, 1.44–6.51; p=0.004) and allogeneic SCT in first remission (HR, 2.17; CI, 1.22–3.87; p=0.008) were associated with significantly worse OS after relapse. In fact, there were no survivors in these two groups of patients. In contrast, age 1–10 years (HR, 0.53; CI, 0.36–0.77; p=0.001), M2 morphology (HR, 0.57; CI, 0.39–0.85; p=0.006), allogeneic SCT after relapse (HR, 0.34; CI, 0.22–0.53; p<0.001), and greater time from diagnosis to relapse (HR, 0.97; CI, 0.95–0.99; p=0.003) had significantly favorable effects on OS. However, outcome was poor even among patients who underwent allogeneic SCT after relapse (2-year OS, 34.5% ± 6.1%) and among patients who relapsed greater than one year from diagnosis (2-year OS, 19.2% ± 4.3%), suggesting that novel therapies are warranted for all patients with relapsed AML.

Upfront Autologous Stem Cell Transplantation (SCT) Ameliorates the Prognostic Disadvantage of an Intermediate/High-Risk FLIPI Score in Patients with Advanced Follicular Lymphoma (FL): Evidence from Two Independent Data Sets.

The Follicular Lymphoma International Prognostic Index (FLIPI) is a useful predictor for the prognosis of patients with FL. It relies on a score consisting of age, stage, hemoglobin, LDH, and number of nodal sites involved at diagnosis, which defines 3 risk groups with different 5-year survival (5-y OS): Low risk (0–1 factor; 5-y OS >90%); intermediate risk (2 factors; 5-y OS 78%); and high risk (>2 factors; 5-y OS 53%). We hypothesized that SCT in first remission might improve the course of patients with advanced FL and high/intermediate risk FLIPI, thereby abrogating the prognostic impact of the FLIPI.Methods: Consecutive patients from two independent data sets (Kiel/Hamburg = training sample (T); Heidelberg = validation sample (V)) who received upfront SCT for FL between 1990 and 2002 and had sufficient baseline information available to assess the FLIPI were analyzed retrospectively. SCT eligibility criteria were similar for both series and comprised first remission of advanced FL, age <60, and performance status <2. Patients were treated with sequential therapy comprising 2–8 cycles of a CHOP-like regimen for remission induction, Dexa-BEAM (T) or HAM (V) for stem cell mobilization, and TBI/CY or BEAM for myeloablation prior to SCT.Results: 49 (T) and 57 (V) patients were eligible. Time from diagnosis to transplant was 9 (5–21) and 14 (5–116) months, respectively. The FLIPI assigned 40 (82%) and 36 (63%) patients to the high/intermediate risk group. With a median follow-up from SCT of 64 (12–134) or 62 (1–132) months, respectively, outcome data were similar in both samples. 5-y OS from diagnosis was 94% (T) and 90% (V) for the high/intermediate risk group vs. 83% (T) and 87% (V) for the low-risk group (p=0.09 and p=0.4). 5-year progression-free survival (PFS) was 62% (T) and 77% (V) vs. 71% (T) and 77% (V) (p=0.35 and p=0.73). Combining all patients (n=106) allowed for examination of each prognostic group separately. Differences in 5-y OS from diagnosis (90% for high risk, 93% for intermediate risk and 85% for low risk) or in 5-y PFS (60% for high risk, 75% for intermediate risk and 78% for low risk) were not statistically significant.Conclusions: Upfront SCT abrogates the prognostic impact of the FLIPI by improving the outcome of intermediate/high-risk patients but not of low-risk patients. Therefore the FLIPI might be a useful tool to select patients for prospective trials on SCT in FL who may particularly benefit from this procedure.

Gemtuzumab Ozogamicin (Mylotarg®) in Children with Refractory or Relapsed Acute Myeloid Leukemia

Background: Gemtuzumab ozogamicin (GO) is an immunoconjugate consisting of the CD33 antibody and calicheamicin, a potent cytotoxic agent. Developed for targeted treatment of CD33-positive AML, studies in adults showed its efficacy in relapsed and refractory AML. Patients and Method: We report 12 children with multiple relapsed or refractory AML receiving GO as compassionate use. 11 children had initially been treated according to the AML-BFM 93 or 98 protocol, 1 girl received relapse treatment (liposomal daunorubicin/FLAG) due to secondary AML. After relapse, 10 children received an intensive relapse therapy (AML-BFM 97 or international AML-Relapse Study 2001/01). 2 of them had been transplanted in first or second CR before GO therapy. Results: 5 of 12 children responded to treatment with blast reduction to below 5%, but no child achieved CR after GO. Time until reoccurrence of blasts in almost all children with GO response was 3–8 months. In 5 children stem cell transplantation (SCT) was performed after GO therapy. 4 of them suffered from further progression of AML, 1 boy is in second remission with a follow-up of 8 months. 2 children had severe side effects. An anaphylactic reaction with severe hypotension was managed by catecholamine support and intensive care. In 1 girl, who relapsed after SCT in first remission, a veno-occlusive disease of the liver occurred, but could be treated successfully with defibrotide. Conclusion: GO therapy can induce blast reduction in children who have no further conventional treatment options. Frequency and severity of adverse events are limited, and therapy seems to be feasible for children with a sufficient general condition. Controlled studies are necessary to learn more about efficacy and side effects, especially implications for further therapy.

Prognostic importance of TLX1 (HOX11) oncogene expression in adults with T-cell acute lymphoblastic leukaemia

The activation of oncogenic transcription factors defines distinct molecular subsets of T-cell acute lymphoblastic leukaemia and has prognostic relevance in children. We investigated the prognostic effect of the expression levels of eight oncogenic transcription factors--TLX1 (HOX11), TLX3 (HOX11L2), TAL1, TAL2, LYL1, OLIG2 (BHLHB1), LMO1, and LMO2--in 52 adults with T-cell acute lymphoblastic leukaemia. The leukaemia-specific survival rate for the 16 TLX1-positive patients was 88% (90% CI 73-100%), compared with 56% (42-70%) for all other cases (p=0.019). Only the TLX1 oncogene expression subgroup showed difference in leukaemia-specific survival. Our results suggest that overexpression of TLX1 confers a good outlook for adults with T-cell acute lymphoblastic leukaemia. Furthermore, our findings lead to questions about whether stem-cell transplantation in first remission is necessary for effective treatment of patients in the low-risk subgroup of patients with TLX1 oncogene expression.

The present role of bone marrow and stem cell transplantation in the therapy of children with acute leukemia.

Hematopoetic stem cell transplantation (SCT) often represents a unique opportunity for curing children with leukemia. Nevertheless, selecting the patient who could really benefit from this procedure remains a controversial issue. The current consensus is as follows: About 20% of children with ALL can be defined as high-risk patients by criteria such as t(9;22), t(4;11), no complete remission at day 42, poor prednisone response, and T-immunophenotype or pre-pre B-ALL, myeloid markers or more than 100,000 white blood cells/microliter. This high-risk group is eligible for alloBMT in first remission, provided a family-matched donor is available. At relapse the majority of patients will benefit from alloBMT, and alternative donor sources can be considered in high-risk patients. Only early alloBMT relapses (up to 6 months after end of initial therapy) are sure candidates, whereas late relapses, especially extramedullary sites, may equally benefit from an intensive conventional relapse treatment. However, any alloBMT relapse beyond second remission should be transplanted with allogeneic stem cells (bone marrow or peripheral stem cells). In particular, family mismatched donors or matched unrelated donors may be acceptable in high-risk cases beyond first remission. In contrast, ASCR in ALL seems not to be superior to conventional therapy. In AML the standard-risk patient, defined by criteria such as FAB M1/M2-Auer rods positive, all FAB M3, and FAB M4, is not a candidate for SCT in first remission. Patients presenting other criteria or more than 5% of blasts in the bone marrow at day 15 are at high risk in first remission and should be considered for allo BMT if a family matched donor is available. ASCR in first remission AML remains a controversial issue. In contrast, in second remission alloBMT as well as ASCR are superior to conventional chemotherapy.

Adult Burkitt's and Burkitt-like non-Hodgkin's lymphoma--outcome for patients treated with high-dose therapy and autologous stem-cell transplantation in first remission or at relapse: results from the European Group for Blood and Marrow Transplantation.

To investigate the results of treatment for adult patients with Burkitt's and Burkitt-like non-Hodgkin's lymphoma (NHL) undergoing high-dose therapy and autologous stem-cell transplantation (ASCT), and to determine prognostic factors for this group. A retrospective analysis of 117 adult patients reported to the lymphoma registry of the European Group for Blood and Marrow Transplantation (EBMT) between June 1984 and November 1994. Seventy of these patients received high-dose therapy and stem-cell transplantation in first complete remission (CR). Data on all patients were reviewed, and prognostic factors were determined by univariate and multivariate analysis. The actuarial overall survival (OS) rate for the entire group was 53% at 3 years. The major factor predicting for outcome after transplantation was disease status: the 3-year actuarial OS rate was 72% for patients transplanted in first CR, compared with 37% for patients in chemosensitive relapse, and 7% for chemoresistant patients. For patients transplanted in first CR, disease bulk at the time of ASCT was the only factor predictive of progression-free survival (PFS) and OS. The results of high-dose therapy and ASCT for patients with relapsed disease, particularly chemosensitive relapse, are superior to those reported for conventional-dose salvage regimens. The results for patients transplanted in first CR require comparison with modern dose-intensive regimens.