Time Of Autologous Stem Cell Transplantation Research Articles

Does Renal Failure Affect Outcome after Autologous Stem Cell Transplantation in Patients with Multiple Myeloma?

Introduction: Renal impairment (RI) is frequent in patients with Multiple Myeloma (MM) and is a proven negative prognostic factor for overall survival (OS). MM patients with impaired renal function often fail to qualify for high-dose chemotherapy and are excluded from autologous stem cell transplantation (ASCT), since a higher transplant-related mortality has been postulated. However, it remains unclear whether these historical inferior outcome data still hold true in times of modern immuno-chemotherapeutical therapy regimen. Further, nephrologic definition criteria for renal impairment have evolved as well and have not yet been fully introduced into MM patient care. We thus aimed at evaluating outcome data of MM patients undergoing ASCT after immuno-chemotherapy applying current nephrologic standard criteria for RI.Methods: MM patients who had undergone ASCT at our center between 1999 and 2015 were included. Renal function was determined and staged both at the time of diagnosis and transplantation by estimated glomerular filtration rate (eGFR according to the MDRD formula).RI was defined as eGFR <90 ml/min/m2. For sub-analyses renal failure was further staged according to KDIGO guidelines (CKD stages II, IIIa and IIIb corresponding to an eGFR of <60, <45 and <30 ml/min/m2). Kaplan-Meier curves and log-rank tests were used for OS and progression-free survival (PFS) calculation.Results: 195 patients with a median age of 54 years were analyzed. Patients were categorized into 3 groups: i) normal renal function at diagnosis and ASCT ii) impaired renal function at diagnosis with normalization before ASCT and iii) impaired renal function both at the time of diagnosis and ASCT. Estimated mean OS from diagnosis was 93 months (90% CI: 77-109). No difference in OS was found comparing these 3 groups (Figure 1). Estimated mean PFS was 83 months (90% CI: 12-61). Again, in our patient cohort, renal impairment did not negatively impact PFS (Figure 2). In addition, even after further stratification according to the degree of renal failure at the time of ASCT (CKD stage II, IIIa and IIIb), no survival disadvantage was detected for patients with mild to moderate renal failure.Conclusions: In this retrospective analysis, a relatively large cohort of MM patients who had undergone ASCT was analyzed regarding survival data in accordance with their renal function. Since RI is associated with poorer outcome in MM patients, we aimed at working out if this holds true for patients receiving ASCT. In contrast to historical data, our data show that neither OS nor PFS were negatively impacted by mild to moderate RI. Therefore, we conclude that ASCT should rather be considered proactively in MM patients with RI than be withheld, since survival in theses patients seems not to be affected in an adverse manner. [Display omitted] [Display omitted] DisclosuresAgis:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

Social Outcomes after High Dose Chemotherapy with Autologous Stem Cell Transplant

Introduction:Diffuse large B-cell lymphoma (DLBCL) is the largest subgroup of malignant lymphoma. Prognosis has increased after introduction of rituximab, and today more than 80% of the patients will achieve partial or complete remission after standard immunochemotherapy. However, approximately 30% will either present with refractory disease or develop relapse. The standard approach for younger patients with relapsed disease and without major comorbidity is salvage treatment followed by high dose therapy with autologous stem cell transplant (ASCT). This potentially curative treatment is toxic with many side effects, and social outcomes for patients need to be investigated.Objectives:Patients with relapse of de novo DLBCL and transformed indolent lymphoma (TIL) were included. The aim was to describe social outcome after ASCT in form of return to work (RTW).Methods: Patients with B-cell lymphoma in the period 2000-2012, who received ASCT as relapse treatment, were extracted from the Danish National Lymphoma Registry. Medical records were reviewed for clinical, pathological, and treatment information. Individual information on socioeconomic factors and social outcomes were achieved by cross-reference to national administrative registries. Patients were included in RTW analyses, if they received public welfare benefits in at least four weeks including the week of stem cell reinfusion. RTW was defined as four consecutive weeks without receiving welfare benefits; retirement, disability pension and death was regarded as competing events. Patients were followed until RTW, emigration, permanent withdrawal from the labour market, death, or December 31, 2015, whichever came first.Results: A total of 369 patients were identified. At the time of ASCT, 164 (44%) patients received public welfare benefits in form of either sick leave or unemployment benefits. Furthermore, 61 (17%) received disability pension or similar, 102 (28%) received old age pension, and 41(11%) patients did not receive any welfare benefits.The 164 patients receiving sick leave or unemployment benefits were included in the analysis. Median age was 54 years (25-65), 16 patients were above the age of 60, and 104 were male (64%). A total of 54 patients had primary refractory disease; median time to relapse was 1.7 years. Both diagnoses were equally represented with 78 (48%) patients with TIL, IPI score at relapse was available for 118 patients, 22 % had a score of high-intermediate or high. Furthermore, socioeconomic factors at time of relapse showed, that 36 (22%) patients had only basic (mandatory) education, 39 (24%) patients lived alone and 60 (37%) patients had a low disposable income, corresponding to the 1st or 2nd quintile of the Danish population with the same gender and in the same age-group. Most of the patients, n=118 (72%), did not have comorbidities, but 46 patients had one or more at time of relapse. (Table 1)Median time to return to work was 420 days, ranging from 13 to 909 days. One year after year after ASCT, 57 (35%) patients had returned to work, 15 (10%) received disability pension, and 7 (4%) received old age pension. A total of 48 (29%) were still on sick leave, and 37 (23%) had died. (Figure 1)Conclusion: In this nationwide population based study we found that after one year only 35% of the patients had returned to work, 14% had been retired and 23% had died. This emphasizes that this patient group is at risk of impaired social status. There is an unmet need of focused social rehabilitation. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Practice Patterns of Re-Initiation of Therapy at Time of Relapse or Progression Post- Autologous Stem Cell Transplant (ASCT) Among Patients with AL Amyloidosis

Background: Among patients with immunoglobulin light chain (AL) amyloidosis, there is little consensus on when reinstitution of chemotherapy should occur (Milani and Dispenzieri, International Society of Amyloidosis 2016). AL amyloidosis patients who are treated with high dose chemotherapy followed by autologous stem cell transplant (ASCT) are a relatively low-risk and homogenous population, making them an ideal group to study practice patterns.Methods: We conducted a retrospective study to evaluate the patterns of relapse or progression and the timing of re-initiation of therapy among 146 patients who were initially treated with ASCT at Mayo Clinic between 1996 and 2009 and who received second-line therapy between 7/9/1997 and 4/12/2012.Results: The median time from ASCT to second-line therapy was 23.6 months and the median follow up post ASCT was 57.5 months. The indications for second-line treatment were: 1) both hematologic and organ progression 24.7% (36 patients); 2) organ progression only 41.1% (60); 3) hematologic relapse only 34.2% (50). The median dFLC at the time of starting second-line therapy was 10.5 mg/dL (1.6 - 59.5 mg/dL), which was 44.9% (13.8-167.2%) of dFLC level at diagnosis. Increase in proteinuria by > 50% from nadir (that was also at least 1g/24 hours, i.e. renal progression) was present in 35.8%. Increase in NT proBNP by >30% from nadir and minimum of 300 pg/mL was present in 48.9% of patients. The respective 4 years overall survival rates from the time of ASCT were 87.8%, 63.9%, and 56.7% (p=0.0016) for patients who had hematologic relapse, organ progression only and both organ and hematologic progression. Comparisons of laboratory markers at diagnosis, nadir of post ASCT and initiation of second-line therapy are listed in the table.Conclusions: Our study investigated the patterns of relapse / progression following upfront ASCT. This provides some insights on practice patterns of when physicians re-initiate therapy. [Display omitted] DisclosuresGertz:NCI Frederick: Honoraria; Celgene: Honoraria; Med Learning Group: Honoraria, Speakers Bureau; Research to Practice: Honoraria, Speakers Bureau; Novartis: Research Funding; Prothena Therapeutics: Research Funding; GSK: Honoraria; Sandoz Inc: Honoraria; Ionis: Research Funding; Alnylam Pharmaceuticals: Research Funding; Annexon Biosciences: Research Funding. Kumar:Millennium: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; AbbVie: Research Funding; Glycomimetics: Consultancy; Janssen: Consultancy, Research Funding; BMS: Consultancy; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Research Funding; Kesios: Consultancy. Kapoor:Celgene: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Dispenzieri:Prothena: Membership on an entity's Board of Directors or advisory committees; Alnylam: Research Funding; Celgene: Research Funding; Jannsen: Research Funding; pfizer: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Prolonged Progression-Free Survival Is Possible in Patients with Diffuse Large B-Cell Lymphoma Receiving > 1 Salvage Therapies before Autologous Stem Cell Transplant

IntroductionWhile 50-60% of patients with diffuse large B-cell lymphoma (DLBCL) are cured with initial chemoimmunotherapy such as R-CHOP, many patients will relapse and require additional therapy. Historically, autologous stem cell transplant (ASCT) has been utilized in chemo-sensitive patients with relapsed DLBCL although the role of ASCT in patients who require > 1 salvage treatment to achieve remission is less defined due to concerns about the likelihood of long-term remission in that population. We evaluated the outcome of ASCT in patients who required >1 salvage therapy.MethodsWe included all patients undergoing ASCT for relapsed/refractory DLBCL at our site between 2005-2016 who received > 1 salvage treatment before transplant, with radiation therapy considered a salvage treatment if given after relapse but before ASCT. We collected demographic, clinical, laboratory and pathologic data on all patients. We defined progression-free survival (PFS) as time from ASCT to date of progression or death from any cause and overall survival (OS) as time from ASCT to date of death from any cause. Living patients were censored at the time of their last follow up. Univariate Cox proportional hazards models of PFS and OS were fit and Kaplan-Meier plots were developed to estimate the impact of variables of interest on survival.ResultsOut of 259 patients undergoing ASCT for DLBCL, 43 received > 1 salvage treatment, the median age was 51 years and 23 patients were male. Twenty patients had stage III/IV disease at diagnosis. The median time to relapse from the time of diagnosis was 9.3 months, and 42% of patients experienced a relapse > 12 months after diagnosis. Twenty-six patients (60%) received radiation as one of their salvage therapies, 25 patients (58%) received R-ICE as their first salvage therapy and 10 (23%) patients received R-ICE as their second salvage treatment. All patients received either 2 (n=39) or 3 (n=4) salvage therapies before ASCT, and the response to the initial salvage therapy received was CR in 4 patients, PR in 14 patients, SD in 1 patient, and PD in 14 patients, with initial response to salvage therapy missing in 10 patients. The median PFS for all patients was 15.9 months and the median OS was 57.2 months (Figure 1a). Receipt of radiation and having disease sensitive to treatment at the time of ASCT were the only factors associated with prolonged PFS and OS. Median PFS has not been achieved in patients who received radiation while patients who did not receive radiation had a median PFS of 4.2 months (HR = 0.36, p = 0.014; Figure 1b). Patients who had a chemo sensitive disease status at transplant had a median PFS of 22.6 months; however, patients with refractory disease at transplant only achieved a median PFS of 3.6 months (HR = 0.30, p=0.008). Remaining factors including conditioning regimen, time to relapse, and number of salvage therapies were not significantly associated with PFS or OS.ConclusionsASCT can result in prolonged PFS/OS in patients requiring > 1 salvage therapy especially in the case of sensitive disease. Radiation as an additional line of therapy is associated with improved PFS/OS, suggesting this can be included to induce remission in patients who fail to achieve CR with initial salvage treatment. While uncommon, patients with chemo-refractory disease can also have durable survival and should not be excluded from transplant. [Display omitted] [Display omitted] DisclosuresCalzada:Seattle Genetics: Research Funding. Flowers:Spectrum, Janssen, Infinity, AbbVie, Acerta, Pharmacyclics, TG Therapeutics: Research Funding; Celgene Corporation: Consultancy, Honoraria; Optum Rx, Seattle Genetics, Genentech/Roche: Consultancy; Gilead: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Seattle Genetics: Research Funding. Cohen:Bristol-Myers Squibb: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

A Comprehensive Assessment of Toxicities in Patients with Central Nervous System Lymphoma Undergoing Autologous Stem Cell Transplantation Using Thiotepa, Busulfan, and Cyclophosphamide Conditioning

High-dose therapy and autologous stem cell transplantation (ASCT) with thiotepa, busulfan, and cyclophosphamide (TBC) conditioning has emerged as an effective postinduction treatment strategy for patients with primary central nervous system lymphoma (PCNSL) or secondary central nervous system lymphoma (SCNSL), but it is associated with considerable toxicity and transplantation-related mortality (TRM) in the modern era. Forty-three adult patients with chemosensitive PCNSL or SCNSL underwent TBC-conditioned ASCT between 2006 and 2015. Twenty-eight of these patients received pharmacokinetically (PK)-targeted busulfan dosing. The median number of clinically relevant individual grade ≥3 nonhematologic toxicities per patient was 5. We found no association between pretransplantation patient characteristics and the presence of more than 5 grade ≥3 nonhematologic toxicities. Patients with elevated first-dose busulfan area under the curve values did not experience more toxicity. Paradoxically, patients treated with more than 2 regimens before undergoing ASCT had lower first-dose busulfan AUC values. With a median follow-up among survivors of 20 months, 1-year progression-free survival (PFS) and overall survival (OS) from the time of ASCT were 83% and 87%, respectively. Although this study reaffirms the favorable PFS and OS associated with TBC-conditioned ASCT for PCNSL or SCNSL, this treatment strategy carries a large toxicity burden.

Upfront Autologous Stem Cell Transplantation for Newly Diagnosed Elderly Multiple Myeloma (MM) Patients: A Prospective Multicenter Study

Introduction: Previous trials have shown that autologous stem cell transplantation (ASCT) is superior to conventional chemotherapy in terms of remission rate and PFS in younger MM patients. Concerns about toxicity and potential efficacy of ASCT in older MM patients lead most centers to limit ASCT indications to patients aged <65 years. However, at the era of novel induction regimens, and because of better patient selection and supportive care, ASCT may prove to be a valid treatment option even in older MM patients. Therefore, some investigators are questioning the widely used 65 years age limit.Patients and Methods: We prospectively analyzed the outcomes of 56 consecutive MM patients who had received ASCT between September 2012 and September 2014 in 6 institutions in France (protocol ClinicalTrials.gov Identifier: NCT01671826). Patients were newly diagnosed MM. For induction therapy, all patients received a bortezomib-based induction regimen (VD, VTD, VCD, or VRD, 4 to 6 cycles) according to center's local guidelines. Mobilization was performed with G-CSF or G-CSF+cyclophosphamide and plerixafor whenever needed. High-dose chemotherapy consisted of either 140 mg/m2 or 200 mg/m2 Melphalan. A short two months consolidation phase post ASCT was allowed (lenalidomide-dexamethasone, VD, VTD, VCD or VRD). No maintenance treatment was given. Response, disease progression and relapse were defined according to the IMWG uniform response criteria. All patients signed an informed consent form according to the EBMT guidelines.Results: At time of diagnosis, median age was 67 (range, 64-74) years with 23% of patients being >70 years. There were 30 males and 26 females. The immunoglobulin subtype was IgG (n=29), IgA (n=15), light chain (n=10), other (n=2). The Salmon and Durie stage was III in 89% of cases (n=47), and the ISS score was I (n=18; 35%), II (n=19; 37%), III (n=14; 27%). Patients had high risk cytogenetics features (t(4;14) and/or del17p) in 9 cases (16%). 10% of patients had a serum creatinine level >176 micromol/L. None of the patients underwent hemodialysis. The Sorror comorbidity score was 0 (34), 1 (6), 2 (2), 3 (6), 6 (1), unknown (7). The median age at time of ASCT was 68 years, and the median time from diagnosis to ASCT was 5 months. In an intention to treat analysis, out of 56 patients, 6 patients could not proceed to ASCT because of an early infectious death (n=1), serious comorbidity (n=2), disease refractoriness to induction (n=1), and failure to collect an adequate PBSC graft (n=2). A median of 5.31x106/Kg CD34+ cells could be collected. Disease status at time of ASCT was: CR (n=12; 24%), VGPR (n=19; 38%), PR (n=17; 34%), and SD/non-responding (n=2; 4%). The conditioning regimen consisted of 140mg/m² melphalan in 18 cases (36%) and 200mg/m2 in 32 patients (64%). Moreover, 4 patients (8%) received a tandem ASCT. The median time for neutrophils and platelets engraftment was 12 days. The day-100 post ASCT non-relapse mortality was 0% and the 2-year NRM was 4.2% (95% CI:[0.3-18.3]). The overall response rate at day 100 was 96% (CR: 34%, VGPR: 47%, PR: 15%, SD/non-responsive: 4%). At 3 months post ASCT, 82% patients were able to receive the planned post ASCT consolidation treatment. After a median follow-up of 12 months, the estimated progression-free (PFS) and overall survival (OS) rates at 2 years were 76% (95%CI: [61.6-94.1]) and 88% (95%CI: [76.7-100]), respectively. The incidences of infectious complications post ASCT, and response rates were comparable between the two melphalan dose levels (p=0.28). However, in the univariate analysis, the 200 mg/m2 melphalan conditioning group showed a better OS rate compared to the 140 mg/m2 group (1-year OS: 100% vs. 67%; p=0.012).Conclusion: These prospective multicenter results indicate that ASCT is a safe and effective treatment modality for elderly, but fit MM patients at the era of novel induction agents. Of note, patients above age 70 did not experience a worse prognosis. Thus, age per se should not be used as an exclusion criterion for ASCT. Longer follow-up data will be presented, but these results already set the frame for a randomized comparison to the non-transplant approaches in this patients' subgroup. DisclosuresGarderet:Bristol-Myers Squibb: Consultancy. Touzeau:AbbVie: Research Funding. Stoppa:Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria. Karlin:Celgene: Honoraria; Janssen: Honoraria; BMS: Honoraria; Amgen: Honoraria; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees. Moreau:Celgene, Janssen, Takeda, Novartis, Amgen: Membership on an entity's Board of Directors or advisory committees.

The Effect of Autologous Stem Cell Transplant (ASCT) on Survival in Californians with Multiple Myeloma (MM) in the Era of Modern Treatment

Background: The use and timing of ASCT on survival after MM in the era of modern therapy remain topics of debate. Using population based data, we evaluated factors associated with the receipt of ASCT and the effect of ASCT on overall survival (OS).Methods: Patients diagnosed with MM during 2000 - 2012 were identified in the California Cancer Registry (CCR) (n=12,714). CCR data were linked to the California Patient Discharge Database (PDD). Logistic regression estimated the odds ratio (OR) of having an early (< 1 year from diagnosis) or late (> 1 year) ASCT (vs. no ASCT). OS was calculated using the Kaplan-Meier (KM) method. To determine the effect of ASCT on OS from diagnosis date, Cox regression models estimated adjusted hazard ratios (aHR) of death treating ASCT as a time dependent covariate. OS time was compared after matching ASCT to no ASCT patients on age, sex, race/ethnicity, neighborhood socioeconomic status (SES), comorbidity at diagnosis, year of diagnosis, and accounting for time to transplant.Results: The majority of MM patients were male (54%) and of non-Hispanic white (58%) race/ethnicity; 19% Hispanic, 12% African American, and 9% Asian. Median age at diagnosis was 67 (range 18 - 104). African Americans and Hispanics were younger than non-Hispanic whites (median age 64 and 65 vs 69). Comorbidity data from the PDD was available in 59% of the patients in the 2 years prior to MM diagnosis: 7.5% had 0, 21% had 1-2, and 31% had ≥3 comorbidities.A total of 2136 (17%) patients underwent ASCT: 1347 < 1 year from and 789 ≥1 year after diagnosis. Time to ASCT did not change over time: among patients diagnosed 2000 - 2003 median time to transplant was 9.2 mo, 10 mo among those diagnosed 2004 - 2007 and 9.7 in those diagnosed 2008 - 2012. Patients who underwent ASCT were younger than those who did not (median age 56 vs 70 respectively). African Americans were less likely to undergo early ASCT (OR 0.7, P<0.001), but not late ASCT (OR 0.8, P=0.07). Patients with ≥3 comorbidities (vs. 0) at diagnosis were less likely to have ASCT (OR 0.42 P<0.001 and OR 0.28 P<0.001 for early and late, respectively), while patients with 1-2 comorbidities were less likely to have late ASCT (OR 0.59 P<0.001). The lowest 2 quintiles of SES was associated with less use of early ASCT (OR 0.62 p<0.001 and 0.65 p<0.001 respectively), but not late ASCT (OR 0.89 p=0.4 and 0.96 p=0.7 respectively). The likelihood of receiving ASCT increased over time: compared to 2000-2003, the ORs for patients diagnosed in 2004 - 2007 were 1.36 for early (P<0.001) and 1.64 (P<0.001) for late ASCT and were 2.64 (P<0.001) for early and 1.80 (P<0.001) for late for those diagnosed in 2008-2012.The median follow-up was 32 months. Median OS from diagnosis for the entire cohort, unadjusted for age, comorbidities, and SES was 37 months. Adjusting for sex, race/ethnicity, age at diagnosis, SES, comorbidities, insurance status and year of diagnosis, OS improved over time: compared to patients diagnosed in 2008 - 2012, aHR of death of those diagnosed 2000-2003 was 1.58 (P<0.001), and 1.35 (P<0.001) for those diagnosed 2004-2007. ASCT at any point was associated with a 23% reduction in the risk of death from all causes (aHR 0.77 P<0.001). Patients who received early ASCT had a 27% reduction (aHR 0.73 P<0.001), while those receiving late ASCT had an 11% decrease (aHR 0.89 P<0.001) in risk of all cause death. In the matched analysis, the median OS from date of transplant, or matched date in the no ASCT cohort, were: no ASCT = 49 mo, early ASCT = 83 mo, and late ASCT 65 mo (P<0.001 Figure 1). The effect of aSCT on OS differed by date of diagnosis (P for interaction <0.001). Improvements in OS due to ASCT were more pronounced in later time periods: aHR for early and late ASCT in 2000-2003 were 0.9 (P = 0.12) and 0.98 (P 0.86) compared with those in 2004-2007 (0.63 P<0.001 and 0.85 P = 0.06) and in 2008-2012 (0.55 P<0.001 and 0.74 P=0.08).Conclusions :ASCT was utilized in 17% of Californians with MM during 2000-2012, and its use increased over time. The use of ASCT, whether within a year of diagnosis or later in the disease course, is associated with improved OS and this effect may be more pronounced in the era of novel agents. Despite the inherent limitations of analyses of administrative databases, the large number of patients and established robust nature of CCR and PDD data makes accurate depiction of results in the community probable. These data support the continued role of ASCT in the management of patients with MM. [Display omitted] DisclosuresJonas:Celgene: Honoraria; Incyte: Honoraria; Onyx: Honoraria; GlycoMimetics: Consultancy.

Daily Weight-Based Busulfan with Cyclophosphamide and Etoposide (Bu/Cy/VP) Produces Comparable Outcomes to 4-Times-Daily Busulfan Dosing for Lymphoma Patients Undergoing Autologous Stem Cell Transplantation (ASCT)

INTRODUCTION:High dose busulfan (Bu) is an integral component of many commonly-used preparative regimens for both allogeneic and autologous transplantation. Data on the efficacy and toxicity of q6 vs. q24 hour dosing are of significant clinical interest. In order to facilitate a therapeutic dose-monitoring protocol, we transitioned from q6 to q24 Bu dosing as part of our standard Bu/Cy/VP ASCT preparative regimen for patients with Hodgkin (HL) and Non-Hodgkin Lymphoma (NHL) in July 2012. We present comparative outcomes of q24 Bu dosing vs historical controls receiving q6 Bu.METHODSWe retrospectively reviewed 400 consecutive eligible lymphoma patients who underwent ASCT from 2007-2013 with Bu/Cy/VP. All patients received Cy 60 mg/kg IV over 4 hours on days -3 and -2 and VP 60 mg/kg as continuous infusion on days -5 and -4. Bu was given at a dose of either 0.8 mg/kg q6 (N = 307) x 14 doses for patients transplanted between 2007-July, 2012 or 2.8 mg/kg q 24 hours (N = 93) on days -9 through -6 for subsequent patients. Outcomes assessed from date of transplant were: relapse, non-relapse mortality (NRM), relapse-free survival (RFS) and overall survival (OS). Toxicity was assessed using pulmonary and liver function tests (PFTs and LFTs) at specified time-points before and after ASCT. In addition, for a subset of 22 patients receiving q24 Bu, we measured serial Bu serum levels after the first dose of Bu with an in-house liquid chromatography-tandem mass spectrometry assay using turbulent flow online extraction technology (Bunch, et al. J Chromatogr B Analyt Technol Biomed Life Sci, 2010. 878(31): p. 3255-8) and subsequently determined the cumulative Bu area-under the curve (AUC).RESULTSBaseline patient and disease characteristics of patients dosed with q6 and q24 Bu were similar. The median age was 55 (range 20-78) years; 63% were males. 18% had HL and 82% had NHL with a comparable distribution of subtypes in both groups. Patients in both groups had comparable rates of prior chemotherapy regimens and of complete/partial remission at the time of ASCT. Due to a change in institutional guidelines, plerixafor was more commonly incorporated in peripheral blood stem cell mobilization regimen in the q24 group compared to q6 cohort (70% vs. 39%, P <0.001). However, CD34+ doses were same in the two dosing cohorts. In terms of toxicity of the two dosing approaches, there was no significant difference in FEV1 or DLCO before and after transplant in the q6 vs q24 cohorts. LFTs measured at four time points were generally lower with q24 Bu, particularly AST and alkaline phosphatase (P=0.007 each), but these difference were not clinically significant. The median follow-up was longer in the q6 than q24 group (48.2 months vs. 21.3 months, P < 0.001). 18 month outcomes of the two dosing cohorts were comparable (see Table and Figure). We observed significant variation in AUC with weight-based dosing of Bu (AUC range 12,104 - 23,084 µM-min) with a median of 17,568 µM -min, which has served as a baseline for subsequent therapeutic-dose monitoring.CONCLUSIONSQ24 Bu dosing in combination with Cy/VP is more convenient than q6 hours, has equivalent outcomes, and results in no increase in either hepatic or pulmonary toxicity. Consistent with previous reports, there is a significant range of Bu AUC levels, with a standard deviation of 12%. These data provide rationale for our prospective clinical trial of real-time therapeutic dose monitoring with q24 Bu dosing.Table 1Q6 dosingQ24 dosingP-valueOS78%80%0.79RFS63%61%0.99NRM5%3%0.95Relapse30%36%0.4618 month outcomes of q6 vs q24 Bu dosing [Display omitted] [Display omitted] DisclosuresHill:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Majhail:Gamida Cell Ltd.: Consultancy; Anthem Inc.: Consultancy.

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.

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.

High Dose Melphalan Followed By Autologous Stem Cell Transplant in AL Amyloidosis: a Single-Center Experience

INTRODUCTIONhigh-dose melphalan (HDM) followed by autologous stem cell transplant (ASCT) has been routinely used as a treatment option for systemic light chain AL amyloisosis since the first report in mid-1990s. The high treatment-related mortality (death before post-transplant day 100) reported in literature (11-40% in different papers) has decreased over the last years with the improvement in patient selection. Particularly, in the largest Mayo Clinic series of 422 subjects, patients with cardiac troponin-T < 0.06 ng/L and NT-proBNP < 5000 ng/L had TRM < 1%; besides, patients achieving hematologic complete response/very good partial remission (CR/VGPR) had superior overall survival than those achieving hematologic partial response (PR) and no response. Here we report our single-center experience of 14 ASCT performed in 10 patients between 2007 and 2014. PATIENTS AND METHODSthe median age at the time of ASCT was 58 years (range 44-68). Five patients had 2 or more involved organs. All 10 patients had: normal troponin-I value, NT-proBNP < 5000 ng/L, PS 0-1, cardiac ejection fraction over 50%, CO diffusion capacity over 50%; only one had creatinine clearance < 50 ml/min. Three patients collected stem cells after cyclophosphamide (1,5 g/m^2), the others after G-CSF alone. Four patients proceeded directly to ASCT after diagnosis, 3 received CyBorD and 3 other induction regimen (5 patients were non responders and 1 was in hematologic PR after “induction therapy” before HDM). Patients received melphalan 200 mg/m^2 (9 ASCT) or dose adjusted HDM (100-140 mg/m^2, 5 ASCT), depending on clinical decision. Four patients received double ASCT. RESULTSmedian follow up is 48 months (range 0,5-80); all patients were alive at the last visit. Of nine evaluable patients (1 patient too early), overall hematologic and organ response rate after ASCT were 78% and 45%. Only 1 of 4 patients with double ASCT improved response after the second course (this patient maintains a hematologic CR without organ involvement after 80 months of follow up). Median hospitalization for ASCT was 24 days (range 17-45), without any threatening-life side effect. Six of 9 evaluable patients needed a 2ndline therapy for progressive disease after a median follow up of 24 months (range 13-52): 4 of them had achieved hematologic PR after ASCT, 1 patient achieved hematologic VGPR and 1 had no hematologic response. Three patients are in follow up without other therapy after ASCT (2 hematologic CR and 1 non response). CONCLUSIONHDM followed by ASCT is a very effective treatment option in AL-amyloidosis, which may be effective even in patients non responding to first-line treatment with non myeloablative drugs. According to the data of the literature, our experience suggests that a careful selection of patients is critical for good outcomes and that particular cardiac biomarkers (cardiac troponin-T < 0.06 ng/L and NT-proBNP < 5000 ng/L) are useful to guide the choice of therapy. Furthermore, consolidation therapy (IMiDs and proteasome inhibitors) should be considered for patients who do not obtain at least a VGPR/CR after HDM. DisclosuresNo relevant conflicts of interest to declare.

Thiotepa Containing Regimen As Conditioning Chemotherapy for Lymphoma Involving Central Nervous System Compared with BuCyE (Busulfan, Cyclophosphamide and Etoposide)

AimsPrimary or secondary central nervous system (CNS) lymphoma is a rare entity which often leads to unsatisfactory outcome. Autologous stem cell transplantation (ASCT) using thiotepa containing regimen as conditioning chemotherapy showed improved outcomes in patients with CNS lymphoma. However, there are insufficient data on response to treatments and safety profile of thiotepa containing regimen in Asian population. We, therefore, aimed to evaluate clinical outcomes including safety profile and response to thiotepa, busulfan and cyclophosphamide (TBC) chemotherapy compared with busulfan, cyclophosphamide and etoposide (BuCyE) as conditioning regimens in patients with CNS lymphoma.MethodsFrom November 2005 to April 2014, patients with primary and secondary CNS lymphoma who underwent one of the two conditioning regimens (TBC or BuCyE) followed by ASCT were included in this retrospective analysis. All patients were less than 66 years of age at the time of ASCT. TBC consists of thiotepa 250 mg/ m2 on day -9 to day -7, busulfan 3.2 mg/kg on day -6 to day-4 and cyclophosphamide 60 mg/kg on day -3 to day -2. BuCyE consists of busulfan 3.2 mg/kg on day -7 to day -5, etoposide 200 mg/m2 twice a day on day -5 to day-4 and cyclophosphamide 50 mg/kg on day -3 and day -2. Patient demographics, ECOG performance status, baseline and follow-up CBC profile, adverse events and radiologic response for 2 years after ASCT were retrospectively reviewed. Response to treatment was assessed by IELSG criteria. Event free survival (EFS), overall survival (OS) and date of engraftment were calculated by Kaplan-Meier method and compared by log-rank test. Adverse events were scored according to National Cancer Institute Common Terminology Criteria of Adverse Event version 4.0. Engraftment was defined as absolute neutrophil count (ANC) > 500 /mm3, and platelet count > 20,000 /mm3.ResultsSixty one patients with primary or secondary CNS lymphoma underwent with TBC (n=26) or BuCyE (n=35) as conditioning regimen followed by ASCT. In TBC group, 17 patients (diffuse large B cell lymphoma: 17) had primary CNS lymphoma and 9 patients (diffuse large B cell lymphoma: 7, angioimmunoblastic lymphoma: 1 and T-lymphoblastic lymphoma: 1) had secondary CNS lymphoma. In BuCyE group, 28 patients (diffuse large B cell lymphoma: 27 and peripheral T-cell lymphoma: 1) had primary CNS lymphoma and 7 patients (diffuse large B cell lymphoma: 5, NK-T cell lymphoma: 1 and mantle cell lymphoma: 1) had secondary CNS lymphoma. Median age of TBC group and BuCyE group at ASCT was 52.5 years (range, 18-64 years) and 54 years (range, 26-64 years), respectively. Median ECOG performance status of TBC group and BuCyE group was 1 (range 0-2) and 1 (range 0-1), respectively. After the induction chemotherapy, 11 patients (42.3%) in TBC group and 21 patients (60%) in BuCyE group had already achieved complete remission (CR). In TBC and BuCyE group, CR had been induced in 9 (64.2%) and 11 (78.5%) among patients in partial remission (PR) after ASCT, respectively. With a median follow up period of 8.6 months (range, 0.2 to 18.5 months), 1-year OS rate did not significantly differ between two arms (76.4% in TBC group and 68.6% in BuCyE group, p=0.634). However, 1-year EFS rate was higher in TBC group (72.8%) compared with BuCyE group (45.7%, p=0.034). TBC group achieved ANC engraftment one day earlier compared to BuCyE group (day 8, range 7-12 days vs. day 9, range 7-12 days) (p= 0.011). However, there was no difference in time to engraftment of platelet between TBC group (median 8 days, range 6 to 34 days) and BuCyE group (median 8 days, range 6 to 22 days, p=0.582). Toxicity profiles are summarized in Table 1.Table 1Toxicity above grade 2TBCBuCyEp-valueMucositis92%14.3%<0.001Nausea72%34.3%0.004Vomiting24%2.9%0.017Diarrhea84%25.7%<0.001AST,ALT elevation15.4%2.9%0.154Bilirubin elevation30.8%5.7%0.014Creatinine elevation7.7%0%0.178Veno-occlusive disease7.7%5.7%1Bleeding3.8%0%0.426ConclusionsTBC seems to be a feasible conditioning chemotherapy for Korean patients with acceptable toxicity and efficacy. DisclosuresNo relevant conflicts of interest to declare.

Autologous Stem Cell Transplantation Achieves Long-Term Survival in a Selected CNS Lymphoma Population

Despite recent advances in care, central nervous system (CNS) lymphoma remains a disease with very poor long-term outcomes. We reviewed outcomes at our centre following the adoption of autologous stem cell transplant (ASCT) for patients achieving remission.Records for 78 consecutive unselected patients diagnosed with cerebral diffuse large B-cell lymphoma (DLBCL) between 2003-2014 were analyzed. 62 of these patients did not undergo ASCT. The median age for the non-ASCT group was 60 years (range 26-80, 32 males, 30 females). Of these 50 had primary CNS lymphoma (PCNSL) and 12 cases had isolated CNS relapse after systemic lymphoma. 5 patients were HIV positive, and 4 patients had post-transplant lymphoproliferative disease. 30 patients received HD-MTX alone and 3 patients received whole brain radiotherapy (WBRT) alone. 10 patients received HD-MTX with salvage WBRT on relapse and 1 patient with CNS relapse post BEAM autograft for systemic disease received HD-MTX & WBRT. 14 patients received palliative treatment and 2 unknown.The remaining 16 DLBCL patients and an additional 3 with mantle cell (2) or ALK positive anaplastic lymphoma (median age 53, range 27-67, male: female 13:6) who were in remission (VGPR/CR) by MRI with adequate performance status (PS) underwent ASCT after HD-MTX-based induction therapy, conditioned with 400mg/m2 BCNU & 10mg/kg Thiotepa. 4 received WBRT post-ASCT as adjuvant therapy. Of the 19 ASCT patients 16 presented with PCNSL, 2 late relapses confined to the CNS following prior systemic DLBCL, 1 mantle cell showed evidence of low-level disease on bone marrow biopsy and all were HIV negative.Median CD34 cell dose was 4.48 x 106. Median times to neutrophil and platelet engraftment were 12 (range 10-57) and 15.5 (range 7-57) days respectively. No deaths occurred from transplant-related complications, including sepsis. 2 year PFS was 67% and OS was 73%. 4 patients relapsed post-transplant (21%), all within 4 months of transplant; 3 subsequently died. 1 patient developed systemic disease progression at time of ASCT and 1 had evidence of a mixed response on MRI pre-ASCT. No patients in CR pre-ASCT have relapsed and 1/11 PR patients has relapsed. The longest remission is now 64 months without use of WBRT, providing evidence for durable long-term response and possible cure in an unselected group of patients.For the non-ASCT patients, median OS post diagnosis was 2.5 months overall, and 7.5 months, excluding palliative patient. Of those receiving MTX therapy 7 achieved CR, 7 PR and 23 had PD. 3 patients failed to tolerate treatment. Of those who achieved CR/PR reasons for not proceeding to ASCT included inadequate PS or lack of willingness to receive further therapy. Outcomes for those who achieve CR are good, with median PFS & OS for patients achieving CR not reached at a median of 32 months follow-up. 5/7 remain in remission; 1 patient has died. Only 1 of these patients received WBRT. The median PFS & OS for patients achieving PR were 5.5 & 8 months respectively (p= 0.041 & 0.027 vs CR).When comparing the two groups, median OS for patients receiving ASCT was not reached vs 5 months for MTX alone (p<0.001) and 29 months for MTX & WBRT (p=0.013).Overall we conclude MTX therapy alone induces CR in only a small number of patients and outcomes for those not achieving CR are dismal. For patients who are able to proceed to ASCT long-term remissions can be obtained. New strategies are required to enable patients to achieve CR in order to receive ASCT and thus achieve a durable long-term survival from CNS lymphoma. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Autologous Stem Cell Transplantation for Multiple Myeloma in the Era of Novel Agents

Autologous Stem Cell Transplantation for Multiple Myeloma in the Era of Novel Agents

Autologous Transplantation Is Safe and Effective For Patients With Multiple Myeloma Related Renal Insufficiency

IntroductionPatients (pts) with MM often present with varying degrees of renal insufficiency (RI) which can cause significant morbidity. In younger pts with MM, high-dose chemotherapy with autologous stem cell transplantation (ASCT) has been shown to enhance remission and possibly improve survival. In pts with RI there has been concern about the safety and efficacy of proceeding to ASCT. At our center, ASCT has been routinely offered to pts with RI. Herein we report the results of MM pts with RI who received ASCT since 2000. Patients and MethodsOutcomes of 50 MM pts with RI were compared to 100 matched ASCT recipients. The matched transplant pts studied were similar with respect to subject-, disease-, and transplant-related characteristics. All pts met standard eligibility criteria for ASCT and pts with RI had a serum creatinine (Cr) level of >2 mg/dL (average Cr = 6.07 with a range of 2 to 11.79 mg/dL), at the time of ASCT. 14 of the 50 pts were on dialysis at the time of ASCT. All patients had active MM requiring therapy and all pts had evidence of stable disease or treatment response prior to transplant. For pts with RI, the average age at transplant was 56 years (range 33 to 69 yrs) and the median time between diagnosis and ASCT was 302 days. The preparative therapy consisted of single agent Melphalan, given on Day (-3) or (-2) with a median administered dose of 140 mg/m2 (range 100-200 mg/m2) while the dose for the matched patients was 200mg/m2. All pts were hospitalized for ASCT and received standard supportive care; >2 x 10e6/Kg CD34(+) cells, G-CSF, transfusions as necessary and appropriate anti-infectives. ResultsThe 30-day and 100-day treatment related mortality (TRM) rates for both the patients with RI and matches were 0%. Amongst the patients with RI, 4 patients required ICU care and the average duration of hospitalization was 23.36 days (range: 14 - 48 days) and duration of hospitalization for matches 19.4 days (range: 11-58 days). Time to ANC > 0.5 x10e9/L was 12 days (range 10-21 days) and 12 days (range 10-22 days) in the RI and matched cohort respectively. Time to platelets > 20 x 10e9/L was 11 days (range: 6-22 days) and 14 days (range 8-51days) in the RI and matched cohort respectively. 32% of pts with RI were in very good partial response (VGPR)+ complete remission (CR) of which 12% were in CR at ASCT. After ASCT, 50% of pts achieved a VGPR+CR of which 34% pts achieved a CR. The mean overall survival (OS) for patients with RI was 4.2 yrs and for controls was 6.5 yrs [Figure 1. HR 2.036, 95% CI (1.204-3.443) p=0.0084]. [Display omitted] ConclusionASCT is a safe and effective treatment option for MM pts with RI including those on dialysis with engraftment characteristics similar to pts without RI. Disclosures:Wolf:Onyx: Honoraria; Millenium: Honoraria; Celgene: Honoraria, Research Funding.

Impact Of Pre-Transplant Rituximab Sensitivity In Relapsed Follicular Lymphoma On Outcome After Autologous Transplant

▪ PurposePrior to the introduction of modern induction and maintenance regimens, autologous stem cell transplantation (ASCT) improved outcomes in chemotherapy-sensitive, relapsed follicular lymphoma (FL). We re-evaluated the impact of Rituximab (R) sensitivity on ASCT for relapsed FL in the current Rituximab era. Methods194 consecutive patients with a confirmed diagnosis of relapsed, grade 1, 2 or 3A FL underwent ASCT at our center from April 1993 to October 2011. They were categorized as R-sensitive, R-refractory, or no R (NoR) if transplanted prior to use of Rituximab. Rituximab refractoriness was defined as failure (at any point in treatment) to achieve at least a PR or documented disease progression within 6 months of receiving the first dose of a full course of single-agent rituximab (³ 4 doses of 375mg/m2 weekly), getting rituximab maintenance (R-maintenance) or completing 2 courses of Rituximab combined with chemotherapy (R-chemotherapy). The statistical significance of differences in event rates was evaluated with the proportional hazards regression model. Two-sided p-values less than 0.05 were considered statistically significant. Kaplan-Meier (K-M) curves were used to estimate the probabilities of overall survival (OS) and progression-free survival (PFS). Cumulative incidence of relapse was calculated in a competing risk data analysis considering non-relapse mortality as a competing event. ResultsThere were 65 rituximab-refractory (RR), 35 rituximab-sensitive (RS) and 94 NoR patients. RS (11%) and RR (12%) patients received R-maintenance. High-risk FL international prognostic index (FLIPI) scores at the time of ASCT was imbalanced between the groups: RS 3%, RR 23% and NoR 26% (P = .009). Baseline characteristics were otherwise comparable between the 3 groups. Median follow-up from ASCT to time of last contact or death was 64 months (range 10-169), 42 months (range 1-157) and 91 months ( range 0.5-231) in the RS, RR and NoR groups, respectively. Univariate analyses showed significantly better OS (P = .003) and PFS (P = .0004) in RS patients with 3-year OS and PFS (Figure 3) of 97% and 85% compared with 63% and 35% in RR and 73.4% and 49% in NoR patients, respectively (Figures 1 & 2). Time to next treatment in relapsing patients was significantly shorter in the RR group compared to the RS and NoR groups. We performed multivariate adjustment for pre-ASCT factors that could affect outcomes i.e. age ≥ 50, FLIPI score ≥ 3, # prior chemotherapy regimens ≥ 3, chemo-resistance, elevated lactate dehydrogenase, prior radiation therapy, bone marrow stem cell source, and remission quotient ≥ 6 (defined as the months from diagnosis to ASCT divided by number of prior therapies). Multivariate adjustment showed OS to be significantly affected only by rituximab sensitivity, with a lower risk of death in RS patients (HR 0.24, P = .01). PFS was also significantly affected by pre-ASCT rituximab sensitivity (HR 0.35, P = .006). Cumulative incidence of relapse was increased in RR patients (HR 2.11, P = .01). The differences in post-ASCT OS, PFS, and relapse rates between the RS and RR patients were maintained independent of transplant conditioning regimen. There were no differences in OS, PFS or relapse whether RR patients were refractory to single-agent rituximab, R-maintenance, or R-chemotherapy. ConclusionsPre-transplant rituximab sensitivity in relapsed FL is a strong independent predictor of post-ASCT outcome. For RR FL patients with limited effective options, nearly half were alive and progression-free at 3 years after ASCT. [Display omitted] [Display omitted] Disclosures:Shustov:Seattle Genetics, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Evolving Strategies in the Initial Treatment of Multiple Myeloma

Until the advents of novel agents, partial response (PR) or better was the established gold standard to initial therapy of multiple myeloma (MM), and treatment goals were focused on relieving symptoms, prevention of organ damage, and modest improvements in survival. With the introduction of autologous stem cell transplant (ASCT), deeper responses, including complete responses (CRs) were more frequent, and contributed to longer survival. In the era of novel therapies, ASCT remains commonly used and its impact on outcome appears superior, albeit less so than when compared with conventional therapy, and its survival benefit is yet to be established in either setting. In addition, in non-transplant candidates, novel therapies have now significantly improved the overall response rates, depth of response, and clinical benefit, to the levels previously only observed with ASCT, which now increasingly challenges the role and timing of ASCT in eligible patients. Nevertheless, the two approaches of treatment, transplant or no transplant, remain commonly accepted. With an improvement in the tolerability of newer regimens and the deferral of ASCT in transplant candidates, the debate has emerged whether the two-pathway approach to the treatment of newly diagnosed myeloma should be re-evaluated. At the same time, treatment goals are also shifting. Many believe that MM can be converted into a chronic disease and that a functional cure maybe a realistic goal, for at least a proportion of patients. This contribution will review these points of discussion and the evolving approach to treatment of newly diagnosed MM.

Is There an Optimal Timing of Autologous Stem-Cell Transplantation for Multiple Myeloma in the Era of Novel Agents?

Is There an Optimal Timing of Autologous Stem-Cell Transplantation for Multiple Myeloma in the Era of Novel Agents?

The impact of ASCT on patients with newly diagnosed multiple myeloma who receive RVD induction

Objective: Lenalidomide-bortezomib-dexamethasone (RVD) is associated with a high-rate of response in newlydiagnosed multiple myeloma (MM). Autologous stem cell transplantation (ASCT) with high-dose melphalan conditioningis a standard of care in MM. The impact of ASCT following RVD induction is not known. This study evaluates the impactof ASCT following RVD induction therapy in MM. Methods: Using our center’s transplant database, we identified 60 patients with newly diagnosed MM who underwentRVD induction followed by ASCT in first response. We describe disease characteristics including International StagingSystem (ISS) stage and cytogenetics, pre- and post-ASCT response, as well as progression-free survival (PFS) from timeof ASCT. Results: The rate of paraprotein complete response prior to and following ASCT was 50% and 60%, respectively. Amongthe 30 patients who did not achieve a paraprotein CR pre-ASCT, 14 (47%) patients had improved response post-transplant.At a median follow-up of 23 months, 90% (90% CI: [81%, 95%]) of the patients were alive without progression 12 monthsafter transplant. Conclusion: ASCT improves the rate of CR in patients with newly diagnosed MM who receive RVD induction therapy.

Early versus delayed autologous stem cell transplant (ASCT) in patients receiving induction therapy with lenalidomide, bortezomib, and dexamethasone (RVD) for newly diagnosed multiple myeloma (MM).

8540 Background: Lenalidomide, bortezomib and dexamethasone (RVD) is an active, tolerable induction regimen with superior response rates (≥VGPR rates of 80%) in newly diagnosed MM pts. However, the optimal timing of ASCT with this triplet combination is uncertain. We have evaluated our institutional experience to provide an insight for the best timing of ASCT, where specific patients were offered delayed ASCT based on risk, response and toxicity of therapy. Methods: 222 consecutive transplant-eligible pts with newly diagnosed MM that received at least 3 cycles of RVD and harvested stem cells were included in the analysis from May 2007 until October 2011. Patients underwent early ASCT (received planned ASCT immediately after stem cell harvest, n=136) or delayed transplant (received planned maintenance therapy after collection with intent to proceed with ASCT at first relapse, n=86). Results: Median age of the patients at the time of diagnosis is 60.5 yrs (32-77) vs. 60 yrs (22-73) for early vs. delayed groups. ISS stage 3 disease was seen in 31% patients and 10% patients; high risk cytogenetics were seen in 11% and 7% patients in early vs. delayed groups, respectively. Median time from initiation of induction therapy to ASCT in early group is 5.45 months (range, 3.19-12.68 months). In the delayed SCT group, 28 patients underwent ASCT at a median time of 26.21 months (range, 13.67-41.72 months) from initiation of therapy. At a median follow up of 32 months, 5-year overall survival from diagnosis was 68% and 88% in patients undergoing early and delayed ASCT, respectively (p = 0.106). Conclusions: Transplantation-eligible patients who receive RVD as initial therapy followed by early vs. delayed ASCT result in comparable overall survival. In carefully selected newly diagnosed myeloma patients with lower ISS stage receiving RVD as induction therapy, planned delayed ASCT results in 5-year survival rates close to 90%.