Amyloid light chain (AL) amyloidosis is a rare and chronic bone marrow disorder. Existing claims data can be used to help understand the real‐world treatment patterns and outcomes of this patient ...population. Various population‐based administrative databases in Alberta, Canada were queried from 2010 to mid‐2019 to identify cases of AL amyloidosis. Baseline patient and disease characteristics, sequencing of pharmacologic therapies, overall survival, and healthcare resource utilization were evaluated. A total of 215 individuals with AL amyloidosis were included. Among patients diagnosed between 2012 and 2019, 149 (85.1%) initiated first‐line, 67 (38.3%) initiated second‐line, 22 (12.6%) initiated third‐line, and 11 (6.3%) initiated fourth‐line systemic therapy. In the first‐line setting, 99/149 (66.4%) received bortezomib, cyclophosphamide, and dexamethasone (CyBorD) and 21/149 (14.1%) received another bortezomib‐based regimen. Survival from time of diagnosis improved over time, with a median overall survival of 25.8 months (95% CI: 9.8, 57.1) for individuals diagnosed in 2010–2011 versus 52.1 months (95% CI: 25.6, NA) for those diagnosed in 2012–2019. Despite this improvement, the proportion of individuals diagnosed in 2012–2019 who survived beyond five‐years remained low (5‐year survival: 48.4%; 95% CI: 40.9, 57.2) which highlights an unmet need for more efficacious therapies.
Mantle cell lymphoma (MCL) is a B-cell lymphoma characterized by cyclin D1 expression. Autologous hematopoietic cell transplantation (AHCT) consolidation after induction chemotherapy is often used ...for eligible patients; however, the benefit remains uncertain in the rituximab era. Herein we retrospectively assessed the impact of AHCT consolidation on survival in a large cohort of transplantation-eligible patients age 65 years or younger.
We retrospectively studied transplantation-eligible adults age 65 years or younger with newly diagnosed MCL treated between 2000 and 2015. The primary objective was to assess for improved progression-free survival (PFS) with AHCT consolidation and secondarily to assess for improved overall survival (OS). Cox multivariable regression analysis and propensity score-weighted (PSW) analysis were performed.
Data were collected from 25 medical centers for 1,254 patients; 1,029 met inclusion criteria. Median follow-up for the cohort was 76 months. Median PFS and OS were 62 and 139 months, respectively. On unadjusted analysis, AHCT was associated with improved PFS (75 v 44 months with v without AHCT, respectively; P < .01) and OS (147 v 115 months with v without AHCT, respectively; P < .05). On multivariable regression analysis, AHCT was associated with improved PFS (hazard ratio HR, 0.54; 95% CI, 0.44 to 0.66; P < .01) and a trend toward improved OS (HR, 0.77; 95% CI, 0.59 to 1.01; P = .06). After PSW analysis, AHCT remained associated with improved PFS (HR, 0.70; 95% CI, 0.59 to 0.84; P < .05) but not improved OS (HR, 0.87; 95% CI, 0.69 to 1.1; P = .2).
In this large cohort of younger, transplantation-eligible patients with MCL, AHCT consolidation after induction was associated with significantly improved PFS but not OS after PSW analysis. Within the limitations of a retrospective analysis, our findings suggest that in younger, fit patients, AHCT consolidation may improve PFS.
Pluripotent stem cells can become any cell type found in the body. Accordingly, one of the major challenges when working with pluripotent stem cells is producing a highly homogenous population of ...differentiated cells, which can then be used for downstream applications such as cell therapies or drug screening. The transcription factor Ascl1 plays a key role in neural development and previous work has shown that Ascl1 overexpression using viral vectors can reprogram fibroblasts directly into neurons. Here we report on how a recombinant version of the Ascl1 protein functionalized with intracellular protein delivery technology (Ascl1-IPTD) can be used to rapidly differentiate human induced pluripotent stem cells (hiPSCs) into neurons. We first evaluated a range of Ascl1-IPTD concentrations to determine the most effective amount for generating neurons from hiPSCs cultured in serum free media. Next, we looked at the frequency of Ascl1-IPTD supplementation in the media on differentiation and found that one time supplementation is sufficient enough to trigger the neural differentiation process. Ascl1-IPTD was efficiently taken up by the hiPSCs and enabled rapid differentiation into TUJ1-positive and NeuN-positive populations with neuronal morphology after 8 days. After 12 days of culture, hiPSC-derived neurons produced by Ascl1-IPTD treatment exhibited greater neurite length and higher numbers of branch points compared to neurons derived using a standard neural progenitor differentiation protocol. This work validates Ascl1-IPTD as a powerful tool for engineering neural tissue from pluripotent stem cells.
Introduction
In 2013, bendamustine/rituximab (BR) replaced RCHOP as standard first line treatment for both transplant eligible and ineligible MCL patients (pts) in BC. Retrospective cohort studies ...report that bendamustine has no adverse effect on peripheral blood stem cell (SC) mobilization but this is discordant with local experience. We sought to compare rates of failed SC collection in MCL pts planned for high dose chemotherapy and autologous stem cell transplant (ASCT) after BR or RCHOP and identify risk factors for failed SC mobilization and collection.
Methods
We identified all pts with MCL in BC treated with BR or RCHOP as first line therapy who underwent SC mobilization from Jan. 1 2003-Dec. 31 2017 using the Leukemia/Bone Marrow Transplant Program of BC and Apheresis Database Standard mobilization was with G-CSF alone (G) until difficulties with SC collection were noted after BR. Different mobilization strategies were then used, including delaying SC collection 2-3 mos after BR, G + cyclophosphamide (G+C) mobilization and/or “rescue” plerixafor if Day 1 SC collection was inadequate. Failure of SC collection was defined as yield <1 x106 CD34+ cells/kg on apheresis Day 1 (D1fail). . All variables significant in univariate analysis (P<0.1) were entered into a multivariate analysis (MVA) logistic regression model to identify factors associated with D1 fail.
Results
A total of 152 pts were identified. 2 were excluded as they had pre-emptive plerixafor prior to apheresis D1 on a trial. Of the remaining 150 pts, 55 (37%) received BR, 95 (63%) RCHOP for a median of 6 cycles (range 1-6). Baseline characteristics were similar between groups (Table 1). Pts receiving BR had higher remission rates compared to RCHOP (CR 58% vs 35%, P=.004) and a longer duration from their last chemotherapy to apheresis D1 (BR 89 d vs RCHOP 39 d, P<0.), reflecting an intentional change in practice. For this same reason, use of G+C mobilization was higher in BR pts (45%) compared with RCHOP pts (1%).
Failure on D1 of SC collection was significantly higher after BR compared to RCHOP (45% vs. 10%, P<.001). This difference persisted when only pts mobilized with G alone were included: D1fail 60% BR vs 10% RCHOP (P<.001), Fig. 1. Among BR pts, D1fail was higher for those mobilized with G compared with G+C (60% vs. 28%, P=.03).
Of the 25 BR pts with D1fail, 20 pts received rescue plerixafor (P) (1 dose: 18, 2 doses: 1, 3 doses: 1) with 17 successfully collecting > 2.0 x106 CD34+ cells/kg, 2 successfully collected after a 2nd round of SC mobilization (Pt1: G+C+P, Pt2: G+P), and 1 pt did not undergo ASCT due to collection failure. Of the 5 pts who did not receive plerixafor, 2 successfully collected with 1-2 additional apheresis days and 3 successfully collected with a 2nd round of SC mobilization (2: G+P, 1: G+C). Among the 9 RCHOP pts with D1fail, 1 had rescue plerixafor with success, 3 successfully collected after 1-2 more apheresis days and 5 had a 2nd round of SC mobilization (1: G, 4: G+P), of which 1 failed and did not proceed to ASCT.
Univariate analysis identified the following associated with D1fail: frontline therapy (BR vs RCHOP, P=<.001), mobilization regimen (G+C vs G, P=.001), gender (P=.002) and D1 platelet count (P=<.001). Delaying SC mobilization in pts who received BR did not improve D1 yield (P=.31). In MVA, frontline therapy with BR had an increased risk of D1fail compared to RCHOP with an odds ratio (OR) of 7.83 (95% CI 2.7-23.1), P<.001. Using G+C significantly improved the odds of a successful collection compared to G alone (OR for D1fail 0.17 95% CI 0.05-0.62, P=.007). Female gender and low platelet count also increased risk of D1fail in MVA (Table 2).
Conclusion
MCL pts who receive BR as first line therapy have an almost 8-times higher risk of failure of D1 SC collection compared to those who receive RCHOP. This failure can be overcome largely with “rescue” plerixafor and partially with planned G+C mobilization such that successful collection can be achieved in >90% of pts. However, these agents add cost and potential toxicity. Platelet count on D1 SC collection is a potential indicator of high risk of failure. Delaying SC mobilization in BR pts does not improve collection yield. The impact of bendamustine in pre-transplant chemotherapy regimens, not only for MCL but also for a broad range of lymphomas where it is being increasingly used, must be considered when planning SC mobilization strategies.
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Sehn:Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.
Small bowel cancers are rare gastrointestinal malignancies and tumor location impact on outcomes is unclear.
A retrospective review was performed on stage I to IV small bowel cancer cases from 2000 ...to 2017 in British Columbia, Canada. Baseline patient characteristics, disease-free survival (DFS) and overall survival (OS) were evaluated by tumor location and systemic therapy use patterns were summarized.
Of 340 patients included, primary tumor distribution was: duodenum (51.2%), ileum (19.1%), jejunum (18.5%), and unspecified (11.2%). Median DFS for stage I to III disease was 37.7, 49.1, and 26.7 months for duodenal, jejunal, and ileal tumors (P = .018). Median OS was 9.6, 35.2, and 20.1 months for duodenal, jejunal, and ileal tumors (P < .0001). Compared to duodenal primaries, both jejunal and ileal tumors were associated with significantly improved OS (HR 0.43, P < .001 for jejunal; HR 0.71, P = .035 for ileal). Adjuvant therapy was given to 21.6% of stage II and 50.6% of stage III cancers. Among patients with metastatic disease, median OS was 4.2, 11.4, and 6.9 months for duodenal, jejunal, and ileal tumors (P = .0019). Jejunal tumors had the best prognosis (HR 0.48, P = .001 vs. duodenum).
Survival differences exist when small bowel cancers were assessed by tumor location, and jejunal tumors portended better prognosis overall.
Our real-world population study demonstrates that tumor location may impact disease-free and overall survival in small bowel cancers, with improved outcomes for jejunal tumors in both localized and advanced cases. Further molecular studies are warranted to better understand possible contributing mechanisms for this finding.
Introduction: Mantle cell lymphoma (MCL) is a CD5+ B-cell lymphoma characterized by cyclin D1 expression. The disease has heterogeneous clinical outcomes: in a subset of patients, it is indolent but ...many others have an aggressive course with poor outcome. Consolidative autologous hematopoietic cell transplant (HCT) in 1st remission is often employed for fit patients ≤65; however the benefit of this approach remains uncertain without prospective validation in the rituximab era. Herein we retrospectively assessed the impact of HCT consolidation following induction therapy on survival in a large multicenter cohort of transplant eligible patients aged ≤65.
Methods: We retrospectively studied adults with newly diagnosed MCL, aged ≤65, transplant eligible at diagnosis, and treated with induction chemotherapy from 2000-2015. Eligibility for transplant was determined by the institutional chart reviewer. 22 US and Canadian academic medical centers contributed. Information on prognostic markers, treatment, response to induction, and survival was collected. The primary objective was to assess for an overall survival (OS) benefit of HCT consolidation in first remission. A landmark survival analysis was restricted to patients surviving >6 months who achieved ≥partial response (PR) after induction, with OS and progression-free survival (PFS) defined as time from diagnosis to event (death or relapse). Cox multivariate regressions were performed to evaluate the effect of HCT consolidation on OS and PFS after adjusting for confounders (age, sex, MIPI, stage, induction regimen, blastoid/pleomorphic phenotype, response to induction (complete response (CR) vs. PR), and maintenance therapy. Due to the differential times of HCT, this was included in the model as a time-varying covariate. Ki67 was excluded from regression models as it was available in <50% of patients.
Results: Data was collected for 1113 patients, and 921 patients met inclusion criteria. HCT was performed in 595 patients (64%). The two most common reasons for not performing HCT were physician (46%) or patient preference (23%). Three centers, who contributed a combined 135 patients, performed HCT in < 50% of eligible patients. Median time from diagnosis to HCT was 7 months. Patients who received consolidative HCT were younger, less likely to have blastoid or pleomorphic morphology, more likely to have received an intensive regimen (e.g. HyperCVAD +/- cytarabine, platinum containing, or maxi-CHOP) and cytarabine, and less likely to have received biological agents (bortezomib, lenalidomide, and ibrutinib) during induction (table 1). Median follow-up for the cohort was 78.1 months (6.5 years), with median PFS of 62.9 months (5.2 years) and OS of 141.5 months (11.7 years). On unadjusted landmark analysis, HCT in 1st remission was associated with improved PFS (p<0.01) (Figure 1A) and improved OS (p=0.03) (Figure 1B). On multivariate analysis, this association persisted, with HCT resulting in improved PFS (HR 0.57, 95%CI 0.47-0.70, p<0.01) and OS (HR 0.73, CI 0.57-0.94, p=0.01). Other variables associated with improved PFS included lower MIPI (HR 0.49, CI 0.36-0.65, p<0.01 for low vs. high MIPI); non-blastoid or pleomorphic morphology (HR 0.60, CI 0.47-0.76, p<0.01); use of an intensive regimen (HR 0.63, CI 0.41-0.98, p=0.04), bendamustine (HR 0.54, CI 0.33-0.89, p=0.01), or biologic agent (HR 0.42, CI 0.20-0.89, p=0.02) during induction; CR with induction (HR=0.51, CI 0.41-0.64, p<0.01); and use of maintenance (HR 0.57, CI 0.45-0.72, p<0.01). Variables associated with improved OS included lower MIPI (HR 0.34, CI 0.24-0.48, p<0.01), non-blastoid or pleomorphic morphology (HR 0.44, CI 0.33-0.58, p<0.01), CR to induction (HR=0.55, CI 0.42-0.72, p<0.01), and use of maintenance (HR 0.61, CI 0.45-0.83, p<0.01). Death within 100 days of transplant occurred in 7 patients (1.2%). 18 patients developed secondary AML or MDS (incidence 2.4% with HCT consolidation (n=14) vs. 1.2% (n=4) without).
Conclusion: In this large cohort of younger transplant eligible patients with MCL, HCT consolidation in first remission was associated with significantly improved OS and PFS after adjusting for prognostic factors and differences in initial treatment. Within the limitations of retrospective analysis and inherent selection bias, our findings support the benefit of HCT consolidation following induction therapy for fit patients ≤65 in the rituximab era.
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Barta:Janssen: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Merck: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding. Villa:Roche: Consultancy, Honoraria, Other: Travel, Research Funding; Lundbeck: Consultancy, Honoraria, Other: Travel; Seattle Genetics: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Honoraria; Abbvie: Other: Travel. Gerrie:Roche: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Lundbeck: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees. Fenske:Celgene: Consultancy; Sanofi: Consultancy; Pharmacyclics: Consultancy. Maddocks:Merck: Research Funding; Pharmacylics: Research Funding; BMS: Research Funding; Novartis: Research Funding. Lansigan:Spectrum Pharmaceuticals: Consultancy, Research Funding; Seattle Genetics: Consultancy. Reddy:Abbvie: Consultancy; BMS: Consultancy; Celgene: Consultancy; Gilead: Speakers Bureau. Landsburg:Curis: Consultancy, Research Funding; Takeda: Research Funding. Karmali:Celgene: Speakers Bureau. Kaplan:Takeda: Research Funding; Millennium: Research Funding; Seattle Genetics: Research Funding; Janssen: Research Funding. Caimi:Celgene: Speakers Bureau; Abbvie: Equity Ownership; Seattle Genetics: Equity Ownership; Incyte: Equity Ownership. Cohen:Takada: Research Funding; Bristol Myers Squibb: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bioinvent: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; LAM Therapeutics, Inc: Research Funding; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees. Calzada:Seattle Genetics: Research Funding. Handorf:Pfizer: Research Funding. Bachanova:Seattle-Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Juno: Membership on an entity's Board of Directors or advisory committees; Oxis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Zymogen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding.
•Patients with blastoid and pleomorphic variant mantle cell lymphoma have suboptimal outcomes•Receipt of auto-HCT, MIPI score, and complete response to induction were associated with PFS. Auto-HCT ...was not associated with OS
Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma; data indicates that blastoid and pleomorphic variants have a poor prognosis. We report characteristics and outcomes of patients with blastoid/pleomorphic variants of MCL. We retrospectively studied adults with newly diagnosed MCL treated from 2000-2015. Primary objectives were to describe progression-free survival (PFS) and overall survival (OS). Secondary objectives included characterization of patient characteristics and treatments. Of 1029 MCL patients studied, a total of 207 neoplasms were blastoid or pleomorphic variant. Median follow up was 82 months (range 0.1-174 months); median PFS was 38 months (95% confidence interval CI 28-66) and OS 68 months (95% CI 45-96). Factors associated with PFS were receipt of consolidative autologous hematopoietic transplant (auto-HCT) (hazard ratio HR 0.52, 95% CI 0.31-0.80, p < 0.05), MCL International Prognostic Index (MIPI) score intermediate (HR 2.3, 95% CI 1.2-4.3, p<0.02) and high (HR 3.8, 95% CI 2.0-7/4, p<0.01), and complete response to induction (HR 0.29 (95% CI 0.17-0.51). Receipt of auto-HCT was not associated with OS (HR 0.69, 95% CI 0.41-1.16, p = 0.16), but was with MIPI intermediate (HR 5.7, 95% CI 2.5-13.2, p< 0.01) and high (HR 10.8, 95% CI 4.7-24.9, p< 0.01). We report outcomes in a large cohort of patients with blastoid/pleomorphic variant MCL. Receipt of auto-HCT after induction was associated with improved PFS for eligible patients, but not OS. Higher MIPI score and auto-HCT ineligibility were associated with worse survival.
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