Autologous Stem Cell Transplantation In First Remission Research Articles

Survival Outcomes for Plasmablastic Lymphoma: An International, Multicentre Study By the Australasian Lymphoma Alliance

Survival Outcomes for Plasmablastic Lymphoma: An International, Multicentre Study By the Australasian Lymphoma Alliance

Ixazomib with or without Rituximab Following Immunochemotherapy and Autologous Stem Cell Transplant in Mantle Cell Lymphoma

Background: Maintenance rituximab administered post autologous stem cell transplant (ASCT) in mantle cell lymphoma (MCL) is associated with improved overall survival (OS). Maintenance approaches with the proteasome inhibitor, bortezomib, are associated with improved progression-free survival (PFS), although its use is limited by peripheral neuropathy (Kaplan et al, 2020). We conducted a phase 1 study to evaluate the safety of maintenance therapy with ixazomib, an oral proteasome inhibitor, alone and in combination with rituximab for patients with MCL completing ASCT in first remission. Methods: Adult patients with MCL completing an ASCT in first partial or complete remission and who remained progression-free were enrolled between days 70-180 post-ASCT. Initially, patients received ixazomib monotherapy in cohorts of three using a standard 3+3 design. Patients self-administered ixazomib on days 1, 8, and 15 of each 28-day cycle at one of 3 dose levels: 2.3mg, 3mg, or 4mg. Patients continued therapy until disease progression, intolerance, or completion of 10 cycles. While we were enrolling to the 4mg dose level, the LYMA trial reported an OS benefit associated with maintenance rituximab (Le Gouill et al, 2017), so the protocol was amended to explore the combination of ixazomib and rituximab. Combination therapy consisted of ixazomib 4mg (given at the same schedule) and rituximab 375 mg/m2 given on day 1 of cycles 1, 3, 5, 7, and 9. The primary objective of the study was to evaluate the safety of this treatment and determine the maximum tolerated dose (MTD) while secondary objectives included efficacy. Results Twelve patients enrolled in the trial and received at least one dose of study therapy. Seven patients received ixazomib monotherapy (3mg = 3 patients, 4mg= 4 patients), and 5 patients received combination with rituximab and 4mg ixazomib. In all patients, the median age was 58 years (range 42-73 years) and 75% of the patients were male. Five patients had a high risk MIPI score. All patients entered the study in complete remission. Pre-transplant induction was R-HyperCVAD (n=6), VR-CAP/R-DHAP (n=2), NORDIC regimen (n=2), R-CHOP/R-DHAP (n=1), and R-DHAX (n=1). Transplant conditioning regimens were BEAM (n=7) or Bu/Cy/VP-16 (n=5). In the monotherapy group, 6 patients completed all 10 cycles of therapy. One patient experienced a dose limiting toxicity (DLT) which consisted of grade 3 neutropenia following cycle 1. In addition to the patient who experienced a DLT, one patient discontinued therapy early due to persistent abdominal pain that was ultimately determined to be unrelated to study therapy after an extensive evaluation. Two patients required dose reductions due to grade 3 hematologic toxicities. Two patients in the combination therapy group completed 10 cycles of therapy. Two patients experienced DLTs which consisted of grade 4 neutropenia, and 1 patient opted to discontinue therapy early due to persistent grade 2 peripheral neuropathy. In all patients, common adverse events (AEs) regardless of attribution were abdominal pain (n=6), leukopenia (n=5), nausea (n=4), thrombocytopenia (n=4), and peripheral neuropathy (n=3). Grade 3/4 AEs were thrombocytopenia (n=1) and neutropenia (n=4). No grade 3/4 peripheral neuropathy was observed. With a median follow up of 29.6 months, no patients experienced disease progression and all are alive. Due to the myelosuppression-related DLT's encountered in the combination arm, the study was closed to further accrual. Conclusions Our findings suggest adding rituximab to ixazomib at the evaluated dose and schedule as post-ASCT maintenance is associated with myelosuppression, and we would suggest future studies evaluate an alternative dose/schedule to mitigate this risk. The lack of early progressions is encouraging, confirming the findings from CALGB50403 that proteasome inhibition may provide therapeutic benefit in this setting. Further evaluation of rituximab-containing post-induction combination therapies may identify a safer dosing strategy while improving long-term remission rates. Disclosures Allen: Bayer: Consultancy, Other; Curio Sciences: Honoraria; Clinical Care Options: Speakers Bureau; Research to Practice: Speakers Bureau; Imbrium: Consultancy, Other. Waller:Verastem Oncology, Inc: Consultancy, Research Funding. Flowers:Bayer: Consultancy; Denovo Biopharma: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; BeiGene: Consultancy; Celgene: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Karyopharm: Consultancy; OptumRx: Consultancy; Pharmacyclics/Janssen: Consultancy; Spectrum: Consultancy; Acerta: Research Funding; Millennium/Takeda: Consultancy, Research Funding; TG Therapeutics: Research Funding; Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; V Foundation: Research Funding; Cancer Prevention and Research Institute of Texas: Research Funding; Kite: Research Funding; Leukemia and Lymphoma Society: Membership on an entity's Board of Directors or advisory committees. Cohen:Genentech, BMS, Novartis, LAM, BioInvent, LRF, ASH, Astra Zeneca, Seattle Genetics: Research Funding; Janssen, Adicet, Astra Zeneca, Genentech, Aptitude Health, Cellectar, Kite/Gilead, Loxo: Consultancy.

Autologous Stem Cell Transplantation in Mantle Cell Lymphoma - Selection Mechanisms and Survival By Age Group

Purpose The second Nordic lymphoma group protocol for mantle cell lymphoma (NLG-MCL 2) includes three courses of maxi-CHOP alternating with three courses of high-dose cytarabine, and followed by consolidation with high-dose therapy and autologous stem-cell transplantation (ASCT). This has been the standard of care for younger MCL patients in Sweden since year 2000. Since 2008, rituximab has been added. On a population level, it is not well described how many patients' complete treatment and undergo consolidation with ASCT and which reasons that govern this decision. Our aim was to describe selection mechanisms to ASCT, and further describe outcome for ASCT transplanted versus non-transplanted patients in different age groups. Methods We investigated 670 MCL patients aged 22-70 years and diagnosed 2000-2014 (among whom 416 were 22-65 years) using data from the Swedish population-based lymphoma register. Clinical, demographical, and comorbidity data was linked to the patient cohort through nationwide health care registers. Severity of comorbidity was defined according to the Charlson comorbidity index (CCI; 0,1 and 2+). Selection mechanisms were analysed by estimating odds ratios (ORs) with 95% confidence intervals (CIs) for being transplanted using univariable and multivariable logistic regression models. Patients that did not reach complete remission during induction chemotherapy and therefore not transplanted were identified and excluded when analyzing other selection mechanisms. Demographic determinants were specifically considered, including marital status (married, not married, divorced and widower) and educational level (up to 9 years, 10-12, and more than 12 years of schooling). Survival functions, by ASCT and age at diagnosis (<50, 50-59, 60-65, 66-70) were estimated using the Kaplan-Meier method. Moreover, hazard ratios (HRs) with 95% confidence intervals (CI) comparing all-cause mortality by ASCT and age were estimated using Cox regression (adjusted for calendar year of diagnosis, age at diagnosis, sex and country of birth). Results Among patients aged up to 70 years, 355 (54%) were not selected for ASCT whereas 299 (46%) were given ASCT in first remission. Among patients up to 65 years, 158/416 (38%) were not selected for ASCT. Sixteen patients did not reach complete remission after induction chemotherapy and were thus not transplanted and not further included. Being a widow, having lower educational level, older age at diagnosis, higher comorbidity burden, diagnosed during an earlier calendar period, stage I disease and a lower mantle cell lymphoma prognostic index (MIPI) (Table 1) was in univariable analyses, associated with a reduced chance of receiving ASCT, while this was not seen for different sex, county, hospital and country of birth. In adjusted analyses of sociodemographic characteristics, being unmarried (compared to married) significantly decreased the odds of receiving ASCT (adj. OR=0.56, 95% CI: 0.34-0.94). Also, patients with any comorbidity, CCI 1 (adj. OR=0.51, 95% CI: 0.29-0.90) and severe comorbidity, CCI 2+ (adj. OR=0.41, 95% CI: 0.25-0.68) had lower chance of receiving ASCT. For patients younger than 60 years at diagnosis MIPI and stage were generally lower in the non-transplanted group and here selection to ASCT was not associated with inferior OS (Figure 1). For patients aged 60-65 who were not selected to transplantation, overall survival was inferior compared to patients who underwent ASCT (p-value from log rank test=0.01, Figure 1). However, this association was attenuated when adjusting for potential confounders in a Cox regression (HR: 0.66, 95% CI 0.42-1.03). Conclusion A surprisingly high proportion of patients (more than 50%) were not treated with ASCT as part of primary treatment. Reasons for not being selected to ASCT included both medical and socioeconomic factors. Patients who were unmarried were less often transplanted. Among younger patients (<60 years), omission of ASCT seemed over-represented for "indolent" cases and no prognostic difference was seen, while for patients 60-65 years of age, omission of transplantation was associated with inferior OS. Improvements in both supportive functions, awareness for clinicians about their decisions and development of alternative, more tolerable, treatment concepts are needed for a large fraction of MCL patients and would likely improve survival. Disclosures Glimelius: Janssen Pharmaceuticals: Honoraria. Smedby:Janssen Pharmaceuticals: Other: This project was partly funded through a private-public collaboration between KI and Janssen pharmaceuticals.; Takeda: Research Funding; Celgene: Honoraria. Albertsson-Lindblad:Janssen Pharmaceuticals: Other: This study was partly funded via the public-private real world evidence collaboration between Karolinska Institutet and Janssen Pharmaceuticals (contract: 5-63/2015). Eloranta:Janssen Pharmaceuticals.: Other: project coordinator for a public-private real world evidence; Karolinska Institutet: Other: coordinator for a public-private real world evidence. Jerkeman:Janssen: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Acerta: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding.

Peripheral Blood Involvement By Flow Cytometry As a Prognostic Factor in Aggressive T Cell Lymphomas Following Autologous Stem Cell Transplantation

Introduction: Aggressive T cell lymphomas (TCL) are a heterogenous group of lymphomas that are frequently associated with poor outcomes. Autologous stem cell transplantation (ASCT) is recommended according to the NCCN guidelines and by practice standards for most subtypes as a consolidation for patients in first remission. A large prospective study of up-front ASCT by the Nordic Lymphoma group identified age, ECOG performance status <2, and bone marrow involvement as important prognostic factors. We have identified peripheral blood involvement by flow cytometry at diagnosis in up to one third of patients with aggressive TCL and analyzed whether this was a prognostic factor for outcomes after ASCT. Methods: We retrospectively analyzed data from consecutively treated patients (pts) with aggressive T-cell lymphomas who underwent ASCT at our institution from July 2009 to February 2019. Patient and disease characteristics were summarized using descriptive statistics. Kaplan-Meier analysis was used to estimate progression free survival (PFS) that was defined as the time from SCT to the first evidence of recurrence, and overall survival (OS) that was defined as the time from SCT to death or last institutional follow up with a hematologist. We collected data on age, co-morbidities, disease subtype, stage, response to therapy and treatment both pre and post SCT. Flow cytometry was obtained at diagnosis and phenotype of atypical circulating cells was compared with immunophenotype from tumor biopsy specimens. Results: 50 pts with TCL who received ASCT were identified for this analysis. Of this population, 41 (80%) of pts had peripheral blood flow available at the time of initial diagnosis. T-cell lymphoma types included peripheral T cell lymphoma not otherwise specified (PTCL NOS, 17 pts), angioimmunoblastic T cell lymphoma (AITCL, 15pts), ALK negative anaplastic large cell lymphoma (ALCL, 1pt), enteropathy-type T-cell lymphoma (EATL, 2pts), extranodal natural killer T-cell lymphoma (NKTCL, 2pts) and panniculitis like T cell lymphoma (2 pts) (Table 1). Median age of the cohort was 62 years (range 20-75 years) and all patients included had an ECOG PS 0-1 at the time of diagnosis. The majority had stage 4 disease (36/41, 87.8%), but analysis included a small number of patients with stage 2 (1/41, 2.4%) and stage 3 (4/41,9.7%) disease. Bone marrow involvement by morphologic criteria was noted on bone marrow biopsy in 8/41 (19.5%) pts; bone marrow was negative in 28/41 or 61% pts and not evaluated in 8/41 or 19.5% pts. Flow cytometry of peripheral blood performed as part of initial staging was positive for circulating malignant cells in 13/41 pts (31.7%) at the time of diagnosis. All patients underwent ASCT in first remission. The median PFS and OS were 15.2 and 29.9 months respectively in the flow positive group, while neither median PFS nor OS were reached in the flow negative group (Figures 1 and 2). Flow cytometry results from time of diagnosis was not strongly associated with PFS (log rank, p = 0.39), however, it was associated with overall survival (log rank, p = 0.012). There were 11 deaths in the cohort- 4 in the flow negative group and 7 in the flow positive group. Further, when bone marrow involvement was evaluated, 7 of 13 pts with positive flow cytometry (53.8%) and 5 of 28 (17.8%) pts with negative flow cytometry had BM involvement, suggesting a correlation between positive bone marrow and detection of lymphoma cells in the peripheral blood at the time of diagnosis. Conclusions: We demonstrate in our cohort of patients that detection of circulating lymphoma cells at diagnosis by flow cytometry was associated with a worse outcome in patients with aggressive T cell lymphomas undergoing ASCT as a consolidation in first remission. Larger cohorts will be needed to validate these findings, but these results suggest peripheral blood involvement by sensitive flow cytometry may identify patients with worse outcomes who might benefit from a more aggressive strategy such as allogeneic stem cell transplantation or alternative consolidation strategies. Disclosures Huntington: Bayer: Consultancy, Honoraria; Pharmacyclics: Honoraria; Celgene: Consultancy, Research Funding; DTRM Biopharm: Research Funding; Genentech: Consultancy; AbbVie: Consultancy. Isufi:Celgene: Consultancy; Novartis: Consultancy; Astra Zeneca: Consultancy. Foss:Seattle Genetics: Consultancy, Other: fees for non-CME/CE services ; Mallinckrodt: Consultancy; miRagen: Consultancy; Spectrum: Other: fees for non-CME/CE services ; Eisai: Consultancy; Acrotech: Consultancy.

Prognostic Variables of Progression Free Survival in Mantle Cell Lymphoma after Autologous Stem Cell Transplantation

Background Autologous stem cell transplant (ASCT) is frequently used as a consolidative therapy option after induction treatment in fit patients with mantle cell lymphoma (MCL) with the goal of prolonging the initial response duration. Despite recent advances there remains a subset of patients who experience early disease relapse after ASCT. We examined predictors of shortened progression-free survival (PFS) and post-relapse overall survival (OS) in a cohort of patients completing ASCT in first remission. Methods We evaluated MCL patients treated at 10 US academic medical centers. Eligible patients were treated from 2000 through 2017, and we collected information on demographic, clinical, and treatment-related variables of interest. Patients were then categorized into three post-ASCT PFS groups: 0-2 years, 2-5 years, and > 5 years, with PFS determined from the date of ASCT until progression or death from any cause. Patients followed for at least 5 years post-ASCT who were relapse free were included in the > 5 sub group. Associations were examined between groups and collected characteristics using chi-squared tests for categorical patient characteristics and ANOVA for numeric patient characteristics. The Kaplan-Meier method was used to estimate overall survival (OS) for each group, using time of relapse after ASCT as the starting point. Results Of 968 total MCL patients, 242 patients completed ASCT in first remission and either had a PFS event or were relapse-free for at least 5 years post-ASCT. Patients were 80% male, and the median age was 59 (Range: 29-83). The patients were divided into groups of post-ASCT PFS 0-2 years (n=74), 2-5 years (n=75), and more than 5 years (n=93). Post-ASCT PFS was shorter in patients with stage 4 disease (p=0.022), splenomegaly at baseline (p=0.005), and a lymph node size > 5 centimeters at baseline (p=0.043). Other variables were not significantly associated with PFS, including time to transplant and use of intensive therapy. Patients with 0-2 year PFS had a shorter median OS (22.1 months, 95% CI: 13.1- 38.1 months) in comparison to 2-5 year PFS (132 months, 95% CI: 36-132 months) and 5+ year PFS not reached (95% CI: 41.2 – N.A; Figure). Conclusion Patients with higher tumor burden at baseline have a shorter post-ASCT PFS and are more likely to relapse within 2 years. As has been seen in other lymphoma subtypes, early relapse is associated with shorter OS. This represents a patient group requiring improved therapies and perhaps are the best candidates for post-ASCT maintenance or consolidation approaches. Further studies integrating minimal residual disease and molecular risk-stratification may better identify patients at high risk for early progression.

Intensive Induction Regimens after Deferring Initial Therapy Are Not Associated with Improved Progression-Free or Overall Survival in Patients with Mantle Cell Lymphoma (MCL)

Intensive Induction Regimens after Deferring Initial Therapy Are Not Associated with Improved Progression-Free or Overall Survival in Patients with Mantle Cell Lymphoma (MCL)

Complex karyotype in patients with mantle cell lymphoma predicts inferior survival and poor response to intensive induction therapy.

Risk stratification of newly diagnosed patients with mantle cell lymphoma (MCL) primarily is based on the MCL International Prognostic Index (MIPI) and Ki-67 proliferative index. Single-center studies have reported inferior outcomes in patients with a complex karyotype (CK), but this remains an area of controversy. The authors retrospectively reviewed 483 patients from 5 academic centers in the United States and described the effect of a CK on survival outcomes in individuals with MCL. A CK was found to be associated with inferior overall survival (OS) (4.5 vs 11.6 years; P<.01) and progression-free survival (PFS) (1.9 vs 4.4 years; P<.01). In patients who underwent high-intensity induction followed by autologous stem cell transplantation (ASCT) in first remission, a CK was associated with poor OS (5.1 vs 11.6 years; P = .04) and PFS (3.6 vs 7.8 years; P<.01). Among patients with a CK, high-intensity induction had no effect on OS (4.5 vs 3.8 years; P = .77) nor PFS (2.3 vs 1.5 years; P = .46). Similarly, ASCT in first remission did not improve PFS (3.5 vs 1.2 years; P = .12) nor OS (5.1 vs 4.0 years; P = .27). On multivariable analyses with Ki-67 and MIPI, only CK was found to be predictive of OS (hazard ratio [HR], 1.98; 95% confidence interval [95% CI], 1.12-3.49 [P = .02]), whereas both CK (HR, 1.91; 95% CI, 1.17-3.12 [P = .01]) and Ki-67 >30% (HR, 1.86; 95% CI, 1.06-3.28 [P = .03]) were associated with inferior PFS. Multivariable analysis did not identify any specific cytogenetic abnormalities associated with inferior survival. CK appears to be independently associated with inferior outcomes in patients with MCL regardless of the intensity of induction therapy and receipt of ASCT. Cytogenetics should be incorporated into the workup of a new diagnosis of MCL and novel therapeutic approaches should be investigated for patients with CK. Cancer 2018;124:2306-15. © 2018 American Cancer Society.

The role of stem cell transplant for lymphoma in 2017.

The role of stem cell transplant for lymphoma in 2017.

Autologous stem cell transplantation for adult acute myelocytic leukemia in first remission-Better outcomes after busulfan and melphalan compared with busulfan and cyclophosphamide: A retrospective study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT).

Autologous stem cell transplantation (ASCT) for adult acute myelogenous leukemia (AML) is a valid therapeutic option for patients with good-risk and intermediate-risk disease. The authors used the registry of the European Society for Blood and Marrow Transplantation to compare combined busulfan and melphalan (BUMEL) with combined busulfan and cyclophosphamide (BUCY) before transplantation. From 2005 to 2013, 853 patients with available cytogenetics underwent ASCT in first remission, including 257 after receiving BUMEL and 596 after receiving BUCY. The proportion of patients with good-risk AML was lower in those who received BUMEL (14% vs 20%; P = .02). More patients who received BUMEL underwent autograft in molecular remission (89% vs 78%; P = .02). Three years after transplantation, the relapse incidence (RI) was 48.7%, the leukemia-free survival (LFS) rate was 47.7%, the overall survival (OS) rate was 66.2%, and the nonrelapse mortality (NRM) rate was 3.6%. Patients who underwent an autograft after receiving BUMEL fared better than those who underwent an autograft after receiving BUCY with a lower RI (39.5% vs 52.2%; hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.49-0.87; P = .003) a better LFS (55.4% vs 44.6%; HR, 0.69; 95% CI, 0.53-0.89; P = .005), and a better OS (73.8% vs 63%; HR, 0.62; 95% CI, 0.47-0.82; P = .0007). There was no difference in the NRM rate (BUMEL vs BUCY, 4.5% vs 3.2%, respectively). Among 74 patients in the BUMEL group and 187 in the BUCY group who underwent autograft in molecular remission, the RI was 30% versus 51%, respectively (univariate analysis; P = .01), and the LFS rate was 66% versus 47%, respectively (univariate analysis; P = .03). In patients with AML in first complete remission who undergo ASCT, the BUMEL combination is a better preparative regimen. Cancer 2017;123:824-31. © 2016 American Cancer Society.

Complex karyotype is associated with aggressive disease and shortened progression-free survival in patients with newly diagnosed mantle cell lymphoma.

Pretreatment cytogenetics are not routinely used to predict patient outcomes in mantle cell lymphoma (MCL). Based on the prognostic utility of cytogenetics in other diseases, we reviewed the effect of a complex karyotype (CK) in MCL. We included patients evaluated between November, 2002, and May, 2011. Those with ≥ 3 chromosomal abnormalities on a pre-treatment cytogenetic evaluation were defined as CK. Demographic, clinical, and survival differences between patients with CK and non-CK (NCK) were assessed. Of 80 patients, 32 (40%) had CK, which was associated with high-risk clinical risk factors. Therapy did not differ between the groups, nor did rate of autologous stem cell transplant (ASCT). The 2-year progression-free survival (PFS) estimates were 70% and 48% for patients with NCK and CK, respectively (P = .02). Two-year overall survival (OS) estimates were also greater in those with NCK versus CK (85% vs. 58%; P = .02). When controlling for high-risk Mantle Cell Lymphoma International Prognostic Index (MIPI) score (P = .006), bulky disease (P = .01), and ASCT in first remission (P = .01), CK was not significantly associated with PFS (P = .18). CK is associated with shortened PFS and OS in MCL but has not been demonstrated to be prognostic independent of other variables in this series.

Long Term Follow-up of High-Dose CD20-Targeted Radioimmunotherapy-Based Autologous Transplantation for Patients with Mantle Cell Lymphoma

Background: Autologous stem cell transplantation (ASCT) is commonly employed in the treatment of mantle cell lymphoma (MCL), though long-term remission following this intervention is relatively uncommon, particularly for patients with relapsed/refractory disease. We hypothesized that high-dose radioimmunotherapy-(RIT) based conditioning prior to ASCT could improve outcomes based on the radiosensitivity of MCL and reduced cross-resistance with chemotherapy.Methods: We evaluated the outcomes of patients with MCL treated with myeloablative conditioning using iodine-131 (131I) conjugated to the anti-CD20 antibody tositumomab with or without additional chemotherapy followed by ASCT on 4 sequential prospective clinical trials. These trials included single agent RIT, RIT + etoposide + cyclophosphamide, and RIT + fludarabine. We retrospectively identified a comparator group of patients at our institution undergoing ASCT for MCL without RIT, using conditioning regimens including carmustine, etoposide, cytarabine, and melphalan (BEAM); busulfan, melphalan, and thiotepa (BuMelT); and 12 Gy of total body irradiation (TBI) plus cyclophosphamide with or without etoposide. We described and compared the outcomes from each group including differences in event rates evaluated by the Cox proportional hazards regression model. To account for imbalanced covariates between subgroups, adjusted estimates of survival were generated (Storer, et al., Lifetime Data Anal, 2008, p. 484). Follow-up was updated as of October 2013.Results: From November 1995 to May 2011, 162 sequential MCL patients received high-dose therapy and ASCT at our center, including 61 (38%) who received RIT-based conditioning. RIT patients received a median of 19.8 GBq (534 mCi; range: 7.6-40.7 GBq [205-1100 mCi]) of 131I to deliver a median of 25 Gy (range: 20-27) absorbed dose to critical organs. Median follow-up from ASCT for all surviving patients was 5.1 yrs (range: 0.3-17.1). Patients treated with RIT-based ASCT were less likely to be in first remission (48% vs 72%; p = 0.002), be in complete remission (CR) at ASCT (26% vs 61%; p < 0.001), or have chemosensitive disease (84% vs 96%; p = 0.006) compared to controls. The 2-year, 5-year, and median PFS were 66%, 49%, and 64 months (respectively) for the control group compared to 70%, 45%, and 54 months (respectively) for the RIT group (p = 0.77; see Table). The 2-year, 5-year, and median OS were 76%, 64%, and 126 months (respectively) for the control group compared to 82%, 62%, and 80 months (respectively) for the RIT group (p = 0.75; see Table). Multivariate analysis (adjusting for chemosensitivity, remission status, ASCT in first remission, and age) indicated that RIT-based conditioning was associated with a reduced risk of mortality and treatment failure (i.e., death or relapse; see Table and Figure). Furthermore, the relative benefit of RIT increased with worsening pre-ASCT disease status (from CR to partial remission to stable/progressive disease), with HRs for mortality 1.1, 0.53, and 0.04, and HRs for treatment failure 1.2, 0.38, and 0.07 (respectively). Incidences were comparable between the RIT and control groups in terms of non-relapse mortality (NRM) (7% vs 8%, respectively) and secondary malignancies (9.8% vs 12%), including acute myeloid leukemia or myelodysplasia (4.9% vs 3%).Conclusions: RIT-based conditioning is associated with improved outcomes following ASCT for MCL after controlling for imbalances in important risk factors, with the greatest benefit among patients with more advanced disease. Rates of NRM and secondary malignancies were comparable with both approaches. These data support the further study of high-dose RIT in a risk-adapted approach to ASCT for MCL.Table:Univariate and multivariable comparison of high-dose RIT-based vs conventional ASCT.ComparisonASCT ConditioningTreatment FailureOverall MortalityHR (95% CI)PHR (95% CI)PUnivariateControl1-1-RIT1.01 (0.69-1.6)0.771.1 (0.67-1.8)0.75MultivariableControl1-1-RIT0.47 (0.27-0.79)0.0050.49 (0.28-0.86)0.01Figure: Estimated PFS after adjusting for chemosensitivity, remission status, ASCT in first remission, and age following high-dose RIT-based or conventional (Control) ASCT for MCL. [Display omitted] DisclosuresOff Label Use: 131I-tositumomab is not FDA approved for autologous stem cell transplant conditioning.. Gopal:Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Honoraria, Research Funding, Speakers Bureau; Janssen: Research Funding; Pfizer: Consultancy, Research Funding; BMS: Research Funding; Gilead: Research Funding; Spectrum: Research Funding; Teva: Research Funding.

Rituximab Maintenance Therapy after Autologous Stem Cell Transplantation Improves Survival of Patients with Mantle Cell Lymphoma

BackgroundHigh dose therapy and autologous stem cell transplantation (ASCT) can improve outcomes for patients with mantle cell lymphoma (MCL), yet relapse ultimately occurs in the majority of patients. Maintenance rituximab (MR) administered after induction chemotherapy has been shown to improve overall survival (OS), but limited comparative data are available regarding the impact of MR following ASCT. We report the impact of MR on outcomes following ASCT in a large series of patients with MCL.MethodsOne hundred sixty four consecutive patients with MCL that underwent ASCT for MCL at our center between November 1995 and May 2011 were included in this retrospective analysis. Patients that received MR after ASCT were compared to patients that did not receive maintenance rituximab after ASCT (no-MR). Two patients underwent tandem autologous/allogeneic stem cell transplants and were excluded from analysis; inadequate follow-up data precluded the evaluation of MR administration in an additional 5 patients. MR was treated as a time-dependent covariate to account for the variability in the time to initiation after ASCT. Statistical significance of differences in event rates between the MR and no-MR groups was evaluated with the Cox proportional hazards regression model. Two-sided p-values less than 0.05 were considered statistically significant.ResultsA total of 157 patients met the above criteria and were evaluated in this study. MR was administered to 50 (32%) patients and the remaining 107 (68%) patients received no MR after ASCT. Median age at the time of ASCT was 58 (range 35–71). All patients in the MR group had received rituximab prior to ASCT, whereas 13 of the 107 patients in the no-MR group had no prior rituximab (p = 0.01). Patients in the MR group were more likely to have had chemo-sensitive disease (p = 0.05) and to have undergone ASCT during first remission (p = 0.0001) and in complete remission (CR) (p = 0.0003). Patients in the no-MR group were more likely to have received radio-immunotherapy based conditioning (p < 0.0001). The groups were well matched for simplified MIPI score (sMIPI) at the time of diagnosis (p = 0.50) and at ASCT (p = 0.88).A median of 8 (range 1 to 16) doses of MR was administered at a dose of 375 mg/m2. MR was initiated at a median of 77 days after ASCT (range 27 to 287) and the last dose was administered at a median of 271 days after ASCT (range 55 to 1074). The most common dosing schedules included weekly dosing for 4 weeks for two cycles separated by 6 months (n = 15), monthly dosing (n = 8), and every 3-month dosing (n = 7); a variety of dosing schedules were used in the remaining cases (n = 20). Grade 4 neutropenia was observed in 16 of 47 evaluable patients (34%) in the MR group, and 16 of 87 evaluable patients (18%) in the no-MR group (p = 0.04). Granulocyte colony stimulating factor (GCSF) was administered for neutropenia in 15 of 47 evaluable patients (32%) in the MR group, and 10 of 85 evaluable patients (12%) in the no-MR group (p = 0.005).MR was associated with a significantly prolonged PFS (HR 0.33, p = 0.0005) and OS (HR 0.40, p = 0.01) following a multivariate adjustment (Table 1) with a median follow up of 4.75 years. Likewise, in a landmark analysis limited to patients alive and without progression at day 100 after ASCT (n = 147), 3-year PFS and OS were 78% and 86%, respectively, in the MR group and 59% and 71%, respectively, in the no-MR group (Figure 1).ConclusionThese data suggest that MR administered following ASCT improves both PFS and OS for patients with MCL with an associated increase in the risk of severe neutropenia and consequent use of GCSF. Randomized, prospective trials are needed to confirm these findings and establish post-ASCT MR as standard of care in treating MCL.Table 1Multivariate Cox proportional hazards modeling using maintenance rituximab as a time-dependent covariateProgression Free Survival1Overall Survival2HRp-valueHRp-valueMaintenance rituximab0.33 (0.18 – 0.62)0.00050.40 (0.20 – 0.81)0.011Adjusted for: Age, B-symptoms, MIPI at time of ASCT, disease status at ASCT, chemo-sensitivity, ASCT in first remission, conditioning regimen2Adjusted for: Age, disease status at ASCT, chemo-sensitivity, ASCT in first remission, conditioning regimen [Display omitted] DisclosuresOff Label Use: Rituximab as maintenance therapy after autologous stem cell transplantation for mantle cell lymphoma.

Autologous Stem Cell Transplantation (ASCT) for the Treatment of Patients with Waldenstrom’s Macroglobulinemia / Lymphoplasmacytic Lymphoma (WM/LPL). a Risk Factor Analysis By the European Society for Blood and Marrow Transplantation (EBMT) Lymphoma Working Party

WM/LPL is a rare distinct indolent lymphoma and the optimal management of the disease remains a major challenge. Combination therapies with old and novel agents have markedly improved the response rates and the quality of response but still the CR rates remain low and so far there is no cure. The role and timing of ASCT in the management of patients with WM/LPL has not been well established. The aim of the present study was to investigate the outcome of ASCT in early vs late WM/LPL.Methods: Eligible for this retrospective study were all patients who had a first ASCT for WM/LPL between 1995 and 2011 and were registered with the EBMT database. Baseline patient, disease, and transplant data were collected from MED-A forms. Statistical analysis used log rank tests to assess the impact of baseline characteristics on survival endpoints. Overall survival (OS) and disease-free survival (DFS) was estimated from the time of ASCT using Kaplan-Meier product-limit estimates. Curves of cumulative of non-relapse mortality (NRM) and incidence of relapse (IR) were compared by Gray’s test in a competing risk framework.Results: Altogether 615 patients fulfilling the inclusion criteria were identified in the database. The median age at ASCT was 53 years (range 19-76), and 428 patients (70%) were male. The median time from diagnosis to ASCT was 19 months (interquartile range: 10-51 months). 537 patients (71%) underwent ASCT after 2002. Disease status at ASCT was first partial (PR1), very good partial (VGPR1) or complete remission (CR1) in 325 patients, whilst 176 patients were autografted in second, third or later response, and 47 patients (4%) had primary refractory or progressive disease at ASCT. High-dose therapy was TBI-based in 82 patients (14%), and stem cell source was from peripheral blood in 598 patients (97%).With a median follow-up of surviving patients of 53 months, the 5-year OS was 65%, DFS was 46%, IR was 47% and NRM was 7%. IR was significantly lower in patients receiving ASCT in first response (CR1, VGPR1, PR1) compared to transplantation in subsequent complete or partial responses or with refractory disease (39% vs 53%; p=0.001), translating into a significant DFS (50% vs 40%, p= 0.004) and OS benefit (71% vs 63%; p= 0.033) for the patients transplanted early. DFS was significantly better for patients receiving ASCT after year 2000 compared to the patients transplanted before (p=0.031) and although the year of ASCT had influence on the OS this did not reach statistical significance (p=0.068). Multivariate analysis considering age, sex, disease status at ASCT, and ASCT year confirmed ASCT beyond 1st remission (HR 1.37, 95%CI 1.04-1.79), along with female gender (HR 0.73, 95%CI 0.54-0.97) and ASCT between 2001-2005 (vs before 2001; HR 0.66, 95%CI 0.47-0.92) as significant predictors of DFS.Conclusions: These results suggest that ASCT is a feasible and effective treatment for WM/LPL. Factors predicting for a favourable DFS are female gender, transplantation in the rituximab era, and ASCT in first remission. However, with DFS and OS of 40% and 63% at 5 years, even the outcome of patients undergoing ASCT with advanced disease is still encouraging. As single-hit ASCT can induce long term response with relatively low toxicity and economic burden, it may serve as benchmark for the upcoming novel targeted therapeutics entering the WM / LPL treatment arena. DisclosuresNo relevant conflicts of interest to declare.

Delayed Haematological recovery after autologous stem cell transplantation is associated with favourable outcome in acute myeloid leukaemia.

Autologous stem cell transplantation (ASCT) is applied to consolidate first remission in patients with acute myeloid leukaemia (AML). However, outcome after ASCT widely varies among AML patients. We analyzed the prognostic significance of haematological recovery for neutrophils [absolute neutrophil count (ANC) >1·0 × 10(9) /l] and platelets (platelet count >20·0 × 10(9) /l), stratifying at day 20 after ASCT in 88 consecutive and homogeneously treated AML patients in first remission. We observed that patients with delayed recovery had better overall survival (OS; ANC: P < 0·0001 and platelets: P = 0·0062) and time to progression (TTP; ANC: P = 0·0003 and platelets: P = 0·0125). Delayed recovery was an independent marker for better OS and TTP in a multivariate analysis including age, gender, number of transfused CD34+ cells, cytogenetics, FLT3-internal tandem duplication and NPM1 mutation. Our results suggest that delayed neutrophil and platelet recovery is associated with longer OS and TTP in AML patients consolidated with ASCT in first remission.

New Strategies in the Treatment of Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is a rare type of non-Hodgkin lymphoma that traditionally has been thought to possess the poor-risk features of both indolent lymphoma, with its incurability, and aggressive lymphoma, with its ability to proliferate rapidly. Although there is considerable debate as to whether MCL can be cured, a number of retrospective studies are beginning to suggest an improvement in overall survival over the past decade, likely coinciding with the introduction of rituximab, more intensive chemotherapy, and the increasing use of autologous stem cell transplant (ASCT) in first remission. At present, intensive induction chemotherapy regimens consistently produce a response rate of >90%, sometimes even 100% in the first-line setting, and consolidation with ASCT in first remission can improve the complete response rate to 90%. The emergence of a more sophisticated understanding of the underlying pathogenesis, coupled with a host of new agents and targets, has again created new opportunities to improve the care of our patients with MCL. Here, we discuss many of these developments and how they may potentially affect the natural history of this disease.

Improving outcomes in mantle cell lymphoma patients treated with R-CHOP using autologous transplant.

e18540 Background: Mantle cell lymphoma (MCL) is a small B cell lymphoma, incurable with standard chemo-immunotherapy. There is no standard upfront therapy, although Phase II trials have shown a survival benefit to dose-intensified regimens in selected patients. However, many patients are not candidates for these regimens secondary to age or comorbidites. These patients are often treated with R-CHOP with consideration for consolidation with ASCT. Methods: We conducted a retrospective cohort analysis to describe and compare the survival experiences of MCL patients at the University of Pennsylvania treated in the first-line setting with R-CHOP (N=32) with or without autologous stem cell transplant (ASCT). The primary study endpoint was PFS as assessed by chart review and confirmed by SSDI database. Results: Median follow up for all pts was 2.5 years. The median age was 62.5, and 80% (n=30) were stage IV at diagnosis. 16 patients underwent consolidative ASCT. Comparing patients treated with R-CHOP vs R-CHOP +ASCT, there were no statistical differences in terms of age, ECOG PS, LDH, WBC, beta-2microglobulin, BM or GI involvement, bulky disease or blastoid variant at baseline. The response rate for all patients was 96.9% and 87.5% of patients achieved CR. Median PFS for all patients was 2.8 years: R-CHOP alone 1.9 years vs. R-CHOP+ ASCT 3.9 years (P=0.02, HR 3.44, 95%CI: 1.2-9.5). Conclusions: Outcomes are poor for MCL patients treated with R-CHOP with continuous recurrence despite excellent initial response. Our data suggest an improved PFS in patients with advanced MCL when R-CHOP is consolidated with ASCT in first remission as compared to R-CHOP alone. Prospective RCTs are needed to determine the optimum treatment for patients who are not candidates for dose-intensive therapy.

Positive HIV ELISA test, autoimmune hemolytic anemia, and generalized lymphadenopathy: A unifying diagnosis

Positive HIV ELISA test, autoimmune hemolytic anemia, and generalized lymphadenopathy: A unifying diagnosis

Improved Survival for Patients Undergoing Autologous Stem Cell Transplant for Primary CNS Lymphoma in First or Later Remission.

Abstract 1222Poster Board I-244 BackgroundSurvival for patients with primary CNS lymphoma (PCNSL), in general, is poor with patients requiring frequent chemotherapy treatments or receiving whole-brain radiation therapy, which can potentially result in significant neurologic decline and dementia. Because of the improved survival of high risk patients with aggressive lymphoma undergoing autologous stem cell transplant (ASCT), we began ASCT for patients with PCNSL in first or later remission with chemotherapy sensitive disease. We now update on outcomes of patients who have had at least 100 day follow up post ASCT. Baseline characteristicsBetween June, 2000 and January, 2009, 22 patients underwent ASCT for PCNSL. Median age at transplant was 50 years old (range 26-67). Median number of prior treatments 1 (range 1-3). Median time from diagnosis to transplant was 7.2 months (range 2.9 to 75.8). Median International Extranodal Working Study Group Prognostic Score: 2 (range 0-3). Disease status at transplant: First CR 10 patients, later CR or PR 12 patients. ResultsTwenty-two patients underwent ASCT for PCNSL and have a minimum of 100 days follow-up. All patients received BEAM conditioning. Median follow up post-transplant was 30 months (range 3-107 months). Eight patients have relapsed at a median of 217 days (range 40-1349). Of the patients who relapsed, four have died of disease progression and the remaining four are alive after additional therapy. Median overall survival from diagnosis or transplant has not been reached. Median progression free survival from transplant was 70 months. ConclusionsAlthough limited by patient selection and retrospective biases, this review suggests that ASCT for PCNSL demonstrates improved overall survival when compared to historical controls with similar PCNSL Prognostic Scores (2 year survival for patients from diagnosis with PS 2-3 was 48% in a prior published study). ASCT in first remission in patients with PCNSL appears promising and may limit the need for additional therapy which can be myelosuppressive or result in neurologic decline secondary to radiation therapy in patients who are appropriate candidates. DisclosuresNo relevant conflicts of interest to declare.

Progress in Mantle-Cell Lymphoma

Progress in Mantle-Cell Lymphoma

178: Improved Survival for Patients Undergoing Autologous Stem Cell Transplant in First or Later Remission for Primary CNS Lymphoma

Background: Survival for patients with primary CNS lymphoma (PCNSL), in general, is poor with patients requiring frequent chemotherapy treatments or receiving whole-brain radiation therapy, which can potentially result in significant neurologic decline and dementia. Because of the improved survival of high risk patients with aggressive lymphoma undergoing autologous stem cell transplant (ASCT), we began ASCT for patients with PCNSL in first or later remission with chemotherapy sensitive disease. We now update the outcomes of patients who have had at least 100 day follow up post ASCT. Baseline Characteristics: Between June, 2000 and March, 2007, 16 patients underwent ASCT for PCNSL. Median age at transplant was 50 years old (range 30–67). Median number of prior treatments 2 (range 1–3). Median time from diagnosis to transplant was 7.5 months (range 2.9 to 75.8). Median International Extranodal Working Study Group Prognostic Score: 2 (range 0–3). Disease status at transplant: First CR 6 patients, later CR or PR 10 patients. Median follow up from diagnosis was 45 months. Results: Sixteen patients underwent ASCT for PCNSL and have a minimum of 100 days follow-up. All patients received BEAM conditioning. Median follow up post-transplant was 32 months (range 3–85 months). Eight patients have relapsed at a median of 217 days (range 40–1349). Of the patients who relapsed, two have died of disease progression and the remaining five are alive after additional therapy. Median overall survival from transplant has not been reached. Three year overall and event free survival from transplant are 82% and 53%, respectively. Median progression free survival from BMT was 45 months. Overall survival from diagnosis at 5 years was 83%. Conclusions: Although limited by patient selection and retrospective biases, this review suggests that ASCT for PCNSL demonstrates improved overall survival when compared to historical controls with similar PCNSL Prognostic Scores (2 year survival for patients from diagnosis with PS 2–3 was 48% in a prior published study). ASCT in first remission in patients with PCNSL appears promising and may limit the need for additional therapy which can be myelosuppressive or result in neurologic decline, secondary to radiation therapy, in patients who are appropriate candidates.