The role of the programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) axis is well established in classical Hodgkin lymphoma (HL), where PD-1 blockade demonstrated spectacular efficacy in ...relapsed/refractory disease. However, little is known about the frequency and cellular distribution of other immune checkpoints in HL samples.
Using immunohistochemistry, we investigated, along with PD-L1 and PD-1, the expression of lymphocyte-activation gene 3 (LAG-3) and T-cell immunoglobulin and mucin-domain containing 3 (TIM-3) in 57 biopsy samples of patients with classical HL.
Hodgkin and Reed/Sternberg (HRS) cells were strongly positive for PD-L1 in nearly all cases. HRS cells were TIM-3 positive in 36% of samples, whereas LAG-3 was rarely expressed (5.2%). In the microenvironment, PD-1, LAG-3, and TIM-3 were expressed by ≥ 5% of cells in 65%, 98%, and 96% of cases, respectively. T-cell rosettes surrounding HRS cells consisted of CD4+ FoxP3− helper T cells expressing both PD-1 and LAG-3, with a variable expression of TIM-3.
This study demonstrates for the first time that LAG-3 and TIM-3 are nearly always expressed in the microenvironment of classical HL. This may constitute the basis for targeting LAG-3 or TIM-3 in combination with anti–PD-1 antibodies in the treatment of relapsed/refractory HL.
•Lymphocyte-activation gene 3 (LAG-3) and T-cell immunoglobulin and mucin-domain containing 3 (TIM-3) are nearly always expressed in the tumor microenvironment of classical Hodgkin lymphoma.•TIM-3 is expressed by Hodgkin and Reed/Sternberg cells in a third of the cases.
Programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) blocking agents are used in relapsed/refractory classical Hodgkin lymphoma (HL), while other immune checkpoints such as lymphocyte-activation gene 3 (LAG-3) and T-cell immunoglobulin and mucin-domain containing 3 (TIM-3) may also play a role. By performing immunohistochemistry on 57 biopsy samples, we found that TIM-3 was expressed by Hodgkin and Reed/Sternberg cells in 36% of the cases, and LAG-3 and TIM-3 were widely expressed in the tumor microenvironment. LAG-3 and TIM-3 may constitute therapeutic targets in the treatment of HL.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Around 30–50% of classical Hodgkin lymphoma (cHL) cases in immunocompetent individuals from industrialized countries are associated with the B-lymphotropic Epstein-Barr virus (EBV). Although natural ...killer (NK) cells exhibit anti-viral and anti-tumoral functions, virtually nothing is known about quantitative and qualitative differences in NK cells in patients with EBV+ cHL vs. EBV- cHL. Here, we prospectively investigated 36 cHL patients without known immune suppression or overt immunodeficiency at diagnosis. All 10 EBV+ cHL patients and 25 out 26 EBV- cHL were seropositive for EBV antibodies, and EBV+ cHL patients presented with higher plasma EBV DNA levels compared to EBV- cHL patients. We show that the CD56
dim
CD16
+
NK cell subset was decreased in frequency in EBV+ cHL patients compared to EBV- cHL patients. This quantitative deficiency translates into an impaired CD56
dim
NK cell mediated degranulation toward rituximab-coated HLA class 1 negative lymphoblastoid cells in EBV+ compared to EBV- cHL patients. We finally observed a trend to a decrease in the rituximab-associated degranulation and ADCC of in vitro expanded NK cells of EBV+ cHL compared to healthy controls. Our findings may impact on the design of adjunctive treatment targeting antibody-dependent cellular cytotoxicity in EBV+ cHL.
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EMUNI, FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OILJ, PNG, SAZU, SBCE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Despite that cytogenetic and molecular analysis of tumor cells can rapidly identify recurring molecular abnormalities, no personalized therapy is currently available in the setting of ...relapsed/refractory multiple myeloma (r/r MM).
MM-EP1 is a retrospective study aimed at comparing a personalized molecular-oriented (MO) versus a non-molecular-oriented (no-MO) approach in r/r MM. Actionable molecular targets and their associated therapies were the BRAF V600E mutation and BRAF inhibitors; t(11;14)(q13;q32) and BCL2 inhibitors; and t(4;14)(p16;q32) with FGFR3 fusion/rearrangements and FGFR3 inhibitors.
One hundred three highly pretreated r/r MM patients with a median age of 67 years (range 44-85) were included. Seventeen (17%) patients were treated using an MO approach with BRAF inhibitors (vemurafenib or dabrafenib,
= 6), BCL2 inhibitor (venetoclax,
= 9), or FGFR3 inhibitor (erdafitinib,
= 2). Eighty-six (86%) patients received non-MO therapies. Overall response rate was 65% in MO patients versus 58% in the non-MO group (
= 0.053). Median PFS and OS were 9 and 6 months (HR = 0.96; CI95 = 0.51-1.78;
= 0.88) and 26 and 28 months (HR = 0.98; CI95 = 0.46-2.12;
= 0.98), respectively, in MO and no-MO patients.
Despite the low number of patients treated with an MO approach, this study highlights the strengths and weakness of a molecular-targeted approach for the treatment of multiple myeloma. Widespread biomolecular techniques and improvement of precision medicine treatment algorithms could improve selection for precision medicine in myeloma.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The constitutive expression of CD70 has been described in various haematological and solid tumour types. In addition, the co-expression of its receptor in tumours has been demonstrated, mediating ...tumour cell proliferation. Although CD70 expression is a prerequisite to enrol patients in solid tumour clinical trials using anti-CD70 immunotherapy, there is currently no standardised test to evaluate CD70 expression. These differences in immunohistochemistry (IHC) protocols make it challenging to compare the expression levels that were obtained in different studies, pointing out the need for one uniform methodology. In this retrospective study, over 600 tumour samples from different solid and haematological malignancies were analysed while using one validated IHC method. CD70 and CD27 expression was demonstrated in a broad range of tumour types. In solid tumours, 43% demonstrated CD70 positivity with the highest degree in renal cell carcinoma (79.5%). Kaposi sarcoma showed no CD70 expression on the tumour cells. In lymphoma samples, 58% demonstrated CD70 positivity. Moreover, the co-expression of CD70 and CD27 was observed in 39% of lymphoma samples. These findings highlight the need to further explore anti-CD70 therapies in a broad range of CD70 expressing tumour types and in doing so, implementing one standardised protocol to define CD70 overexpression to use it as a diagnostic tool.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background: Resistance to anti-PD-1 remains a considerable clinical challenge for the treatment of patients with classical Hodgkin lymphoma (cHL), and mechanisms of anti-PD-1 resistance remain ...unknown. This pilot study aims to investigate the tumor microenvironment in patients with cHL relapsing after anti-PD-1. Methods: This study investigated tumor samples of eight patients with cHL, including four patients exposed to anti-PD-1 with a paired longitudinal histological analysis before and after anti-PD-1, and four patients not exposed to anti-PD-1 who served as control for the cellular biological investigations. Fresh cells tumor microenvironment analysis included phenotypic characterization of their T cell surfaces immune checkpoint markers PD-1, PD-L1, ICOS, TIM-3, LAG-3, 41-BB and BTLA. Tumor tissues immunohistochemistry staining included CD30, CD4, CD8, CD68, CD163, PD-L1, PD-1, LAG-3 and TIM-3. Findings: Paired longitudinal tumor tissues analysis in the tumor microenvironment found a CD8+ lymphocytes tumor depletion and an increase of LAG-3 staining after anti-PD-1 exposure. The fresh cells analysis of the tumor microenvironment in patients exposed to anti-PD-1 found CD8+ lymphocyte depletion, with an elevated CD4+/CD8+ lymphocytes ratio (median ratio 9.77 in exposed anti-PD-1 versus 2.39 in not-exposed anti-PD-1 patients; p = 0.0943). On the cell surfaces of CD4+ lymphocytes, the median positive expression of LAG-3 was significantly higher in the samples exposed to anti-PD-1 compared to the controls (15.05 IQR:17.91–10.65 versus 3.84 IQR 1.87–6.57; p = 0.0376). Interpretation: This pilot study proposes hypotheses for understanding the resistance to immunotherapies in patients with Hodgkin lymphoma. Hodgkin lymphoma exposed to anti-PD-1 correlated in tumor microenvironment with an immune depletion of CD8+ T lymphocytes and overexpression of LAG-3 on CD4+ helper T lymphocytes.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The most recent progress in the oncology field has led to a paradigm shift in the management of cancer with the tsunami of immune checkpoint inhibitors that are associated with a particular pattern ...of immunological adverse events. This is a case of a 54-year-old woman that demonstrated a granulomatous reaction in the same dermatomal distribution of a previously treated shingles infection during treatment with an anti-programmed death 1 agent (pembrolizumab) for a newly diagnosed stage IV Hodgkin lymphoma. The purpose of this case is to increase the awareness of oncologists dealing with a new pattern of side effects taking into account the patient's background and recent exposures to latent viruses such as herpes zoster to prevent unnecessary diagnostic and therapeutic measures.
According to World Health Organization (WHO) classification, presence of a plasma cell disorders (PCDs) should be investigate to avoid CNL misdiagnosis. ...serum G-CSF dosage could be the most ...powerful tool to make a prompt diagnosis of reactive neutrophilia to PCD which could have avoid, in our patient, inefficient therapy (as ruxolitinib), AHSCT morbidity, and donor-cell MDS. ...this report describes a correlated response to BD between PB neutrophils, spleen size, monoclonal component, and serum G-CSF level.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Purpose
In patients with indolent B‐cell non‐Hodgkin's lymphoma (B‐NHL), one course of low‐dose radiotherapy (LD‐RT) 2 × 2 Gy is emerging as new option of therapy in palliative setting. Efficacy of ...LD‐RT when repeated remains to be determinate. This study aims to assess the efficacy of repeated LD‐RT given in patients with indolent B‐NHL.
Materials and Methods
All consecutive adult patients who received two or more courses of LD‐RT 2 × 2 Gy for indolent B‐NHL at Gustave Roussy institution, during the period 1990‐2015 were retrospectively investigated.
Results
Thirty‐three patients received two or more courses of LD‐RT for indolent B‐NHL during the study period. The median age was 57 (range 37‐80) years, histological types were distributed among follicular lymphoma (n = 24 pts; 73%), marginal‐zone lymphoma (n = 6 pts; 18%), and primary cutaneous follicle center lymphoma (n = 3 pts; 9%). The median number of low‐dose radiation therapy courses given per patients was 2 (range 2‐6). The overall response rates following the first and the second course of LD‐RT were 96% and 88%, respectively (P = .31). The 1‐ and 2‐years local control rates following the first courses of LD‐RT were 94% (CI 95: 86‐100) and 94% (CI 95: 86‐98); and were 91% (CI 95: 82‐100) and 88% (CI 95: 77‐100) following the second course of LD‐RT (P = .39).
Conclusion
The repeated courses of LD‐RT offered similar efficacy compare with the first course in patients with indolent B‐NHL. LD‐RT repeated is a simple, easy to give, and non‐toxic asset that could be investigated as treatment option in patients with indolent B‐NHL.
Low dose radiotherapy is a valuable and non‐toxic treatment option in the form of indolent lymphoma. The effectiveness of low‐dose radiotherapy is similarly maintained when repeated once or even twice (RT1, RT2 and RT3).
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Investigational drugs for T-cell lymphoma Ghez, David; Danu, Alina; Ribrag, Vincent
Expert opinion on investigational drugs,
02/2016, Volume:
25, Issue:
2
Journal Article
Peer reviewed
Introduction: Peripheral T-cell lymphomas (PTCL) represent a heterogeneous group of malignancies frequently associated with a poor outcome. The frontline treatment strategy for PTCL relies mostly on ...CHOP or CHOP-like regimens, which are associated with a high failure rate and frequent relapses.
Areas covered: In this review, the authors present recently registered drugs and their positioning in the therapeutic armamentarium against PTCL and new drugs currently in development. The successful results in CD30-positive anaplastic large cell lymphomas suggest that a better characterization of these lymphomas could open new areas of efficient drug development.
Expert opinion: Advances in the field of molecular biology have started to unravel the anomalies associated with T-cell malignancies. Recent knowledge on potential epigenetic modifiers like IDH2, which is frequently mutated in angioimmunoblastic T-cell lymphoma, opens new areas of research and confirms that epigenetic drugs could represent an attractive area of clinical research. The recently developed immune checkpoints regulators might represent another area of potential interest.
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