First-line Autologous Stem Cell Transplantation Research Articles

Long-Term Remissions after First-Line Autologous Stem Cell Transplantation for Mantle Cell Lymphoma

Introduction: The role for autologous stem cell transplantation (ASCT) in mantle cell lymphoma (MCL) has been recently called into question by the TRIANGLE trial, which demonstrated similar 3-year outcomes with or without ASCT among patients treated with R-CHOP/R-DHAP and 2 years of maintenance ibrutinib +/- rituximab. However, long-term follow-up is necessary to determine the durability of remissions and ascertain the true value of first-line ASCT for MCL. Methods: This retrospective population-based study included all patients ≥18 years old who received ASCT as part of first-line therapy for MCL in the province of Alberta, Canada between 2000-2022. The primary objective was to determine freedom from progression (FFP), which was measured from the time of ASCT to disease progression. Secondary objectives were to determine progression-free survival (PFS) and overall survival (OS). FFP, PFS, and OS were estimated using the Kaplan-Meier method. Cumulative incidences of relapse and non-relapse mortality (NRM) were determined using competing risks analysis. Univariable and multivariable Cox regression was performed to identify risk factors for FFP. Results: The study population included 141 patients with median age at ASCT of 60 years (range 34-71). At diagnosis, 130 (92%) patients had advanced stage disease, 52 (37%) had intermediate/high risk MIPI score, 35 (25%) had Ki67 >30%, 32 (23%) had B symptoms, and 17 (12%) had blastoid/pleomorphic histology. Induction protocols included R-CHOP/cytarabine combinations (n=93), R-bendamustine/cytarabine combinations (n=36), or alternative regimens (n=12). PET-defined pre-transplant disease status was complete metabolic response in 75 (82%) and partial metabolic response in 17 (18%) patients. ASCT conditioning consisted of melphalan plus total body irradiation (n=93), BEAM (n=40), or other regimens (n=8). Maintenance rituximab was received by 96 (68%) patients. With median follow-up time 7.6 years (range 0.4-23.2), the median FFP was not reached (Figure 1) while the median PFS was 11.3 years and median OS was 14.0 years. At 8 years after ASCT, FFP was 67% (95% CI 56-75%), PFS was 57% (95% CI 46-66%), and OS was 70% (95% CI 60-78%). FFP at 8 years was 76% (95% CI 59-86%) with maintenance rituximab versus 49% (95% CI 33-63%) without maintenance rituximab (p<0.001). Multivariable analysis revealed that maintenance rituximab was associated with improved FFP (HR 0.26, 95% CI 0.10-0.72) and B symptoms were associated with inferior FFP (HR 8.45, 95% CI 2.86-25.0), whereas age, Ki67, blastoid/pleomorphic histology, and MIPI score were not significantly associated with FFP. The cumulative incidence of relapse at 8 years was 32% (95% CI 23-41%) and the mean relapse rate appeared to decrease over time, from 4.4%/year during years 0-5 to 2.5%/year during years 6-12 after ASCT. In a subgroup analysis to evaluate the very long-term outcomes of 49 patients who underwent ASCT >10 years ago, median follow-up time was 12.5 years (range 0.4-23.2) and 13-year FFP was 40% (95% CI 26-54%), PFS was 32% (95% CI 19-46%), and OS was 54% (95% CI 35-68%). No relapse occurred >11.2 years after ASCT. Twenty patients remain alive and in remission for >10 years, 5 patients for >15 years, and 1 patient for >20 years after ASCT. There were no cases of NRM within 1 year of ASCT. Therapy-related myeloid neoplasms occurred in 3 (2%) patients. Conclusions: This long-term follow-up study demonstrates that first-line ASCT frequently achieves durable remissions in MCL, with median PFS >11 years, a declining relapse rate over time, and notably high FFP rates among those who receive maintenance rituximab. A subset of patients experienced remissions lasting >10-20 years and may be functionally cured of their lymphoma, although additional follow-up is warranted to confirm the emergence of a plateau on the FFP curve. Given the durability of remissions and possibility of cure in some patients, longer follow-up of the TRIANGLE trial should be awaited before first-line ASCT is prematurely abandoned for MCL.

Renal Response of Selinexor, Pomalidomide, Bortezomib and Dexamethasone in Newly Diagnosed Multiple Myeloma Patients with Renal Impairment: A Prospective, Open-Label, Multicenter, Phase 2 Study

Background Renal impairment (RI) is one of the cardinal features of newly diagnosed multiple myeloma (NDMM), contributing to dismal outcomes and high risk of early death. Improved renal function is associated with prolonged survival for NDMM. The triplet combination of pomalidomide with bortezomib and dexamethasone (PVD) has been proven to be effective in MM patients with RI [1] (The manuscript in preparation). However, the best renal overall response rate (ORR) was 78.8% and 21.2% of patients had no renal response to PVD. Here we reported an interim analysis to evaluate the renal and hematologic response of SPVD (Selinexor, pomalidomide, bortezomib, dexamethasone) regimen as first-line therapy in NDMM with RI in this prospective, open-label, multicenter, phase 2 study (ChiCTR2200064695). Methods Eligible NDMM with RI (defined as estimated glomerular filtration rate (eGFR) by MDRD < 40ml/min) were enrolled in the study. Sample size was designed to recruit 62 patients. RI caused by other reasons than tubular nephropathy was excluded. Patients received SPVD (Selinexor 40mg on days 1,8,15, pomalidomide 4mg on days1-14, bortezomib 1.3mg/m2 on days 1,4,8,11, and dexamethasone 20mg on day of and after bortezomib, 21days/cycle) for a maximum of 9 cycles. Autologous stem cell transplantation (ASCT) was administrated after 3 to 6 SPVD cycles for transplant-eligible patients. The primary endpoint was renal ORR at 3 months. Secondary endpoints included major renal response (≥partial response) at 3 months, hematological ORR, minimal residual disease (MRD), progression-free survival (PFS), overall survival (OS), and safety. The definition of both hematological response and renal response was according to the International Myeloma Working Group (IMWG) criteria. Results Between Oct 28, 2022 and Jun 23, 2023, 31 patients were enrolled across 17 centers, with a median age of 61 years (range: 45-80). The proportion of R-ISS III was 35.5%. Median serum creatine level and eGFR were 365μmol/L [interquartile range (IQR): 214.5-508] and 14.5 mL/min (IQR: 10.5-22.64), respectively. There were 10/31 (32.3%) patients requiring dialysis at diagnosis and 8 patients with high-risk cytogenetic abnormalities [t(4;14), t(14;16), or del(17p)]. At the data cut-off date of July 11, 2023, the median number of SPVD treatment cycles was 3 (range: 1-8). The median follow-up time was 4 months. Two patients received first-line ASCT after induction therapy. The primary endpoint of renal ORR at 3 months was 74.2%, including 6.5% renal PR, and 25.8% renal CR (Table 1). The ORR of the best hematological response was 70.9% (45.1% ≥VGPR, 16.1% CR)(Table 1). The most common treatment emergent adverse events (TEAEs) (incidence >10%) were infection (45.2%), myelosuppression (45.2%), hepatic impairment (12.9%), nausea (12.9%), and hypokalemia (12.9%) (Table 2). Grade 3 or more hematologic toxicity was seen in 35.5% of the patients, the most common being thrombocytopenia (19.4%)(Table 2). Dose reduction or interruption of pomalidomide occurred in 5 patients due to myelosuppression and infection events. Three patients had dose reduction of selinexor due to nausea or vomiting. Notably, among non-hematologic toxicities, 4 patients developed hepatic impairment, and of those, one patient suffered tumor lysis syndrom, hepatic failure and severe infection and then died. Median PFS and OS were not reached. Conclusion This study demonstrated SPVD is an effective combination in NDMM patients with RI. The toxicity profile was consistent with the reported research, but hepatic impairment during treatment should be noted with caution. Reference [1] JIAN Y, CHANG L, SHI M, et al. Renal Response of Pomalidomide with Bortezomib and Dexamethasone in Newly Diagnosed Multiple Myeloma Patients with Renal Impairment: A Prospective, Open-Label, Multicenter, Phase 2 Study [J]. Blood, 2022, 140(Supplement 1): 10167-9. doi:10.1182/blood-2022-159361.

Thiotepa, Busulfan, Cyclophosphamide: Effective but Toxic Conditioning Regimen Prior to Autologous Hematopoietic Stem Cell Transplantation in Central Nervous System Lymphoma.

In primary central nervous system lymphoma, two-year progression-free survival rates of up to 63 percent have been reported for first-line autologous stem cell transplantation after conditioning with the thiotepa busulfan cyclophosphamide regimen. However, 11 percent of the patients died due to toxicity. Besides conventional survival, progression-free survival and treatment related mortality analyses, a competing-risk analysis was applied to our cohort of twenty-four consecutive patients with primary or secondary central nervous system lymphoma who underwent autologous stem cell transplantation after thiotepa busulfan cyclophosphamide conditioning. The two-year overall survival and progression-free survival rates were 78 percent and 65 percent, respectively. The treatment-related mortality rate was 21 percent. The competing risks analysis demonstrate that age 60 or over and the infusion of less than 4.6 × 106/kg CD34+ stem cells were significant adverse prognostic factors for overall survival. Autologous stem cell transplantation with thiotepa busulfan cyclophosphamide conditioning was associated with sustained remission and survival. Nevertheless, the intensive thiotepa busulfan cyclophosphamide conditioning regimen was highly toxic, especially in older patients. Thus, our results suggest that future studies should aim at identifying the subgroup of patients who will really benefit of the procedure and/or to reduce the toxicity of future conditioning regimen.

Is t(11;14)(q13;q32) good or bad for newly diagnosed multiple myeloma?

Is t(11;14)(q13;q32) good or bad for newly diagnosed multiple myeloma?

Bortezomib-Based Induction Regimen Followed By Autologous Stem Cell Transplantation (ASCT) after Conditioning with MEL200 Is Highly Effective and Well Tolerated in Elderly Multiple Myeloma (MM) Patients up to the Age of 75 Years

Introduction: The age limit of 65 for performing Autologous stem cell transplantation (ASCT) in elderly patients with Multiple Myeloma (MM) is currently debated, since efficacy and safety have been recently improved but no conclusive data are still available. Over the last years the policy of our Center was to treat fit patients up to the age of 75 with the same program adopted for younger patients, i.e. bortezomib-based induction followed by ASCT. Herein we report the outcome of the series of consecutive patients aged >65 undergoing first-line ASCT at our center together with an analysis of potential prognostic parameters.Patients and Methods: From January 2009 to December 2016 86 of 270 (31,8%) newly diagnosed symptomatic MM patients aged 65-75 years (M/F: 46/40 , median age 68, 35% aged ≥ 70) received bortezomib-based induction (VTD 91%, VD 7%, VCD 2%) followed by ASCT as first-line treatment. Standard conditioning was melphalan 200 mg/sqm (MEL200) and patients not achieving CR after ASCT were to receive a second ASCT 3-6 months after the first if grade IV non hematological toxicities were not observed with first transplant. According to physician judgement based on age, comorbidities and fitness, MEL dose could be reduced to 140 or to 100mg/sqm. Overall 38% of patients received a single and 62% a double transplant and MEL200 was given to 63%, MEL140 to 9% and MEL100 to 28% of patients, respectively. ECOG PS at diagnosis was ≥2 in 21% of patients. The impact of age, ECOG PS and MEL dosage on progression-free (PFS) and overall survival (OS) was analyzed. Results: Complete remission (CR) after the first ASCT was 34% and very good partial response (VGPR) was 39%. Rate of grade 4 non-hematologic toxicity was 16% (5% mucositis, 10% infections; one Idiopathic Pneumonia Syndrome 60 days after ASCT was also observed). Median hospital stay was similar between patients aged 65-69 years and ≥ 70 years (18 vs 18 days). Transplant related mortality (TRM) was 0%; death rate was 13% and was due to progressive disease in 91% of cases (the latter 9% concerns a cardiac arrest secondary to aspiration pneumonia in a patient in VGPR 3 months after first ASCT). After a median follow-up of 2.5 years, 2-year PFS was 75% and OS 91%. No significant survival difference was seen between patients aged 65-69 and ≥ 70 years (2-year PFS 75% vs 70% and OS 92% vs 91%, respectively). PS 0-1 vs ≥ 2 at diagnosis significantly impacted on OS (2-year PFS 74% vs 60%, p=0.65; OS 97% vs 69%, p 0.01, respectively). A significantly better outcome was seen in patients receiving MEL200 conditioning, compared to lower MEL doses (2-year PFS 86% vs 57%, p 0.036; 2-year OS 100% vs 82%, p 0.005; Figure 1). In the subgroup of 51 patients receiving VTD and MEL200 median OS was not reached. Of note, 44% of patients in the PS ≥ 2 subgroup received MEL200, suggesting that impaired long term survival is only partially influenced by a less intensive treatment. Conclusion: According to our single center experience a significant proportion of newly diagnosed MM patients aged up to 75 years can successfully receive a bortezomib-based (VTD) induction regimen followed by ASCT. Efficacy is highest with MEL200 as conditioning before ASCT and survival Is better in patients with PS <2. Objective methods are warranted to assess transplant eligibility and the optimal dosage of the conditioning regimen in the single patient in order to optimize the use and the efficacy of ASCT in elderly MM.Figure 1: outcome according to MEL dosage [Display omitted] DisclosuresRossi:Celgene: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees.

Mortality from Multiple Myeloma Within One Year Following Autologous Stem Cell Transplantation: Defining an Ultra-high Risk Population

Despite improvements in therapy, approximately 5% of patients who undergo autologous stem cell transplantation (ASCT) experience early mortality (EM), death within 1 year of transplant (EM post-ASCT). Such patients tend to have few comorbidities suggesting their EM is owing to aggressive underlying disease. We sought to characterize this ultra-high risk population through a retrospective review of patients with newly diagnosed multiple myeloma (MM) treated with first-line ASCT. Patients who died within 1 year of ASCT were matched for age, sex, and year of transplant in a 1:2 fashion with a control group.Of 962 transplants performed between January 1, 2007, and May 1, 2019, 41 patients (4.3%) died within 1 year of ASCT from MM-related causes. In a multivariate analysis, anemia, hypercalcemia, high-risk cytogenetics, and elevated lactate dehydrogenase were associated with EM post-ASCT. Forty patients (97.6%) received at least 1 novel agent. Most patients with EM post-ASCT received second-line chemotherapy (80.5%), although survival from initiation of second-line chemotherapy was only 2.1 months. The primary reason for not receiving second-line therapy was rapid relapse.Clinical parameters reflecting disease burden, as well as high-risk cytogenetics, are associated with EM post-ASCT. These patients have a dismal overall survival despite significant advances in treatment of patients with relapsed or refractory myeloma. Further study of these ultra-high risk patients is required to improve disease management and may give further insights into the biology of relapse and resistance in myeloma.

Upfront autologous stem cell transplantation for untreated diffuse large B cell lymphoma patients in rituximab era: a systematic review and meta-analysis.

To assess the survival outcomes and adverse events (AEs) of high-intermediate- or high-risk patients with diffuse large B cell lymphoma (DLBCL) who underwent conventional chemotherapy plus rituximab with or without first-line autologous stem cell transplantation (ASCT). Related studies published on Medline, Embase, Cochrane Library, and Web of science were searched, comprising both retrospective and randomized clinical trials (RCTs). The primary endpoints were overall survival (OS) and progression-free survival (PFS). The meta-analysis was performed using the software RevMan v5.3. Four RCTs and six retrospective trials with a total of 1811 patients were identified. Pooled data indicated that conventional chemotherapy plus rituximab followed by ASCT as the first-line therapy contributed to better PFS (HR = 0.73, 95% CI 0.62-0.86, p = 0.0002) but did not significantly improve OS (HR = 0.74, 95% CI 0.55-1.01, p = 0.06) of high-intermediate/high-risk patients. Subgroup analyses of patients with complete remission after induction chemotherapy may benefit from the upfront ASCT (OS, HR = 0.48, 95% CI 0.28-0.82, p = 0.008). The incidences of grade ≥ 3 hematological and non-hematological AEs occurred more frequently in the transplantation group. High-intermediate or high-risk untreated patients with DLBCL only achieved short-term survival benefit with the upfront ASCT.

Impact of extramedullary disease in patients with newly diagnosed multiple myeloma undergoing autologous stem cell transplantation: a study from the Chronic Malignancies Working Party of the EBMT

We investigated extramedullary disease in newly diagnosed multiple myeloma patients and its impact on outcome following first-line autologous stem cell transplantation. We identified 3744 adult myeloma patients who received up-front single (n=3391) or tandem transplantation (n=353) between 2005 and 2014 with available data on extramedullary involvement at diagnosis. The overall incidence of extramedullary disease was 18.2% (n=682) and increased per year from 6.5% (2005) to 23.7% (2014). Paraskeletal involvement was found in 543 (14.5%) and extramedullary organ involvement in 139 (3.7%). More patients with extramedullary organ involvement had multiple involved sites (≥2; P<0.001). In a comparison of patients with single sites with patients without the disease, up-front transplantation resulted in at least similar 3-year progression-free survival (paraskeletal: P=0.86, and extramedullary organ: P=0.88). In single paraskeletal involvement, this translated less clearly into worse 3-year overall survival (P=0.07) while single organ involvement was significantly worse (P=0.001). Multiple organ sites were associated with worse outcome (P<0.001 and P=0.01). First-line treatment with tandem compared with single transplantation resulted in similar survival in patients with extramedullary disease at diagnosis (P=0.13 for both).

The role of ixazomib as an augmented conditioning therapy in salvage autologous stem cell transplant (ASCT) and as a post-ASCT consolidation and maintenance strategy in patients with relapsed multiple myeloma (ACCoRd [UK-MRA Myeloma XII] trial): study protocol for a Phase III randomised controlled trial

BackgroundMultiple myeloma (MM) is a plasma cell tumour with an approximate annual incidence of 4500 in the UK. Therapeutic options for patients with MM have changed in the last decade with the arrival of proteasome inhibitors and immunomodulatory drugs. Despite these options, almost all patients will relapse post first-line autologous stem cell transplantation (ASCT). First relapse management (second-line treatment) has evolved in recent years with an expanding portfolio of novel agents, driving response rates influencing the durability of response. A second ASCT, as part of relapsed disease management (salvage ASCT), has been shown to prolong the progression-free survival and overall survival following a proteasome inhibitor-containing re-induction regimen, in the Cancer Research UK-funded National Cancer Research Institute Myeloma X (Intensive) study. It is now recommended that salvage ASCT be considered for suitable patients by the International Myeloma Working Group and the National Institute for Health and Care Excellence NG35 guidance.Methods/designACCoRd (Myeloma XII) is a UK-nationwide, individually randomised, multi-centre, multiple randomisation, open-label phase III trial with an initial single intervention registration phase aimed at relapsing MM patients who have received ASCT in first-line treatment. We will register 406 participants into the trial to allow 284 and 248 participants to be randomised at the first and second randomisations, respectively.All participants will receive re-induction therapy until maximal response (four to six cycles of ixazomib, thalidomide and dexamethasone). Participants who achieve at least stable disease will be randomised (1:1) to receive either ASCTCon, using high-dose melphalan, or ASCTAug, using high-dose melphalan with ixazomib. All participants achieving or maintaining a minimal response or better, following salvage ASCT, will undergo a second randomisation (1:1) to consolidation and maintenance or observation. Participants randomised to consolidation and maintenance will receive consolidation with two cycles of ixazomib, thalidomide and dexamethasone, and maintenance with ixazomib until disease progression.DiscussionThe question of how best to maximise the durability of response to salvage ASCT warrants clinical investigation. Given the expanding scope of oral therapeutic agents, patient engagement with long-term maintenance strategies is a real opportunity. This study will provide evidence to better define post-relapse treatment in MM.Trial registrationISRCTN, ISRCTN10038996. Registered on 15 December 2016.

The role of stem cell transplant for lymphoma in 2017.

The role of stem cell transplant for lymphoma in 2017.

Pilot Study of Anti-CD19 Chimeric Antigen Receptor T Cells (CTL019) in Conjunction with Salvage Autologous Stem Cell Transplantation for Advanced Multiple Myeloma

Background: Though CD19 is expressed only rarely on multiple myeloma (MM) plasma cells (PC), rare CD19+ B cells can be identified in MM patients that are clonally related to the MM PC. These clonotypic B cells may exhibit properties of cancer stem cells (enhanced MM-propagating properties and drug resistance compared to MM PC) and thus be a potential therapeutic target in conjunction with therapies that target MM PC. CTL019 consists of autologous T cells transduced via lentiviral vector with an anti-CD19 scFv coupled to CD3-zeta and 4-1BB signaling domains and expanded ex vivo with anti-CD3/CD28-conjugated beads. To target both clonotypic B cells and MM PC, we conducted a pilot clinical trial of CTL019 administered after high-dose melphalan and autologous stem cell transplantation (ASCT) in relapsed/refractory MM patients who had previously undergone first-line ASCT with short progression-free survival (PFS).Methods: Subjects were required to be medically fit for ASCT and have progressed within 1 year of a prior ASCT performed as part of first-line therapy. Study therapy consisted of ASCT with melphalan 140-200 mg/m2 followed by 1-5x107 CTL019 cells 12-14 days later. The primary endpoint was safety and feasibility of CTL019 manufacturing and administration in this clinical setting. Secondary endpoints included assessments of CTL019 in vivo persistence and activity against normal B cells, plasma cell immunophenotype as a response biomarker, and PFS after ASCT + CTL019 in comparison to PFS after initial ASCT.Results: Twelve subjects enrolled, and 10 received study therapy; autologous T cells failed to expand ex vivo in one enrolled subject, and one enrolled subject elected to pursue off-study therapy. Median age was 61 (range 48-68). Median prior lines of therapy was 6 (range 2-10). Poor-prognosis features were present in 8/10 subjects (6/10 with poor-prognosis cytogenetics, 2/10 with BRAF V600E mutations, 1/10 with secondary plasma cell leukemia). Median PFS after first-line ASCT was 258 days (range 100-342). In pre-ASCT bone marrow (BM), the dominant MM PC population was CD19-negative by flow cytometry in 9/9 evaluable subjects, though 7/9 exhibited rare CD19+ subsets comprising 0.05-1.5% of MM PC. Melphalan dose was 140 (N=7) or 200 (N=3) mg/m2. All subjects infused received the maximum target dose of 5x107 CTL019 cells. Adverse events (AE) consisted mostly of expected ASCT toxicities. Grade ³3 AE that were at least possibly related to CTL019 included grade 3 autologous GVHD (N=1, resolved with corticosteroids) and oral mucositis (N=1). Grade 1 cytokine release syndrome occurred in 1 subject. There was no ASCT-related mortality. After infusion, CTL019 cells were detectable in peripheral blood (PB) of all subjects and persisted for median of 44 days (range 14-156). Presence of PB CTL019 cells was associated with absence of PB B cells. Notably, CTL019 cells were detected in BM in 9/10 subjects at day 42 and/or 100 post-ASCT. Median PFS after ASCT + CTL019 was 185 days (range 42-479); all subjects have progressed. The peak BM CTL019 frequency correlated significantly with favorable PFS (SpearmanÕs rho=0.77, P=0.009). There was no association between PFS and peak frequency of CTL019 or duration of CTL019 persistence in PB. In 3/10 subjects, PFS after ASCT + CTL019 met or exceeded PFS after first-line ASCT (Figure). For comparison, in a historical cohort of 18 patients who received first-line and salvage ASCT at our institution since 2008, no patients exhibited longer PFS after salvage ASCT.Conclusion: CTL019 manufacturing and administration post-ASCT is safe and feasible in patients with advanced MM. Correlation of PFS with CTL019 frequency in BM and prolonged PFS in 3 subjects is suggestive of clinical efficacy. A phase-two study of CTL019 using a 10-fold higher dose after first-line ASCT in high-risk MM patients is ongoing. [Display omitted] DisclosuresGarfall:Medimmune: Consultancy; Bioinvent: Research Funding; Novartis: Consultancy, Research Funding. Stadtmauer:Novartis: Consultancy; Takada: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Teva: Consultancy; Celgene: Consultancy. Maus:Novartis: Patents & Royalties: related to CTL019, Research Funding. Hwang:Novartis: Research Funding. Vogl:Takeda: Consultancy, Research Funding; GSK: Research Funding; Calithera: Research Funding; Teva: Consultancy; Constellation: Research Funding; Celgene: Consultancy; Acetylon: Research Funding; Karyopharm: Consultancy. Cohen:Bristol-Meyers Squibb: Consultancy, Research Funding; Janssen: Consultancy. Weiss:Novartis: Consultancy. Porter:Genentech: Employment; Novartis: Patents & Royalties, Research Funding. Frey:Novartis: Research Funding; Amgen: Consultancy. Milone:Novartis: Patents & Royalties, Research Funding. Mangan:Novartis: Speakers Bureau. Lacey:Novartis: Research Funding. Melenhorst:Novartis: Patents & Royalties: Novartis, Research Funding. Ambrose:Novartis: Research Funding. Chen:Novartis: Research Funding. Kulikovskaya:Novartis: Research Funding. Levine:Novartis: Patents & Royalties, Research Funding; GE Healthcare Bio-Sciences: Consultancy. June:Johnson & Johnson: Honoraria; Tmunity Therapeutics: Equity Ownership; Novartis: Honoraria, Patents & Royalties, Research Funding; Immune Design: Consultancy, Equity Ownership; Celldex: Consultancy, Equity Ownership; Novartis: Honoraria, Patents & Royalties, Research Funding; Pfizer: Honoraria.

Analysis of Long-Term Survival in Multiple Myeloma Patients after First-Line Autologous Stem Cell Transplantation: Impact of Clinical Risk Factors and Duration of Response

Background: In the last decade, the introduction of novel agents into multiple myeloma (MM) therapy has significantly improved response rates and enabled long-term survival in a subset of patients. Yet, clinical characteristics of these long-term survivors as well as the exact impact of depth and sustainment of response still remain a matter of debate.Methods: MM patients treated at our center with high-dose melphalan supported by autologous stem cell transplantation (ASCT) as part of their first-line therapy between June 1992 and July 2014 were retrospectively analyzed. Response assessment was performed 100 days after ASCT according to EBMT criteria, since 2008 response according to IMWG criteria was also available. Overall survival (OS) and progression-free survival (PFS) were calculated from day of first ASCT. Additionally, landmark analyses regarding OS were performed at 1, 2, 3, and 5 years after ASCT. Impact of variables on PFS and OS were analyzed using multivariate Cox regression models. Furthermore, in order to assess evolution of prognosis over time, the conditional survival CS(t|s), which expresses the conditional probability of surviving further t years, was calculated as the ratio of two Kaplan-Meier estimates Ŝ(t) with .Results: 865 patients were included in this analysis, median age was 57.0 years (range 24-74), 509 were male. New agents based induction therapy was administered in 358 patients, 258 patients underwent tandem ASCT. Following ASCT, 386 patients received maintenance therapy, mainly with interferon or thalidomide. 75 patients proceeded to allogeneic transplantation and were censored at that time. Median PFS was 2.1 years, median OS was 6.4 years.Analysis of clinical influence factors revealed novel agent based induction therapy (p<0.01), maintenance therapy (p<0.01) and achievement of complete response (CR) (p=0.01) to be significantly associated with prolonged PFS, while older age (p=0.01) and thrombocytes at diagnosis < 150/nl (p=0.02) were identified as risk factors; a negative trend was seen for ISS stage 3 (p=0.067). With regard to OS, novel agent based induction therapy (p<0.01), maintenance therapy (p<0.01) and duration of time to progression (p<0.01) showed a highly significant positive impact, older age (p<0.01) and renal insufficiency at diagnosis (p=0.048) exerted a negative influence.To assess the importance of duration of response, landmark analyses were performed at 1, 2, 3, and 5 years after ASCT evaluating OS of patients with sustained CR, sustained inferior responses (non-CR), lost CR and lost non-CR at these respective time points. Remarkably, sustainment of any response showed a highly significant impact on survival at each of these time points (p<0.01) with no discernable difference between sustained CR and sustained non-CR patients. Landmark analysis at 1 year is shown in Figure 1. Administration of maintenance therapy independently improved outcome (p<0.01).Conditional survival regarding the probability to survive further three years CS(3|s) was calculated starting from the time of first ASCT stratified for the different response cohorts (see Figure 2). No significant differences could be found between patients with complete and partial response. In contrast, patients with progressive disease (PD) at day 100 after ASCT had a much lower probability of surviving the following three years after ASCT compared to patients responding to ASCT. However, those patients with PD that did survive the first year after ASCT, achieved a similar conditional three-year survival to that of patients responding initially.Conclusions: In this large retrospective study, sustainment of response after first-line ASCT was revealed as a major impact factor for OS independent of the depth of response. Administration of maintenance therapy further improved outcome, supporting the hypothesis that interventions prolonging responses achieved after ASCT are essential to reach long-term survival. [Display omitted] [Display omitted] [Display omitted] DisclosuresHillengass:Amgen: Consultancy, Honoraria; Celgene: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Novartis: Research Funding; Sanofi: Research Funding. Goldschmidt:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Raab:Amgen: Consultancy, Research Funding; BMS: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Research Funding.

Pattern of First Relapse in Multiple Myeloma (MM) Patients (Pts) after a Cybord Induction Regimen and Autologous Stem Cell Transplantation (ASCT): Impact of Maintenance Therapy in the Real-World Setting

IntroductionMaintenance therapy after first-line ASCT improves outcomes, although virtually all pts eventually relapse. The pattern of first relapse shows significant heterogeneity. The literature is scarce about the impact of maintenance on the pattern of relapse and about predictors of a more aggressive or indolent relapse course. Our objectives were, in a cohort of transplant-eligible MM pts treated with a CyBorD induction regimen followed by ASCT as part of first-line therapy, to describe the pattern of first relapse, to determine if patterns differ between pts with and without maintenance and to identify predictors for patterns of first relapse, early relapse, PFS, OS and OS after relapse in the real-world setting.MethodsInclusion criteria were MM pts who received at least 2 cycles of induction with a CyBorD regimen with their induction regimen start date from January 2007 to December 2012. Pts then underwent single (126) or tandem ASCT (10) in first-line. Primary refractory disease was excluded. Charts were retrospectively reviewed for descriptive and univariate analysis. The pattern of relapse was categorized as biochemical, clinical, clinical with extramedullary disease or clinical with plasma cell leukemia.ResultsMedian follow-up of the 136 pts was 43.4 months (mos). Pt and first-line treatment characteristics are presented in Table 1. Most pts presented with anemia and bone lesions. The maintenance (n= 82; lenalidomide= 84%, thalidomide= 13%, lenalidomide and bortezomib= 2%) and no maintenance (n= 44) groups were similar, except for fewer pts with high-risk cytogenetics in the no maintenance group (9% vs 19%). All 10 tandem ASCT pts had maintenance. Response rates at 3 mos post-ASCT and best response rates after ASCT were similar between the maintenance and no maintenance groups (VGPR or better response rates were respectively 70% and 83% for the maintenance group and 75% and 85% for the no maintenance group) (Table 1). The median duration of maintenance was 11.1 mos (0.5-55.1) and 56% had stopped for progression.Overall median PFS was 41.3 mos (95%CI= 34.6-54.3) and overall median OS was 96.7 mos (95%CI lower bound= 64.9). For pts on lenalidomide maintenance, median PFS was 51.5 mos (95%CI= 35.9-61.8) and median OS was not reached on the study duration. Pts on maintenance had a significantly shorter median OS after relapse when compared to pts without maintenance (9.2 vs 19.9 mos, p= 0.006).Sixty-eight pts relapsed (50%), 40 in the maintenance group and 27 in the no maintenance group (Table 2). Overall, biochemical relapse was the most frequent type of relapse (56%) in all pts. However, pts receiving maintenance more often relapsed clinically and pts in the no maintenance group more often experienced biochemical relapses. Six of the 7 cases of FLC escape (86%) were in the maintenance group. Clinical relapsers usually had at least 1 component of the clinical presentation at relapse that was the same as at diagnosis (Dx). Overall, the most frequent types of clinical relapse involved bone lesions (51%), anemia (43%) and extramedullary disease (34%), the latter being more frequent in the maintenance group (40% vs 22%).Correlations between hypercalcemia at Dx and at relapse (positive correlation; coefficient= 0.45, p= 0.0064) and extramedullary disease at Dx and at relapse (positive correlation; coefficient= 0.39, p= 0.0201) were significant.By univariate analysis, maintenance (OR= 3.866, 95%CI= 1.333-11.211, p= 0.013) and high LDH at Dx (OR= 1.009, 95%CI= 1.001-1.016, p= 0.027) were associated with a clinical pattern of relapse. Bone lesions versus no bone lesions at progression were: 1) less likely to relapse early (OR= 0.178, 95%CI= 0.037-0.849, p= 0.030); 2) had a significantly longer median PFS (34.3 vs 15.6 mos, p= 0.0002); 3) had a longer OS (79.4 vs 36.3 mos, p= 0.031) and 4) had a longer OS after relapse (13.9 vs 3.7 mos, p= 0.003).ConclusionsThe most common pattern of first relapse was biochemical. Although we cannot exclude an effect of pt bias regarding use of maintenance, we observed an impact of maintenance on the pattern of relapse, with more clinical relapses. For pts relapsing on maintenance, cases of FLC escape and of extramedullary disease at relapse were also more frequent and OS after relapse tended to be shorter. High LDH at Dx was also associated with a clinical pattern of relapse. Interestingly, pts presenting with bone lesions at progression had better outcomes. [Display omitted] [Display omitted] DisclosuresCote:Takeda: Honoraria; Janssen: Honoraria. Reece:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Merck: Research Funding; Otsuka: Honoraria, Research Funding. Chen:Takeda: Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Prica:Celgene: Honoraria; Janssen: Honoraria. Tiedemann:Janssen: Honoraria; Celgene: Honoraria. Trudel:Amgen: Honoraria; Oncoethix: Research Funding; BMS: Honoraria; Glaxo Smith Kline: Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Equity Ownership, Honoraria. Kukreti:Lundbeck: Honoraria; Celgene: Honoraria; Amgen: Honoraria.

Clinical response of multiple myeloma treated by first-line autologous stem cell transplantation combined with thalidomide as maintenance treatment

Clinical response of multiple myeloma treated by first-line autologous stem cell transplantation combined with thalidomide as maintenance treatment

Long-term clinical and molecular remissions in patients with mantle cell lymphoma following high-dose therapy and autologous stem cell transplantation

Long-term clinical and molecular remissions in patients with mantle cell lymphoma (MCL) following high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) have been evaluated in only a few studies. Thirty-six patients with MCL received ASCT in our institution (27 patients undergoing first-line therapy, 8 patients undergoing second-line therapy, and 1 patient undergoing third-line therapy). In the case of long-term remission (≥5years; n = 8), peripheral blood was tested for minimal residual disease (MRD) by t(11; 14) polymerase chain reaction (PCR) and immunoglobulin heavy-chain (IGH) PCR at the last follow-up. Ten-year overall survival (OS), progression-free survival (PFS), and freedom from progression (FFP) after first-line ASCT were 42%, 43%, and 54%; after second-line ASCT, these were all 0%. Four-year OS, PFS, and FFP for the first-line cohort were 75%, 48%, and 61%, respectively. Four-year OS, PFS, and FFP after second-line ASCT were 55%, 30%, and 30%, respectively. Treatment-related mortality (3months after ASCT) was 0%. The only prognostic factor for OS, PFS, and FFP was treatment line (p = 0.011, p = 0.046, and p = 0.023, respectively). No relapses occurred after 5years following ASCT. So far, eight patients developed sustained long-term clinical and molecular complete remissions of up to 14.6years following ASCT in the first treatment line. Sustained long-term clinical and molecular remissions can be achieved following ASCT in the first treatment line and apparently less frequent in the second treatment line.

Long-term clinical and molecular remissions in patients with follicular lymphoma following high-dose therapy and autologous stem cell transplantation

BackgroundLong-term clinical and molecular remissions in patients with follicular lymphoma (FL) following high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) have been evaluated in only a few studies. Results are especially limited for second-line HDT with BEAM (BCNU, etoposide, cytarabine and melphalan). Patients and methodsSixty patients with FL received ASCT in our institution (18 first-line with total body irradiation and cyclophosphamide, 34 second-line with BEAM and 8 ≥third-line with BEAM). In the case of long-term remission (>6 years; N = 17), peripheral blood was tested for minimal residual disease by t(14;18)- and IGH-PCR. ResultsTen-year overall survival, progression-free survival and freedom from progression (FFP) after first-line ASCT were 79%, 57% and 64% after second-line ASCT 41%, 35% and 42%, respectively. Prognostic factors for FFP were treatment line and FLIPI (Follicular Lymphoma International Prognostic Index). Ten-year FFP for second-line ASCT and low-risk FLIPI was 57%, intermediate risk 37% and high risk 33%. No relapses occurred after 6 years following ASCT. Sixteen patients developed sustained long-term clinical and molecular remissions of up to 17.5 years. ConclusionSustained long-term clinical and molecular remissions can be achieved following ASCT, including HDT with BEAM in second line.

Treatment and outcomes of patients with relapsed, high‐risk neuroblastoma: Results of German trials

The prognosis of high-risk neuroblastoma patients has improved over the last decades. However, many patients experience relapse after successful initial treatment. We retrospectively analyzed the long-term outcome of relapsed patients of three consecutive national neuroblastoma trials. Patients were included when they fulfilled all of the following criteria: Age at diagnosis being 1 year or older, first diagnosis between 1990 and 2007, stage 4 disease or stage 3 neuroblastoma with MYCN amplification, and relapse or progression after successful first-line autologous stem cell transplantation (ASCT). A total of 451 high-risk neuroblastoma patients 1 year or older underwent ASCT during first-line treatment, 253 experienced recurrence of disease, 158 received salvage chemotherapy, and 23 of them finally underwent a second ASCT. These 23 patients had a better median survival (2.08 years) and 3-year survival rate from recurrence (43.5 ± 10.9%) compared to 74 patients who had no second chemotherapy (median survival 0.24 years, 3-year survival rate 4.0 ± 2.6%) and 135 patients who underwent second-line chemotherapy but did not undergo second ASCT (median survival of 0.89 years, 3-year survival rate 9.6 ± 2.8%, P < 0.001). By February 2010, 3/23 patients were in complete remission, 3/23 in very good partial remission, 1/23 in partial remission, 14/23 patients died of disease after successful second ASCT, and 2/23 died of complications due to second ASCT. Intensive second-line therapy is feasible. A small subgroup of relapsed high-risk neuroblastoma patients may benefit from intensive relapse chemotherapy and second ASCT. The potential of long-term survival justifies clinical trials on intensive second-line treatment.

The Outcome of Different Types of Second-Line Therapy in Multiple Myeloma Patients Relapsing After Uniform Front-Line Treatment with High-Dose Melphalan and Autologous Stem Cell Transplantation.

Abstract 2892Poster Board II-868 Background and aim.While multiple myeloma (MM) still remains largely incurable, therapeutic options for patients with MM are expanding. However the best way to use the different effective regimens, either in combination or in sequence, during the course of MM in the single patient is still unknown. Data from controlled studies rarely report the treatments received before and after the enrollment of patients in the clinical trial, which may significantly impact on response and survival. As an example, the best treatment for patients relapsing after first-line high-dose melphalan (HD-Mel) and autologous stem cell transplantation (ASCT) is not standardized. To this end we have retrospectively analyzed an uniform cohort of such patients treated at our Institution, comparing their outcome according to the type of second-line and further consolidation treatment received. Patients and methods.In 156 patients affected by MM and treated between 1997 and 2008 with HD-Mel and ASCT as first line therapy, relapse has occurred in 92 (59%). Females were 39 (42%), males 53 (58%), median age was 60 (range 34-75). As induction therapy before ASCT, 89 (97%) had received VAD regimen, and only 3 (3%) thalidomide/bortezomib-based regimen. Sixty-one patients (66%) had received a single ASCT and 31 a double ASCT (34%). A second-line therapy was given to 87/92 patients. They were subdivided in 3 subgroups according to the type of second-line treatment received: 1) thalidomide-based regimens (THAL) were given to 55 pts (63%) followed by a consolidation ASCT in 13 (24%) 2) bortezomib-based regimens (BORT) were used in 13 (15%) and subsequent ASCT in 3 of them (23%) 3) chemotherapy and/or steroids (CHEMO) were used in 19 (22%) followed by ASCT in 15 (79%). Median follow-up from diagnosis was 57 (13-145) in THAL, 39 (17-140) in BORT and 59 months (25-113) in CHEMO respectively. The baseline characteristics, including age, of the three subgroups were similar as well as the CR/VGPR and ORR rates obtained after first-line treatment (THAL 47% and 87%; BORT 69% and 100%; CHEMO 53% and 100%, respectively). The subgroups also did not differ in median duration of first response, which ranged from 13 to 15 months and median time to second treatment, which was 26 months in all subgroups. The proportion of patients receiving a double ASCT were significantly higher in BORT (69%) compared to THAL (34%) (P=0.03) and CHEMO (5%) (p=0.002), and in THAL (34%) compared to CHEMO (5%) (p=0.015). Results.After second line therapy the ORR (CR+VGPR+ PR) of the three subgroups was: THAL 60%, BORT 77% and CHEMO 58%. (p=NS). The second CR/VGPR rate was non significantly higher after BORT (46%) than after THAL (25%) or CHEMO (21%) (p=0.17). Moreover, when considering patients not undergoing second-line consolidation ASCT, the ORR was significantly better in THAL and BORT subgroups compared to CHEMO (50%, 70% and 0%, respectively p=0.03). After a median follow-up from second-line treatment of 28 months (range 1-99), the 2-y PFS was 38% after THAL (median 18 months), 34% after BORT (median 16 months) and 17% after CHEMO (median 12 months) (p=NS). The 2-y OS was 78% (median 49 months), 70% (median not reached), and 70% (median 33 month) after THAL, BORT and CHEMO, respectively (p=NS). However when considering patients not undergoing second-line consolidation ASCT, the 2-y OS was significantly better after THAL and BORT than after CHEMO (p=0.024). Conclusion.In spite of having frequently received a first-line double ASCT, BORT patients seemed to achieve responses of better quality. However, in patients relapsing after first-line HD-Mel and ASCT, the choice of THAL, BORT or CHEMO-based regimens as second-line therapy did not seem to impact on overall response rates and survival, provided that patients treated with CHEMO could be consolidated with a second ASCT. Hence newer drugs may be reserved for those patients not fit for ASCT, preserving them for effective third-line treatment in the other patients. Disclosures:No relevant conflicts of interest to declare.

Rituximab Improves the Outcome of Upfront Autologous Stem Cell Transplantation in Mantle Cell Lymphoma: A Comparison of Different Strategies.

Introduction: First-line autologous stem cell transplantation (SCT) is an accepted therapy for mantle cell lymphoma (MCL). We have recently shown that 2 standard doses of rituximab significantly improve the outcome of TBI-based upfront SCT in MCL when administered peritransplant (Haematologica 92:42; 2007). The purpose of the present retrospective analysis was to compare this approach with alternative rituximab-based strategies. Patients and treatment strategies: 34 consecutive patients treated in KI-HH received 3–6 cycles of CHOP prior to stem cell mobilization with Dexa-BEAM (n=20) or DHAP (n=14), followed by TBI-cyclophosphamide-rituximab myeloablation and SCT (CHOP/R-TBI-CY group). Patients treated in HD received 3–8 cycles of R-CHOP for cytoreduction (n=28) and mobilization (n=23; the remaining 5 patients were mobilized with R-DHAP/HAM) followed by BEAM and SCT (R-CHOP/BEAM group). 12 patients of this group received additional rituximab maintenance after SCT.Results: With a median follow-up of 38 months (9–111), estimated 4-year progression-free survival (PFS) from diagnosis of patients treated with CHOP/R-TBI-CY and R-CHOP/BEAM was 83% and 72% (log rank, p=.38), respectively. Of note, with a median follow-up of 30 months (14–57) there was no relapse in the 12 pts receiving maintenance therapy with rituximab, translating into a significantly better 4-y PFS in patients receiving R-CHOP/BEAM with rituximab maintenance vs those without (100% vs. 56%; p=.021). The PFS difference between the R-CHOP/BEAM group and the CHOP/R-TBI-CY group became borderline significant after omitting the rituximab maintenance patients (p=.055).Conclusions: In advanced-stage MCL, addition of rituximab improves disease control provided by first-line SCT. Whereas the exact dose and timing of rituximab administration remains to be settled, prospective investigation of post-transplant rituximab maintenance appears to be particularly promising.

Poor-Prognosis Germ Cell Tumors: We Have Not Yet Crossed the Finish Line

Poor-Prognosis Germ Cell Tumors: We Have Not Yet Crossed the Finish Line