Among patients who survive over two years post-allo-HSCT, cGVHD and subsequent cancers represent a significant source of morbidity and mortality. Long-term treatment with immunosuppressive agents and ...cGVHD-related immune dysregulation may promote the development of subsequent cancers. The burden of subsequent cancers has not yet been described in patients with the most severe manifestations of cGVHD, who likely represent a high-risk population.
439 patients were enrolled on the prospective NIH Chronic GVHD Natural History Study from 2004 to 2019, underwent one-week evaluation by subspecialists, and were scored in accordance with 2005 NIH criteria. Follow-up data were collected by annual survey in which patients self-reported cancer diagnoses and provided consent for confirmatory medical records. Cumulative incidence was estimated for non-melanoma skin cancer (NMSC) competing with death, relapse, or cancer other than NMSC and for cancer other than NMSC competing with death or relapse using the method of Gooley. Potential predictors of subsequent cancers including demographics, transplant characteristics, and cGVHD-related factors were assessed using Gray's test in univariable analysis and Cox proportional hazards models in multivariable analysis. Patients must have been free of post-transplant relapse, NMSC (for NMSC analyses only), and cancer other than NMSC at evaluation to be included in analysis.
22 NMSC and 19 cancers other than NMSC were observed among 205 eligible patients, with cumulative incidences at 60 months of 11.2% (95% CI: 6.9-16.7) and 7.3% (95% CI 4.1-11.8), respectively. The most common cancers other than NMSC were oral squamous cell carcinoma and melanoma (n=6 each).
Factors associated with NMSC in univariable analysis were older age at transplant, older age at evaluation, having received sirolimus for cGVHD, having received extracorporeal photopheresis or psoralen-ultraviolet therapy for cGVHD as well as higher CRP, higher NK cell count, and greater BMI at evaluation. Only older age at transplant (HR=2.12; 95% CI: 1.35-3.31) and higher CRP (HR=9.61; 95% CI: 1.29-71.73) remained associated in the multivariable model. Factors associated with subsequent cancers other than NMSC in univariable analysis were T-cell depletion, lymphoid malignant indication for transplant, and increasing severity of oral cGVHD by NIH score. Only lymphoid malignant indication for transplant (HR=2.58; 95% CI: 1.31-5.07) remained significant in multivariable analysis.
The association of CRP with NMSC may represent an effect of cGVHD-related inflammation, with CRP previously associated with cGVHD severity. Interestingly, sirolimus was associated with increased risk of NMSC despite its purported antineoplastic effects. One study has previously reported increased risk of NMSC in allo-HSCT recipients treated with sirolimus, however, numerous studies have reported that sirolimus reduces risk of NMSC in solid organ recipients. In this study population, sirolimus was often prescribed later in patients already with refractory cGVHD and adjustment for measures of disease severity attenuated this association in multivariable modeling. The association of lymphoid indication with cancers other than NMSC may be attributable to age as patients with lymphoid malignancies were older at transplant than those with other indications. Additionally, differences in pre-transplant therapies for lymphoid vs. other indications may also contribute to this observation.
Post-transplant patients with cGVHD are at high risk of developing subsequent cancers, with higher incidence of NMSC than other cancers. This study identifies potential risk groups for subsequent cancers, highlights patients who may benefit from increased surveillance, and reiterates the need for effective cGVHD therapy to mitigate risks associated with long-term immunosuppression and immune dysfunction.
Display omitted
Cowen:UpToDate: Other: Royalties; Elsevier: Other: Royalties.
Background: Autologous stem cell transplantation (ASCT) remains a standard of care for patients with high-risk and recurrent diffuse large B cell lymphoma (DCLBL), T cell lymphoma (TCL) and multiple ...myeloma (MM). The discovery that differences in the composition of the gut microbiome contribute to the heterogeneity of response to chemotherapies or immunotherapies has prompted us to investigate the influence of the gut microbiome on progression-free survival (PFS) and overall survival in these patient populations treated with combined nivolumab (Nivo) and ipilimumab (Ipi) in the post-ASCT consolidation setting.
Methods: Longitudinal analysis of the gut microbiome was performed on stool samples collected from 26 patients (6 de novo DLBCL, 5 recurrent DLBCL, 1 de novo high-risk T cell lymphoma 2 recurrent TCL, 7 transplant-naïve high-risk MM, 4 recurrent MM) treated with Nivo + Ipi, 14-28 days post-ASCT. Stool samples were collected from patients prior to conditioning and ASCT (baseline) and at engraftment (within 72 hrs of absolute neutrophil count ≥ 500/mcL). Stool samples were then collected serially on Weeks 1, 4, 7, 12, 18 and 26 of treatment, 9, 12 and 18 months post-ASCT and at relapse of disease. The composition of the gut microbiome was identified using 16S rRNA sequencing of the V4 amplicon and bioinformatic analysis of α- and β-diversity metrics was performed using the Second Genome Microbiome Discovery Platform. Patients were classified as early relapsers, (n=5), PFS <6 months (Short-PFS) versus patients (n=21), with PFS, ≥ 6 months (Long-PFS).
Results: An average of 267 operational taxonomic units (OTUs) was identified per patient sample with a Shannon diversity index of 2.85. The top phyla in DLBCL, TCL and MM included Firmicutes, Bacteroides, Actinobacteria, Proteobacteria, Verrucomicrobia and Euryarchaeota and most samples were dominated by Firmicutes. The top families included Lachnospiraceae, Ruminococcaceae, Bacteroidaceae, Enterococcaceae, Erysipelotrichaceae, Bifidobacteriaceae, Enterobacteriaceae and Streptococcaceae.
The Shannon diversity index was reduced at engraftment (2.26) compared to at time of conditioning (3.15) and full recovery of diversity was attained at week 18 of treatment (3.15). At conditioning, Firmicutes, followed by Actinobacteria, and Bacteroides dominated the microbiomes in all indications and at the family level, Lachnospiraceae followed by Ruminococcaceae were major components of the microbiome. The microbiome, at the phylum and family levels, also varied considerably between conditioning and at relapse. While significant shifts in microbiome β-diversity appeared to be associated with indication and timepoint (PERMANOVA, P<0.001 and P<0.01 respectively), the samples did not separate in the weighted ordination, unweighted ordination and hierarchical clustering analyses by indication or timepoint.
A significant change of the relative abundance of the Bacteroidetes phylum at conditioning, engraftment, prior to consolidation and on-treatment (Week 7) was observed in the Short-PFS group (Friedman Test, 0.0638, P<0.02). A shift from high to low abundance of Bacteroidetes was observed in the Short-PFS group at conditioning and during engraftment prior to consolidation therapy (Kruskal-Wallis test, P<0.025 and P<0.01 respectively). A repeated measures Poisson regression model assessed patient's relative risk (RR) of response to treatment based on the relative abundance of specific gut microbiota. Relative abundances were categorized by tertile into low, medium, and high abundance groups. The regression model estimated the RR of response for medium and high abundance compared to low abundance groups. Compared to patients with a low abundance of Verrucomicrobia, those with medium and high abundance showed a 2% (RR= 1.022; p=0.078) and 4% (RR=1.035; p=0.078) trend toward predictive capability of patients falling into the Long-PFS group respectively.
Conclusions: Our interim taxonomic analyses of 26 patients suggest that the taxonomic identity of the microbiomes were largely similar across indications and timepoints, but the relative abundances of the phylotypes differed between samples. While our results suggest that Bacteroidetes and Verrucomicrobia at conditioning and engraftment may correlate with the likelihood of Short-PFS versus Long-PFS, our results need to be validated in ongoing cohort expansion studies.
Biran:Celgene: Consultancy, Honoraria, Speakers Bureau; Merck: Research Funding; Takeda: Consultancy, Speakers Bureau; BMS: Research Funding; Amgen: Consultancy, Speakers Bureau. Siegel:Takeda: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Vesole:Amgen: Speakers Bureau; Takeda: Speakers Bureau. Munshi:Kite: Speakers Bureau. Atkins:BMS: Consultancy; Merck: Consultancy. Feldman:Johnson and Johnson: Speakers Bureau; Portola: Research Funding; Celgene: Speakers Bureau; KITE: Speakers Bureau; Janssen: Speakers Bureau; Seattle Genetics: Research Funding, Speakers Bureau; Pharmacyclics: Speakers Bureau. Skarbnik:Genentech: Honoraria, Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.
BACKGROUND: High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is now the standard of care for newly diagnosed MM and refractory DLBCL patients. However, relapse remains ...the primary cause of morbidity and mortality, and thus, new therapeutic strategies are required to improve overall survival. In recent years, treatment with immune checkpoint inhibitors Nivolumab (Nivo), an anti-PD1 mAb, or Ipilimumab (Ipi), an anti-CTLA4 mAb, as single agents have achieved durable responses in patients with advanced solid tumors, and may prove to be useful for the treatment of hematological malignancies.
RATIONALE: In patients with advanced cancers including melanoma and Hodgkin's lymphoma, combined Nivo/Ipi therapy resulted in superior clinical efficacy compared to monotherapy. The immediate post-ASCT period provides an ideal window to introduce combined therapy because disease burden is at a minimum and the conditioning-induced inflammatory environment may enhance checkpoint inhibition effects on anti-tumor immune responses.
OBJECTIVE: To study the Treg and memory T cell compartments in the peripheral blood (PB) of high-risk MM and DLBCL patients, within the first 12 wks post-ASCT, during a Nivo/Ipi treatment regimen.
STUDY DESIGN: The interim longitudinal analyses of early Treg and memory T cell profiles was performed on PB sampled from patients up to 12 wks post-ASCT and treated with Nivo + Ipi, with a focus on four patient disease groups: A=de novo DLBCL; B=recurrent high-risk DLBCL; E=de novo high-risk MM; and F=recurrent MM. PB samples obtained from patients at initial screening (PB0) served as a baseline. The MM patients underwent conditioning with CDE or melphalan 200 mg/m2 followed by mobilization with filgrastim, apheresis, and hematopoietic progenitor cell reinfusion. Lymphoma patients were conditioned with BEAM. Starting 2-4 wks later, they were administered double therapy (Ipi 1mg/kg; 6 doses at wks 1, 4, 7, 10, 16, 22 and Nivo 3 mg/kg; 12 doses at wks 1, 4, 7, 10, 12, 14, 16, 18, 20, 22, 24, 26). PB was collected just prior to any treatment at various time points.
RESULTS:Table 1 summarizes the mean ± sem % of total lymphocytes for the Treg compartment at all time points. The % of naïve (RO-) Tregs was decreased up to wk 12 in all the groups (A; PB0 0.17; PB12 0.05), (B; PB0 0.16; PB12 0.03), (E; PB0 0.40; PB12 0.02), (F; PB0 0.32; PB12 0.00); and in memory (RO+) Tregs, except for F, (A; PB0 0.86; PB12 0.48), (B; PB0 0.16; PB12 0.03), (E; PB0 1.26; PB12 0.39), (F; PB0 0.32; PB12 0.53). Similar results were observed in the absolute numbers of Tregs for all groups.
In the memory T cell compartment, summarized in Table 2, by wk 12, the % effector memory (EM) CD4+ T cells increased in the A and F groups, but were decreased in B and E (A; PB0 4.69; PB12 5.33), (B; PB0 4.12; PB12 2.45), (E; PB0 5.69; PB12 2.99), (F; PB0 3.27; PB12 5.14). In contrast, EM CD8+ T cells in the A and E groups decreased in this compartment (A; PB0 2.91; PB12 1.49) (E; PB0 16.57; PB12 0.46), while the B group markedly increased by wk 12 (B; PB0 0.65; PB12 17.91), and the F group remained equivalent (F; PB0 0.18; PB12 0.24). Moreover, the centralmemory (CM) CD4+ T cell compartment was moderately decreased in all groups, except the F group (A; PB0 2.59; PB12 1.04), (B; PB0 4.12; PB12 2.5), (E; PB0 5.6; PB12 0.82), (F; PB0 1.62; PB12 1.5). Finally, the % of CD4+CCR7+RO-terminally differentiated (TEMRO-) cells was decreased in A, E and F, but not in B, groups (A; PB0 0.80; PB12 0.20), (B; PB0 0.23; PB12 0.26), (E; PB0 1.82; PB12 0.23), (F; PB0 0.66; PB12 0.43). In contrast, the % of CD8+CCR7+RO- TEMRO- cells was increased in B (PB0 1.52; PB12 11.73) and E (PB0 0.76; PB12 2.93), but not in A (PB0 3.12; PB12 2.08) and F (PB0 0.02; PB12 0.0.00) groups. Similar trends were observed with the absolute numbers of subsets.
CONCLUSIONS: Combined Nivo + Ipi therapy administered early post-ASCT exhibited a trend of decreased presence of naïve Tregs, in all groups, and memory Tregs in all groups but F by wk 12. In addition, there was an increased trend in the presence of CD8+ EM T cells in group B, and of the CD4+ EM T cells in groups A and F. Increased EM activity could potentially enable the immune system to continue to target tumor cells while in therapy. Finally, there was an increased trend in both CD4+ and CD8+ TEMRO- T cells in group B, which were consistent with the notion of exhaustion of longer surviving EM T cells.
Display omitted
Munshi:Kite: Speakers Bureau. Atkins:Merck: Consultancy; BMS: Consultancy. Biran:Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Merck: Research Funding; BMS: Research Funding; Amgen: Consultancy, Speakers Bureau. Siegel:Takeda: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Novartis: Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Feldman:Portola: Research Funding; Seattle Genetics: Research Funding, Speakers Bureau; Johnson and Johnson: Speakers Bureau; KITE: Speakers Bureau; Pharmacyclics: Speakers Bureau; Janssen: Speakers Bureau; Celgene: Speakers Bureau. Skarbnik:Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Honoraria, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Speakers Bureau.
The use of ASCT is highly established as consolidation or salvage for multiple myeloma (MM) and post salvage therapy in non-Hodgkin Lymphomas (NHL), particularly diffuse large B-cell lymphoma (DLBCL) ...with chemosensitive disease, as well as upfront consolidation in PTCL given poor outcomes after standard therapy (Philip et al., NEJM 1995, Kewalramani et al., Br J Haematol 2006, Gisselbrecht et al., J Clin Oncol 2010, Kumar et al., Leukemia 2012). Although a significant number of pts experience long-term disease-free survival following ASCT, those with high-risk disease (i.e.high-risk cytogenetics in MM, primary refractory DLBCL) are likely to present early relapses, particularly in the first 18 months post-ASCT, illustrating the need for better disease control strategies following ASCT. The rapidly rising impact of checkpoint inhibitors in oncology provides an opportunity for its usage as post-ASCT consolidation, especially given the favorable immunologic milieu found in the immediate post-ASCT setting (i.e. decreased T-regs, increased effector T-cells) and minimal expected tumor burden at that time. Here, we report preliminary safety and efficacy data of a Phase I trial evaluating I and N as post-ASCT consolidation.
Pts with the following malignancies were eligible, if they presented at least stable disease after most recent line of therapy: DLBCL: primary refractory or relapsed, PTCL: de novo stage III/IV or relapsed, MM: transplant-naïve with high-risk cytogenetics or relapse within 3 years of upfront ASCT.
Pts were enrolled prior to ASCT, starting in July 2016. Total accrual goal is 42 patients. All pts with DLBCL/PTCL received BEAM (carmustine 300 mg/m2 day -6, etoposide 200 mg/m2 and cytarabine 200 mg/m2 days -5 to -2, melphalan 140 mg/m2 day -1) as conditioning regimen for ASCT, all pts with MM received melphalan 200 mg/m2 on day -1.
For pts who achieved appropriate hematologic recovery (ANC >800/mm3 and platelets > 20,000/mm3), I/N were started between days 14 and 28 post ASCT. The infusion schedule was:
• I: 1 mg/kg; 6 doses Weeks 1, 4, 7, 10, 16, 22
• N: 3 mg/kg; 12 doses Weeks 1, 4, 7, 10, 12, 14, 16, 18, 20, 22, 24, 26
At this time, 25 patients have been enrolled and received at least one dose of I/N. Additional pts are in screening and results will be updated.
Median follow-up from time of first I/N infusion is 24 weeks (range 2-49). Adverse events (AEs) were documented starting week 1, day 1 of I/N infusion. AEs deemed at least possibly related to I and/or N were termed immune-related (irAEs) with 80% of pts developing irAEs of any grade (table 1). Treatment-related AEs of any grade that led to discontinuation of I/N occurred in 6 pts (24% total: colitis 12%, pneumonitis 4%, adrenal crisis 4% and hepatotoxicity 4%). One death attributable to I/N occurred (due to recurrent pneumonitis complicated by parainfluenza). Therapy with systemic steroids for management of irAEs was required for 19 pts (76%). 70% of irAEs improved within one week and 65% resolved within 2 weeks of initiation of steroids. Median time on treatment with I/N for development of irAEs was 9 weeks (range 2-25). For pts who discontinued treatment due to toxicity, the median time on I/N was 5 weeks (range 3-14). Incidence of irAEs was similar across disease groups.
With a median follow-up of 24 weeks, OS is 92% and PFS is 88% for the entire cohort. 100% of the pts with relapsed MM after first ASCT (50% of whom had less than CR to 1st ASCT) are now in stringent complete remission (sCR). 100% of pts with primary refractory DLBCL are in CR (table 2).
The toxicity profile of consolidation with I/N following ASCT was within expectations. Although there has been a significant number of irAEs (80%) given the mechanism of action of these drugs, this rate is not higher than what has been previously reported with I/N combination in other disease settings (Larkin et al., NEJM 2015, Postow et al., NEJM 2015) and all patients except 1 had resolution of irAEs with the use of systemic steroids . With a median follow-up of 6 months, 84% of pts across disease groups are in complete remission. Interestingly, 5 of 6 patients who had early discontinuation due to AEs, presented sustained remission. Correlative studies evaluating blood immunophenotype are being reported in a separate abstract.
Display omitted
Skarbnik:Novartis: Speakers Bureau; Genentech: Speakers Bureau; Gilead: Speakers Bureau; Abbvie: Other: Ad board, Speakers Bureau; Seattle Genetics: Speakers Bureau. Goy:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics / J&J: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Siegel:Merck: Consultancy; Celgene, Takeda, Amgen Inc, Novartis and BMS: Consultancy, Speakers Bureau. Biran:Takeda: Speakers Bureau; Celgene, Amgen: Consultancy, Speakers Bureau. Richter:Janssen: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Feldman:Kite Pharma: Speakers Bureau; Seattle Genetics: Honoraria, Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Pharmacyclics: Speakers Bureau; Janssen: Speakers Bureau; Bristol-Myers Squibb: Consultancy; AbbVie: Speakers Bureau. Leslie:seattle genetics: Speakers Bureau; KITE pharma: Speakers Bureau; celgene: Speakers Bureau. McKiernan:Novartis: Speakers Bureau. McNeill:pharmacyclics: Speakers Bureau; celgene: Speakers Bureau; seattle genetics: Speakers Bureau. Pecora:Caladrius Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; COTA: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.
Multiple myeloma (MM) is a hematological malignancy characterized by the uncontrolled growth of clonal plasma cells. High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is ...now standard of care for newly diagnosed MM patients with improved outcome. However, high-risk MM patients relapse after 1 to 2 years post-ASCT. Immune checkpoint blockade using nivolumab (Nivo), an anti-PD1 monoclonal antibody or ipilimumab (Ipi), an anti-CTLA4 monoclonal antibody, as single agents have achieved durable responses in patients with advanced solid tumors.
In a murine melanoma model, Nivo or Ipi monotherapy partially reduced tumor burden, whereas combined Nivo and Ipi therapy eliminated tumor burden. In patients with advanced cancers such as melanoma and non-small lung cancer, combined Nivo+Ipi resulted in superior clinical efficacy compared to patients treated with single agents. Since monotherapy with Nivo did not show an objective response rate in relapsed/refractory MM patients, we hypothesized that high-risk MM patients treated with consolidation therapy consisting of Nivo plus Ipi post-ASCT would achieve a more durable response and improve progression-free survival.
While the objective of the clinical trial focused on safety and efficacy of the combination therapy approach, our study focused on blood immune analysis by flow cytometry, and particularly on the regulatory (Treg) and memory T cell compartments.
In a phase Ib-IIA study, patients were grouped into 6 cohorts (7 patients each) with various hematological malignancies. This abstract focuses on results from the transplant-naive high-risk MM group: those carrying 1q amplifications, 1p, 13q, or p53 deletions, high-risk GEP 70 scores, t(4;14), t(14;16) and t(14;20), or hypodiploidy). Peripheral blood (PB) samples obtained from patients at time of initial screening served as a baseline (PB0). The patients underwent hematopoietic progenitor cell (HPC) mobilization (high-dose cyclophosphamide, dexamethasone and etoposide followed by filgrastim), apheresis, conditioning with melphalan 200 mg/m2, and HPC reinfusion. Starting 2-4 wks later, they were administered double therapy (Ipi. 1mg/kg; 6 doses at week 1, 4, 7, 10, 16, 22 and Nivo. 3 mg/kg; 12 doses at week 1, 4, 7, 10, 12, 14, 16, 18, 20, 22, 24, 26). PB was collected just prior to any treatment at various time points (see Figure), and normal healthy donor PB served as population standards for flow cytometry.
This information includes the reported % mean + interquartile range data for the high risk MM group up to week 26, given that the study is still on-going. Thus far, the gated % of Tregs CD4+RO+CD25+CD127- decreased throughout the therapy: 1.4%, (PB0), 0.1%, (PB4), 0.3%, (PB7), 0.4%, (PB18), 0.1%, (PB26). Moreover, the CD4+CD39+RO+ (Memory) Tregs initially decreased and then rebounded with double therapy administration: 69%, (PB0), 54% (PB4), 68% (PB7), 68% (PB18), and 51% (PB26). Moreover, the percent of CTLA4+RO+ Tregs was altered after the first combination treatment: 3.2% (PB0), 1.3% (PB4), 0% (PB7), but was restored by PB18 (3.0%) and PB26 (3.6%). Similar results were observed in the absolute numbers of these populations. Furthermore, there was a marked increase in CD4+ effector memory (EM) T cells at PB4 (5.5%) and PB18 (4.5%) compared to PB0 (4.0%). And CD8+ EM T cells were not affected at PB4 (1.1%) and PB18 (1%), compared to PB0 (1.1%). In contrast, both CD8+ and CD4+ central memory (CM) T cell compartments were low at all time points. Interestingly, while CD4+CCR7+RO- terminally differentiated (TEMRO-) T cells did not recover to PB0 levels, the %CD8+CCR7+RO- TEMRO- T cells steadily increased up to PB18, but then decreased by PB26: 1.8% (PB0), 2.4%(PB7), 2.5%(PB18), and 1.2%(PB26). Similar results were observed using the absolute number of cells.
Combination Nivo+Ipi checkpoint inhibitors can decrease the presence of memory Tregs overall as well as CTLA4+ Tregs. In addition, the approach was able to increase the percentage and absolute numbers of the CD4/CD8 EM T cell compartments, but did not affect the CD4/CD8 CM T cell compartments, thus enabling the immune system to potentially still be able to target cancer cells while in therapy. Finally, the increase in CD8+ TEMRO- T cells were consistent with the exhaustion of longer surviving EM T cells.
Display omitted
Biran:Celgene, Amgen: Consultancy, Speakers Bureau; Takeda: Speakers Bureau. Richter:Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Speakers Bureau. Siegel:Celgene, Takeda, Amgen Inc, Novartis and BMS: Consultancy, Speakers Bureau; Merck: Consultancy. Skarbnik:Gilead: Speakers Bureau; Genentech: Speakers Bureau; Abbvie: Other: Ad board, Speakers Bureau; Novartis: Speakers Bureau; Seattle Genetics: Speakers Bureau.
Here, we report interim results from ZUMA-5, a Phase 2 study of axi-cel, an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy, in patients with relapsed/refractory iNHL.
Adults with ...relapsed/refractory follicular lymphoma (FL) or marginal zone lymphoma (MZL) after ≥2 lines of therapy (including an anti-CD20 monoclonal antibody with an alkylating agent) were eligible. Patients were leukapheresed and received conditioning chemotherapy followed by axi-cel at 2 × 106 CAR T cells/kg. The primary endpoint was objective response rate (ORR) by central review (Cheson, et al. J Clin Oncol. 2014). Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, and blood levels of CAR T cells.
As of 8/20/19, 94 patients (80 FL; 14 MZL) received axi-cel (median follow-up, 11.5 months). Median age was 63 years, 51% of patients had ≥3 FLIPI, 59% had high tumor bulk, 66% progressed < 2 years after first chemoimmunotherapy (POD24), and 73% were refractory to the last treatment. Of 87 patients evaluable for efficacy, ORR was 94% (79% complete response CR rate). Patients with FL (n=80) had an ORR of 95% (80% CR rate). Patients with MZL (n=7) had an ORR of 86% (71% CR rate). Overall, 68% of patients had ongoing responses as of the data cutoff. Updated data will be presented. Of 94 patients evaluable for safety, 83% experienced Grade ≥ 3 adverse events, most commonly neutropenia (33%) and anemia (28%). Grade ≥ 3 cytokine release syndrome (CRS) and neurologic events (NEs) occurred in 11% and 19% of patients, respectively. Median times to onset of CRS and NEs were 4 and 7 days; median durations were 6 and 14.5 days. There were 2 Grade 5 adverse events: multisystem organ failure in the context of CRS (related to axi-cel) and aortic dissection (unrelated to axi-cel). Median peak and AUC0-28 CAR T cell levels were 44 cells/μL and 490 cells/μL × day, respectively.
Axi-cel showed significant clinical benefit, with high response rates, and a manageable safety profile in patients with relapsed/refractory iNHL. Funding provided by Kite, a Gilead Company.
Age 60 or older and remission status at time of allo-HCT (CR2/PIF/Relapse vs CR1) was predictive of inferior overall survival.
Use of myeloablative conditioning with total body irradiation was ...predictive for improved DFS and reduced risk of relapse.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with a poor prognosis and considered incurable with standard conventional chemotherapy. Small observational studies have shown that allogeneic hematopoietic cell transplantation (allo-HCT) offers durable remissions in patients with BPDCN, particularly in patients undergoing the procedure in first complete remission (CR1). Here, we report an analysis of patients with BPDCN who received an allo-HCT using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). To describe outcomes of allo-HCT in BPDCN and identify predictors of post-transplant relapse and survival. We conducted an analysis of 164 patients with BPDCN from 78 centers who underwent allo-HCT between 2007-2018 using the CIBMTR database. Median follow up of survivors was 49 months (range 6-121). The 5-year overall survival (OS), disease-free survival (DFS), relapse, and non-relapse (NRM) rates were 51.2% (95% confidence interval 95%CI: 42.5-59.8%), 44.4% (95%CI: 36.2-52.8%), 32.2% (95%CI: 24.7–40.3%), and 23.3% (95%CI: 16.9-30.4%), respectively. Disease relapse was the most common cause of death. On multivariate analyses, age ≥60 was predictive for inferior OS (hazard ratio HR= 2.16, 95% CI 1.35–3.46, p= 0.001), and a higher NRM HR= 2.19, 95% CI 1.13–4.22, p= 0.02. Remission status at time of allo-HCT (CR2/PIF/Relapse vs CR1) was predictive of inferior OS HR= 1.87, 95% CI 1.14–3.06, p= 0.01 and DFS HR= 1.75, 95% CI 1.11–2.76, p= 0.02. Use of myeloablative conditioning with total body irradiation was predictive for improved DFS and reduced risk of relapse. This study demonstrates allo-HCT is effective in providing durable remissions and long-term survival in BPDCN. Younger age and allo-HCT in CR1 predicted for improved survival, while myeloablative conditioning with total body irradiation predicted for less relapse and improved disease free survival. Novel strategies incorporating allo-HCT are needed to further improve outcomes.
PDF
