T-cell Lymphoma Patients Research Articles

PRO140 Health-Related Quality of Life Associated with Mycosis Fungoides-Type Cutaneous T-Cell Lymphoma Patients: Determination of Utility Values from a UK-Based Clinician Questionnaire

Utility studies quantify the impact of disease on patients’ health-related quality of life (HRQoL). In rare diseases particularly, utility data are often limited. Where direct elicitation of data from patients is unfeasible, indirect methods are required to determine health state utility values (HSUVs). Here, we present indirect elicitation of HSUVs for patients with mycosis fungoides (MF), a rare skin lymphoma characterised by painful, itchy skin patches and plaques, which can progress into tumours and may involve blood, lymph nodes and viscera. Twelve distinct vignettes were prepared, based on published literature and expert opinion. The vignettes were validated by a MF patient expert and described typical MF patients with varying disease stage (IA-IVB) and skin burden, as assessed by the modified Severity Weighted Assessment Tool (mSWAT). Other included patient characteristics (age, Eastern Cooperative Oncology Group [ECOG] score) were informed by a patient registry. UK clinicians, working at key NHS lymphoma treatment centres (N=7), acted as respondents and completed the EQ-5D-5L questionnaire (proxy version 2) electronically for each vignette, responding as they believed MF patients would. Responses were converted into HSUVs using the UK value set. In every disease stage, HSUVs decreased with increasing mSWAT score. Similarly, for each mSWAT range HSUVs decreased as disease stage advanced. This demonstrates the effect of increasing skin burden and disease progression on HRQoL. Despite this, HSUVs associated with mSWAT score=0 were similar, regardless of disease stage (0.945 in Stage IA, 0.924 in Stage IB-IIA and 0.917 in Stage IIB-IV). The results of this investigation suggest that proxy-reporting via EQ-5D represents a potential option for generating HRQoL data, if published estimates are not available. Despite the small sample size and indirect elicitation of data, the finding that HRQoL decreases with increased mSWAT score is aligned with published literature.

Profiling T-Cell Receptor Diversity and Dynamics during Lymphoma Immunotherapy Using Cell-Free DNA (cfDNA)

Profiling T-Cell Receptor Diversity and Dynamics during Lymphoma Immunotherapy Using Cell-Free DNA (cfDNA)

VAV1-GFP Fusion Protein Generated By Intron-Based Genome Editing through CRISPR/Cas9 Leads to Spontaneous Activation in TCR Signaling

Recurrent VAV1 mutations and gene fusions (VAV1-THAP4, VAV1-MYO1F, and VAV1-S100A7) have been identified in peripheral T-cell lymphoma (PTCL) including angioimmunoblastic T-cell lymphoma (AITL) patients. A common theme of these genetic aberrations is the loss of the auto-inhibitory C-terminal SH3 domain of VAV1 resulting in aberrant activation of VAV1 independent of normal activation events. Although mouse models support VAV1 mutation/fusion as having a driver oncogenic role in the pathogenesis of PTCL, investigations on VAV1 activity in human cells were performed mainly on the Jurkat cell line with exogenous expression of VAV1 fusion proteins. This approach has un-physiological expression of VAV1 and the functions of VAV1 fusion/mutation under normal endogenous regulation need to be explored. In this study, we introduced a fusion gene, similar to what has been observed in PTCL, into the endogenous VAV1 locus. The fusion gene was under normal regulatory controls instead of being over-expressed by a viral vector, thus providing a more accurate assessment of its function in vivo. To simulate VAV1 fusion, we knocked in a green fluorescence protein (GFP) sequence followed by a simian virus 40 (SV40) poly(A) signal into intron 25 of VAV1 locus by clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9) technology. A homologous DNA repair (HDR) template with tandem homologous sequences of VAV1 gene, GFP gene, and a SV40 transcription poly(A) signal was electroporated into Jurkat cells together with the Cas9/sgRNA ribonucleoprotein (RNP) complex. This knock-in disrupted the transcription of exon 26 and exon 27, resulting in an in-frame fusion protein with GFP fused to the C-terminal of SH2 of VAV1 (VAV1SH2-GFP)(Figure A). Because our guide RNA targeted the intron 25 sequence by CRISPR/Cas9 system, any possible indels caused by non-homologous end joining will occur within the intron and will not change the protein sequence of the wild type VAV1. The GFP expressing cells were isolated from the edited cell population by FACS. The fusion of GFP with VAV1 in the sorted cells was confirmed by western blot (Figure B) and these cells displayed a heterozygous VAV1SH2-GFP fusion/wild type (WT) phenotype that mimicked the VAV1 translocations observed in PTCL patients. Jurkat cells with VAV1SH2-GFP showed spontaneous activation of the T-cell receptor (TCR) signaling pathway. Analysis of signaling events downstream of VAV1 demonstrated increased phosphorylation in ITK, LCK, and subsequent ERK in Jurkat cells with VAV1SH2-GFP compared with WT Jurkat cells by western blot (Figure B). We also observed consistently elevated pERK in Jurkat cells with VAV1SH2-GFP by flow cytometry (Figure C). Notably, this elevation in pERK was spontaneous and independent of TCR stimulation with anti-CD3 antibody. VAV1SH2-GFP fusion protein also led to marked activation of downstream NFAT and NF-κB pathways as shown by Luciferase reporter assays (Figure D). Similarly, the enhanced NFAT and NF-κB pathway activation in Jurkat with the fusion protein was independent of TCR stimulation. Interestingly, with antiCD3 stimulation, Jurkat cells with VAV1SH2-GFP showed significantly lower pERK, NFAT and NF-κB activity compared to WT Jurkat cells with anti-CD3 stimulation. In conclusion, in Jurkat cells genetically edited with VAV1SH2-GFP, spontaneous activation of TCR signaling and subsequently increased NFAT and NF-κB activity were observed. Our findings further support that VAV1 C-terminal SH3 domain plays an important regulatory role in blocking VAV1 activity in the absence of proper activation. Removing C-terminal SH3 domain or replacing it with GFP or other protein relieves this inhibition, allowing spontaneous activation independent of TCR stimulation. Our study also indicates the sensitivity of the TCR signaling pathway to the level of activation and hyperactivation is detrimental. To validate the function of VAV1SH2-GFP in normal T cells, we have also successfully edited primary CD4+ T cells with VAV1SH2-GFP and the TCR signaling pathway in edited primary CD4+ T cell is currently being evaluated with and without anti-CD3/CD28 stimulation. Figure Disclosures No relevant conflicts of interest to declare.

Brentuximab Vedotin As Single Agent in the Treatment of Relapsed/Refractory CD30 Positive Peripheral T-Cell Lymphoma Patients: A Phase 2 Study of the Fondazione Italiana Linfomi

Brentuximab Vedotin As Single Agent in the Treatment of Relapsed/Refractory CD30 Positive Peripheral T-Cell Lymphoma Patients: A Phase 2 Study of the Fondazione Italiana Linfomi

Treatment Guided By Next Generation Functional Drug Screening Provides Clinical Benefit in Advanced Aggressive Hematological Malignancies: Final Evaluation of the Open Label, Single Arm Exalt Trial

Background: Aggressive hematological malignancies in relapsed/refractory setting bear a dire prognosis with low cure rates and short survival. Matching these patients to therapies is challenged by complexity due to spatial and temporal tumor evolution and incomplete understanding of genotype to phenotype correlations. Direct functional testing could address these impediments. The EXALT trial is an interventional, one-arm study designed to assess the clinical value of next generation functional drug screening (ngFDS). An interim analysis on 17 patients suggested a clinical benefit (Snijder et al., Lancet Hematol. 2017). Methods: We applied image-based ngFDS to quantify differential ex-vivo sensitivity of primary patient tumor cells to respective non-tumor cells towards 136 small molecule drugs, including EMA approved for any indication or experimental. We screened bone marrow, peripheral blood or lymph node material from 143 patients who suffered from late stage aggressive hematological malignancies (acute leukemias, aggressive B- and T-cell lymphomas) , discussed the results in a multidisciplinary tumor board and recommended treatments to physicians (A). The primary endpoint of this study was the percentage of patients reaching a PFS-ratio (PFS(ngFDS treatment)/PFS(previous treatment)) of ≥1.3 with an H0 hypothesis < 15% patients. The secondary endpoint was overall response rate (ORR) defined as proportion of patients reaching complete remission (CR) or partial remission (PR). Additionally, we performed a post hoc analysis to evaluate the matching of ngFDS to drugs used in actual treatment (matching score of received treatment). Results: 56 (39%) patients were evaluable and treated according to ngFDS based recommendations. With 30 of 56 (54%) ngFDS guided patients experiencing a PFS ratio of ≥1.3, the primary study endpoint was reached. 11 patients (37%) had ongoing response at censoring date (B). The median follow-up was 718 days. The median number of days from sampling to treatment was 21 (range 4-77). The ngFDS treatment regimens consisted of a median of 2 drugs (range: 1-6). ORR was 55% for all evaluable ngFDS treated patients, 60% for the lymphoid subgroup and 41% for the myeloid subgroup. Patients on ngFDS guided treatment with performance status ECOG ≤ 1 had a median PFS of 207 days compared to a median PFS of 29 days for patients with higher ECOG (p < 0.001, C). 24 of 39 (62%) patients with ECOG ≤ 1 had a PFS ratio of ≥1.3 (D). In disease specific subgroup analysis median PFS of T-cell lymphoma patients was 235 days versus 60 days for B-cell lymphoma patients (p = 0.018, E). Age (≤60 vs. >60), sex, lineage (myeloid vs. lymphoid), number of previous treatment lines (≤2 vs. >2), and clinical presentation (leukemia vs. lymphoma) did not have an impact on PFS of ngFDS guided treatment. Post hoc analysis including additional 17 non-ngFDS treated patients demonstrated that only patients receiving treatment with a positive ngFDS matching score demonstrated clinical benefit (HR: 0.53, p=0.005; vs. HR: 1.4, p=0.4). ngFDS matched treatments resulted in higher PFS for patients with tumor samples that had a cancer cell fraction of 10-50% in comparison to patients with samples of lower or higher cancer cell percentage (HR:0.35, p=0.01). Conclusion: ngFDS could be integrated in the routine clinical work flow. ngFDS guided treatments led to high rates of PFS prolongation compared to previous treatments of individual patients. ngFDS guided treatment is feasible and effective in patients with late stage aggressive hematological malignancies. These results prompted a prospective randomized trial comparing treatment guidance based on ngFDS or comprehensive genomic profiling or physician's choice (EXALT-2 trial, NCT04470947). Figure Disclosures Vladimer: Allcyte GmbH: Current Employment, Current equity holder in private company, Other: Founder. Jaeger:Karyopharm: Honoraria; Amgen: Honoraria; Gilead: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; True North: Honoraria, Research Funding; Miltenyi: Consultancy, Honoraria; CDR Life AG: Consultancy, Research Funding; F. Hoffmann-La Roche: Honoraria, Research Funding; Infinity: Honoraria; Takeda: Honoraria; Novartis: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria. Krall:Allcyte GmbH: Current Employment, Current equity holder in private company, Other: Founder. Valent:Allcyte GmbH: Research Funding; Cellgene: Honoraria, Research Funding; Pfizer: Honoraria. Wolf:Celgene: Honoraria, Research Funding. Zielinski:MSD: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Imugene: Consultancy, Honoraria, Speakers Bureau; Ariad: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Merrimack: Consultancy, Honoraria, Speakers Bureau; Merck KGaA: Consultancy, Honoraria, Speakers Bureau; Fibrogen: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Tesaro: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Speakers Bureau; Shire: Consultancy, Honoraria, Speakers Bureau; Eli Lilly: Consultancy, Honoraria, Speakers Bureau; Athenex: Consultancy, Honoraria, Speakers Bureau. Superti-Furga:Allcyte GmbH: Current equity holder in private company, Other: Founder. Snijder:Allcyte GmbH: Current equity holder in private company, Other: Founder. Staber:Roche: Consultancy, Honoraria, Research Funding; Astra Zeneca: Consultancy, Honoraria; Celgene/ BMS: Consultancy, Honoraria; msd: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria.

Abstract PO-51: Drug combination analytics platform for accurate prediction of treatment response in refractory and relapsed lymphomas

Abstract While 5-year survival rates for non-Hodgkin lymphoma have improved with effective first-line therapies, refractory and relapsed lymphomas continue to suffer from poor response rates and low median overall survival. The increased availability of targeted therapies has been critical to improving response rates in lymphomas. As the number of therapeutic options increases, however, identifying the most appropriate patient-specific drug combination from among a range of available drug sets is virtually impossible by conventional methods due to the large search space. Further complicating this clinical decision is the diversity in interpatient therapeutic responses due to lymphoma patient heterogeneity. Math and AI-based analytical tools are beginning to positively impact all facets of drug development and personalized medicine. Rather than aggregating large datasets from other sources (data repositories, text mining, etc.) to develop predictive models, we developed an experimentally driven small dataset analytics platform, Quadratic Phenotypic Optimization Platform (QPOP), to identify and rank drug combinations from a specific drug set search space. QPOP identifies optimal drug combinations from queried drug sets against specific biologic systems of interests, including patient-derived primary cancer cells. Utilizing small datasets built from drug combination tests designed by orthogonal array composite design, QPOP analyzes drug combination sensitivity data to identify and rank possible drug combinations. Recently, we applied QPOP towards patient-specific clinical decision support applications in refractory and relapsed non-Hodgkin lymphoma. Utilizing 1 million patient-derived primary lymphoma cells for 155 drug combination tests, QPOP ranked 531,441 possible therapeutic options from a 12-drug search set within 6 days of patient sample biopsy. Across a series of refractory and relapsed T-cell lymphoma patients, effective treatment options were accurately predicted that included both standard salvage regimens, such as gemcitabine-dexamethasone-cisplatin, as well as targeted regimens, such as bortezomib-panobinostat. For a hepatosplenic T-cell lymphoma case that had previously progressed following 6 lines of treatment, analysis by QPOP was able to accurately identify patient-specific bortezomib-panobinostat treatment that resulted in a complete response. Furthermore, QPOP-predicted drug combination sensitivity results from our study were compared to historical outcomes of a phase 2 trial of bortezomib-panobinostat in peripheral T-cell lymphoma (NCT00901147), with 20% predicted response in our QPOP-analyzed cohort mirroring 21.7% complete response observed in the previous trial. These results provide evidence that ex vivo drug combination sensitivity platforms may be useful tools for clinical decision support, for both personalized medical applications as well as enhanced clinical trial patient selection and parallel outcome tracking. Citation Format: Jasmine Goh, Sanjay de Mel, Anand D. Jeyasekharan, Edward K.H. Chow. Drug combination analytics platform for accurate prediction of treatment response in refractory and relapsed lymphomas [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr PO-51.

Resistance to histone deacetylase inhibitors confers hypersensitivity to oncolytic reovirus therapy

AbstractDespite the promising antilymphoma activity of histone deacetylase (HDAC) inhibitors as a drug class, resistance is a significant clinical issue. Elucidating the molecular mechanisms driving HDAC inhibitor resistance and/or the specific targets that are altered in drug-resistant cells may facilitate the development of strategies that overcome drug resistance and are more effective for refractory patients. We generated novel T-cell lymphoma (TCL) cell line models of acquired resistance to the HDAC inhibitor belinostat to identify potential effective therapies. Belinostat-resistant cells displayed significant cross-resistance to other HDAC inhibitors including romidepsin, panobinostat, and vorinostat. Consistent with a lack of sensitivity to HDAC inhibitors, the resistant cells failed to induce increased acetylated histones. Drug-resistant cells featured significantly decreased expression of the key antiviral mediators IRF1 and STAT1. On the basis of these findings, we investigated the efficacy of the clinical formulation of reovirus (Reolysin) in parental and drug-resistant models. Our investigation revealed that HDAC inhibitor–resistant cells displayed enhanced vulnerability to reovirus replication and cell death in both in vitro and in vivo models compared with their parental counterparts. Importantly, Reolysin also significantly increased the antilymphoma activity of belinostat in HDAC inhibitor–resistant cells. Our data demonstrate that Reolysin alone or in combination with belinostat is a novel therapeutic strategy to treat TCL patients who develop resistance to HDAC inhibitors.

LW-213 induces cell apoptosis in human cutaneous T-cell lymphomas by activating PERK-eIF2α-ATF4-CHOP axis.

Cutaneous T-cell lymphoma (CTCL) is characterized by a heterogeneous group of extranodal non-Hodgkin lymphomas, in which monoclonal T lymphocytes infiltrate the skin. LW-213, a derivative of wogonin, was found to induce cell apoptosis in chronic myeloid leukemia (CML). In this study, we investigated the effects of LW-213 on CTCL cells and the underlying mechanisms. We showed that LW-213 (1-25 μM) dose-dependently inhibited human CTCL cell lines (Hut-102, Hut-78, MyLa, and HH) with IC50 values of around 10 μM, meanwhile it potently inhibited primary leukemia cells derived from peripheral blood of T-cell lymphoma patients. We revealed that LW-213-induced apoptosis was accompanied by ROS formation and the release of calcium from endoplasmic reticulum (ER) through IP3R-1channel. LW-213 selectively activated CHOP and induced apoptosis in Hut-102 cells via activating PERK-eIF2α-ATF4 pathway. Interestingly, the degree of apoptosis and expression of ER stress-related proteins were alleviated in the presence of either N-acetyl cysteine (NAC), an ROS scavenger, or 2-aminoethyl diphenylborinate (2-APB), an IP3R-1 inhibitor, implicating ROS/calcium-dependent ER stress in LW-213-induced apoptosis. In NOD/SCID mice bearing Hut-102 cell line xenografts, administration of LW-213 (10 mg/kg, ip, every other day for 4 weeks) markedly inhibited the growth of Hut-102 derived xenografts and prolonged survival. In conclusion, our study provides a new insight into the mechanism of LW-213-induced apoptosis, suggesting the potential of LW-213 as a promising agent against CTCL.

Successful treatment of mogamulizumab-resistant mycosis fungoides with mogamulizumab plus etoposide combined therapy: Investigation of the immunomodulatory effects of etoposide on the tumor microenvironment.

Mogamulizumab shows cytotoxicity against CCR4+ lymphoma cells by antibody-dependent cell-mediated cytotoxicity (ADCC) in advanced cutaneous T-cell lymphoma (CTCL) patients. Although mogamulizumab is used as one of the anchor drugs for the treatment of advanced CTCL, its efficacy is unsatisfactory, especially in mycosis fungoides (MF). Therefore, additional drugs to enhance the antitumor effects of mogamulizumab are needed to further optimize its use for the treatment of MF. In this report, two cases of mogamulizumab-resistant MF successfully treated with additional administration of etoposide are presented. Moreover, the possible mechanisms of mogamulizumab-etoposide combined therapy for the treatment of MF were investigated based on the modulation of chemokine profiles in vivo using an EL-4 mouse T-cell lymphoma model. Intraperitoneal administration of etoposide significantly increased the mRNA expressions of CCL17, CXCL5, and CXCL10, suggesting that CCR4+ CTCL cells gather around the tumor-associated macrophagess. Furthermore, the immunomodulatory effects of etoposide on the mRNA expressions of these chemokines were validated using monocyte-derived M2 macrophages in vitro. Since mogamulizumab shows cytotoxicity against CCR4+ lymphoma cells by ADCC that depends on the contact between the lymphoma cells and the effector cells, these chemokines could enhance the therapeutic effect of mogamulizumab.

Ultrasensitive multiplex detection of structural rearrangements in ALK, RET, ROS1 and PD-L1 using a comprehensive next-generation sequencing assay.

3572 Background: Oncogenic structural rearrangements (SR) in ALK, RET and ROS1 are well-described in lung cancer, and confer sensitivity to targeted therapy. SR disrupting the 3’UTR of PD-L1 gene have been reported in multiple cancer types and can potentially predict response to checkpoint immunotherapy. An amplicon-based next-generation sequencing (NGS) platform technology (AmpliMARK), previously optimized for detection of single nucleotide variations (SNVs), microsatellite instability and viral DNA, was extended to the multiplex detection of SR in ALK, RET, ROS1 and PD-L1 in cell-free DNA (cfDNA) and tumor tissue DNA. Methods: A hybrid primer-extension and adapter-ligation based method allowing detection of SR in a fusion-partner agnostic manner was utilized for multiplex target capture of genomic regions of ALK, RET, ROS1 and PD-L1 SR. Analytical validation was performed using admixtures of fragmented genomic DNA from an ALK SR-positive cell line, commercial standards containing RET and ROS1 SR, and synthetic PD-L1 SR gene constructs. Clinical performance was assessed in cfDNA samples from lung cancer patients and tumor tissue DNA samples from natural killer(NK)/T-cell lymphoma patients. Results: Detection of SR could be achieved to an allele frequency detection limit of 0.5% with sensitivity of 89.5% and specificity of 100% in admixture samples mimicking cfDNA. In an unselected series of 374 lung cancer cases, actionable SR for ALK, RET and ROS1 were detected in cfDNA of 9 samples, for an overall detection rate of 2.4%, and 1.8% (3 out of 168) when restricted to treatment-naive lung cancer cases only. In 29 NK/T-cell lymphoma tumor tissue samples, 9 samples were positive for PD-L1 SR, which were orthogonally confirmed by whole-genome sequencing, targeted sequencing or Sanger sequencing for a concordance rate of 100% across all samples. For 1 NK/T-cell lymphoma tumor tissue sample where matched plasma was available, the same PD-L1 SR was also detected in cfDNA. Conclusions: We have demonstrated and validated a comprehensive amplicon-based NGS assay for ultrasensitive multiplex detection of structural rearrangements in ALK, RET, ROS1 and PD-L1 across both cfDNA and tumor tissue DNA in analytical and clinical contexts. Ongoing studies will further evaluate the performance and utility of this assay across a larger number of clinical samples for the detection of these SR as well as additional cancer-associated SR involving NTRK1/2/3, FGFR2/3 and TMPRSS2.

Prevalence and outcomes of pneumocystis pneumonia in patients with T-cell lymphoma.

e20057 Background: T-cell lymphomas (TCL) are a heterogeneous group of rare, but aggressive non-Hodgkin lymphomas. CD4+ and CD8+ T-cell function plays a vital role in the immunologic response to P.jirovecii infection. Our study aims to define the prevalence of Pneumocystis jirovecii pneumonia (PJP) in HIV-uninfected TCL patients. Methods: All patients at Mayo Clinic, Rochester MN diagnosed with TCL and a positive Pneumocystis PCR assay from either bronchoalveolar lavage (BAL) fluid or other respiratory specimens were identified from March 2005 until November 2019. Patients with TCL and a diagnosis of PJP made outside of our medical center were identified through Advanced Cohort Explorer, a query building tool. Results: A total of 922 patients with TCL were identified, and only 14 cases (1.5%) had confirmed PJP. In confirmed PJP cases, the median age of TCL diagnosis was 62 years (IQR 51-70 years), 79% were male, and the median number of chemotherapy lines was 1.5 (IQR of 1-3). Half of the cases (6/12) received CHOP as first-line of therapy, followed by CHOEP (25%, 3/12). The median time to PJP diagnosis relative to chemotherapy was 18 days (IQR 14-27 days). Peripheral TCL, not otherwise specified was the most common TCL, followed by angioimmunoblastic TCL, and CD30+ T-cell lymphoproliferative disorders (64%, 29% and 7%, respectively). The primary specimen type sampled for PJP diagnosis was BAL fluid (n = 9, 64%), followed by sputum (n = 3, 22%), induced sputum (n = 1, 7%), and transbronchial lung biopsy (n = 1, 7%). Three patients had a prior autologous stem cell transplant (ASCT), and all three cases had relapsed TCL one year after ASCT. 77% of cases received oral prednisone equivalents (median dose of 25 mg, IQR 20-40 mg) 30 days prior to PJP diagnosis. Two patients developed PJP despite anti- Pneumocystis prophylaxis with aerosolized pentamidine. At the time of PJP diagnosis, most patients had lymphopenia (88%, 8/9), and CD4+ T-cells measurement was obtained only in one patient (CD4+ of 100 cells/mL). 71% of the cases were treated with trimethoprim/sulfamethoxazole (TMP/SMX). After the initial PJP episode, 36% of the cases were transitioned to TMP/SMX for secondary prophylaxis. All cause 30-day and 90-day mortality was 7% and 29%, respectively. Mortality attributed to PJP was 7% (n = 1). Conclusions: In our TCL cohort, the occurrence of PJP was low. Primary prophylaxis should be individualized in this population.

Outcomes of GDPT (gemcitabine, cisplatin, prednisone,thalidomide) versus CHOP in newly diagnosed peripheral T-cell lymphoma patients.

8018 Background: Peripheral T-cell lymphoma(PTCL) is highly heterogeneous invasive NHL.There is no consensus standard treatment for it now. So outcomes of GDPT versus CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) in treating newly diagnosed PTCL were compared. Methods: An open-label prospective clinical trial with 153 newly diagnosed PTCL patients conducted between January 2010 and December 2018 was designed. Patients were randomly assigned to the GDPT group (77 cases) and CHOP group (76 cases). Patients in each group were further divided into four subgroups: PTCL-NOS, ALCL, AITL, and an other types, in accordance with pathological patterns. Based on expression of RRM1, TOP2A, TUBB3 and ERCC1, patients were divided into groups with high and low gene expression levels. Clinical characteristics, side effects, efficacy, PFS and OS were compared. Results: There were no significant differences in the basic clinical features or side effects between the GDPT and CHOP groups. The ORR of the GDPT group was better than that of the CHOP group (66.3%vs. 50.0%, P= 0.042), as was the CR rate (42.9% vs. 27.6%, P= 0.049). Patients in the GDPT group had a longer PFS and OS than the CHOP group. The 4-year PFS and OS rates in the GDPT group were both superior to those in the CHOP group (63.6% vs. 53.0% for PFS, P= 0.035; 66.8% vs. 53.6% for OS, P= 0.039).In the GDPT group, the difference in CR between the four subgroups was statistically significant (P = 0.046).In the CHOP group, differences in both CR and ORR among the four subgroups were statistically significant ( P= < 0.001 and P= 0.005, respectively).There were also statistically significant differences in CR between patients treated with CHOP and GDPT in the PTCL-NOS subgroup, AITL subgroup, and the other types subgroup( P= 0.015; P= 0.003; P= 0.005, respectively).The data also showed a significant difference in OS among the four subgroups within the GDPT group ( P= 0.001).The OS of AITL was shorter than that of the other three subgroups. Four subgroups of CHOP showed a significant difference in PFS ( P= 0.019). There was no statistical association between responses and the gene expression levels of RRM1, ERCC1, TUBB3 and TOP2A. Conclusions: The GDPT group had better response rates and prolonged the patients’ PFS and OS. As a promising new regimen, GDPT is expected to become the first-line therapy for PTCL. New agents should be applied to patients who do not achieve good responses with previous treatment, such as those diagnosed with angioimmunoblastic T cell lymphoma. Clinical trial information: NCT01664975 .

The Novel Role of Antibiotic Treatment in the Management of Cutaneous T-Cell Lymphoma (CTCL) Patients

The Novel Role of Antibiotic Treatment in the Management of Cutaneous T-Cell Lymphoma (CTCL) Patients

Outcomes of Patients with Transformed Mycosis Fungoides: Analysis from a Prospective Multicenter US Cohort Study

IntroductionWe examined patient characteristics, treatments, and outcomes of patients with transformed mycosis fungoides (tMF) from COMPLETE: a large, multicenter, prospective cohort study of peripheral T-cell lymphoma patients in the United States. MethodsPatients with tMF were enrolled in COMPLETE at the time of transformation. For this analysis, we identified patients with tMF with completed baseline, treatment, and follow-up records. Median survival was assessed using Kaplan-Meier methodology. ResultsOf the 499 patients enrolled in COMPLETE, 17 had tMF. Median age was 61; 53% were male, 9 had elevated lactate dehydrogenase, and 9 had lymph node involvement. Approximately one-quarter of the patients were African American and 47% had CD30+ disease. Median time to transformation was 53 months. All patients received systemic therapy, with 19% receiving concomitant radiotherapy. Most patients (87%) received single agents, including liposomal doxorubicin, pralatrexate, and gemcitabine. Eight patients (50%) had reported responses to therapy. Median survival was 18 months. One- and 2-year survival rates were 56% and 44%, respectively. ConclusionstMF often expresses CD30 and presents with lymph node involvement. Responses have been seen with single agents, but survival remains poor. Novel treatment approaches are urgently needed to improve outcomes.

PMD8 COST-EFFECTIVENESS OF EXTRACORPOREAL PHOTOPHERESIS FOR THE TREATMENT OF ERYTHRODERMIC (STAGE T4, MO) CUTANEOUS T-CELL LYMPHOMA PATIENTS IN THE AUSTRALIAN SETTING

The objective of this study was to assess the cost-effectiveness of extracorporeal photopheresis (ECP) compared with standard of care (SoC) therapy for the treatment of erythrodermic (stage T4, MO) cutaneous T-cell lymphoma (CTCL) patients, who are refractory to one or more systemic treatments. The perspective of the analysis was that of the Australian health care system.

Pralatrexate induced durable response in a relapsed/refractory peripheral T-cell lymphoma patient with a history of autologous stem cell transplantation: Case report of a patient followed-up over 3 years under pralatrexate treatment: Erratum.

Pralatrexate induced durable response in a relapsed/refractory peripheral T-cell lymphoma patient with a history of autologous stem cell transplantation: Case report of a patient followed-up over 3 years under pralatrexate treatment: Erratum.

Artemisinin improves the efficiency of anti-PD-L1 therapy in T-cell lymphoma

Abstract Although immune checkpoint inhibitors targeting PD-1/PD-L1 pathway have obtained favorable results in T-cell lymphoma clinical trials, the majority of T-cell lymphoma patients appear to be minimally sensitive to PD-1/PD-L1 blockade. The malaria drug artemisinin has previously been identified as a potent anti-lymphoma drug and was tested as a combination treatment with anti-PD-L1 antibody in T-cell lymphoma. In this study, we found that artemisinin caused ferroptosis by up-regulating ROS levels and increasing misfolded protein in T-cell lymphoma via down-regulating ERK pathway. As expected, artemisinin or anti-PD-L1 monoclonal antibody therapy alone could inhibit EL4 T-cell lymphoma growth in Balb/c nude mice. Interestingly, combination therapy with artemisinin greatly improved the anti-lymphoma efficiency of anti-PD-L1 monoclonal antibody. These results provide further rationale for the combination therapy of artemisinin with anti-PD-L1 antibody in preclinical settings. This work was supported by the National Natural Science Foundation of China (Grant 81501356 and Grant 81373112), the Shenzhen Basic Science Research Project (Grants JCYJ20170413153158716 and JCYJ20170818164619194), Nanshan pilot team project (LHTD20160004), Start-up funding (CYZZ20180307154657923), Guangdong Provincial Research Award for Thousand Talents Program Scholars.

The Th9 Axis Reduces the Oxidative Stress and Promotes the Survival of Malignant T Cells in Cutaneous T-Cell Lymphoma Patients.

Immune dysfunction is critical in pathogenesis of cutaneous T-cell lymphoma (CTCL). Few studies have reported abnormal cytokine profile and dysregulated T-cell functions during the onset and progression of certain types of lymphoma. However, the presence of IL9-producing Th9 cells and their role in tumor cell metabolism and survival remain unexplored. With this clinical study, we performed multidimensional blood endotyping of CTCL patients before and after standard photo/chemotherapy and revealed distinct immune hallmarks of the disease. Importantly, there was a higher frequency of "skin homing" Th9 cells in CTCL patients with early (T1 and T2) and advanced-stage disease (T3 and T4). However, advanced-stage CTCL patients had severely impaired frequency of skin-homing Th1 and Th17 cells, indicating attenuated immunity. Treatment of CTCL patients with standard photo/chemotherapy decreased the skin-homing Th9 cells and increased the Th1 and Th17 cells. Interestingly, T cells of CTCL patients express IL9 receptor (IL9R), and there was negligible IL9R expression on T cells of healthy donors. Mechanistically, IL9/IL9R interaction on CD3+ T cells of CTCL patients and Jurkat cells reduced oxidative stress, lactic acidosis, and apoptosis and ultimately increased their survival. In conclusion, coexpression of IL9 and IL9R on T cells in CTCL patients indicates the autocrine-positive feedback loop of Th9 axis in promoting the survival of malignant T cells by reducing the oxidative stress. IMPLICATIONS: The critical role of Th9 axis in CTCL pathogenesis indicates that strategies targeting Th9 cells might harbor significant potential in developing robust CTCL therapy.

Non-Hodgkin lymphoma after liver and kidney transplantation in children. Experience from one center.

Post-transplantation lymphoproliferative disorder (PTLD) is a complication of organ transplantation and a life-threatening condition. Children who underwent organ transplantation are at risk of developing lymphoproliferative disorders and, among them, non-Hodgkin lymphoma (NHL) is the most serious. The objective of this study was to describe the clinical course of NHL after liver and kidney transplantation. Retrospective analysis of medical records of children who underwent liver/kidney transplantation and developed NHL. Nine children were identified, all girls, 6 after liver and 3 after kidney transplantations. Age at transplantation ranged from 1 year to 13 years (median: 4 years), while age at lymphoma diagnosis from 4 to 17 years (median: 12 years). Time from transplantation to lymphoma diagnosis ranged from 7 months to 12 years (median: 9 years). All but 1 patient developed mature B-cell lymphoma, 4 children - diffuse large B-cell lymphoma (DLBCL), 2 children - Burkitt's lymphoma, 1 child - mature B-cell leukemia, 1 child - Burkitt-like lymphoma, while 1 patient was diagnosed with T-cell lymphoblastic lymphoma. High levels of Epstein-Barr virus (EBV) DNA were found in blood of 3 patients, and EBV in tissue samples was detected in 4 patients. Six patients presented with stage III and 2 with stage IV disease. Two patients had graft involvement. Three children received chemotherapy according to R-CHOP, 3 LMB protocol (2 with addition of rituximab), while 1 received CHOP and 5 courses of COP. T-cell lymphoma patient was treated with Euro-LB protocol. Six out of 8 treated patients are alive with a median follow-up of 6 years. Two children died from disease progression during treatment and 1 from cerebral herniation before starting therapy. All patients experienced at least 1 toxic episode of grade 3 and 4 according to Common Toxicity Criteria Adverse Event (CTCAE). Complications of chemotherapy were manageable and there were no transplanted organ failures. Our study provides further data on the treatment and outcome of monomorphic PTLD and indicates that it is feasible to treat solid organ recipients with multiagent chemotherapy.

Second neoplasm in cutaneous T-cell lymphoma patients: a marker of worse prognosis?

Epidemiologic studies have shown that cutaneous T-cell lymphoma (CTCL) patients have an increased risk of the development of a second neoplasm (SN). The aim of our study was to evaluate the risk of SN and to correlate any possible change in CTCL course after the diagnosis of a subsequent neoplasm. A ten-year retrospective study was carried out in two centers (Bologna and Florence) all the patients who developed a SN six months at least after a CTCL were included. Two groups were selected: group 1 featuring patients who developed a SN and group 2 characterized by patients affected by MF age and sex-matched with group 1 (control group). Data concerning any stage change after SN, time between MF and SN onset, modified Severity Weighted Assessment Tool (mSWAT) score before and after SN, concerning Group 1 and after a median time of 36 months in Group 2 were analyzed. Thirteen patients were detected. Before SN onset, early MF patients were mainly present, while SN cases in advanced stage (ten patients) were observed. SN type predominant was lung cancer, along with prostate and pancreatic cancer, while isolated cases presenting with vulvar, colon, mammalian, prostate cancer along with Hodgkin's Lymphoma. Mean mSWAT at MF diagnosis and after SN showed a significant difference (P value = 0.0037). After SN diagnosis, nine patients experienced an MF stage progression and ten patients died at follow-up. In all the instances, statistical analysis showed that mean mSWAT score before/after SN diagnosis had a significantly difference (P=0.0037) suggesting that patients with a SN may have a worse clinical outcome. By secreting immunosuppressive cytokines or recruiting immunosuppressive cells, a sort of mutual help between the two neoplasms may be prompted. Our data suggested that SN development in MF patients may be regarded as a worse prognostic marker.