Background: Autologous stem cell transplantation (ASCT) prolongs survival in patients (pts) with multiple myeloma (MM) as shown by randomized trials. However, most studies included younger pts, usually 65 or less, and the outcome for older pts, especially those over 70, is unclear. We retrospectively reviewed our experience with ASCT for MM in pts over 70 years. Methods: We identified 35 pts with MM who were ≥70 years at the time of their ASCT. We matched them to 70 pts (two matches per pt), based on status at transplant (primary refractory, plateau phase, relapse off therapy, or relapse on therapy), Durie Salmon stage, high or low labeling index, conventional cytogenetics (abnormal vs normal), presence of circulating plasma cells at time of stem cell collection, in that order of priority. Results: The median age of the groups were 55.3 (range, 37.3–64.8) and 71.7 (70–75.8) years at transplant. The median time to transplant from diagnosis was similar (6.4 for the older pts compared to 6.9 mos for the other, P = NS). Ten of the 35 older pts received reduced dose melphalan (140 mg/2) compared to 3 pts in the control group; P < .01. The median follow up from transplant was 10.1 months for the older pts compared to 18 months for the control group. The overall response rate was similar (97.1% for the older pts compared to 95.5% for the control group). Eleven (31%) of the older pts and 17 (24%) of the control pts achieved a CR (P = NS). The post transplant progression free survival estimate at 1 year post transplant was 65.3% for the older pts compared to 66% for the control group (P = .3). The 2-year estimated overall survival from transplant was similar; 58% for the older pts compared to 67% for the control group. The overall survival from diagnosis was similar for the two groups (P = .6). The median number of days hospitalized was 9 days for the older population compared to 5 days for the control group (P = .37). Four pts died within the first one hundred days, one among the older patient group. Conclusions: ASCT is feasible in selected pts with MM over 70 years. It is likely that older pts were selected based on their overall performance status, a factor that is difficult to analyze in this retrospective review. Nearly 70% of the elderly pts received full dose melphalan for conditioning (200 mg/m2). The toxicity of transplant and outcome appears to be similar to the younger pts. Pts with MM should not be excluded from ASCT solely on the basis of their age.
Seventeen patients with advanced epidermoid carcinoma of the esophagus were treated with ifosfamide (IFOS) 1.5 mg/m2/day intravenously on days 1–5 every 28 days. Mesna was given concurrently at 20% of the IFOS dose prior to and 4 and 8 h after IFOS for uroprotection. Toxicity in this trial was severe since life-threatening leukopenia occurred in one patient, Grade 3 nausea and vomiting (necessitating termination of treatment) in two patients, and Grade 3 neurotoxicity (cerebellar dysfunction) in two patients. Two patients developed severe infections (Grade 3). Only four patients experienced no toxicity. One patient had a partial response with a response duration of 8 weeks. The median survival of all patients is 10 weeks. It is concluded that IFOS as given in this trial has limited activity in esophagus carcinoma with severe toxicity.
Exhausted T cells typically express PD-1, but expression of PD-1 is not limited to exhausted cells, and many PD-1 expressing cells are simply activated and exhibit appropriate immune function. In this study, we therefore sought to determine which PD-1+ T cells were truly exhausted. Although expected to be functionally suppressed, we found that the population of intratumoral PD-1+ T cells were predominantly responsible for production of cytokines and granules. This surprising finding prompted us to explore the involvement of other exhaustion markers including LAG-3 to specifically identify functionally exhausted T cells. We found that LAG-3 was expressed on a subset of intratumoral T cells from FL and LAG-3+ T cells almost exclusively came from the population of PD-1+ cells. CyTOF analysis revealed that intratumoral LAG-3+ T cells were phenotypically heterogeneous as LAG-3 was expressed on a variety of types of T-cell subsets. In contrast to PD-1+LAG-3− cells, intratumoral PD-1+LAG-3+ T cells exhibited reduced capacity to produce cytokines (IL-2 and IFN-γ) and granules (perforin and granzyme B). LAG-3 expression could be substantially upregulated on CD4+ or CD8+ T cells by IL-12, a cytokine that has been shown to induce T-cell exhaustion and be increased in the serum of lymphoma patients. Furthermore, we found that blockade of both PD-1 and LAG-3 signaling enhanced the function of intratumoral CD8+ T cells resulting in increased IFN-γ and IL-2 production. Clinically, LAG-3 expression on intratumoral T cells correlated with a poor outcome in FL patients. Taken together, we find that LAG-3 expression is necessary to identify the population of intratumoral PD-1+ T cells that are functionally exhausted and, in contrast, find that PD-1+LAG-3− T cells are simply activated cells that are immunologically functional. These findings may have important implications for immune checkpoint therapy in FL. Keywords: follicular lymphoma (FL); immunosuppression; T-cells.
Abstract Elevated B-cell–activating factor (BAFF; TNFSF13B) levels have been found in patients with B-cell malignancies and autoimmune diseases, suggesting that it may play a pathogenic role. We previously found that a single nucleotide polymorphism (SNP) in the TNFSF13B promoter resulted in increased transcription, suggesting that genetic variation in TNFSF13B may influence its expression. We therefore wanted to determine if genetic variation in TNFSF13B is associated with high BAFF levels and non–Hogkin lymphoma (NHL) risk. We genotyped 9 tagSNPs within TNFSF13B in a clinic-based study of 441 NHL cases and 475 matched controls and evaluated the association of individual SNPs with risk of NHL; 3 tagSNPs were significant (P < 0.05). When categorized into low-, moderate-, and high-risk groups based on risk alleles, we found the permutation-corrected odds ratio for the trend to be 1.43 (P = 0.0019) for risk of B-cell NHL, 1.69 (P = 0.0093) for diffuse large B-cell lymphoma, 1.43 (P = 0.029) for follicular lymphoma, and 1.06 (P = 0.21) for chronic lymphocytic leukemia/small lymphocytic lymphoma. The mean serum BAFF level in those who carried the low-risk alleles was 2 ng/mL compared with 4.3 ng/mL in those with the high-risk alleles (P = 0.02). Taken together, our data suggest that genetic variation in the TNFSF13B gene is significantly associated with NHL risk and elevated serum BAFF levels. [Cancer Res 2009;69(10):4217–24]
The growth of non-Hodgkin lymphomas can be influenced by tumor-immune system interactions. Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a negative regulator of T-cell activation that serves to dampen antitumor immune responses. Blocking anti-CTLA-4 monoclonal antibodies improves host resistance to immunogenic tumors, and the anti-CTLA-4 antibody ipilimumab (MDX-010) has clinical activity against melanoma, prostate, and ovarian cancers.We did a phase I trial of ipilimumab in patients with relapsed/refractory B-cell lymphoma to evaluate safety, immunologic activity, and potential clinical efficacy. Treatment consisted of ipilimumab at 3 mg/kg and then monthly at 1 mg/kg x 3 months (dose level 1), with subsequent escalation to 3 mg/kg monthly x 4 months (dose level 2).Eighteen patients were treated, 12 at the lower dose level and 6 at the higher dose level. Ipilimumab was generally well tolerated, with common adverse events attributed to it, including diarrhea, headache, abdominal pain, anorexia, fatigue, neutropenia, and thrombocytopenia. Two patients had clinical responses; one patient with diffuse large B-cell lymphoma had an ongoing complete response (>31 months), and one with follicular lymphoma had a partial response lasting 19 months. In 5 of 16 cases tested (31%), T-cell proliferation to recall antigens was significantly increased (>2-fold) after ipilimumab therapy.Blockade of CTLA-4 signaling with the use of ipilimumab is well tolerated at the doses used and has antitumor activity in patients with B-cell lymphoma. Further evaluation of ipilimumab alone or in combination with other agents in B-cell lymphoma patients is therefore warranted.
Clinical successes with immune check-point blockers have demonstrated the potency of the immune system in controlling cancers, most strikingly in Hodgkin lymphoma (HL), where overall response rates to PD1/L1 inhibitors approach 90%. Complete or durable responses, however, are uncommon, therefore targeting the PD1/L1 axis alone is not sufficient. Recent work analyzing the spatial arrangement of PD1 and PDL1 expressing cells has given us new insight into the mechanism of action of PD1/L1 inhibitors, however this work limited itself to studying a single check point marker on a subset of cells. We hypothesize that comprehensive profiling of the frequency and spatial arrangement of immune cells in the Hodgkin lymphoma tumor immune microenvironment (TME) will provide new insights into the mechanism of checkpoint blockers and identify novel targets for immune therapy. Until now, multiparameter spatial analysis of the immune microenvironment was limited by technical challenges. Flow and mass cytometry are able to identify immune subsets of interest but spatial information is lost. Multiplex tissue imaging methods are limited to 6-8 simultaneous markers and cannot capture the full complexity of the immune phenotypes. The Fluidigm Hyperion imaging mass cytometry (IMC) system combines a CyTOF mass cytometer with a laser ablation system allowing for 40+ parameter simultaneous immunophenotyping on a single slide of FFPE tissue, with sub-cellular resolution. We have developed a panel of 34 antibodies that allow for comprehensive characterization of CD4, CD8 and myeloid cells components in the TME of Hodgkin lymphoma using IMC. Here we report on our spatial analysis of TIM3 and LAG3 expressing CD4+ lymphocytes. Our data suggests LAG3+CD4+ and TIM3+CD4+ lymphocytes had shorter mean nearest distance to PDL1+Hodgkin Reed-Sternberg (HRS) cells upon comparison to PDL1- HRS cells (t-test, p=1.703e-08,p=1.126e-14). Future studies should explore multiple exhausted marker models that seeks to further understand the presence of simultaneous exhaustion signals in the niche environment. These data suggest that therapies that target TIM3 and/or LAG3 should be tested in Hodgkin Lymphoma and that spatial analysis of immune subsets by IMC should be explored as selective and pharmacodynamic biomarkers.Citation Format: Anthony R. Colombo, Monirath Hav, Erik Gerdtsson, Jose Bisnesto-Villasboas, Stephen Ansell, James Hicks, Peter Kuhn, Akil Merchant. Revisiting immune exhaustion in Hodgkin's lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1189.
