Upfront Autologous Stem Cell Transplantation Research Articles

Autologous Followed By Allogeneic Versus Tandem-Autologous Stem Cell Transplant in Newly Diagnosed FISH-del13q Myeloma

▪Background In multiple myeloma (MM), the introduction of novel compounds into first-line intensive treatment pathways has clearly improved patients’ prognosis. Very recently however, specific molecular cytogenetic abnormalities, lactate dehydrogenase elevation and International Staging System 3 disease were identified to be associated with dismal prognosis despite upfront autologous (auto) stem cell transplant (SCT). Consolidative allogeneic (allo) following initial auto SCT was shown to extend progression-free survival (PFS) as well as overall survival (OS) in some prospective studies on newly diagnosed MM patients (pts). Relatively little is known on the impact of cytogenetic features other than chromosome 13q deletion (del13q) on the outcomes of pts undergoing upfront auto followed by allo (auto/allo) SCT.Patients and methods When the DSMM V treatment program was designed del13q detected by fluorescence in situ hybridisation (FISH) was accepted as one of the distinct risk factors in MM. We therefore used FISH del13q to define the study’s “high-risk” group and aimed to compare tandem high-dose melphalan 200 mg/m² (Mel) with one cycle of Mel followed by reduced-intensity conditioning (RIC) allo SCT. Allocation to either transplant regimen was by availability of an HLA-matched (at least 9/10 matches) related (MRD) or unrelated donor (MUD). Initially, all pts underwent non-novel compound cytoreduction and chemomobilization of peripheral blood stem cells (PBSC). RIC allo SCT was prepared by fludarabine and melphalan (plus ATG in MUD cases). PFS was the primary endpoint. The study was powered to detect an improvement of 2-year PFS from 20% (tandem Mel) to 40.3% (HR, 1.769).Results 199 out of 225 del13q pts with a median age of 53 (range, 30 – 60) yrs who had been enrolled between 10/2001 and 03/2007, were included in the intent-to treat population. Allo SCT was performed in 126/199 pts (63%), 74 of whom (59%) received MUD allografts. At a median follow-up of 49.2 months (mo), 2-year PFS (calculated from day 1 of second SCT) was 59% with auto/allo SCT versus 47% with tandem Mel. Median PFS with auto/allo SCT was 34.5 mo versus 21.8 mo, respectively (p=.005). Two-year non-relapse mortality (NRM) associated with auto/allo SCT was 11.9%. As of yet, there is no difference in OS between the groups, with the median not yet reached for either transplant modality. PFS/OS in auto/allo SCT were independent of donor source (MRD vs MUD). As definitions of cytogenetic risk have evolved over time, we analyzed further FISH abnormalities in pts’ baseline samples: in addition to uniform del13q, 13.6% of pts displayed del17p. Median PFS for del13q/del17p pts after HD Mel was 6 mo versus not reached with auto/allo SCT, respectively (p=.0002). Median OS in del13q/del17p after HD Mel was 23.4 mo versus not reached, respectively (p=.011). In translocation (4;14)/del13q pts (20.7%), median PFS with tandem Mel was 19.3 mo versus 19.1 with auto/allo SCT, respectively (p=.251).Conclusions This prospective trial shows auto/allo SCT to significantly extend PFS when compared to tandem HD Mel in a large cohort of del13q MM pts. It is the first study to demonstrate allo SCT in MM can be safely performed from matched unrelated donors at a reasonable rate of NRM. Utilizing a comprehensive set of FISH cytogenetics, our data for the first time demonstrate allo SCT to specifically benefit patients with high-risk features (del13q/del17p). Incremental gain of PFS when compared to tandem Mel was more than 20 months. Extended OS data on the whole study will be presented. DisclosuresNo relevant conflicts of interest to declare.

Long Term Outcomes after Autologous Stem Cell Transplantation for Peripheral T Cell Lymphomas

Consolidative autologous stem cell transplantation (ASCT) is a commonly utilized treatment modality for peripheral T cell lymphomas (PTCL) and has been shown to improve progression free survival. The optimal timing of ASCT for PTCL is not well defined and studies have included upfront ASCT or ASCT at the time of relapse. However, long-term outcomes of ASCT, especially when used as upfront consolidation, have not been well described.Previously published data, including the one from our institution, (Smith S et al BMT. 2007;40:239-243) revealed inferior outcomes following ASCT in relapsed PTCL. We performed a retrospective study to describe our institutional experience in a relatively large cohort of patients with PTCL who were treated with ASCT (N=78) between 1996 and 2013 and had a median follow up of 55 months.Among these, 62% were male, 89% Caucasian and 84% had a Karnofsky performance score ³90. The subtypes included 26 peripheral T cell lymphomas (PTCL) (33%), 19 anaplastic large cell lymphoma (ALCL) alk- (24%), 13 ALCL alk+ (17%) 16 angioimmunoblastic T cell lymphoma (AITL) (21%) and 4 extranodal NK/T cell nasal type (5%). Prominent disease characteristics at diagnosis included stage III-IV in 80%, and IPI score of 0-3 in 73%. Only 26% had bone marrow (BM) involvement. Majority of the patients (76%) received 2 or more prior therapy. 99% of the transplants was performed using Busulfan, Cyclophosphamide, and Etoposide (Bu/Cy/VP16) preparative regimen. While 27 (35%) patients received ASCT as part of their initial treatment, 51 (65%) patients were transplanted after their disease had relapsed. About one third of our cohort (31%) attained a complete response (CR) post ASCT. The 5-year relapse rate (RR) for CR1, CR2 and PR1 were 22%, 53% and 66% (Figure 1) implying that both the disease status and response prior to transplant are key determinant factors for long-term outcome. The RR curve plateaued after 8 years indicating that a proportion of patients had attained a durable remission. At the time of analysis, 42% were alive. Disease relapse was the cause of death in 76% of the cases. Our 10-year RR, relapse free survival (RFS) and overall survival were 64%, 25% and 31% respectively. On univariate analysis disease status, BM involvement and stage were prognostic for RFS and OS, but only disease status (RFS: HR 2.27, p=0.023; OS: HR 4.75, p=0.006) and BM involvement (RFS: HR 3.10, p=0.019; OS: HR 2.94, p=0.018) retained significance on multivariate analysis. Moreover, disease status was also predictive for relapse in both univariate and multivariate analyses (HR 2.12, 95% CI 1.05-4.27, p=0.035).Conclusions: In a relatively large cohort of PTCL patients with long-term follow up after ASCT, upfront consolidative autologous stem cell transplantation in chemo sensitive patients resulted in lower RR and improved RFS and OS. [Display omitted] [Display omitted] DisclosuresHill:Millenium: Research Funding; Novartis: Research Funding.

Induction treatment with SMILE and consolidation with autologous stem cell transplantation for newly diagnosed stage IV extranodal natural killer/T-cell lymphoma patients.

The aim of this study was to investigate the impact of the induction treatment with SMILE (dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide) chemotherapy and consolidation with upfront autologous stem cell transplantation (ASCT) on clinical outcomes of patients with stage IV extranodal natural killer/T-cell lymphoma (ENKTL). We analyzed the treatment response to SMILE and toxicity, and explored the feasibility of upfront ASCT in 27 patients with stage IV ENKTL out of patients who were enrolled into our prospective cohort studies. The median age of patients was 45years (range: 17-65 years), and all patients had disseminated disease. The overall response rate to SMILE induction treatment was 59% (16/27) including nine complete responses. However, five patients died due to grade IV febrile neutropenia during SMILE and six patients did not respond to SMILE. Eleven patients could undergo ASCT, and there was no transplantation-related mortality. The survival outcome of patients underwent ASCT was better than patients who could not (P < 0.05). However, four patients relapsed even after ASCT, thus, the median overall survival was 10.6months, and the median progression-free survival was 5.1months. Pretreatment Epstein-Barr virus (EBV) DNA titer was only independent prognostic factor for overall survival. In conclusion, our results suggest SMILE followed by ASCT might be an effective treatment strategy for stage IV ENKTL. However, considering frequent occurrences of disease relapse and treatment-related mortality, additional efforts are required to improve treatment outcomes of stage IV ENKTL patients.

Upfront autologous stem-cell transplantation with melphalan, cyclophosphamide, etoposide, and dexamethasone (LEED) in patients with newly diagnosed primary central nervous system lymphoma.

Treatment of primary central nervous system lymphoma (PCNSL) improved in recent years. However, the high neurotoxicity and low survival rates associated with this condition remain unresolved. We report 13 consecutive patients with PCNSL for whom upfront melphalan, cyclophosphamide, etoposide, and dexamethasone (known as LEED) followed by autologous stem-cell transplantation (ASCT) was planned at the Anjo Kosei Hospital. All patients were pathologically diagnosed with diffuse large B-cell lymphoma and were negative for human immunodeficiency virus. All patients were to receive three cycles of high-dose methotrexate-based induction chemotherapy, two cycles of high-dose AraC-based chemotherapy, and LEED followed by ASCT. All 13 patients achieved a partial response, and the 3-year overall survival (OS) rate was 76.2 %. Seven of the 13 patients were alive at the last follow-up, without any adverse events, including neurotoxicity. Six of the 13 (46.2 %) patients underwent ASCT and the 3-year OS rate was 80.0 %. Although this study included only a limited number of patients, these preliminary signs of efficacy and tolerability merit further consideration. To make further improvements in survival, the rate of patients undergoing ASCT should be increased. Other prospective studies involving greater numbers of patients are required to confirm these findings.

Is there a role for therapy response assessment with 2-[fluorine-18] fluoro-2-deoxy-d-glucose–positron emission tomography/computed tomography in mantle cell lymphoma?

2-[Fluorine-18] fluoro-2-deoxy-d-glucose–positron emission tomography/computed tomography (FDG-PET/CT) scanning is used for response assessment in mantle cell lymphoma (MCL). However, its ability to predict outcome is debatable. We retrospectively evaluated the prognostic impact of interim and post therapy FDG-PET/CT scan on outcome of 58 consecutive MCL patients. Scans performed at diagnosis, mid-therapy, post-chemotherapy and post-transplant were reviewed and outcome analyzed. Median age was 59; MCL International Prognostic Index (MIPI) was low in 45%, intermediate in 41% and high in 14%. Thirty-four patients (58%) received R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone) or R-CHOP-like chemotherapy, 24 (42%) underwent upfront autologous stem-cell transplant (ASCT). Three-year overall (OS) and progression-free-survival (PFS) were 81% and 45%, respectively. No differences in OS or PFS between PET-positive and PET-negative groups both for interim and post-therapy scans were observed. We conclude that in patients treated with R-CHOP, using the International-Harmonization-Project criteria for FDG-PET/CT interpretation, there is no role for interim or post-therapy PET.

European Myeloma Network recommendations on the evaluation and treatment of newly diagnosed patients with multiple myeloma

Multiple myeloma management has undergone profound changes in the past thanks to advances in our understanding of the disease biology and improvements in treatment and supportive care approaches. This article presents recommendations of the European Myeloma Network for newly diagnosed patients based on the GRADE system for level of evidence. All patients with symptomatic disease should undergo risk stratification to classify patients for International Staging System stage (level of evidence: 1A) and for cytogenetically defined high- versus standard-risk groups (2B). Novel-agent-based induction and up-front autologous stem cell transplantation in medically fit patients remains the standard of care (1A). Induction therapy should include a triple combination of bortezomib, with either adriamycin or thalidomide and dexamethasone (1A), or with cyclophosphamide and dexamethasone (2B). Currently, allogeneic stem cell transplantation may be considered for young patients with high-risk disease and preferably in the context of a clinical trial (2B). Thalidomide (1B) or lenalidomide (1A) maintenance increases progression-free survival and possibly overall survival (2B). Bortezomib-based regimens are a valuable consolidation option, especially for patients who failed excellent response after autologous stem cell transplantation (2A). Bortezomib-melphalan-prednisone or melphalan-prednisone-thalidomide are the standards of care for transplant-ineligible patients (1A). Melphalan-prednisone-lenalidomide with lenalidomide maintenance increases progression-free survival, but overall survival data are needed. New data from the phase III study (MM-020/IFM 07-01) of lenalidomide-low-dose dexamethasone reached its primary end point of a statistically significant improvement in progression-free survival as compared to melphalan-prednisone-thalidomide and provides further evidence for the efficacy of lenalidomide-low-dose dexamethasone in transplant-ineligible patients (2B).

R-CHOP chemoimmunotherapy followed by autologous transplantation for the treatment of diffuse large B-cell lymphoma.

BackgroundWe investigated factors that influence outcomes in diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab combined with the CHOP regimen (R-CHOP) followed by upfront autologous stem cell transplantation (Auto-SCT).MethodsWe retrospectively evaluated survival differences between subgroups based on the age-adjusted International Prognostic Index (aaIPI) and revised-IPI (R-IPI) at diagnosis, disease status, and positron emission tomographic/computerized tomographic (PET/CT) status at transplantation in 51 CD20-positive DLBCL patients treated with R-CHOP followed by upfront Auto-SCT.ResultsPatients had either stage I/II bulky disease (5.9%) or stage III/IV disease (94.1%). The median patient age at diagnosis was 47 years (range, 22-66 years); 53.3% and 26.7% had high-intermediate and high risks according to aaIPI, respectively. At the time of Auto-SCT, 72.5% and 27.5% experienced complete (CR) and partial remission (PR) after R-CHOP, respectively. The median time from diagnosis to Auto-SCT was 7.27 months (range, 3.4-13.4 months). The 5-year overall (OS) and progression-free survival (PFS) were 77.3% and 72.4%, respectively. The 5-year OS and PFS rates according to aaIPI, R-IPI, and PET/CT status did not differ between the subgroups. More importantly, the 5-year OS and PFS rates of the patients who achieved PR at the time of Auto-SCT were not inferior to those of the patients who achieved CR (P=0.223 and 0.292, respectively).ConclusionSurvival was not influenced by the aaIPI and R-IPI at diagnosis, disease status, or PET/CT status at transplantation, suggesting that upfront Auto-SCT might overcome unfavorable outcomes attributed to PR after induction chemoimmunotherapy.

Prognostic impact of monocyte count at presentation in mantle cell lymphoma - response to Georgeet al

The use of front-line aggressive strategies including autologous stem cell transplantation (ASCT) and the introduction of rituximab represented major advances in the management of mantle cell lymphoma (MCL) and may improve the long-term outcome in these cases (Geisler et al, 2012). However, a large proportion of MCL patients are not young or fit enough to undergo transplantation and often have a short survival. Moreover, the identification of a subset of patients with indolent disease course questioned the need of ASCT upfront for all MCL patients, and highlighted the importance of prognostic indexes for patient risk stratification (Vose, 2012). We recently reported the independent prognostic value of the absolute monocyte count (AMC) at diagnosis in MCL patients in a retrospective study of 97 consecutive cases (Aprile von Hohenstaufen et al, 2013). Our findings were then confirmed in a series of 132 MCL patients from the Mayo Clinic (Porrata et al, 2013). In our series, only a small minority (6%) was treated with ASCT (Aprile von Hohenstaufen et al, 2013), while the Mayo Clinic report included 43 (33%) cases treated with stem cell transplant, but no specific information on the outcome of the transplanted patients was given (Porrata et al, 2013). The letter of George and colleagues, expressly focused on 37 MCL cases treated with rituximab-containing chemotherapy followed by ASCT upfront, may therefore be relevant. They postulate that front-line aggressive immunochemotherapy followed by ASCT may overcome the detrimental effect of the high monocyte count at diagnosis in MCL patients. Indeed, targeting not only the tumour B-cell but also the microenvironment may be critical for effective disease control in MCL, as suggested by the clinical activity of lenalidomide in relapsing patients (Goy et al, 2012). However, the visual difference in the estimated survival curve tails in the analysis reported by Anupkumar et al might suggest that the lack of statistical significant difference between curves in this report could be related to the small sample size (37 patients), and that the study was probably not powered to show any difference. Larger studies are needed to confirm their interesting hypothesis and will also be useful for the definition of the most accurate AMC cut-off value, which is still a controversial issue (Tadmor et al, 2013).

Single Centre Analysis Of Autologous Stem Cell Transplant Outcomes In Multiple Myeloma In 338 Consecutive Patients: Maintenance/Consolidation Is Associated With Superior Survival, But Early Relapse Is The Single Most Important Predictor Of Survival and May Override Genetic Risk

IntroductionHigh dose therapy with autologous stem cell transplant (ASCT) represents the standard of care for untreated patients with multiple myeloma (MM) who are young and fit. Novel agents are changing the landscape of pre- and post-ASCT therapies, but benefits may not apply to all patients. We report 338 MM patients treated with up-front ASCT at University College Hospital London from September 1993 - December 2010. ResultsPatient characteristics are described in Table 1. 90 (27%) received novel agents (thalidomide, bortezomib or lenalidomide) prior to transplant, and the remainder had VAD (vincristine, doxorubicin, dexamethasone)-based regimens. Most patients (64%) had 1 line of therapy prior to ASCT, 26% had 2 lines and 11% >/=3 lines. Responses to first line therapy were 24% >/= VGPR, 45% PR, ORR 69%. Best response prior to ASCT was: 27% >/= VGPR, 59% PR, ORR of 86%. 42 patients (12%) had stable disease or worse pre-ASCT.Transplant-related mortality at 100 days was 3.3%, 166 patients (49%) attained >/= VGPR at 3 months and 126 (37%) PR. Maintenance/consolidation regimens were interferon or thalidomide-based. Median follow-up was 6.1 yrs, progression-free survival (PFS) 2.0 yrs and overall survival was (OS) 5.8 yrs from ASCT and 6.8 yrs from diagnosis. 266 patients have relapsed, and 169 have died.On multivariate analysis, international staging system (ISS) stage 1, female gender, use of novel agents first-line and disease response (>/=VGPR pre- and 3 months post-ASCT) predicted longer PFS (p's < 0.05). Timing of relapse was the most important predictor of survival (median OS 1.6yrs if relapse within 12 months vs 7.2yrs if not, HR = 6.7, p<0.001. Shorter OS was also associated with male gender, advanced ISS, non-IgG isotype, CD56-negativity, older age at ASCT, <PR post ASCT (p's < 0.05) and later year of ASCT (median OS 6.2 yrs 2005-10 v 4.9 yrs 1993-2004, HR = 0.8, p = 0.006). Use of novel agents at first line predicted longer OS on univariate but not multivariate analysis. Prior lines of therapy and time from diagnosis to ASCT did not impact PFS or OS. Post-ASCT maintenance/ consolidation therapy was associated with prolonged PFS (adj HR 0.6, [95% CI 0.4-0.8] and OS (adj HR 0.5 [0.3-0.7]. Adverse cytogenetics (CGN) was associated with reduced PFS (HR 1.7 [1.1 – 2.7]) and OS (HR 2.2 [1.2-4.0]). In patients with adverse CGN who did not relapse early, OS was similar to patients with standard risk CGN (OS 5.6 yrs v 7.2 yrs, p = NS, Fig 1). Outcomes for those relapsing early were similar in pre-2005 and later (>/= 2005) cohorts (OS 1.6 v 1.7 yrs, p = NS, Fig 2). [Display omitted] [Display omitted] Median post-relapse survival (PRS) was 2.6 yrs. Factors predicting longer PRS included IgG isotype, CD56-positivity, later year of ASCT and of relapse, younger age at ASCT, longer PFS from ASCT and the use of novel agents at relapse. Patients relapsing in 2005 and later had longer PRS (3.6 v 1.3 yrs, HR = 0.4, p = 0.0001). Prior treatment with maintenance/consolidation did not impact PRS (PRS 3.1 v 2.4 yrs, p = NS). ConclusionsThese data indicate that post-ASCT strategies and choice of agent at relapse may be as important determinants of outcome as disease response pre-ASCT. Early relapse was the most important predictor of death following ASCT and may outweigh the impact of adverse CGN. The adverse outcome of patients relapsing early is not salvaged using contemporary treatment strategies at relapse. The benefit of CD56 expression on OS, but not on PFS suggests this denotes disease that remains chemo-responsive disease through relapses. Maintenance or consolidation therapy following ASCT appears to prolong PFS and OS without impacting post-relapse survival. Disclosures:No relevant conflicts of interest to declare.

Lenalidomide and Dexamethasone Alone Is Equivalent To Lenalidomide and Dexamethasone With Autologous Stem Cell Transplant In Newly Diagnosed Multiple Myeloma: Interim Study Results Of a Randomized Trial

The current standard of care for patients with newly diagnosed multiple myeloma (MM) aged less than 65 years is high-dose chemotherapy combined with autologous stem cell transplantation (ASCT) based on improved progression free survival (PFS) and overall survival (OS) compared with conventional chemotherapy. The introduction of novel agents, for example lenalidomide and bortezomib over the last decade, has substantially improved MM outcomes providing similar response rates to ASCT. As a consequence, the role of upfront ASCT has become more controversial. Therefore, this randomized clinical trial aims to determine the role of upfront ASCT in patients with newly diagnosed MM patients receiving lenalidomide and low-dose dexamethasone as induction therapy.Patients enrolled into the study were aged ≥18 years with newly diagnosed MM, transplant eligible, and meeting CRAB criteria. Patients were randomized to receive 4 cycles of lenalidomide (25 mg days 1–21) plus low-dose dexamethasone (40 mg days 1, 8, 15, 22) followed by ASCT conditioned with 200 mg/m2 melphalan (Arm A; LD+ASCT) or 8 cycles of lenalidomide plus low-dose dexamethasone (Arm B; LD alone). Both groups received lenalidomide maintenance therapy 10-15 mg for up to 2 years. Patients in both treatment arms received stem cell collection after 4 cycles of lenalidomide plus dexamethasone if at least a partial response was achieved. Patients with stable disease or progressive disease (PD) went off study. The primary objective was to compare the best response between patients treated with lenalidomide plus dexamethasone followed by ASCT and patients treated with lenalidomide plus dexamethasone alone. Secondary objectives were to compare the duration of response (DOR), PFS, and OS between the two treatment arms and to evaluate the secondary malignancies in both arms.Fifty patients with newly diagnosed MM were randomized between February 2008 and May 2013, and 47 patients were eligible for evaluation in this interim analysis; 25 patients randomized to Arm A (LD+ASCT) and 22 patients randomized to Arm B (LD alone). Overall, patients had a median age of 61.6 years (range 48–75), 60% were male, 34% ISS Stage I, 49% ISS Stage II, 17% ISS Stage III. The data were analyzed according to the IMWG response criteria (Blood. 2011 May 5;117(18):4691-5). In an intention-to-treat analysis, there was a trend towards improved overall response rate (ORR) in patients receiving LD+ASCT (96%) compared with patients receiving LD alone (77%; p=0.08) (Table 1). After a median follow-up of 36.8 months (range 1.1–62.7), the median DOR was 13.9 months (95% confidence interval [CI] 4.0–34.1) in the LD+ASCT group compared with 21.2 months (95% CI 11.0–22.9) in the LD group. Overall, 18 patients have PD (10 patients in the LD+ASCT arm and 8 patients in LD arm), and 8 patients have died (4 patents in the LD+ASCT arm and 4 patients in the LD arm). Median PFS for LD+ASCT versus LD was 17.0 months (95% CI 15.5–not estimable) versus 25.2 months (95% CI 9.0–not estimable; p=0.94). Median OS for LD+ASCT versus LD was 57.6 months (95% CI 48.0–not estimable) versus not reached (p=0.94). Two patients in the LD alone arm developed a secondary malignancy, including 1 patient with myelodysplastic syndrome (MDS) 13 months after the start of therapy.This interim analysis of an ongoing randomized clinical study comparing lenalidomide plus low-dose dexamethasone induction with and without upfront ASCT in patients with newly diagnosed MM suggests that addition of ASCT resulted in a trend towards improved ORR. This did not result in a significant difference in terms of PFS or OS between the two treatment arms. In contrast there was a trend of better DOR in the LD alone arm. The data show that LD alone can achieve similar results as LD+ASCT, however careful interpretation is required due to the low patient number and relatively short follow-up. The incidence of secondary malignancy was low, including the development of 1 MDS. Disclosures:Schecter:Celgene: Honoraria, Speakers Bureau. Mapara:Celgene: Research Funding, RO1 Other. Lentzsch:Celgene: Research Funding.Table 1Best response and survivalBest response, n (%)Arm A (LD+ASCT) (n=25)Arm B (LD alone) (n=22)Stringent complete response1 (4.0)1 (4.6)Complete response4 (16.0)5 (22.7)Very good partial response8 (32.0)6 (27.3)Partial response11 (44.0)5 (22.7)Stable disease1 (4.0)5 (22.7)Progressive disease00Overall response rate24 (96.0)17 (77.3)

Frontline Intensive Chemotherapy Brings Survival Benefit In Young, Risky Patients With Follicular Lymphoma: Pair-Matched Analysis From The Czech Lymphoma Study Group (CLSG) Database

BackgroundFollicular lymphoma (FL) is a disease with very heterogeneous course ranging from the indolent forms to rapidly progressive cases with poor outcome. Optimal therapy in FL patients with high tumor burden is immunochemotherapy (R-CHOP is the most frequent regimen used), followed by maintenance treatment. Data from randomized prospective studies (PRIMA) showed poorer outcome in those with high risk disease in terms of lower CR rate, higher risk of relapse and lower efficacy of maintenance therapy. Data comparing up-front intensive approach in younger fit patients and R-CHOP are limited. AimTo analyze long term results of intensive treatment protocol (R-sequential chemotherapy) in comparison with age, FLIPI and maintenance delivery matched (R-CHOP) controls. MethodsHere we analyzed data of 48 prospectively enrolled FL patients who were treated by sequential (R-SQ) chemotherapy with or without up-front autologous stem cell transplant (ASCT) as a part of stratified risk adapted treatment in one institution. For R-SQ regimen were indicated patients<65 years with INT-FLIPI (with at least 2 additional risk factors: bulk and/or elevated B2M>3mg/L and/or thymidine kinase>15 IU/L) or HIGH-FLIPI patients (irrespective of additional risk factors). R-SQ protocol consists of alternating three cycles of etoposide-doxorubicine regimen (PACEBO), one methotrexate-ifosfamide regimen (IVAM), and one cycle of high dose cytarabine regimen (HAM). Remission was consolidated with 6th cycle of chemotherapy (PACEBO) in INT-FLIPI patients (n=22, 46%) or with ASCT with BEAM-200 conditioning (n=26, 54%) in HIGH-FLIPI patients. Maintenance immunotherapy was applied for historical reasons in 24 patients (50%). Controls were randomly selected from the Czech Lymphoma Study Group (CLSG) database from 626 cases with confirmed FL grade I to IIIa, treated with R-CHOP. Pair matching was performed on 1:3 basis, controls were matched by age, FLIPI and rituximab maintenance application. In the end, we analyzed intensive SQ-group (n=44) and standard control R-CHOP-group (n=144). Maintenance therapy was delivered to 24 patients (50%) in R-SQ group and to 72 patients (50%) in R-CHOP-group (P=1.00). ResultsMedian age of SQ-group was 47.6 years compared to 48.7 years in R-CHOP (P=0.44), FLIPI index was equally distributed: INT-FLIPI (43% vs 43%), HIGH-FLIPI (57% vs 57%, P=1.00). Treatment response quality was higher in SQ-group than in R-CHOP-group: CR/CRu 93.8% vs 70%, PR 6.2% vs 23% and SD/PD 0% vs 8% respectively (P=0.01). During the follow-up, (median 3.5 and 6.1 years in R-CHOP and SQ-group respectively, P<0.01) 10 patients (20.8%) relapsed or progressed in the R-SQ-group, and 41 (29%) in the R-CHOP-group (P=0.01). Only two of 48 patients (4.2%) died in the R-SQ-group, whereas twelve (8.7%) died in the R-CHOP-group (P=0.03). Five-year progression-free survival (PFS) was superior in the R-SQ-group with 78.5% (95% CI 0.66-0.91) survival compared to 53.8% (95% CI 0.43-0.65, P=0.005, HR=0.37) in the R-CHOP-group. Five-year overall survival (OS) was 100% in the R-SQ-group and 91.9% (95% CI 0.86-0.97, P=0.027, HR=0.18) in the R-CHOP group. When analyzing patients who received maintenance therapy, we found no difference in OS (P=0.13), but there was still significant difference in 5-year PFS in favor of the R-SQ-arm (88.4% and 58.2%, P=0.034). ConclusionsIn risky FL patients, intensive front-line therapy brings about 24% advantage in CR rate, about 25% higher 5-year PFS (reduces risk of relapse/progression by 62%) and about 10% advantage in 5-year OS (reduces risk of death by 82%). Maintenance immunotherapy application overshadows OS but not PFS advantage of intensive chemotherapy. Finally, in younger physically fit risky patients, more intensive induction regimen leads to superior disease control a remission duration compared to standard R-CHOP. AcknowledgmentSupported by grants: LF-2013-004, IGA NT12193-5/2011 and PRVOUK-27/LF1/1. We would like to thank to all referring physicians: Jan Pirnos (Ceske Budejovice), Katerina Kubackova (FN Motol), Lucie Barsova (Liberec), Petr Kessler (Pelhrimov), Jitka Jakesova (Pribram), Milan Lysy (Usti n. Labem), Jindra Ciberova (Znojmo), Dagmar Adamova (Opava), Milan Matuska (Ostrava), Martin Brejcha (Novy Jicin). [Display omitted] Disclosures:Trneny:Roche: Honoraria, Research Funding.

Peripheral T-Cell Lymphomas (PTCL) Treated With Or Without Upfront Autologous Stem Cell Transplantation: Results Of a Retrospective Single Center Analysis

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of rare diseases, characterized by an aggressive behavior and a poor clinical outcome. High-dose therapy followed by autologous stem cell transplantation (ASCT) has been used as salvage and upfront treatment with conflicting results. However, no standard therapy has so far been established due to the lack of randomized studies.The records of 54 untreated patients with a confirmed diagnosis of PTCL managed at our Institute between 2001 and 2011 were reviewed. The histologic subtypes were: 37 (68%) peripheral T-cell lymphomas unspecified (PTCL-U), 13 (24%) anaplastic large cell lymphomas (ALCL), of which 4 (30%) ALK-positive, 2 (4%) angio-immunoblastic lymphomas (AITL) and 2 (4%) enteropathy-associated T-cell lymphomas (EATL). The clinical characteristics were: median age 56 years (range 18-79); 40 men and 14 women; 13 (24%) and 41 (76%) patients were, respectively, in Ann Arbor stages I-II and III-IV. An elevated serum LDH was present in 33% of patients, 48% had B symptoms and 24% had a bone marrow involvement. The ECOG performance status was 2-3 in 28% of patients. According to the International Prognostic Index (IPI) and the prognostic index for T-cell lymphomas (PIT), 11% and 22% were classified as low risk, 30% and 33% as low-intermediate risk, 12% and 33% as high-intermediate risk and 29% and 12% as high risk, respectively. CHOP-like regimens were given to 32 (59%) patients, 14 of whom received the CHOEP regimen. The remaining 22 (41%) patients were treated with more intensive third generation regimens (MACOP-B like). ASCT was planned as upfront consolidation therapy for 16/54 (30%) patients.A complete response (CR) was obtained in 30/54 (55.5%) patients, a partial response in 7 (13%), while 17 (31.5%) patients showed a lymphoma progression during induction therapy. No difference in terms of CR rate was observed between the CHOP-like and MACOP-B-like regimens. At a median follow-up of 19 months (range 3-138), the 5-years OS and 5-years PFS were 32% (95% CI 25.3-38.5) and 27% (95% CI 20.2-34.5), respectively. At univariate analysis, bone marrow involvement (p=0.003), PIT high risk group (p<0.001) and lymphocytopenia (p=0.06) predicted a shorter PFS. Five of 16 (31%) patients did not receive the planned ASCT consolidation due to early progression. Patients who received an ASCT as consolidation therapy presented a slightly better 5-year PFS than patients treated with chemotherapy alone (95% CI 37.7% vs 25%; p=0.08).The prognosis of PTCLs remains poor despite the use of intensive chemotherapy regimen including upfront ASCT. More active induction chemotherapy regimens, including novel agents, should be designed in an attempt to increase the quality of response before ASCT consolidation therapy. Disclosures:No relevant conflicts of interest to declare.

Cyclophosphamide, Bortezomib and Dexamethasone (CyBorD) Induction Therapy For Newly Diagnosed Light Chain Amyloidosis

Cyclophosphamide, Bortezomib and Dexamethasone (CyBorD) Induction Therapy For Newly Diagnosed Light Chain Amyloidosis

Serum Ferritin Level As a Prognostic Marker For Peripheral T-Cell Lymphoma.

BackgroundPeripheral T-cell lymphoma (PTCL) is known to have an aggressive clinical course and be associated with poor survival. The International Prognostic Index (IPI) score and the Prognostic Index for T-cell lymphoma (PIT) have been suggested as methods to predict the prognosis of PTCL. Ferritin, the iron storage protein, is associated with chronic inflammation. Although higher levels of serum ferritin are detected in many cancer patients, the significance of elevated serum ferritin as a prognostic factor for lymphoma has yet to be established. Thus, our retrospective study aimed to examine the prognostic value of serum ferritin levels in PTCL. Patients and MethodsSerum ferritin levels were evaluated in 78 patients with PTCL, who were treated with anthracycline-containing regimens in 8 institutions affiliated to the Yokohama City University Hematology Group between 1998 and 2011. Fourteen patients received cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP); 44 receivedpirarubicin, cyclophosphamide, vincristine, and prednisone (THP-COP); 3 received THP-COP followed by radiotherapy; 3 received up-front autologous peripheral blood stem cell transplantation; and 14 received THP-COP at 2-week intervals in a clinical trial. ResultsThe study population comprised 50 male and 28 female patients with a median age of 64 years at the time of diagnosis (range, 16–83 years). With regard to the PTCL subtype, 39 patients had PTCL, not otherwise specified, and 39 had angioimmunoblastic T-cell lymphoma. Twelve patients had localized disease and 66 patients had advanced Ann Arbor stage lymphoma. Twenty-three patients had a poor Eastern Cooperative Oncology Group performance status (PS) of 2–4. B symptoms were present in 34 patients. Risk stratification according to the IPI was as follows: low risk, 9 patients; low–intermediate risk, 20 patients; high–intermediate (HI) risk, 30 patients; and high (H) risk, 19 patients. According to the PIT, 4 patients were categorized into group 1, 25 into, group 2 , 28 into, group 3, 21 into, as group 4. The median observation period for the surviving patients was 50 months. The median serum ferritin level was 183 ng/ml (range, 5–14,622 ng/ml). Factors associated with a poor overall survival (OS) in univariate analysis were HI and H risk status with regard to IPI (P = 0.024), assignment to group 3 or 4 with regard to PIT (P = 0.017), poor performance status (P< 0.001), and ferritin levels ≥ 300 ng/ml (P< 0.001). The 4-year OS rate of all 78 patients was 54%. The 4-year OS rate was poorer in patients with serum ferritin levels ≥300 ng/ml (n = 21) than in those with serum ferritin levels< 300ng/ml (n = 57; 22% vs. 65%; P< 0.001) (Figure). Multivariate analysis including each factor comprising the IPI (age, lactate dehydrogenase level, PS, Ann Arbor stage, and number of extranodal lesions), gender, bone marrow involvement, and serum ferritin level showed that poor PS (P = 0.002, relative risk [RR] 3.6) and a serum ferritin level ≥300 ng/ml (P = 0.014, RR 2.7) were independent risk factors for poor OS. [Display omitted] ConclusionThe serum ferritin level is a useful prognostic marker for PTCL. Disclosures:No relevant conflicts of interest to declare.

Simplified MIPI Is a Valid Prognostic Index In The Rituximab Era: Multicenter MCL Study In Japan

BackgroundMantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma (NHL) which is characterized by the t(11;14)(q13;q32) translocation leading to overexpression of cyclin D1 that consists of around 3% of NHL. Most cases are diagnosed at advanced stage and despite the progress in the treatment, the prognosis remains poor. Appropriate prognostification of the disease is essential to consider risk stratified treatment to improve the outcome. Although MCL international prognostic index (MIPI) has been reported as the specific prognostic index of MCL, most of the patients included in the study received chemotherapy without rituximab. Validation of MIPI in rituximab era has been done by several studies but the result remains controversial. Patients and MethodsTo evaluate the treatment outcome and prognostic factors of MCL in Japan, we conducted a multicenter retrospective study. Medical records of 633 patients with MCL newly diagnosed and treated from 63 hospitals between 1992 and 2012 were reviewed and analyzed. Pretreatment characteristics and treatment regimens were evaluated for their association with overall survival (OS) and progression free survival (PFS) by hazard ratio (HR). Since the patients received various chemotherapy regimens, treatment were adjusted to analyze prognostic factors. ResultsThe median age of patients was 66 years old (range 22-92). Ninety percent of the patients were in stage III/IV, 70% had bone marrow involvement and 12% had poor performance status. According to the simplified MIPI (s-MIPI), 191 patients (32%) were classified as low risk, 233 patients (39%) were classified as intermediate risk and 169 patients (29%) were classified as high risk. Among the patients, 504 patients (82%) received rituximab containing chemotherapy, 55% received CHOP-like regimen, 32% received high-dose Ara-C containing regimen (HDAC) and 17% received autologous stem cell transplantation (ASCT) at the first-line treatment. With a median follow up duration of 43.4 months, overall 3-years PFS and OS was 36% and 73%, respectively. By limiting the analysis to the patients who received rituximab at the first-line treatment, s-MIPI was still a valid prognostic index for both PFS and OS even in the rituximab era (Figure), with 3-years PFS for low, intermediate and high MIPI of 62%, 36% and 14%, respectively. Multivariate analysis by Cox model revealed that Hb<12mg/L (HR: 1.4 [1.0-2.0]), beta 2-microglobulin≥4.0 µg/L (HR: 2.4 [1.4-4.0]) and total protein<6.0g/dl (HR: 1.8 [1.2-2.9]) were significantly associated with shorter OS independent to s-MIPI. With the stratification by s-MIPI at the analysis, treatment regimen was significantly associated with the outcome in rituximab era that 3-years PFS for CHOP, CHOP+ASCT, HDAC, HDAC+ASCT of 21%, 54%, 52% and 76%, respectively. HDAC regimen was significantly associated with longer PFS than CHOP regimen (HR: 0.40 [0.31-0.52]). With focusing on ASCT, upfront-ASCT were associated with longer PFS both in CHOP (HR: 0.39 [0.19-0.81]) and HDAC regimen (HR: 0.66 [0.42-1.1]). [Display omitted] Conclusions-MIPI is a valid prognostic index even in the rituximab era. We also identified three prognostic factors independent to s-MIPI including anemia, high beta 2-microglobulin and low total protein. Upfront ASCT showed survival benefit both in CHOP and HDAC regimen. Disclosures:No relevant conflicts of interest to declare.

P2–111 - Up-Front Autologous Stem Cell Transplantation for Elderly Patients with Diffuse Large B-Cell Lymphoma

P2–111 - Up-Front Autologous Stem Cell Transplantation for Elderly Patients with Diffuse Large B-Cell Lymphoma

Low Uptake of Upfront Autologous Transplantation for Myeloma in a Jurisdiction With Universal Health Care Coverage: A Population-Based Patterns of Care Study in Australia

Guidelines for the management of symptomatic multiple myeloma (MM) recommend upfront autologous stem cell transplantation (ASCT) for transplant-eligible patients. Using population-based data, we examined the characteristics of transplant-eligible patients who do not undergo upfront ASCT. Altogether, 686 newly diagnosed MM cases were identified through the population-based central cancer registry in Victoria, Australia from 2008 to 2009. We performed a detailed review of clinical notes and follow-up for at least 12 months after diagnosis for a subset of 225 patients who were aged< 70 years at diagnosis and had symptomatic MM. Of these 225 patients, 123 (55%) proceeded to receive upfront ASCT. Patient and disease factors associated with not receiving upfront ASCT were the presence of severe medical comorbidities, MM-associated renal impairment, and initial referral to a medical oncologist rather than a hematologist. Place of residence (rural vs. metropolitan) was not significant. Of 121 patients aged< 65 years at diagnosis who had minor or no comorbidities, only 75 (62%) proceeded to upfront ASCT. A substantial percentage of apparently transplant-eligible patients with newly diagnosed MM do not proceed to upfront ASCT. Community practice appears to diverge from clinical guidelines. Thereasons for this divergence require further study but reasons may include perceptions of toxicity vs. benefits of upfront ASCT.

Upfront Autologous Stem Cell Transplantation for Untreated High-Risk Diffuse Large B-Cell Lymphoma in Patients Up to 60 Years of Age

Although rituximab added to CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) is the standard chemotherapy for untreated DLBCL, its therapeutic effect is limited in younger patients with high-intermediate risk or high-risk disease according to the age-adjusted international prognostic index. In fact, the efficacy and safety of HDT plus rituximab followed by ASCT for such patients remain unclear. We retrospectively investigated the safety and effectiveness of HDT/ASCT in patients with untreated DLBCL. Twenty-two patients, aged 60 years and younger, with untreated DLBCL (classified as high-intermediate [n=14 (64%)] or high [n=8 (32%)] risk) underwent upfront HDT/ASCT between January 2004 and December 2008, achieving either a complete response (CR; n= 15 (68%)) or a partial response (PR; n= 7 (32%)). The 5-year overall survival rate was 81.0% and the progression-free survival rate was 73.0%, with no significant difference between risk groups based on the international prognostic index. The most common nonhematologic toxicity was febrile neutropenia [n=9 (41%)]. The cause of all 3 fatalities was exacerbation of the underlying disease, and no treatment-related mortality was observed. No variables with a significant influence on overall survival were identified, but a correlation of the treatment response before transplanation with progression-free survival was suggested (CR vs. PR: 92% vs. 30%, P= .002). These results suggest that adding rituximab to upfront HDT/ASCT is feasible and can improve the outcome in untreated patients with poor-prognosis DLBCL. In the future, upfront HDT/ASCT should be more extensively evaluated in clinical trials.

A Retrospective Study to Evaluate the Survival Rates in R-CHOP Chemotherapy Followed by Autologous Stem Cell Transplantation for the Treatment of Diffuse Large B Cell Lymphoma

AbstractAbstract 4517Prognosis in diffuse large B cell lymphoma (DLBCL) is highly associated with the International Prognostic Index (IPI) score, which was proposed to assign prognosis to patients with aggressive non-Hodgkin lymphoma undergoing treatment with doxorubicin-containing chemotherapy. The addition of rituximab to CHOP or CHOP-like regimens has resulted in significant improvements in the overall survival (OS) rate of CD20 positive DLBCL. In addition, the original IPI scoring system has been validated even in patients receiving rituximab-based chemotherapy. However, OS and progression-free survival (PFS) in patients with high-intermediate or high IPI DLBCL were not satisfactory, and the upfront autologous stem cell transplantation (ASCT) was reported to improve the survival rates in these patients subset. Therefore, we retrospectively evaluated the survival rates in patients with DLBCL with CD20+, who were treated with R-CHOP followed by ASCT.We analyzed 40 DLBCL patients who underwent an ASCT, reported to the Korean Blood and Marrow Transplant Registry between 2005 and 2011 by 12 centers. Patients characteristics at diagnosis: 60% male, 5% stage II with bulky disease, 95% stage III or IV, 42.5% bone marrow involvement, 65% high-intermediate or high risk by IPI score. Patients characteristics at ASCT: median age 47 years (range, 23–66) and 82.5% of patients received ≥6 cycles of R-CHOP. Response to R-CHOP: 62.5% CR and 37.5% PR. 17.5% of patients received involved field radiotherapy prior to ASCT for bulky disease or residual lymphoma. Disease status at ASCT: 72.5% CR and 27.5% PR. Median time from diagnosis to ASCT was 7.85 months (range, 4.4–16.1).Median follow-up period from diagnosis was 36.2 months (range, 6.3–84.8). 2-year estimates of PFS, OS and relapse from diagnosis were 73.8%, 86.4% and 24.3%, respectively. 5-year estimates of PFS, OS and relapse were 70.8%, 68.3% and 27.4%, respectively. 3-year estimates of PFS and OS according to IPI score were not significantly different among 4 risk groups (P=0.890 and P=0.855, respectively).The upfront ASCT following R-CHOP induction therapy may improve survival for patients with advanced high risk DLBCL. Prospective evaluation of the treatment outcome of R-CHOP followed by ASCT is needed for high risk DLBCL on a large scale. Disclosures:No relevant conflicts of interest to declare.

Population Survey of Mantle Cell Lymphoma (MCL) in British Columbia (BC) – A Heterogeneous Disorder with Improved Outcomes in the Modern Era

Abstract 1602 Introduction: MCL presents a therapeutic challenge remaining incurable with standard therapy. Most pts exhibit aggressive behaving advanced (adv) stage disease at diagnosis and require multi-agent chemotherapy, while others may have an indolent course. Improved outcomes with rituximab (R) and autologous stem cell transplant (ASCT) have been reported for select pts within the context of small clinical trials. In the province of BC, a new policy was introduced in 2003 recommending upfront ASCT for all eligible pts with adv stage MCL. This largely coincided with the availability of R which was included in the protocol: 6 cycles R-CHOP induction followed by ASCT and 2 cycles R maintenance (R weekly × 4 at 2 and 6 mo). The aim of this study was to review the clinical profile of MCL within a non-selected population of pts and to evaluate outcomes before and after this policy change. Methods: Using the BC Cancer Agency Centre for Lymphoid Cancer database, we identified all pts diagnosed with MCL between Jan 1990 and Dec 2010. Pathology was centrally reviewed and clinical data was retrieved from the database and medical records. Within this grp, we identified a SCT eligible cohort (<66 y with adv stage, excluding pts initially observed) and outcomes were evaluated in the pre and post SCT era, based on the policy initiation date of Jan 2003. Results: In total 535 pts were identified, median age 67 y (range 22–94), 71% male, 88% adv stage, 8% limited (lim) stage (stage I/II, bulk 10 y), mainly diagnosed prior to SCT policy (where f/up is shorter) and were treated with various regimens. Within this grp, median age was 57 y and 28% had lim stage, but no obvious associated clinical parameters were noted. To evaluate the impact of initial SCT, we compared outcomes in SCT eligible pts (n=179), diagnosed prior to (pre-SCT, n=93) and following its introduction in 2003 (post-SCT, n=86). Clinical characteristics were comparable between the pre-SCT and post-SCT grps; median age 56 y, MIPI score 20% high, 28% intermed, 52% low. Within the pre-SCT grp, initial treatment included CHOP-like chemo (n=46), intensive chemo (n=20), non-anthracycline-based tx (n=20) and SCT (n=3, 1 allo; received prior to policy initiation), median f/up 11 y. Within the post-SCT grp, initial treatment included SCT (n=50, 2 allo), CHOP-like chemo (n=31), non-anthracycline-based tx (n=5), median f/up 4.4 y. Thirty-six post-SCT pts did not undergo SCT (13 co-morbidities, 13 progressive disease during induction, 6 unknown/not offered, 4 declined). R was received by 8/93 (9%) pre-SCT pts and 81/86 (94%) post-SCT pts. Based on era of treatment, outcomes were significantly improved in the post-SCT grp compared with the pre-SCT grp, median OS not reached v 3.4 y, p=0.001 (5-y OS 58% v 34%) and median PFS 3.5 y v 1.3 y, p<0.001 (5-y PFS 38% v 16%). (see figure) An analysis based on actual initial treatment received (SCT v no-SCT), demonstrates favorable outcome associated with SCT (5-y OS 78% v 31%; 5-y PFS 55% v 15%). Conclusion: Outcomes for MCL have significantly improved in the modern era following the introduction of upfront ASCT in BC. Availability of rituximab coincided with this policy change and likely contributed to this improvement. Similar to prior observations, a subset of pts with indolent behaving disease can be observed without impacting OS. Patients with limited stage disease have a more favorable outcome, but no survival plateau was noted. ![Figure][1] ![Figure][1] Disclosures: den Brok: F Hoffmann-La Roche (Roche Canada): Consultancy, Research Funding. Song: F Hoffmann-La Roche (Roche Canada): Consultancy, Research Funding. OLeary: F Hoffmann-La Roche (Roche Canada): Consultancy, Research Funding. Klasa: F Hoffmann-La Roche (Roche Canada): Consultancy, Research Funding. Savage: Roche: Research Funding. Shenkier: F Hoffmann-La Roche (Roche Canada): Consultancy, Research Funding. Villa: F Hoffmann-La Roche (Roche Canada): Consultancy, Research Funding. Slack: F Hoffmann-La Roche (Roche Canada): Consultancy, Research Funding. Shepherd: F Hoffmann-La Roche (Roche Canada): Consultancy, Research Funding. Gascoyne: F Hoffmann-La Roche (Roche Canada): Consultancy, Research Funding. Connors: F Hoffmann-La Roche (Roche Canada): Consultancy, Research Funding. Sehn: F. Hoffmann-La Roche (Roche Canada): Research Funding. [1]: pending:yes