Publications by authors named "Andrés J M Ferreri"

221 Publications

MYD88 L265P mutation and interleukin-10 detection in cerebrospinal fluid are highly specific discriminating markers in patients with primary central nervous system lymphoma: results from a prospective study.

Br J Haematol 2021 Feb 23. Epub 2021 Feb 23.

Pathology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Reliable biomarkers are needed to avoid diagnostic delay and its devastating effects in patients with primary central nervous system (CNS) lymphoma (PCNSL). We analysed the discriminating sensitivity and specificity of myeloid differentiation primary response (88) (MYD88) L265P mutation (mut-MYD88) and interleukin-10 (IL-10) in cerebrospinal fluid (CSF) of both patients with newly diagnosed (n = 36) and relapsed (n = 27) PCNSL and 162 controls (118 CNS disorders and 44 extra-CNS lymphomas). The concordance of MYD88 mutational status between tumour tissue and CSF sample and the source of ILs in PCNSL tissues were also investigated. Mut-MYD88 was assessed by TaqMan-based polymerase chain reaction. IL-6 and IL-10 messenger RNA (mRNA) was assessed on PCNSL biopsies using RNAscope technology. IL levels in CSF were assessed by enzyme-linked immunosorbent assay. Mut-MYD88 was detected in 15/17 (88%) PCNSL biopsies, with an 82% concordance in paired tissue-CSF samples. IL-10 mRNA was detected in lymphomatous B cells in most PCNSL; expression of IL-6 transcripts was negligible. In CSF samples, mut-MYD88 and high IL-10 levels were detected, respectively, in 72% and 88% of patients with newly diagnosed PCNSL and in 1% of controls; conversely, IL-6 showed a low discriminating sensitivity and specificity. Combined analysis of MYD88 and IL-10 exhibits a sensitivity and specificity to distinguish PCNSL of 94% and 98% respectively. Similar figures were recorded in patients with relapsed PCNSL. In conclusion, high detection rates of mut-MYD88 and IL-10 in CSF reflect, respectively, the MYD88 mutational status and synthesis of this IL in PCNSL tissue. These biomarkers exhibit a very high sensitivity and specificity in detecting PCNSL both at initial diagnosis and relapse. Implications of these findings in patients with lesions unsuitable for biopsy deserve to be investigated.
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http://dx.doi.org/10.1111/bjh.17357DOI Listing
February 2021

Consensus Recommendations for MRI and PET Imaging of Primary Central Nervous System Lymphoma: Guideline Statement from the International Primary CNS Lymphoma Collaborative Group (IPCG).

Neuro Oncol 2021 Feb 9. Epub 2021 Feb 9.

Department of Radiology, Neuroradiology Division, Mayo Clinic, Phoenix, AZ USA.

Advanced molecular and pathophysiologic characterization of Primary Central Nervous System Lymphoma (PCNSL) has revealed insights into promising targeted therapeutic approaches. Medical imaging plays a fundamental role in PCNSL diagnosis, staging, and response assessment. Institutional imaging variation and inconsistent clinical trial reporting diminishes the reliability and reproducibility of clinical response assessment. In this context, we aimed to: 1) critically review the use of advanced PET and MRI in the setting of PCNSL; 2) provide results from an international survey of clinical sites describing the current practices for routine and advanced imaging, and 3) provide biologically based recommendations from the International PCNSL Collaborative Group (IPCG) on adaptation of standardized imaging practices. The IPCG provides PET and MRI consensus recommendations built upon previous recommendations for standardized brain tumor imaging protocols (BTIP) in primary and metastatic disease. A biologically integrated approach is provided to addresses the unique challenges associated with the imaging assessment of PCNSL. Detailed imaging parameters facilitate the adoption of these recommendations by researchers and clinicians. To enhance clinical feasibility, we have developed both "ideal" and "minimum standard" protocols at 3T and 1.5T MR systems that will facilitate widespread adoption.
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http://dx.doi.org/10.1093/neuonc/noab020DOI Listing
February 2021

ALK-negative anaplastic large cell lymphoma: features and outcomes of 235 patients from the International T-Cell Project.

Blood Adv 2021 Feb;5(3):640-648

CHIMOMO Department and.

Anaplastic lymphoma kinase-negative anaplastic large cell lymphoma (ALK- ALCL) is an aggressive neoplasm of T-cell/null-cell lineage. The T-Cell Project is a global prospective cohort study that consecutively enrolled patients newly diagnosed with peripheral T-cell lymphoma, registered through a centralized computer database between September 2006 and February 2018. Of 1553 validated cases from 74 sites in 13 countries worldwide, 235 were reported as ALK- ALCL. The median age at diagnosis was 54 years (range, 18-89 years), with a male predominance (62%). Stage III to IV disease was identified in 71% of patients, bulky disease and bone marrow involvement were uncommon, and 66% of patients presented with a low (0-1) International Prognostic Index score. Of all treated patients, 85% received multiagent initial chemotherapy, and 8% were consolidated with autologous hematopoietic cell transplantation. The initial overall and complete response rates were 77% and 63%, respectively. After a median follow-up of 52 months (95% confidence interval [CI], 41-63), the median progression-free survival (PFS) and overall survival (OS) were 41 months (95% CI, 17-62) and 55 months (95% CI, 36-75), respectively. The 3- and 5-year PFS rates were 52% and 43%, and the 3- and 5-year OS rates were 60% and 49%. Treatments containing both anthracycline and etoposide were associated with superior OS (P = .05) but not PFS (P = .18). In this large prospective cohort study, outcomes comparable to those previously reported in the retrospective International Peripheral T-Cell Lymphoma Project were observed. The study underscores the need for introducing novel platforms for ALK- ALCL and establishes a benchmark for future clinical trials. This trial was registered at www.clinicaltrials.gov as #NCT01142674.
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http://dx.doi.org/10.1182/bloodadvances.2020001581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876884PMC
February 2021

MATRix-RICE therapy and autologous haematopoietic stem-cell transplantation in diffuse large B-cell lymphoma with secondary CNS involvement (MARIETTA): an international, single-arm, phase 2 trial.

Lancet Haematol 2021 Feb;8(2):e110-e121

Department of Haematology, University College Hospital, London, UK.

Background: Secondary CNS lymphoma is a rare but potentially lethal event in patients with diffuse large B-cell lymphoma. We aimed to assess the activity and safety of an intensive, CNS-directed chemoimmunotherapy consolidated by autologous haematopoietic stem-cell transplantation (HSCT) in patients with secondary CNS lymphoma.

Methods: This international, single-arm, phase 2 trial was done in 24 hospitals in Italy, the UK, the Netherlands, and Switzerland. Adults (aged 18-70 years) with histologically diagnosed diffuse large B-cell lymphoma and CNS involvement at the time of primary diagnosis or at relapse and Eastern Cooperative Oncology Group Performance Status of 3 or less were enrolled and received three courses of MATRix (rituximab 375 mg/m, intravenous infusion, day 0; methotrexate 3·5 g/m, the first 0·5 g/m in 15 min followed by 3 g/m in a 3 h intravenous infusion, day 1; cytarabine 2 g/m every 12 h, in 1 h intravenous infusions, days 2 and 3; thiotepa 30 mg/m, 30 min intravenous infusion, day 4) followed by three courses of RICE (rituximab 375 mg/m, day 1; etoposide 100 mg/m per day in 500-1000 mL over a 60 min intravenous infusion, days 1, 2, and 3; ifosfamide 5 g/m in 1000 mL in a 24 h intravenous infusion with mesna support, day 2; carboplatin area under the curve of 5 in 500 mL in a 1 h intravenous infusion, day 2) and carmustine-thiotepa and autologous HSCT (carmustine 400 mg/m in 500 mL glucose 5% solution in a 1-2 h infusion, day -6; thiotepa 5 mg/kg in saline solution in a 2 h infusion every 12 h, days -5 and -4). The primary endpoint was progression-free survival at 1 year. Overall and complete response rates before autologous HSCT, duration of response, overall survival, and safety were the secondary endpoints. Analyses were in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02329080. The trial ended after accrual completion; the database lock was Dec 31, 2019.

Findings: Between March 30, 2015, and Aug 3, 2018, 79 patients were enrolled. 75 patients were assessable. 319 (71%) of the 450 planned courses were delivered. At 1 year from enrolment the primary endpoint was met, 42 patients were progression free (progression-free survival 58%; 95% CI 55-61). 49 patients (65%; 95% CI 54-76) had an objective response after MATRix-RICE, 29 (39%) of whom had a complete response. 37 patients who responded had autologous HSCT. At the end of the programme, 46 patients (61%; 95% CI 51-71) had an objective response, with a median duration of objective response of 26 months (IQR 16-37). At a median follow-up of 29 months (IQR 20-40), 35 patients were progression-free and 33 were alive, with a 2-year overall survival of 46% (95% CI 39-53). Grade 3-4 toxicity was most commonly haematological: neutropenia in 46 (61%) of 75 patients, thrombocytopenia in 45 (60%), and anaemia in 26 (35%). 79 serious adverse events were recorded in 42 (56%) patients; four (5%) of those 79 were lethal due to sepsis caused by Gram-negative bacteria (treatment-related mortality 5%; 95% CI 0·07-9·93).

Interpretation: MATRix-RICE plus autologous HSCT was active in this population of patients with very poor prognosis, and had an acceptable toxicity profile.

Funding: Stand Up To Cancer Campaign for Cancer Research UK, the Swiss Cancer Research foundation, and the Swiss Cancer League.
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http://dx.doi.org/10.1016/S2352-3026(20)30366-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844712PMC
February 2021

Lenalidomide maintenance after autologous haematopoietic stem-cell transplantation in mantle cell lymphoma: results of a Fondazione Italiana Linfomi (FIL) multicentre, randomised, phase 3 trial.

Lancet Haematol 2021 Jan 22;8(1):e34-e44. Epub 2020 Dec 22.

Department of Translational and Precision Medicine, Sapienza University of Rome, Roma, Italy.

Background: Fit patients with mantle cell lymphoma aged 18-65 years are usually given cytarabine and rituximab-based induction regimens followed by autologous haematopoetic stem-cell transplantation (HSCT). We investigated whether post-autologous HSCT maintenance with lenalidomide improves progression-free survival in this population.

Methods: This open-label, randomised, multicentre, phase 3 trial was done at 49 haematology and oncology units in Italy and Portugal. Eligible patients had Ann Arbor stage III or IV treatment-naive mantle cell lymphoma (or stage II plus bulky disease [≥5 cm] or B symptoms), and had evidence of cyclin D1 overexpression or the translocation t(11;14)(q13;q32). Patients were aged 18-59 years with Eastern Cooperative Oncology Group (ECOG) performance status 0-3, or aged 60-65 years with ECOG 0-2. After an optional prephase with vincristine and steroids (intravenous vincristine 1·4 mg/m on day 1, oral prednisone 100 mg [total dose] on days 1-5), patients were given three courses of R-CHOP (21-day cycle, intravenous rituximab 375 mg/m on day 1; intravenous doxorubicin 50 mg/m, vincristine 1·4 mg/m, and cyclophosphamide 750 mg/m on day 2; oral prednisone 100 mg/m on day 2-6). Patients then received one cycle of high-dose CTX (intravenous cyclophosphamide 4 g/m on day 1, intravenous rituximab 375 mg/m on day 4). After restaging, patients received two cycles of R-HD-cytarabine (high-dose intravenous cytarabine 2 g/m every 12 h on days 1-3, intravenous rituximab 375 mg/m on days 4 and 10). Patients with complete remission or partial remission proceeded to autologous HSCT and responding patients (complete remission or partial remission) with haematological recovery were randomly assigned (1:1) to receive 24 courses of oral lenalidomide maintenance (15 mg per day for patients with platelets >100 × 10 cells per L or 10 mg per day for platelets 60-100 × 10 cells per L, days 1-21 every 28 days) for 24 months, or observation. The primary endpoint was progression-free survival, measured in the randomised population. This study is registered with EudraCT (2009-012807-25) and ClinicalTrials.gov (NCT02354313).

Findings: Between May 4, 2010, and Aug 24, 2015, 303 patients were screened for inclusion and 300 patients were enrolled (median age 57 years, IQR 51-62; 235 [78%] male). 95 patients were excluded before randomisation, mostly due to disease progression, adverse events, and inadequate recovery. 104 patients were randomly assigned to the lenalidomide maintenance group and 101 patients to the observation group. 11 (11%) of 104 patients assigned to lenalidomide did not start treatment (3 withdrew, 6 adverse events or protocol breach, 2 lost to follow-up). At a median follow-up of 38 months after randomisation (IQR 24-50), 3-year progression-free survival was 80% (95% CI 70-87) in the lenalidomide group versus 64% (53-73) in the observation group (log-rank test p=0·012; hazard ratio 0·51, 95% CI 0·30-0·87). 41 (39%) of 104 patients discontinued lenalidomide for reasons including death or progression. Treatment-related deaths were recorded in two (2%) of 93 patients in the lenalidomide group (1 pneumonia, 1 thrombotic thrombocytopenic purpura), and one (1%) of 101 in the observation group (pneumonia). 59 (63%) of 93 patients in the lenalidomide group had grade 3-4 haematological adverse events versus 12 (12%) of 101 patients in the observation group (p<0·0001). 29 (31%) of 93 patients in the lenalidomide group and eight (8%) of 101 patients in the observation group had grade 3-4 non-haematological adverse events (p<0·0001), of which infections were the most common.Serious adverse events were reported in 22 (24%) of 93 patients in the lenalidomide group and five (5%) of 101 patients in the observation group. Pneumonia and other infections were the most common serious adverse events.

Interpretation: Despite non-negligibile toxicity, lenalidomide after autologous HSCT improved progression-free survival in patients with mantle cell lymphoma, highlighting the role of maintenance in mantle cell lymphoma.

Funding: Fondazione Italiana Linfomi and Celgene.
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http://dx.doi.org/10.1016/S2352-3026(20)30358-6DOI Listing
January 2021

The neutrophil to lymphocyte ratio (NLR) and the presence of large nodal mass are independent predictors of early response: A subanalysis of the prospective phase II PET-2-adapted HD0607 trial.

Cancer Med 2020 Dec 6;9(23):8735-8746. Epub 2020 Nov 6.

Ematologia, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy.

Background: The neutrophil to lymphocyte ratio (NLR) and the lymphocyte to monocyte ratio (LMR) can reflect both the myeloid dysfunction and T-cell immune suppression and have prognostic significance.

Methods: In 771 newly diagnosed advanced-stage Hodgkin Lymphoma (HL) patients we evaluated the baseline values of NLR and LMR as predictors of clinical outcome. According to the multicenter prospective phase II GITIL-HD0607 trial, all patients received two ABVD courses and if PET-2 negative received four additional ABVD cycles while if PET-2-positive patients were randomized to either BEACOPP escalated (Be) plus BEACOPP baseline (Bb) (4 + 4 courses) or Be + Bb (4 + 4) and Rituximab. PET scans were centrally reviewed by an expert panel by Blinded Independent Central Review.

Results: Higher NLR and lower LMR were associated with a PET-2 positivity and failure to achieve long-term disease control, respectively. By univariate and multivariate analysis, large nodal mass (>7 cm), IPS ≥ 3, NLR > 6 were strong independent predictors of early PET-2 response after ABVD. Only NLR > 6 and IPS ≥ 3 were strong independent predictors of outcome at diagnosis; however, when PET-2 status was added, only PET-2-positive status and IPS ≥ 3 were independent predictors of PFS. Focusing on PET-2-negative patients, those with NLR > 6 had an inferior 3-year PFS compared to patients with NLR ≤ 6 (84% vs 89% months, P = .03).

Conclusion: In advanced-stage HL patients treated with a PET-2-driven strategy, IPS ≥ 3 and NLR > 6 are independent predictors of outcome at diagnosis while the presence of large nodal mass, IPS ≥ 3, and NLR > 6 at diagnosis are independent predictors of early ABVD response.
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http://dx.doi.org/10.1002/cam4.3396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724487PMC
December 2020

Aggressive B-cell Lymphoma with MYC/TP53 Dual Alterations Displays Distinct Clinicopathobiological Features and Response to Novel Targeted Agents.

Mol Cancer Res 2021 02 5;19(2):249-260. Epub 2020 Nov 5.

Duke University Medical Center, Division of Hematopathology and Department of Pathology, Durham, North Carolina.

Diffuse large B-cell lymphoma (DLBCL) is the major type of aggressive B-cell lymphoma. High-grade B-cell lymphoma (HGBCL) with / double-hit (DH) represents a distinct entity with dismal prognosis after standard immunochemotherapy in the current WHO lymphoma classification. However, whether mutation synergizes with MYC abnormalities ( rearrangement and/or Myc protein overexpression) contributing to HGBCL-like biology and prognosis is not well investigated. In this study, patients with DLBCL with MYC/TP53 abnormalities demonstrated poor clinical outcome, high-grade morphology, and distinct gene expression signatures. To identify more effective therapies for this distinctive DLBCL subset, novel MYC/TP53/BCL-2-targeted agents were investigated in DLBCL cells with MYC/TP53 dual alterations or HGBCL-/-DH. A BET inhibitor INCB057643 effectively inhibited cell viability and induced apoptosis in DLBCL/HGBCL cells regardless of // status. Combining INCB057643 with a MDM2-p53 inhibitor DS3032b significantly enhanced the cytotoxic effects in HGBCL-DH without mutation, while combining with the BCL-2 inhibitor venetoclax displayed potent therapeutic synergy in DLBCL/HGBCL cells with and without concurrent mutation. Reverse-phase protein arrays revealed the synergistic molecular actions by INCB057643, DS3032b and venetoclax to induce cell-cycle arrest and apoptosis and to inhibit AKT/MEK/ERK/mTOR pathways, as well as potential drug resistance mechanisms mediated by upregulation of Mcl-1 and RAS/RAF/MEK/ERK pathways. In summary, these findings support subclassification of DLBCL/HGBCL with dual MYC/TP53 alterations, which demonstrates distinct pathobiologic features and dismal survival with standard therapy, therefore requiring additional targeted therapies. IMPLICATIONS: The clinical and pharmacologic studies suggest recognizing DLBCL with concomitant mutation and MYC abnormalities as a distinctive entity necessary for precision oncology practice. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/19/2/249/F1.large.jpg.
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http://dx.doi.org/10.1158/1541-7786.MCR-20-0466DOI Listing
February 2021

XPO1 expression worsens the prognosis of unfavorable DLBCL that can be effectively targeted by selinexor in the absence of mutant p53.

J Hematol Oncol 2020 11 4;13(1):148. Epub 2020 Nov 4.

Division of Hematopathology, Department of Pathology, Duke University Medical Center, Durham, NC, 27710, USA.

The XPO1 inhibitor selinexor was recently approved in relapsed/refractory DLBCL patients but only demonstrated modest anti-DLBCL efficacy, prompting us to investigate the prognostic effect of XPO1 in DLBCL patients and the rational combination therapies in high-risk DLBCL. High XPO1 expression (XPO1) showed significant adverse prognostic impact in 544 studied DLBCL patients, especially in those with BCL2 overexpression. Therapeutic study in 30 DLBCL cell lines with various molecular and genetic background found robust cytotoxicity of selinexor, especially in cells with BCL2-rearranged (BCL2-R) DLBCL or high-grade B-cell lymphoma with MYC/BCL2 double-hit (HGBCL-DH). However, expression of mutant (Mut) p53 significantly reduced the cytotoxicity of selinexor in overall cell lines and the BCL2-R and HGBCL-DH subsets, consistent with the favorable impact of XPO1 observed in Mut-p53-expressing patients. The therapeutic effect of selinexor in HGBCL-DH cells was significantly enhanced when combined with a BET inhibitor INCB057643, overcoming the drug resistance in Mut-p53-expressing cells. Collectively, these data suggest that XPO1 worsens the survival of DLBCL patients with unfavorable prognostic factors such as BCL2 overexpression and double-hit, in line with the higher efficacy of selinexor demonstrated in BCL2-R DLBCL and HGBCL-DH cell lines. Expression of Mut-p53 confers resistance to selinexor treatment, which can be overcome by combined INCB057643 treatment in HGBCL-DH cells. This study provides insight into the XPO1 significance and selinexor efficacy in DLBCL, important for developing combination therapy for relapsed/refractory DLBCL and HGBCL-DH.
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http://dx.doi.org/10.1186/s13045-020-00982-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641823PMC
November 2020

A dose-dense short-term therapy for human immunodeficiency virus/acquired immunodeficiency syndrome patients with high-risk Burkitt lymphoma or high-grade B-cell lymphoma: safety and efficacy results of the "CARMEN" phase II trial.

Br J Haematol 2021 01 21;192(1):119-128. Epub 2020 Oct 21.

Division of Hematology, Ospedali Civili di Brescia, Brescia, Italy.

A few prospective trials in HIV-positive patients with Burkitt lymphoma (BL) or high-grade B-cell lymphoma (HGBL) have been reported. Investigated therapies have shown good efficacy but relevant safety problems, with high rates of interruptions, severe mucositis, septic complications, and fungal infections. Here, we report the results of a multicentre phase II trial addressing a new dose-dense, short-term therapy aimed at maintaining efficacy and improving tolerability. The experimental programme included a 36-day polychemotherapy induction followed by high-dose cytarabine-based consolidation and response-tailored BEAM (carmustine, etoposide, cyatarabine, and melphalan)- conditioned autologous stem cell transplantation (ASCT). This therapy would be considered active if ≥11 complete remissions (CR) after induction (primary endpoint) were recorded among 20 assessable patients. HIV-positive adults (median age 42, range 26-58; 16 males) with untreated BL (n = 16), HGBL (n = 3) or double-hit lymphoma (n = 1) were enrolled. All patients had high-risk features, with meningeal and bone marrow infiltration in five and nine patients respectively. The experimental programme was safe and active in a multicentre setting, with only two episodes of grade 4 non-haematological toxicity (hepatotoxicity and mucositis), and no cases of systemic fungal infections; two patients died of toxicity (bacterial infections). Response after induction (median duration: 47 days; interquartile range 41-54), was complete in 13 patients and partial in five [overall response rate = 90%; 95% confidence interval (CI) = 77-100]. All responders received consolidation, and five required autologous stem cell transplant. At a median follow-up of 55 (41-89) months, 14 patients are relapse-free and 15 are alive, with a five-year progression-free survival and an overall survival of 70% (95% CI = 60-80%) and 75% (95% CI = 66-84) respectively. No patient with cerebrospinal fluid (CSF)/meningeal lymphoma experienced central nervous system recurrence. With respect to previously reported regimens, this programme was delivered in a shorter period, and achieved the main goal of maintaining efficacy and improving tolerability.
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http://dx.doi.org/10.1111/bjh.17188DOI Listing
January 2021

Clinical Experience in a Large Cohort of Patients with Vitreoretinal Lymphoma in a Single Center.

Ocul Immunol Inflamm 2020 Aug 26:1-7. Epub 2020 Aug 26.

Department of Ophthalmology, IRCCS San Raffaele Scientific Institute , Milan, Italy.

Background/aims: To report our five-year experience on vitreoretinal lymphoma (VRL) as a single-center tertiary hospital.

Methods: The ophthalmic, cytopathology, and onco-hematologic records of patients with VRL consecutively seen from 2014 to 2019 were reviewed.

Results: Fifty-nine eyes of 31 patients with large B-cell VRL were included. Eighty-one percent has developed central nervous system lymphoma at the end of follow-up. Several different imaging findings were noted, including vitritis, leopard spot appearance, Bruch's membrane/RPE infiltrations, and ellipsoid zone disruption. A variable combination of MYD88-L265P mutation in the aqueous and/or in the vitreous and positive cytology/histology allowed to reach a definite diagnosis in all the patients. Therapies included intravitreal injections of methotrexate and rituximab, systemic chemotherapy, pan-encephalic radiotherapy, and hematopoietic stem cell transplantation.

Conclusion: No definite guidelines exist for VRL management. It is crucial to collect as much data as possible from tertiary referral hospitals, which suitably manage a conspicuous number of VRL patients.
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http://dx.doi.org/10.1080/09273948.2020.1787460DOI Listing
August 2020

NGR-TNF Engineering with an N-Terminal Serine Reduces Degradation and Post-Translational Modifications and Improves Its Tumor-Targeting Activity.

Mol Pharm 2020 10 3;17(10):3813-3824. Epub 2020 Sep 3.

Tumor Biology and Vascular Targeting Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy.

The therapeutic index of cytokines in cancer therapy can be increased by targeting strategies based on protein engineering with peptides containing the CNGRC (NGR) motif, a ligand that recognizes CD13-positive tumor vessels. We show here that the targeting domain of recombinant CNGRC-cytokine fusion proteins, such as NGR-TNF (a CNGRC-tumor necrosis factor-α (TNF) conjugate used in clinical studies) and NGR-EMAP-II, undergoes various post-translational modification and degradation reactions that lead to the formation of markedly heterogeneous products. These modifications include N-terminal cysteine acetylation or the formation of various asparagine degradation products, the latter owing to intramolecular interactions of the cysteine α-amino group with asparagine and/or its succinimide derivative. Blocking the cysteine α-amino group with a serine (SCNGRC) reduced both post-translational and degradation reactions. Furthermore, the serine residue reduced the asparagine deamidation rate to isoaspartate (another degradation product) and improved the affinity of NGR for CD13. Accordingly, genetic engineering of NGR-TNF with the N-terminal serine produced a more stable and homogeneous drug (called S-NGR-TNF) with improved antitumor activity in tumor-bearing mice, either when used alone or in combination with chemotherapy. In conclusion, the targeting domain of NGR-cytokine conjugates can undergo various untoward modification and degradation reactions, which can be markedly reduced by fusing a serine to the N-terminus. The SCNGRC peptide may represent a ligand for cytokine delivery to tumors more robust than conventional CNGRC. The S-NGR-TNF conjugate (more stable, homogeneous, and active than NGR-TNF) could be rapidly developed for clinical trials.
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http://dx.doi.org/10.1021/acs.molpharmaceut.0c00579DOI Listing
October 2020

Improving the antitumor activity of R-CHOP with NGR-hTNF in primary CNS lymphoma: final results of a phase 2 trial.

Blood Adv 2020 08;4(15):3648-3658

Università Vita-Salute San Raffaele, Milan, Italy.

Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the standard treatment of diffuse large B-cell lymphoma (DLBCL). Primary DLBCL of the central nervous system (CNS) (primary central nervous system lymphoma [PCNSL]) is an exception because of the low CNS bioavailability of related drugs. NGR-human tumor necrosis factor (NGR-hTNF) targets CD13+ vessels, enhances vascular permeability and CNS access of anticancer drugs, and provides the rationale for the treatment of PCNSL with R-CHOP. Herein, we report activity and safety of R-CHOP preceded by NGR-hTNF in patients with PCNSL relapsed/refractory to high-dose methotrexate-based chemotherapy enrolled in a phase 2 trial. Overall response rate (ORR) was the primary endpoint. A sample size of 28 patients was considered necessary to demonstrate improvement from 30% to 50% ORR. NGR-hTNF/R-CHOP would be declared active if ≥12 responses were recorded. Treatment was well tolerated; there were no cases of unexpected toxicities, dose reductions or interruptions. NGR-hTNF/R-CHOP was active, with confirmed tumor response in 21 patients (75%; 95% confidence interval, 59%-91%), which was complete in 11. Seventeen of the 21 patients with response to treatment received consolidation (ASCT, WBRT, and/or lenalidomide maintenance). At a median follow-up of 21 (range, 14-31) months, 5 patients remained relapse-free and 6 were alive. The activity of NGR-hTNF/R-CHOP is in line with the expression of CD13 in both pericytes and endothelial cells of tumor vessels. High plasma levels of chromogranin A, an NGR-hTNF inhibitor, were associated with proton pump inhibitor use and a lower remission rate, suggesting that these drugs should be avoided during TNF-based therapy. Further research on this innovative approach to CNS lymphomas is warranted. The trial was registered as EudraCT: 2014-001532-11.
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http://dx.doi.org/10.1182/bloodadvances.2020002270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7422104PMC
August 2020

Mantle cell lymphoma.

Crit Rev Oncol Hematol 2020 Sep 4;153:103038. Epub 2020 Jul 4.

Medizinische Klinik III der Universität München-Grosshadern, München, Germany.

MCL is a well-characterized generally aggressive lymphoma with a poor prognosis. However, patients with a more indolent disease have been reported in whom the initiation of therapy can be delayed without any consequence for the survival. In 2017 the World Health Organization updated the classification of MCL describing two main subtypes with specific molecular characteristics and clinical features, classical and indolent leukaemic nonnodal MCL. Recent research results suggested an improving outcome of this neoplasm. The addition of rituximab to conventional chemotherapy has increased overall response rates, but it did not improve overall survival compared to chemotherapy alone. The use of intensive frontline therapies including rituximab and consolidation with autologous stem cell transplantation ameliorated response rate and prolonged progression-free survival in young fit patients, but any impact on survival remains to be proven. Furthermore, the optimal timing, cytoreductive regimen and conditioning regimen, and the clinical implications of achieving a disease remission even at molecular level remain to be elucidated. The development of targeted therapies as the consequence of better understanding of pathogenetic pathways in MCL might improve the outcome of conventional chemotherapy and spare the toxicity of intense therapy in most patients. Cases not eligible for intensive regimens, may be considered for less demanding therapies, such as the combination of rituximab either with CHOP or with purine analogues, or bendamustine. Allogeneic SCT can be an effective option for relapsed disease in patients who are fit enough and have a compatible donor. Maintenance rituximab may be considered after response to immunochemotherapy as the first-line strategy in a wide range of patients. Finally, since the optimal approach to the management of MCL is still evolving, it is critical that these patients are enrolled in clinical trials to identify the better treatment options.
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http://dx.doi.org/10.1016/j.critrevonc.2020.103038DOI Listing
September 2020

A refined cell-of-origin classifier with targeted NGS and artificial intelligence shows robust predictive value in DLBCL.

Blood Adv 2020 07;4(14):3391-3404

Division of Hematopathology and Department of Pathology, Duke University Medical Center, Durham, NC.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous entity of B-cell lymphoma. Cell-of-origin (COO) classification of DLBCL is required in routine practice by the World Health Organization classification for biological and therapeutic insights. Genetic subtypes uncovered recently are based on distinct genetic alterations in DLBCL, which are different from the COO subtypes defined by gene expression signatures of normal B cells retained in DLBCL. We hypothesize that classifiers incorporating both genome-wide gene-expression and pathogenetic variables can improve the therapeutic significance of DLBCL classification. To develop such refined classifiers, we performed targeted RNA sequencing (RNA-Seq) with a commercially available next-generation sequencing (NGS) platform in a large cohort of 418 DLBCLs. Genetic and transcriptional data obtained by RNA-Seq in a single run were explored by state-of-the-art artificial intelligence (AI) to develop a NGS-COO classifier for COO assignment and NGS survival models for clinical outcome prediction. The NGS-COO model built through applying AI in the training set was robust, showing high concordance with COO classification by either Affymetrix GeneChip microarray or the NanoString Lymph2Cx assay in 2 validation sets. Although the NGS-COO model was not trained for clinical outcome, the activated B-cell-like compared with the germinal-center B-cell-like subtype had significantly poorer survival. The NGS survival models stratified 30% high-risk patients in the validation set with poor survival as in the training set. These results demonstrate that targeted RNA-Seq coupled with AI deep learning techniques provides reproducible, efficient, and affordable assays for clinical application. The clinical grade assays and NGS models integrating both genetic and transcriptional factors developed in this study may eventually support precision medicine in DLBCL.
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http://dx.doi.org/10.1182/bloodadvances.2020001949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391158PMC
July 2020

Prevention of CNS relapse in diffuse large B-cell lymphoma: common sense prevails where science fails.

Br J Haematol 2020 09 12;190(5):645-647. Epub 2020 May 12.

Lymphoma Unit, Department of Onco-Hematology, IRCCS San Raffaele Scientific Institute, Milano, Italy.

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http://dx.doi.org/10.1111/bjh.16719DOI Listing
September 2020

Long-lasting efficacy and safety of lenalidomide maintenance in patients with relapsed diffuse large B-cell lymphoma who are not eligible for or failed autologous transplantation.

Hematol Oncol 2020 Aug 5;38(3):257-265. Epub 2020 May 5.

Vita-Salute San Raffaele University, Milan, Italy.

We report final results of a phase II trial addressing efficacy and feasibility of lenalidomide maintenance in patients with chemosensitive relapse of diffuse large B-cell lymphoma (DLBCL) not eligible for or failed after autologous stem cell transplantation (ASCT). Patients with relapsed DLBCL who achieved at least a partial response to salvage chemoimmunotherapy were enrolled and treated with lenalidomide 25 mg/day for 21 of 28 days for 2 years or until progression or unacceptable toxicity. Primary endpoint was 1-year PFS. Forty-six of 48 enrolled patients were assessable. Most patients had IPI ≥2, advanced stage and extranodal disease before the salvage treatment that led to trial registration; 28 (61%) patients were older than 70 years. Lenalidomide was well tolerated. With the exception of neutropenia, grade-4 toxicities occurred in <1% of courses. Three patients died of complications during maintenance and three died due to second cancers at 32 to 64 months. There were 13 SAEs recorded in 12 patients; all these patients but two recovered. Lenalidomide was interrupted due to toxicity in other 6 patients, and 25 patients required dose reduction (transient in 21). At 1 year from registration, 31 patients were progression free. After a median follow-up of 65 (range 39-124) months, 22 patients remain progression free, with a 5-year PFS of 48% ± 7%. The duration of response to lenalidomide was longer than response to prior treatment in 30 (65%) patients. Benefit was observed both in de novo and transformed DLBCL, germinal-center-B-cell and nongerminal-center-B-cell subtypes. Twenty-six patients are alive (5-year OS 62% ± 7%). With the limitations of a nonrandomized design, these long-term results suggest that lenalidomide maintenance might bring benefit to patients with chemosensitive relapse of DLBCL not eligible for or failed after ASCT. Lenalidomide was associated with durable disease control and was well tolerated in this elderly population. Further investigations on immunomodulatory drugs as maintenance in these high-risk patients are warranted.
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http://dx.doi.org/10.1002/hon.2742DOI Listing
August 2020

Treatment of MALT lymphoma of the conjunctiva with intralesional rituximab supplemented with autologous serum.

Blood Adv 2020 03;4(6):1013-1019

Ophthalmology Unit, and.

Patients with indolent conjunctival lymphomas exhibit good prognosis, with exceptional cases of dissemination, and are suitable candidates for intralesional therapies. We report the first prospective phase 2 trial using intralesional rituximab supplemented with autologous serum in adults with relapsed/refractory indolent CD20+ lymphoma of the conjunctiva (NCT01514344). Patients received 4 weekly intralesional injections of rituximab, followed by 6 monthly injections; 500 μL of autologous serum was added to rituximab in patients with lymphoma unresponsive to weekly doses. Safety, activity, and antitumor effect of autologous serum were investigated. Twenty patients with mucosa-associated lymphoid tissue (MALT)-type lymphoma were enrolled. Tolerability was excellent, with only 3 mild local reactions. After weekly injections, 11 patients achieved tumor regression, 8 had stable disease, and 1 experienced progressive disease; 9 patients received autologous serum, with response improvement in 4 cases (3 complete responses, 1 partial response). At the end of treatment, 12 patients achieved a complete remission, and 1 achieved a partial response, with an overall response rate of 65% (95% confidence interval, 45-85). At a median follow-up of 42 months (range, 10-78), 12 patients remain relapse free, with 5-year progression-free survival and time-to-next-treatment rates of 59% ± 11% and 69% ± 11%, respectively. Three patients with local relapse were retreated with intralesional rituximab and serum; 2 achieved a complete response that lasted 25+ and 38+ months. Thus, intralesional rituximab is a safe and active therapy in patients with relapsed conjunctival MALT lymphoma. The addition of autologous serum improves response in some cases. Retreatment of local relapses can result in a second durable remission.
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http://dx.doi.org/10.1182/bloodadvances.2020001459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7094013PMC
March 2020

Patience and commitment needed to fight very rare tumours.

Lancet Oncol 2020 04 11;21(4):483-484. Epub 2020 Mar 11.

Lymphoma Unit, Department of Onco-Hematology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. Electronic address:

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http://dx.doi.org/10.1016/S1470-2045(20)30098-XDOI Listing
April 2020

Induction therapy with the MATRix regimen in patients with newly diagnosed primary diffuse large B-cell lymphoma of the central nervous system - an international study of feasibility and efficacy in routine clinical practice.

Br J Haematol 2020 06 29;189(5):879-887. Epub 2020 Jan 29.

Lymphoma Unit, Department of Onco-Hematology, IRCCS San Raffaele Scientific Institute, Milan, Italy.

The MATRix chemoimmunotherapy regimen is highly effective in patients with newly diagnosed primary diffuse large B-cell lymphoma of the central nervous system (PCNSL). However, nothing is known about its feasibility and efficacy in everyday practice, where patients are more often older/frailer than those enrolled in clinical trials. We conducted a retrospective study addressing tolerability/efficacy of MATRix in 156 consecutive patients with newly diagnosed PCNSL treated outside a clinical trial. Median age and ECOG Performance Status of considered patients were 62 years (range 28-78) and 2 (range 0-4). The overall response rate after MATRix was 79%. Nine (6%) treatment-related deaths were recorded. After a median follow-up of 27.4 months (95% confidence interval [CI] 24.4-31.9%), the two-year progression-free and overall survival were 56% (95% CI 48.4-64.9%) and 64.1% (95% CI 56.7-72.5%) respectively. Patients not eligible for the IELSG32 trial were treated with lower dose intensity and had substantially worse outcomes than those fulfilling inclusion criteria. This is the largest series of PCNSL patients treated with MATRix outside a trial and recapitulates the IELSG32 trial outcomes in the non-trial setting for patients who fit the trial criteria. These data underscore the feasibility and efficacy of MATRix as induction treatment for fit patients in routine practice.
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http://dx.doi.org/10.1111/bjh.16451DOI Listing
June 2020

A First-in-human Study of Tenalisib (RP6530), a Dual PI3K δ/γ Inhibitor, in Patients With Relapsed/Refractory Hematologic Malignancies: Results From the European Study.

Clin Lymphoma Myeloma Leuk 2020 02 23;20(2):78-86. Epub 2019 Oct 23.

Lymphoma Unit, Department of Onco-Hematology, IRCCS San Raffaele Scientific Institute, Milano, Italy.

Background: Tenalisib (RP6530) is a novel, highly specific, dual phosphoinositide-3 kinases (PI3K) δ/γ inhibitor with nano-molar potency.

Material And Methods: This was a phase I, open-label, 3 + 3 dose escalation, maximum tolerated dose determination study to evaluate the safety, pharmacokinetics, and efficacy of tenalisib in patients with relapsed/refractory hematologic malignancies. Tenalisib was administered orally twice/thrice daily in 28-day cycles with starting dose of 25 mg twice daily.

Results: Thirty-five patients were enrolled across 11 dose levels. No dose limiting toxicity was reported at any of the dose levels. The most common treatment-emergent adverse events irrespective of causality were asthenia and cough in 15 (43%) patients and pyrexia in 13 (37%) patients. The most frequently reported related treatment-emergent adverse events were diarrhea, nausea, and vomiting. Related grade 3/4 adverse events were limited to events of hypertriglyceridemia, neutropenia, and diarrhea. Pharmacokinetics showed rapid absorption. Based on maximum plasma concentration and area under the plasma-concentration time curve, dose proportionality was observed up to 400 mg dose. Of 31 patients included in the efficacy analysis, complete response was seen in 2 (7%) patients and partial response in 4 (13%) patients, with an overall response rate of 19% and a disease-control rate of 61%. The median duration of response was 5.7 months. Responders demonstrated a marked downregulation of phospho-AKT on C1D8.

Conclusion: Tenalisib demonstrated acceptable safety up to 1200 mg twice a day with no dose-limiting toxicities. Consistent clinical response was seen at doses 200 mg BID and above. Pharmacodynamics correlated well with clinical outcome. Further phase I/II studies are being undertaken to evaluate efficacy across different histologies.
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http://dx.doi.org/10.1016/j.clml.2019.10.013DOI Listing
February 2020

Immunoglobulin somatic hypermutation has clinical impact in DLBCL and potential implications for immune checkpoint blockade and neoantigen-based immunotherapies.

J Immunother Cancer 2019 10 22;7(1):272. Epub 2019 Oct 22.

Hematopathology Division, Department of Pathology, Duke University School of Medicine, Durham, NC, 27710, USA.

Background: Diffuse large B-cell lymphoma (DLBCL) harbors somatic hypermutation (SHM) in the immunoglobulin heavy chain and light chain variable region genes, IGHV and IGK/LV. Recent studies have revealed that IGV SHM creates neoantigens that activate T-cell responses against B-cell lymphoma.

Methods: To determine the clinical relevance of IGV SHM in DLBCL treated with standard immunochemotherapy, we performed next-generation sequencing of the immunoglobulin variable regions and complementarity determining region 3 (CDR3) for 378 patients with de novo DLBCL. The prognostic effects of IGV SHM and ongoing SHM or intra-clonal heterogeneity were analyzed in the training (192 patients), validation (186 patients), and overall DLBCL cohorts. To gain mechanistic insight, we analyzed the predicted IG-derived neoantigens' immunogenicity potential, determined by the major histocompatibility complex-binding affinity and the frequency-of-occurrence of T cell-exposed motifs (TCEMs) in a TCEM repertoire derived from human proteome, microbiome, and pathogen databases. Furthermore, IGV SHM was correlated with molecular characteristics of DLBCL and PD-1/L1 expression in the tumor microenvironment assessed by fluorescent multiplex immunohistochemistry.

Results: SHM was commonly found in IGHV and less frequently in IGK/LV. High levels of clonal IGHV SHM (SHM) were associated with prolonged overall survival in DLBCL patients, particularly those without BCL2 or MYC translocation. In contrast, long heavy chain CDR3 length, the presence of IGHV ongoing SHM in DLBCL, and high clonal IGK/LV SHM in germinal center B-cell-like (GCB)-DLBCL were associated with poor prognosis. These prognostic effects were significant in both the training and validation sets. By prediction, the SHM groups harbored more potentially immune-stimulatory neoantigens with high binding affinity and rare TCEMs. PD-1/L1 expression in CD8 T cells was significantly lower in IGHV SHM than in SHM patients with activated B-cell-like DLBCL, whereas PD-1 expression in CD4 T cells and PD-L1 expression in natural killer cells were higher in IGK/LV SHM than in SHM patients with GCB-DLBCL. PD-L1/L2 (9p24.1) amplification was associated with high IGHV SHM and ongoing SHM.

Conclusions: These results show for the first time that IGV SHM and ongoing SHM have prognostic effects in DLBCL and potential implications for PD-1/PD-L1 blockade and neoantigen-based immunotherapies.
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http://dx.doi.org/10.1186/s40425-019-0730-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6806565PMC
October 2019

Rituximab in primary central nervous system lymphoma-A systematic review and meta-analysis.

Hematol Oncol 2019 Dec 9;37(5):548-557. Epub 2019 Oct 9.

Department of Medical Oncology, University Hospital Basel and University of Basel, Basel, Switzerland.

The CD-20 antibody rituximab is a standard component of treatment of non-Hodgkin B-cell lymphomas, including diffuse large B-cell lymphoma (DLBCL). Primary DLBCL of the central nervous system, also called primary central nervous system lymphoma (PCNSL), is a DLBCL confined to the central nervous system. There has been debate whether intravenous rituximab accumulates sufficiently in the central nervous system to exert an effect. In this systematic review, we assess the benefits and harms of rituximab in the treatment of immunocompetent patients with PCNSL. By searching MEDLINE, CENTRAL, and ClincialTrials.gov up to March 2019, we identified randomized controlled trials (RCTs) investigating the effect of rituximab in patients with PCNSL. We extracted study characteristics and results, assessed risk of bias, performed trial-level random-effects meta-analyses, and graded the certainty of evidence. The protocol was registered with PROSPERO (CRD42019121965). Main outcomes were overall survival (time to death), progression-free survival (time to progression or death), quality of life, grades 3 and 4 toxicity, and treatment-related mortality. We included two RCTs with a total of 343 participants. Overall survival was not statistically significantly improved (HR 0.76; 95% CI, 0.52-1.12; low certainty), with 187 fewer to 39 more deaths after 2 years in 1000 treated patients. Low certainty of evidence indicated that rituximab improved progression-free survival (HR 0.65; 95% CI, 0.45-0.95), which translated into 137 fewer progressions or deaths after 2 years in 1000 treated patients (231 to 18 fewer). None of the RCTs provided data on quality of life. We found no evidence that rituximab increased grades 3 and 4 toxicity or treatment-related mortality (RR 0.53; 95% CI, 0.20-1.37; low certainty). Overall, the available evidence suggests with low certainty that rituximab in combination with methotrexate-based chemotherapy may improve progression-free survival in immunocompetent patients with newly diagnosed PCNSL, the pooled effect estimates did not show evidence for improvement of overall survival.
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http://dx.doi.org/10.1002/hon.2666DOI Listing
December 2019

R-CHOP preceded by blood-brain barrier permeabilization with engineered tumor necrosis factor-α in primary CNS lymphoma.

Blood 2019 07 22;134(3):252-262. Epub 2019 May 22.

Neuroradiology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Patients with primary central nervous system lymphoma (PCNSL) are treated with high-dose methotrexate-based chemotherapy, which requires hospitalization and extensive expertise to manage related toxicity. The use of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) could overcome these difficulties, but blood-brain barrier (BBB) penetration of related drugs is poor. Tumor necrosis factor-α coupled with NGR (NGR-hTNF), a peptide targeting CD13 vessels, induces endothelial permeabilization and improves tumor access of cytostatics. We tested the hypothesis that NGR-hTNF can break the BBB, thereby improving penetration and activity of R-CHOP in patients with relapsed/refractory PCNSL (NCT03536039). Patients received six R-CHOP21 courses, alone at the first course and preceded by NGR-hTNF (0.8 μg/m) afterward. This trial included 2 phases: an "explorative phase" addressing the effect of NGR-hTNF on drug pharmacokinetic parameters and on vessel permeability, assessed by dynamic contrast-enhanced magnetic resonance imaging and Tc-diethylene-triamine-pentacetic acid-single-photon emission computed tomography, and the expression of CD13 on tumor tissue; and an "expansion phase" with overall response rate as the primary end point, in which the 2-stage Simon Minimax design was used. At the first stage, if ≥4 responses were observed among 12 patients, the study accrual would have continued (sample size, 28). Herein, we report results of the explorative phase and the first-stage analysis (n = 12). CD13 was expressed in tumor vessels of all cases. NGR-hTNF selectively increased vascular permeability in tumoral/peritumoral areas, without interfering with drug plasma/cerebrospinal fluid concentrations. The NGR-hTNF/R-CHOP combination was well tolerated: there were only 2 serious adverse events, and grade 4 toxicity was almost exclusively hematological, which were resolved without dose reductions or interruptions. NGR-hTNF/R-CHOP was active, with 9 confirmed responses (75%; 95% confidence interval, 51-99), 8 of which were complete. In conclusion, NGR-hTNF/R-CHOP was safe in these heavily pretreated patients. NGR-hTNF enhanced vascular permeability specifically in tumoral/peritumoral areas, which resulted in fast and sustained responses.
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http://dx.doi.org/10.1182/blood.2019000633DOI Listing
July 2019

Short regimen of rituximab plus lenalidomide in follicular lymphoma patients in need of first-line therapy.

Blood 2019 07 17;134(4):353-362. Epub 2019 May 17.

Unit of Hematology, Department of Medicine at Huddinge, Karolinska Institutet, Stockholm, Sweden.

The SAKK 35/10 phase 2 trial, developed by the Swiss Group for Clinical Cancer Research and the Nordic Lymphoma Group, compared the activity of rituximab vs rituximab plus lenalidomide in untreated follicular lymphoma patients in need of systemic therapy. Patients were randomized to rituximab (375 mg/m IV on day 1 of weeks 1-4 and repeated during weeks 12-15 in responding patients) or rituximab (same schedule) in combination with lenalidomide (15 mg orally daily for 18 weeks). Primary end point was complete response (CR)/unconfirmed CR (CRu) rate at 6 months. In total, 77 patients were allocated to rituximab monotherapy and 77 to the combination (47% poor-risk Follicular Lymphoma International Prognostic Index score in each arm). A significantly higher CR/CRu rate at 6 months was documented in the combination arm by the investigators (36%; 95% confidence interval [CI], 26%-48% vs 25%; 95% CI, 16%-36%) and confirmed by an independent response review of computed tomography scans only (61%; 95% CI, 49%-72% vs 36%; 95% CI, 26%-48%). After a median follow-up of 4 years, significantly higher 30-month CR/CRu rates and longer progression-free survival (PFS) and time to next treatment (TTNT) were observed for the combination. Overall survival (OS) rates were similar in both arms (≥90%). Toxicity grade ≥3 was more common in the combination arm (56% vs 22% of patients), mainly represented by neutropenia (23% vs 7%). Addition of lenalidomide to rituximab significantly improved CR/CRu rates, PFS, and TTNT, with expected higher, but manageable toxicity. The excellent OS in both arms suggests that chemotherapy-free strategies should be further explored. This trial was registered at www.clinicaltrials.gov as #NCT01307605.
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http://dx.doi.org/10.1182/blood-2018-10-879643DOI Listing
July 2019

Targeted therapies make room, anti-CD79b agents are coming.

Lancet Oncol 2019 07 14;20(7):898-900. Epub 2019 May 14.

Lymphoma Unit, Department of Onco-Haematology, IRCCS San Raffaele Scientific Institute, Milan, Italy. Electronic address:

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http://dx.doi.org/10.1016/S1470-2045(19)30182-2DOI Listing
July 2019

Evolving Treatments for Primary Central Nervous System Lymphoma.

Am Soc Clin Oncol Educ Book 2019 Jan 17;39:454-466. Epub 2019 May 17.

4 University of California, San Francisco, CA.

Primary central nervous system (CNS) lymphoma (PCNSL) is an aggressive form of non-Hodgkin lymphoma that remains confined to the CNS neuroaxis during its natural history of disease and is therefore considered stage IE disease. PCNSL is diffuse large B-cell lymphoma (DLBCL) morphology in more than 95% of patients and is designated primary diffuse large B-cell lymphoma of the CNS on the basis of the 2017 World Health Organization classification of hematopoietic and lymphoid tumors. Rapidly evolving therapeutic paradigms have been linked to evidence of progress in PCNSL, a disease long considered to be incurable. Increasing evidence supports the need for efficient diagnosis, staging, and initiation of therapy, ideally at centers with experience with this type of brain cancer. High-dose methotrexate (MTX) remains a cornerstone of induction regimens, and most data support the use of rituximab. However, clinical research challenges must address key questions, including the development of ever more effective and less toxic induction regimens and the selection of the most appropriate and effective consolidation approaches, as well as the fact that, increasingly, PCNSL affects older patients who do not tolerate strong genotoxic irradiation or high-dose chemotherapy (HDC)-based strategies. Maintenance therapy, immunotherapy, and the implementation of targeted agents on the basis of the molecular and biologic properties of the disease create opportunities for precision medicine and the potential for long-term disease-free survival and cure, with minimal treatment-related neurotoxicity, for a greater fraction of patients.
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http://dx.doi.org/10.1200/EDBK_242547DOI Listing
January 2019

Immune Profiling and Quantitative Analysis Decipher the Clinical Role of Immune-Checkpoint Expression in the Tumor Immune Microenvironment of DLBCL.

Cancer Immunol Res 2019 04 11;7(4):644-657. Epub 2019 Feb 11.

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

PD-1/L1 and CTLA-4 blockade immunotherapies have been approved for 13 types of cancers and are being studied in diffuse large B-cell lymphoma (DLBCL), the most common aggressive B-cell lymphoma. However, whether both PD-1 and CTLA-4 checkpoints are active and clinically significant in DLBCL is unknown. Whether PD-1 ligands expressed by tumor cells or by the microenvironment of DLBCL are critical for the PD-1 immune checkpoint is unclear. We performed immunophenotypic profiling for 405 patients with DLBCL using a MultiOmyx immunofluorescence platform and simultaneously quantitated expression/coexpression of 13 immune markers to identify prognostic determinants. In both training and validation cohorts, results demonstrated a central role of the tumor immune microenvironment, and when its functionality was impaired by deficiency in tumor-infiltrating T cells and/or natural killer cells, high PD-1 expression (but not CTLA-4) on CD8 T cells, or PD-L1 expression on T cells and macrophages, patients had significantly poorer survival after rituximab-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) immunochemotherapy. In contrast, tumor-cell PD-L2 expression was associated with superior survival, as well as PD-L1CD20 cells proximal (indicates interaction) to PD-1 CD8 T cells in patients with low PD-1 percentage of CD8 T cells. Gene-expression profiling results suggested the reversibility of T-cell exhaustion in PD-1/PD-L1 patients with unfavorable prognosis and implication of /, and upregulation in the microenvironment dysfunction with PD-L1 expression. This study comprehensively characterized the DLBCL immune landscape, deciphered the differential roles of various checkpoint components in rituximab-CHOP resistance in DLBCL patients, and suggests targets for PD-1/PD-L1 blockade and combination immunotherapies.
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http://dx.doi.org/10.1158/2326-6066.CIR-18-0439DOI Listing
April 2019

Lymphomas associated with chronic hepatitis C virus infection: A prospective multicenter cohort study from the Rete Ematologica Lombarda (REL) clinical network.

Hematol Oncol 2019 Apr 22;37(2):160-167. Epub 2019 Feb 22.

Division of Hematology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

Chronic hepatitis C virus (HCV) infection is related with an increased risk of non-Hodgkin lymphomas (NHL). In indolent subtypes, regression of NHL was reported after HCV eradication with antiviral therapy (AT). In 2008 in Lombardy, a region of Northern Italy, the "Rete Ematologica Lombarda" (REL, Hematology Network of Lombardy-Lymphoma Workgroup) started a prospective multicenter observational cohort study on NHL associated with HCV infection, named "Registro Lombardo dei Linfomi HCV-positivi" ("Lombardy Registry of HCV-associated non-Hodgkin lymphomas"). Two hundred fifty patients with a first diagnosis of NHL associated with HCV infection were enrolled; also in our cohort, diffuse large B cell lymphoma (DLBCL) and marginal zone lymphoma (MZL) are the two most frequent HCV-associated lymphomas. Two thirds of patients had HCV-positivity detection before NHL; overall, NHL was diagnosed after a median time of 11 years since HCV survey. Our data on eradication of HCV infection were collected prior the recent introduction of the direct-acting antivirals (DAAs) therapy. Sixteen patients with indolent NHL treated with interferon-based AT as first line anti-lymphoma therapy, because of the absence of criteria for an immediate conventional treatment for lymphoma, had an overall response rate of 90%. After a median follow-up of 7 years, the overall survival (OS) was significantly longer in indolent NHL treated with AT as first line (P = 0.048); this confirms a favorable outcome in this subset. Liver toxicity was an important adverse event after a conventional treatment in 20% of all patients, in particular among DLBCL, in which it is more frequent the coexistence of a more advanced liver disease. Overall, HCV infection should be consider as an important co-pathology in the treatment of lymphomas and an interdisciplinary approach should be always considered, in particular to evaluate the presence of fibrosis or necroinflammatory liver disease.
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http://dx.doi.org/10.1002/hon.2575DOI Listing
April 2019

PD-1/PD-L1 expression and interaction by automated quantitative immunofluorescent analysis show adverse prognostic impact in patients with diffuse large B-cell lymphoma having T-cell infiltration: a study from the International DLBCL Consortium Program.

Mod Pathol 2019 06 21;32(6):741-754. Epub 2019 Jan 21.

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Programmed cell death protein 1/programmed cell death protein ligand1 (PD-1/PD-L1) interaction is an important immune checkpoint targeted by anti-PD-1/PD-L1 immunotherapies. However, the observed prognostic significance of PD-1/PD-L1 expression in diffuse large B-cell lymphoma treated with the standard of care has been inconsistent and even contradictory. To clarify the prognostic role of PD-1/PD-L1 expression and interaction in diffuse large B-cell lymphoma, in this study we used 3-marker fluorescent multiplex immunohistochemistry and Automated Quantitative Analysis Technology to assess the CD3, PD-L1, and PD-1CD3 expression in diagnostic samples and PD-1/PD-L1 interaction as indicated by presence of PD-1CD3 cells in the vicinity of PD-L1 cells, analyzed their prognostic effects in 414 patients with de novo diffuse large B-cell lymphoma, and examined whether PD-1/PD-L1 interaction is required for the prognostic role of PD-1/PD-L1 expression. We found that low T-cell tissue cellularity, tissue PD-L1 expression (irrespective of cell types), PD-1CD3 expression, and PD-1/PD-L1 interaction showed hierarchical adverse prognostic effects in the study cohort. PD-1/PD-L1 interaction showed higher sensitivity and specificity than PD-1 and PD-L1 expression in predicting inferior prognosis in patients with high CD3 tissue cellularity ("hot"/inflammatory tumors). However, both PD-1 and PD-L1 expression showed adverse prognostic effects independent of PD-1/PD-L1 interaction, and PD-1/PD-L1 interaction showed favorable prognostic effect in PD-L1 patients without high CD3 tissue cellularity. Macrophage function and tumor-cell MYC expression may contribute to the PD-1-independent adverse prognostic effect of PD-L1 expression. In summary, low T-cell tissue cellularity has unfavorable prognostic impact in diffuse large B-cell lymphoma, and tissue PD-L1 expression and T-cell-derived PD-1 expression have significant adverse impact only in patients with high T-cell infiltration. PD-1/PD-L1 interaction in tissue is essential but not always responsible for the inhibitory effect of PD-L1/PD-1 expression. These results suggest the benefit of PD-1/PD-L1 blockade therapies only in patients with sufficient T-cell infiltration, and the potential of immunofluorescent assays and Automated Quantitative Analysis in the clinical assessment of PD-1/PD-L1 expression and interaction.
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http://dx.doi.org/10.1038/s41379-018-0193-5DOI Listing
June 2019

Comprehensive approach to diagnosis and treatment of newly diagnosed primary CNS lymphoma.

Neuro Oncol 2019 02;21(3):296-305

Departments of Neurology and Radiation Oncology, Division of Hematology and Oncology, Boston, Massachusetts.

Primary central nervous system lymphoma (PCNSL) is a rare form of non-Hodgkin lymphoma that affects the brain parenchyma, spinal cord, eyes, and cerebrospinal fluid without evidence of systemic, non-CNS involvement. PCNSL is uncommon and only a few randomized trials have been completed in the first-line setting. Over the past decades, the prognosis of PCNSL has improved, mainly due to the introduction and widespread use of high-dose methotrexate, which is now the backbone of all first-line treatment polychemotherapy regimens. Despite this progress, durable remission is recorded in only 50% of patients, and therapy can be associated with significant late neurotoxicity. Here, we overview the epidemiology, clinical presentation, staging evaluation, prognosis, and current up-to-date treatment of immunocompetent PCNSL patients.
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http://dx.doi.org/10.1093/neuonc/noy192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6380418PMC
February 2019