Role Of High-dose Therapy Research Articles

Consolidative Radio therapy in Place of Autologous Stem Cell Transplant in Patients with Low-Risk Relapsed/Refractory (R/R) Classic Hodgkin Lymphoma (cHL) Treated with Nivolumab plus Brentuximab Vedotin: CheckMate 744

Standard of care treatment for patients with relapsed and refractory classic Hodgkin lymphoma (RRHL) involves second line therapy followed by high dose therapy and autologous stem cell transplant (HDT/ASCT) and carries with it significant costs and toxicities to the patient. Some patients with RRHL may not require such intensive therapy, especially in the era of targeted chemotherapy and checkpoint inhibitors. CheckMate 744 (NCT02927769) evaluated a novel second-line therapy that omits HDT/ASCT by combining brentuximab vedotin (BV) and a nivolumab (N) followed by consolidative ISRT for low risk RRHL. Pts were aged 5-30 y and had one prior treatment without HDT/ASCT. Low-risk RRHL were those at relapse without B symptoms or extranodal disease, limited sites of relapse (≤4 sites of disease above the diaphragm or ≤3 sites above/below the diaphragm) AND with initial Stage IA, IIA with relapse <1 year if they received ≤3 cycles of chemotherapy and no RT OR Stage IA/B, IIA/B, IIIA ≥ 1 year. Patients received 4 cycles of N + BV induction. Patients with complete metabolic response (CMR) received an additional 2 cycles of N + BV before RT consolidation. Patients with suboptimal response received 2 cycles of BV + bendamustine intensification. Those patients achieving CMR proceeded to RT consolidation. RT was delivered to a dose of 30-30.6 Gy at 1.5-1.8 Gy/fraction to an ISRT volume. Among 28 pts treated, the median age (range) was 17 (6-27) years old and 64% of patients were aged < 18 y. Most (79%) pts had stage II disease at diagnosis and 82% had relapsed ≥ 12 months after first line treatment. Of 27 pts continuing in study after induction N + BV, 6 received bendamustine + BV intensification, and 92.9% achieved complete metabolic response. Twenty-two patients received RT consolidation. RT consolidation was delivered using 3D-CRT, IMRT, or proton therapy. After a median (range) follow-up of 31.8 (2.2-55.1) months, the 3-y event-free survival rate and progression-free survival were 86.9% (69.5-94.7%) and 95% (76.7-99%), respectively. A novel combination of N + BV followed by ISRT was an effective second line therapy. This treatment regimen allowed patients to forgo high dose therapy and transplant in favor of consolidative radiotherapy using ISRT. Larger studies challenging the role of high dose therapy and transplant are needed for RRHL.

Survival after high-dose chemotherapy for refractory and recurrent Ewing sarcoma

Backgroundoutcome of primary refractory or recurrent Ewing sarcoma (RRES) is poor and the role of high-dose therapy (HDT) remains uncertain. We retrospectively reviewed all patients treated for RRES in the London Sarcoma Service (LSS) over a 22-year period with the aim of adding to the current literature and developing a prognostic risk score to aid clinical decision-making. Methods and resultsOne hundred and ninety-six patients were included; 64 patients received HDT, 98 standard non-HDT chemotherapy and 34 no systemic therapy. At RRES, median age was 20 years and seventy-four per cent of patients had progressed or relapsed within 24 months. Median overall survival for HDT and non-HDT patients was 76 months (95% CI 34.8–117.2) and 10.5 months (95% CI 8.9–12.1), respectively. Two and five-year post-relapse survival (PRS) for HDT patients was 67.9% (SE 5.9) and 52.7% (SE 6.5), and for non-HDT patients, 20.5% (SE 4.2) and 2% (SE 1.5). Four prognostic factors significant on multivariate analysis were assigned a score of one point each, creating good (score 0), intermediate (score 1–2) and poor (score 3–4) prognosis groups. The increased score was significantly associated with reduced PRS. ConclusionOur study demonstrates that in RRES, HDT is associated with superior outcomes compared with non-HDT chemotherapy. RRES patients can be risk-stratified according to a predictive prognostic index we have developed, with the potential benefit of HDT observed even in patients with poor prognostic scores.

First-line high-dose therapy and autologous blood stem cell transplantation in patients with primary central nervous system non-Hodgkin lymphomas\u2014a single-centre experience in 61 patients

Primary central nervous system non-Hodgkin lymphomas (PCNS-NHLs) are extranodal B-cell lymphomas with poor prognosis. The role of high-dose therapy (HDT) followed by autologous blood stem cell transplantation (ASCT) as first-line therapy is still not clear. We retrospectively collected long-term follow up data of 61 consecutive patients with PCNS-NHL at the University Hospital Düsseldorf from January 2004 to December 2016. Thirty-six patients were treated with conventional chemoimmunotherapy (cCIT) only (CT-group). Seventeen patients received an induction cCIT followed by HDT and ASCT. In the CT-group, the overall response rate (ORR) was 61% (CR 47%, PR 14%), and there were 8% treatment-related deaths (TRD). Progression-free survival (PFS) was 31.8 months, and overall survival (OS) was 57.3 months. In the HDT-group, the ORR was 88% (59% CR, 29% PR), and there were 6% TRD. Median PFS and OS were not reached at 5 years. The 5-year PFS and OS were 64.7%. After a median follow up of 71 months, 10 patients (59%) were still alive in CR/PR following HDT and ASCT, one patient was treated for progressive disease (PD), and 7 had died (41%, 6 PD, 1 TRD). All patients achieving CR prior to HDT achieved durable CR. In the CT-group, 8 patients (22%) were alive in CR/PR after a median follow-up of 100 months. Twenty-eight patients died (78%, 24 PD, 2 TRD, 2 deaths in remission). In the univariate analysis, the HDT-group patients had significantly better PFS (not reached vs 31.8 months, p = 0.004) and OS (not reached vs 57.3 months, p = 0.021). The multivariate analysis showed HDT was not predictive for survival. Treatment with HDT + ASCT is feasible and offers the chance for long-term survival with low treatment-related mortality in younger patients. In this analysis, ORR, PFS and OS were better with HDT than with conventional cCIT alone. This result was not confirmed in the multivariate analysis, and further studies need to be done to examine the role of HDT in PCNSL.

The role of stem cell transplant for lymphoma in 2017.

The role of stem cell transplant for lymphoma in 2017.

Autologous stem cell transplant (ASCT) for newly diagnosed multiple myeloma (MM) in the era of novel agents: A meta-analysis of phase III randomized controlled trials.

8022 Background: Given the unprecedented deep response rates with the novel agent induction, the role of high dose therapy (HDT) followed by ASCT in MM pts. has been questioned, and was re-evaluated in a number of randomized clinical trials (RCTs). Although, the results of most studies suggest the continued benefit of HDT/ASCT, some RCTs suggest no overall survival (OS) benefit. We undertook a systematic review and meta-analysis of phase III randomized RCTs evaluating the role of HDT compared to standard therapy (SDT) in the context of novel agent induction Methods: We searched the PubMed, Scopus and Cochrane Collection of Controlled Trial databases using the term myeloma combined with autologous or transplant or myeloablative or stem cell from 2000-2016. A total of 2480 articles identified, of which 4 large phase III RCTs compared upfront HDT with SDT with novel agents use. Two individuals independently extracted the data. Reported hazard ratio (HR) and survival data were pooled using random effects models (STATA v14, College Station, Tx). Heterogeneity was assessed using I2. Results: Four studies comprising 2421 patients were included (Table 1). One study did not report the HR for death and hence OS analysis was limited to 3 studies. The combined hazard for progression with HDT was 0.55 (95% CI 0.40-0.71) (p &lt; 0.005). The combined hazard for death with HDT was 0.65 (95% CI 0.29-1.0) (p = 0.007). Sensitivity and sub-group analysis showed no difference in PFS (p = 0.06) and OS (p = 0.22) with HDT. Significant heterogeneity was demonstrated by I2 of 71.4% for PFS (p = 0.01) and 68.4% for OS (p = 0.04). Conclusions: Based on our analysis, even in the novel agent era, HDT appears to be beneficial and should be considered standard of care for all transplant eligible MM pts. [Table: see text]

The role of high-dose therapy and autologous stem cell transplantation in the treatment of patients with multiple myeloma

Introduction. Limited efficacy of standard chemotherapy initiated the introduction of high-dose therapy followed by autologous stem cell transplantation in the treatment of patients with multiple myeloma. The aim of the study was to analyse results of treatment with high-dose therapy followed by autologous stem cell transplantation in 110 newly diagnosed multiple myeloma patients during the period May 2015 - January 2016. Material and Methods. Patient group consisted of 51 female and 59 male patients with average age of 57 years. Most of the patients were diagnosed with IgG myeloma (58.2%) and clinical stage III (74.5%, Salmon&amp;Durie). Renal impairment initially existed in 26 patients. By 2008, patients were treated with 4-6 cycles of induction chemotherapy according to the protocol VAD (33 patients, 30%); and afterward according to the CTD protocol (72 patients, 65.5%). Mobilization of the stem cell was performed according to the protocol CAD followed by granulocyte colony-stimulating factor 5-10 ?g/kg body weight/day starting on day 9, until the apheresis around day 14 of mobilization (? 1-2 days). Within 4-8 weeks after mobilization, HDT with Melphalan 200 mg/m2 accompanied with autologous stem cell transplantation was performed. Results. Applied induction treatment resulted in the achievement of at least partial remission in 80% patients. The average number of CD34+ in the product of apheresis was 8.1x106/kgBW, while during HDT with autologous stem cell transplantation, median was 4x106/kg body weight CD34+ cells. Average recovery was registered around +15 days after autologous stem cell transplantation, characterized by a minimal number of febrile days (median 2 days, range 0-10 days). In 95% patients, partial remission was recorded +100 days after autologous stem cell transplantation with average duration of 45 months, and achievement of complete remission in 29% pts with median overall survival of 100 months. This treatment approach resulted in overall survival longer than 45 months in more than 90% patients. The factors found to affect the duration of remission and overall survival are: ISS score ?2. Conclusion. High-dose therapy followed by autologous stem cell transplantation is an efficient and safe treatment approach to multiple myeloma patients. Along with biological characteristics of the disease, complete remission achievement after such treatment is of essential significance for the course and outcome of multiple myeloma patients.

Abstract IA27: New insights into therapeutic targets in multiple myeloma.

Abstract Multiple myeloma (MM) is a remarkable example of rapid bench-to-bedside translation in new drug development. Our laboratory and animal studies have shown that the proteasome inhibitor bortezomib (V) and immunomodulatory drug (IMiD) lenalidomide (R) target MM cells, the tumor-host interaction, and the bone marrow (BM) microenvironment to overcome conventional drug resistance. We translated these studies to clinical trials as initial, consolidation, salvage and maintenance therapy, which have already extended MM patient survival two to three fold. Combinations of targeted therapies such as RV with dexamethasone (D) achieve unprecedented extent and universal responses, and the role of high dose therapy and stem cell transplantation is being re-evaluated in this context. Immune-based therapies under development include: elotuzumab (anti-CS1) and daratumumab (anti-CD38) MoAbs; MM cell-dendritic cell vaccines to treat minimal residual disease posttransplant or CD138, CS-1, and XBP-1 peptide vaccines to inhibit progression of smoldering to active MM; as well as TLR-9 agonists targeting plasmacytoid dendritic cells to abrogate their MM-promoting and augment their immunostimulatory activity. Next-generation targeted agents include: deubiquitinating enzyme (USP14/UCHL5) inhibitors to target protein degradation upstream of the proteasome and thereby overcome proteasome inhibitor resistance; chymotryptic (carfilzomib, opromazib, ixazomib) and more broad (marizomib) proteasome inhibitors; and next generation IMiD pomalidomide. Rationally-based combination therapies include proteasome inhibitors (carfilzomib, opromazib, ixazomib, marizomib) with IMiDs (lenalidomide and pomalidomide) to trigger dual intrinsic and extrinsic apoptotic signaling; MoAbs elotuzumab and daratumamab with IMiDs, which upregulate antibody dependent cellular cytotoxicity; proteasome inhibitors (carfilzomib, opromazib, ixazomib) with histone deacetylase (HDAC) inhibitors (vorinostat, panobinostat, and ACY1215) to block proteasomal and aggresomal degradation of protein, respectively. Novel targets include inhibitors of Btk, bromodomain 4, kinesin spindle protein, nuclear transport, and Akt. Finally, genomics has defined disease heterogeneity and novel targets (BRAF mutations); identified mechanisms of resistance (PSMB5 mutations conferring proteasome inhibitor resistance); and discovered novel treatment strategies. For example, we recently demonstrated that low expression of YAP1 in hematologic malignancies allows tumor cells to survive despite ongoing DNA damage; and conversely, that genetic knockdown of STK4 upregulates YAP1 and related P73 mediated apoptosis. These studies provide the framework for a synthetic lethal treatment paradigm using kinase inhibitor targeting STK4 to upregulate YAP1 and related apoptotic signaling in MM and other hematologic malignancies. Citation Format: Kenneth C. Anderson. New insights into therapeutic targets in multiple myeloma. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr IA27.

Early high-dose therapy and autologous stem-cell transplantation in angioimmunoblastic T-cell lymphoma: Outcome study using the National Cancer Data Base.

8560 Background: Angioimmunoblastic T-cell lymphoma (AITL) is a rare aggressive non-Hodgkin lymphoma with a poor outcome. The role of high-dose therapy followed by autologous stem-cell transplantat...

High-dose therapy and autologous hematopoietic cell transplantation as front-line consolidation in chronic lymphocytic leukemia: a systematic review.

High-dose therapy (HDT) followed by autologous hematopoietic cell transplantation (auto-HCT) is offered to patients with chronic lymphocytic leukemia (CLL) both as front-line consolidation and in the relapsed setting. The role of HDT in the front-line consolidation setting in CLL is uncertain. Literature search of PUBMED and Cochrane until 14 November 2014 and the last 2 years of abstracts from relevant conferences was undertaken. End points included benefits (overall survival; OS, PFS, event-free survival; EFS) and harms (adverse events, secondary malignancies, treatment-related mortality). The search identified 495 references of which four studies met inclusion criteria. Altogether, 301 patients were randomized to the HDT/auto-HCT arm and 299 patients to the control arm. Offering front-line HDT/auto-HCT did not result in statistically significant improvement in OS (Hazard ratio (HR)=0.91; 95% confidence interval (CI)= 0.62, 1.33) or PFS (HR=0.70; 95% CI= 0.32, 1.52). There was a statistically significant advantage favoring HDT/auto-HCT for EFS (HR=0.46; 95% CI= 0.26, 0.83). Moreover, HDT/auto-HCT did not result in higher rate of secondary malignancy (risk ratio=1.06; 95% CI=0.55, 2.05) or treatment-related mortality (risk ratio=1.32; 95% CI= 0.43, 4.06). Offering HDT/auto-HCT as front-line consolidation in patients with CLL does not improve OS. At present this approach should not be offered outside the context of a clinical trial.

Autologous Stem Cell Transplantation Improves Survival for Patients with Follicular Lymphoma in First or Second Relapse: Results of a Comparative Effectiveness Instrumental Variable Analysis

IntroductionThe role of high dose therapy with autologous stem cell transplantation (ASCT) in relapsed follicular lymphoma (FL) remains controversial, with lack of comparative studies in the Rituximab (R) era. We conducted a comparative effectiveness analysis to evaluate the use of ASCT at first or second (1st/2nd) relapse on survival outcome in two cancer centers in Alberta. Both centers treat a similar catchment population within the same government-funded health care system, providing simultaneous access to new cancer treatments. Treatment center A however, routinely offers ASCT at 1st/2nd FL relapse whereas treatment center B tends to offer ASCT later or never. Both centers occasionally offer allogeneic transplantation later in the disease course.MethodsThe Alberta Cancer Registry was interrogated to identify FL patients diagnosed between 2001 and 2010. Patients who were aged 18-60 years at initial diagnosis and experienced a relapse post initial chemotherapy treatment regardless of first-line management (watch and wait, chemotherapy, chemoimmunotherapy or radiation) were included in this analysis. Patients who had grade 3B or areas of concurrent diffuse large B-cell lymphoma at initial diagnosis were excluded.ResultsA total of 568 patients aged 18-60 years were diagnosed with FL during the 10 year study period in Alberta, and 180 patients meeting inclusion criteria experienced relapse from chemotherapy and received treatment at center A (n=96) or center B (n=84). There were no statistically significant differences in patient and disease characteristics at diagnosis or at relapse between the two centers. The median follow-up was 104.4 months (28.1-156.1) from diagnosis and 65.3 months (0.3-151.8) from first relapse post chemotherapy.The proportion of patients ever receiving ASCT was higher at center A compared to B (61.46% vs.16.67%, p<0.001) especially those receiving at 1st/2nd relapse (58.3% vs. 7.1%, p<0.001). Center A also utilized allogeneic transplantation more frequently (16.7% vs. 3.6%, p=0.004). The use of R-chemotherapy (89.6% vs. 82.1%, p=0.46), R-maintenance therapy (34.4% vs. 39.3%, p=0.50), Doxorubicin-based chemotherapy (60.4% vs. 61.9%, p=0.84), Fludarabine (19.8% vs. 29.8%, p=0.12) were similar for center A vs. B, respectively, although center A less commonly enrolled patients on clinical trials (12.5% vs. 39.3%, p<0.01).The projected 5-year overall survival (OS) from first relapse was significantly higher in center A vs. B (88.9% vs. 59.5%, HR 3.24, p<0.001) (Figure 1). For these 180 patients, the projected 10-year OS from initial diagnosis was 85.4% in center A vs. 60.5% in center B (HR 3.02, p=0.003).The factors associated with improved OS from relapse at univariate analysis were female gender (p=0.01), no co-morbidities (p=0.01), FLIPI score 0-2 at diagnosis (p<0.001) and TTP >1 year (p=0.002). Receiving ASCT was highly associated with improved OS (p=0.006) as well as timing of the ASCT (p<0.001). Patients receiving ASCT at 1st/2nd relapse had projected 5-year OS of 92.4% vs. 66.5% for no ASCT vs. 62.5% for ASCT beyond second relapse (p<0.001) (Figure 2). In contrast, allogeneic transplantation did not affect OS (p=0.62).In multivariate analysis, factors that were independently associated with improved OS were treatment center A (HR 3.16, p=0.001), FLIPI score 0-2 at diagnosis, no transformation, ever use of Rituximab with chemotherapy, and ever use of R-maintenance. Another multivariate model examining the OS of all patients without considering treatment center found that ASCT at 1st/2nd relapse was associated with improved OS (HR 4.55, p=0.002) independent of FLIPI score 0-2 at diagnosis, no transformation, ever use of Rituximab with chemotherapy, and ever use of R-maintenance. Because treatment center and use of ASCT at 1st/2nd relapse were highly correlated, they could not be combined within the same multivariate model.ConclusionsThis is the first study assessing the comparative effectiveness of different treatment approaches in FL patients in their first relapse post chemotherapy, in particular the use of ASCT. Our results illustrate significantly improved survival in patients treated with high dose therapy with ASCT as well as highlighting the importance of timing of ASCT. We therefore support the use of ASCT at 1st/2nd relapse in relapsed FL patients. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Hematopoietic stem cell transplantation in chemotherapy-sensitive lymphoblastic lymphoma: Treatment outcome and prognostic factor analysis.

e19560 Background: The role of high-dose therapy followed by hematopoietic stem cell transplantation (HSCT) in the treatment of lymphoblastic lymphoma (LBL) has not been fully defined. Methods: Thi...

Role of Consolidation Therapy in Transplant Eligible Multiple Myeloma Patients

The role of high-dose therapy and autologous stem-cell transplantation (ASCT) in the treatment of multiple myeloma (MM) has continued to evolve in recent years. The novel agents thalidomide, bortezomib, and lenalidomide have been successfully incorporated into induction therapy in preparation for ASCT and are currently being investigated also as post-ASCT consolidation and maintenance therapy. Consolidation treatment is generally short term and aims to increase the frequency and depth of response obtained with the previous treatment phases, including novel agent-based induction therapy and ASCT. This review will focus on recent trials of novel agents as post-ASCT consolidation therapy, offering an overview of pros and cons of this new treatment strategy in the ASCT sequence for MM patients.

Indications for hematopoietic stem cell transplantation in patients with follicular lymphoma: a consensus project of the EBMT-Lymphoma Working Party

The aim of this project was to define indications for hematopoietic stem cell transplantation in follicular lymphoma in Europe. In the absence of evidence-based data, a RAND-modified Delphi procedure was used by an expert panel. After pre-defining statements, these were individually/anonymously scored by each participant using a 9-point scale. Consensus was reached that: 1) high-dose therapy with autologous stem cell rescue is not an appropriate option to consolidate first remission in patients responding to immuno-chemotherapy outside clinical trials; 2) in patients with first chemo-sensitive relapse, high-dose therapy with autologous stem cell rescue is an appropriate option to consolidate remission, especially in patients with a short response after immuno-chemotherapy or with high-risk FLIPI; 3) high-dose therapy with autologous stem cell rescue is also appropriate in second/subsequent chemo-sensitive relapses; 4) allotransplant (preferably a reduced intensity conditioning-allotransplant) should be considered at relapse after high-dose therapy with autologous stem cell rescue. No consensus was reached on the role of high-dose therapy with autologous stem cell rescue in low-risk first relapse, or on when an allotransplant should be preferred over high-dose therapy with autologous stem cell rescue. In the absence of evidence-based data, the consensus method used was a valuable tool to define indications for hematopoietic stem cell transplant in follicular lymphoma.

Long-Term Disease-Free Survival in Patients with Relapsed/Refractory Follicular Lymphoma After Autologous Stem Cell Trasplantation

AbstractAbstract 2031 Background:The role of High-Dose Therapy (HDT) and Autologous Stem Cell Transplantation (ASCT) as salvage therapy in relapsed Follicular Lymphoma (FL) has been questioned since the introduction of Rituximab in the treatment of FL. Our objectives were to evaluate the long-term event-free survival (EFS) and overall survival (OS) rates of patients with relapsed or refractory FL who received HDT and ASCT as salvage therapy. Our secondary objective was to compare EFS of patients who received ASCT before and after 2002 (the year Rituximab become fully available for use in our country). Patients and Methods:We conducted a retrospective analysis of 123 consecutive patients with relapsed or refractory FL who had received HDT and ASCT as salvage therapy in five Argentinean transplant centers from 1992 to 2012. Results:One hundred twenty tree patients (median age: 48 years, range: 23–72) were transplanted, 71 (58%) male, 37/106 (35%) had FL Grade 1, 47/106 (44%) FL Grade 2 and 22/106 (21%) FL Grade 3; 75/102 (73%) of patients have a stage III-IV disease at the moment of diagnosis and 27/102 (26%) have a disease stage I-II. Before transplantation 78/121 (64%) patients were in Complete Response (CR), 42/121 (35%) were in Partial Response (PR) and one patient had a Progressive Disease. Fifty four patients (44%) were transplanted before 2002 (before Rituximab era in our country). The conditioning regimens used were CBV 94 (76%), BEAM/BEAC 27 (22%), others regimens two patients; only one patient received TBI containing conditioning regimen and was excluded for conditioning regimen PFS curve calculation. The median time from FL diagnosis to ASCT was 29 (range 1–300) months. The transplant related mortality (until day 90 after ASCT) was 5%. With a median follow-up of 52 (range 0–247)months, the median EFS was reached at 44 months and a plateau on the EFS curve was evident starting at 6 years after ASCT. The 10 years-projected EFS was 36% (Figure 1). The median OS was not reached during follow-up. Median EFS for patients who were transplanted before 2002 (before Rituximab era) and for those who were transplanted after 2002 was 41 months and 47 months respectively [HR 1.01; IC (0.61–1.65); p=0.97]. EFS rates difference was not statically significant between patients who previously transplantation have achieved a CR or a PR, median EFS 47 and 68 months respectively [HR 0,94; IC (0,56–1,58); p= 0,82]. There was no difference in EFS rates between patients who received CBV as conditioning regimen and patients who received BEAM/BEAC, median EFS 57.6 months and 16.3 months respectively [HR 0.67; IC (0,34–1.35); p=0.2]. The median EFS rate for patients with FL Grade 1, FL Grade 2 and FL grade 3 were 58, 44 and 16 months respectively, P for trend = 0.78.Seven cases (5,7%) of secondary malignancies were detected, six cases (6/94; 6,4%) in patients who received CBV as conditioning regimen (urotelial carcinoma, pancreas carcinoma, lynfoprolipherative disorders, non-melanoma skin malignancies and prostate carcinoma) and one case (1/27; 3,7%) in patients who received BEAM (urotelial carcinoma), p=0,85; there were no reports of secondary myelodysplastic syndromes/acute myeloid leukemia. Conclusion:In this study, 50% of the patients analyzed were free from progression after 44 months of ASCT and approximately a 30% of patients achieve long term remission. According to this, patients with relapsed or refractory FL can achieve long-term EFS with HDT followed by ASCT. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

High-Dose Therapy and Autologous Stem Cell Transplantation for Extra-Nodal NK/T Lymphoma in Western Patients; A Study From the European Group for Blood and Marrow Transplantation (EBMT).

AbstractAbstract 3148Extra-nodal NK/T lymphoma (ENKTL) is an aggressive malignancy with a unique geographical distribution; rare in Western countries and more frequently encountered in East Asia. ENKTL is invariably associated with Epstein Barr Virus (EBV) and characteristically involves the nasal cavity, though extra-nasal disease is not uncommon. For a majority of patients, treatment outcomes are unsatisfactory. For localised disease, radiotherapy is effective although up to 50% of patients will relapse, usually within a year of first-line therapy. The outcome of advanced stage and relapsed/refractory disease is extremely poor. The role of high-dose therapy and autologous stem cell transplantation (HDT-ASCT) in the treatment algorithm of ENKTL remains unclear. Moreover, there is a paucity of data available on patients undergoing HDT-ASCT for ENKTL outside East Asia.The objective of this study was to analyse the outcome of Western patients with W.H.O-classified ENKTL who had undergone HDT-ASCT from 2000–2009. The European Group for Blood and Marrow Transplantation (EBMT) database identified 102 such patients. Following an invitation to contribute detailed study-specific data, including investigator review of the original histopathology report, a total of 28 patients with full dataset were included for analysis. All patients had a histological diagnosis of ENKTL, with a natural killer (NK) or cytotoxic T cell phenotype in accordance with the W.H.O classification. A majority of biopsies had demonstrable evidence of EBV by EBER or LMP1 staining. For cases where EBV data was not available, cases were only included if a NK or cytotoxic T cell phenotype was demonstrable together with characteristic clinical and radiological features of ENKTL.The median age at ASCT was 47.4 years and the median time from diagnosis to ASCT was 22.4 months. There were no discernible difference in characteristics or outcome between the 28 study patients and the remaining patients recorded on the registry. The median follow-up was 32.8 months post-ASCT.At diagnosis of ENKTL, 57.2% of patients had stage I/II disease. All patients had received at least one line of chemotherapy prior to HDT-ASCT (median 2 lines), whilst only 32.1% had previously received involved-field RT. Remission status at HDT-ASCT was: 43% in first complete remission (CR1); 18% in second or subsequent CR; 21% classified as partial response; and 18% patients with refractory or progressive disease. The 2 year estimates of disease-free survival and overall survival were 40.7% (95%CI: 25.9–64.2) and 52.3% (95%CI: 36.4–75.1) respectively. Disease relapse beyond 12 months was not seen following HDT-ASCT. The 1-year and 2 year non-relapse mortality (NRM) estimates were 11.1% (95%CI 2.7–26.3) and 22.2% (95%CI 8.7 – 39.5) respectively.The 2 year DFS estimate for patients undergoing HDT-ASCT in CR1 was 63.6% (95%CI 40.7–99.5) compared with 25% (10.7–58.4) for patients not in CR1, although this difference did not reach statistical significance (p=0.068). There was no apparent impact of age, stage or number of previous lines of therapy on NRM, DFS or OS. Interestingly, the 2 year DFS and OS for those with stage III/IV disease were 33.3% (95%CI 13.2–84) and 40% (95%CI 18.7–85.5) respectively, with evidence of a survival plateau after 1 year, indicating a proportion of patients with advanced stage ENKTL can be effectively salvaged by HDT-ASCT.This is the largest analysis of HDT-ASCT for patients with WHO-classified ENKTL reported from the Western hemisphere. Survival outcomes are comparable to those reported in East Asian cohorts, although detailed comparison is inherently limited by the nature of the study. Non-relapse mortality is higher than anticipated for a relatively young HDT-ASCT population. Most relapses occurred within 1 year of HDT-ASCT. Outcomes are encouraging for patients with advanced disease. Prospective studies are now urgently required to allow more definitive recommendations to be made on the role of HDT-ASCT for patients with ENKTL. Disclosures:No relevant conflicts of interest to declare.

AUTOLOGOUS STEM CELL TRANSPLANTATION FOR AGGRESSIVE LYMPHOMAS

The role of high-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) in the treatment armamentarium of aggressive B- and T-cell non-Hodgkin lymphoma (NHL) is still a matter of debate. In the pre-Rituximab era, the PARMA study demonstrated the superiority of HDT/ASCT over conventional salvage chemotherapy in chemosensitive, relapsed patients. Subsequently, HDT/ASCT has become a standard approach for relapsed NHL. With the advent of Rituximab in the landscape of NHL, transplantation as part of first-line therapy has been challenged. However, no benefit in terms of disease-free or overall survival of HDT/ASCT over standard therapy was shown when Rituximab was added to both arms. Moreover, the superiority of HDT/ASCT over conventional salvage therapy in patients relapsing from first-line therapy including Rituximab was not confirmed. From these disappointing results, novel strategies, which can enhance the anti-lymphoma effect, at the same time reducing toxicity have been developed, with the aim of improving the outcome of HDT/ASCT in aggressive NHL. In T-cell lymphoma, few publications demonstrated that consolidation of complete remission with HDT/ASCT is safe and feasible. However, up to one-third of patients may never receive transplant, mostly due to progressive disease, and relapse still remains a major concern even after transplant.

An international strategy to determine the role of high dose therapy in recurrent Wilms’ tumour

PurposeTo review event-free (EFS) and overall survival (OS) from publications describing outcome for children with relapsed Wilms’ tumour. Comparisons are made between those receiving myeloablative high dose chemotherapy with autologous stem-cell rescue (HDT) and those not (NoHDT). Materials and methodsRelevant information was extracted from individual patient or summary data and 3-year EFS and OS rates established. These rates were combined in a weighted manner to derive hazard ratios (HRs). ResultsNineteen publications were identified (5 HDT, 6 NoHDT, 8 both). Pooling all studies suggested an advantage to HDT with a hazard ratio (HR) for EFS of 0.87 (95% confidence interval (CI) 0.67–1.12) and 0.94 (0.71–1.24) for OS. A stratified analysis confined to studies that provided individual patient data on both HDT and NoHDT gave HRs of 0.83 (0.56–1.24) and 0.92 (0.59–1.41). Further, analyses of risk groups, defined by treatment and/or histology prior to first relapse, suggested a HR for EFS of 0.90 (95% CI 0.62–1.31) for those of high and 0.50 (CI 0.31–0.82) for the very high risk patients. ConclusionThe evidence suggests, although there are many caveats since the information summarised here is not from randomised trials, a great deal of uncertainty concerning the role of HDT in patients following relapse after treatment for their Wilms’ tumour. For each risk group we propose a randomised trial comparing a standard with a more intensive therapy with specific choice of regimen tailored to the risk group (and co-operative groups) concerned. A synthesis of updated evidence from studies in this overview together with any emerging studies and future trial information will form the basis for future evidence-based clinical decision-making.

The Roel of High Dose Chemotherapy and Autologous Stem Cell Transplantation (ASCT) In PATIENTS with POEMS SYNDROME: A Retrospective study of the MM Subcommittee of the Chronic Leukemia Working Party of the EBMT,

Abstract 4115 Introduction:Polyneuropathy, organomegaly, endocrinopathy, skin changes associated with a paraproteinaemia (POEMS syndrome) is a rare paraneoplastic syndrome secondary to a plasma cell dyscrasia. Effective treatment, including ASCT, of the underlying plasma cell dyscrasia can control the disease and often dramatically control symptoms. Limited data is available for ASCT in POEMS. Specific Aim: The aim of this study was to describe the clinical outcome of ASCT for patients with POEMS syndrome, determining the impact of patient and disease-specific factors on prognosis. The incidence of engraftment syndrome and the presentation of relapse were examined. Methodology: Patient-, disease-, and transplant-related variables were collected according to the data entries in the EBMT database, including tracking incomplete data entries from participating centers. Results: 116 patients underwent an ASCT between 1997–2009 and satisfied the entry criteria. The median age was 50 yrs (range 26–69) with 56.8% of patients ’50 year of age. 58.6% had peripheral neuropathy, 66.2% volume overload, 48.3% had organomegaly, 19.8% had papiloedema, 46.6% had dermopathies and 34.5% had sclerotic bone lesions at presentation. The median time from diagnosis to ASCT was 7.8 mns (range 1–346) with 34.5% of patients receiving an ASCT >12 months from diagnosis. The graft source was PBSC in 100% of patients. Disease status at ASCT was: 32% CR/PR, 30% SD/MR/untreated and 5 in PD. Missing information on stage in 33% of the cases. The conditioning regimen was Melphalan ≥200mg/m2 in 52.5%, Melphalan <200mg/m2 in 9.3% (38.1 of data on dose is missing) and TBI-containing only 1 patient. Engraftment was seen in 112 (96.6%) patients with failed engraftment reported in 3 patients (2.5%). Details of the occurrence of engraftment syndrome are currently under collection and analysis though peri-engraftment fever was reported in 23.4% and pulmonary infiltrates in 4.8%. Haematological response was characterized as CR in 31%, PR in 20.7%, <PR in 20.7% and currently unknown in 27.6%. Best disease response, in terms of end-organ response is under evaluation. With a median follow-up of 30.1 mns (range 0.1–161), 90.5 % of patients are alive and only 8.6% of patients have relapsed. The non-relapse mortality was 6.9%. Causes of death: 5 died of infection, 2 from graft failure, 1 from cardiac toxicity. The 3-year probabilities of PFS and OS are 82% and 94%, respectively. The 5-year probabilities of PFS and OS are 80% and 92%, respectively. The data analyzed in this study, to-date, demonstrates that ASCT can be an effective and safe therapeutic modality for patients with POEMS syndrome. The role of high dose therapy compared with more conventional dose therapies warrants further investigation. Disclosures:No relevant conflicts of interest to declare.

International Myeloma Working Group consensus approach to the treatment of multiple myeloma patients who are candidates for autologous stem cell transplantation

AbstractThe role of high-dose therapy followed by autologous stem cell transplantation (ASCT) in the treatment of multiple myeloma (MM) continues to evolve in the novel agent era. The choice of induction therapy has moved from conventional chemotherapy to newer regimens incorporating the immunomodulatory derivatives thalidomide or lenalidomide and the proteasome inhibitor bortezomib. These drugs combine well with traditional therapies and with one another to form various doublet, triplet, and quadruplet regimens. Up-front use of these induction treatments, in particular 3-drug combinations, has affected unprecedented rates of complete response that rival those previously seen with conventional chemotherapy and subsequent ASCT. Autotransplantation applied after novel-agent-based induction regimens provides further improvement in the depth of response, a gain that translates into extended progression-free survival and, potentially, overall survival. High activity shown by immunomodulatory derivatives and bortezomib before ASCT has recently led to their use as consolidation and maintenance therapies after autotransplantation. Novel agents and ASCT are complementary treatment strategies for MM. This article reviews the current literature and provides important perspectives and guidance on the major issues surrounding the optimal current management of younger, transplantation-eligible MM patients.

Outcome after high-dose therapy with autologous stem cell rescue with BEAM for relapsed follicular lymphoma.

e18512 Background: The role of high-dose therapy with autologous stem cell rescue (HDT-ASCR) remains a major challenge in the management of patients (pts) with follicular lymphoma (FL), particularly in view of the undoubted clinical impact of rituximab and the advent of therapeutic options such as reduced intensity conditioning allotransplants. Cyclophosphamide/total body irradiation (Cy-TBI) is associated with a high incidence of secondary myelodysplasia/acute myeloid leukaemia (sMDS/AML) in heavily pretreated pts, but it is not known if the number of prior therapy lines also influences prognosis in pts treated with BEAM for relapsed FL. This is currently of special relevance to decide the best timing for this therapy as it is pts who did not receive 1st-line rituximab (R) that are presenting with recurrent FL. Methods: From 1997 to 2008, 80 pts (41M/39F; median age: 51 yrs, range: 31-67), including 30 with transformed FL (tFL), received HDT-ASCR with BEAM for relapsed FL at our center. Results: The median time from diagnosis to HDT was 41 months (range: 4-165). The median number of previous treatment lines was 3, 61% of the pts having received >3. Thirty-eight pts (49%) received R before HDT (as part of the 1st line therapy: 1; as part of the salvage therapy before BEAM: 28; as part of the HDT: 4). There was a trend for a higher use of R before BEAM in pts with FL (56%) in comparison with those with tFL (33%, p=0.05). After a median follow-up of 76 months (range: 14-160), 2 pts developed sMDS/AML. Five-year overall survival (OS) was 71% and progression-free survival (PFS) 44%. There were no differences in PFS or OS according to the number of previous treatment lines or episodes of disease. Likewise, histology at relapse did not impact on PFS or OS. Comparison with a historical control of pts treated with Cy-TBI showed no significant differences in PFS or OS. Conclusions: Deferring HDT with BEAM until 3rd response does not impair OS in pts with FL. 5-yr PFS (%) P value 5-yr OS (%) P value Histology FL (50) tFL (30) 43 45 0.5 75 63 0.1 Episodes 1-2 (58) >3 (22) 47 33 0.4 74 61 0.1 Treatment lines 1-2 (31) >3 (49) 49 41 0.5 79 65 0.1 Prior R Yes (38) No (42) 50 40 0.2 69 71 0.6 Conditioning regimen Cy-TBI (132) BEAM (80) 59 44 0.06 65 71 0.4