Molecular diagnosis of primary CNS lymphoma in 2024 using MYD88Leu265Pro and IL-10.

Early diagnosis is crucial for the successful treatment of primary CNS lymphoma (PCNSL), a rapidly progressing tumour. Suspicion raised on brain MRI must be confirmed by a histopathological diagnosis of a tumour specimen collected by stereotactic biopsy. In rare cases, cerebrospinal fluid (CSF) or vitreous humour might aid in providing a cytological diagnosis. Several disease-related, patient-related, and treatment-related factors affect the timing and accuracy of diagnosis and patient outcome. Some molecules detected in CSF, aqueous and vitreous humour, and peripheral blood were proposed as diagnostic biomarkers for PCNSL; however, detection methods for most of these molecules are not yet standardised, have a long turnaround time, are expensive, and have little reproducibility among labs. By contrast, the MYD88Leu265Pro somatic hotspot mutation, revealed by PCR-based assay, is currently and reliably used during the diagnosis of some lymphomas, and IL-10, measured by enzyme-linked immunosorbent assay, is routinely used to diagnose and monitor different common metabolic and immunological diseases. Several independent studies have shown that MYD88Leu265Pro and IL-10 can be easily assessed in peripheral blood, plasma, aqueous and vitreous humour, and CSF of patients with PCNSL with substantial sensitivity and specificity, especially when evaluated in combination. In this Viewpoint, evidence supporting the routine use of MYD88Leu265Pro and IL-10 in diagnosing PCNSL is considered, and some examples of the frequent difficulties found in the diagnosis of PCNSL are provided, highlighting the role and indications of these two biomarkers to improve the timely recognition of this aggressive tumour.

Local radiotherapy and measurable residual disease-driven immunotherapy in patients with early-stage follicular lymphoma (FIL MIRO): final results of a prospective, multicentre, phase 2 trial.

BACKGROUND: The mainstay of treatment for early-stage follicular lymphoma is local radiotherapy, with a possible role for anti-CD20 monoclonal antibody (mAb). We aimed to evaluate the effect of these treatments using a measurable residual disease (MRD)-driven approach. METHODS: This prospective, multicentre, phase 2 trial was conducted at 27 centres of the Fondazione Italiana Linfomi (FIL) in Italy. Eligible participants were adults (≥18 years) with newly diagnosed, histologically confirmed follicular lymphoma (stage I or II; grade I-IIIa). Patients were initially treated with 24 Gy involved-field radiotherapy over 12 days; those who were MRD-positive after radiotherapy or during follow-up received eight intravenous doses (1000 mg per dose; one dose per week) of the anti-CD20 mAb ofatumumab. The primary endpoint was the proportion of patients who were MRD-positive after involved-field radiotherapy and became MRD-negative after ofatumumab treatment. Patients were included in the primary endpoint analysis population if they were positive for BCL2::IGH rearrangement at enrolment in peripheral blood or bone marrow samples. MRD positivity was defined as the persistence of BCL2::IGH rearrangement in peripheral blood or bone marrow, assessed centrally by laboratories of the FIL MRD Network. The trial was registered with EudraCT, 2012-001676-11. FINDINGS: Between May 2, 2015, and June 1, 2018, we enrolled 110 participants, of whom 106 (96%) were eligible and received involved-field radiotherapy. Of these, 105 (99%) were White, one (1%) was Black, 50 (47%) were male, and 56 (53%) were female. Of 105 participants in whom BCL2::IGH status was evaluable, 32 (30%) had a detectable BCL2::IGH rearrangement at baseline. After radiotherapy, 12 (40%) of 30 patients reached MRD-negative status, which was long-lasting (at least 36 or 42 months) in three (25%). In those who were MRD-positive after radiotherapy, ofatumumab induced MRD-negativity in 23 (92%; 95% CI 74-99) of 25 evaluable patients. After a median follow-up of 46·1 months (IQR 42·8-50·8), 14 (61%) of these 23 patients remain in complete response and are MRD-negative. The most common grade 3-4 adverse events were infusion-related reactions, observed in four patients. INTERPRETATION: Local radiotherapy is frequently not associated with the eradication of follicular lymphoma. An MRD-driven, anti-CD20 monoclonal antibody consolidation enables molecular remission to be reached in almost all patients and is associated with a reduced incidence of relapse over time. A clinical advantage of an MRD-driven consolidation is therefore suggested. FUNDING: AIRC Foundation for Cancer Research in Italy, Novartis International, and GlaxoSmithKline.

Germinal Center Dark Zone harbors ATR-dependent determinants of T-cell exclusion that are also identified in aggressive lymphoma.

The germinal center (GC) dark zone (DZ) and light zone (LZ) regions spatially separate expansion and diversification from selection of antigen-specific B-cells to ensure antibody affinity maturation and B cell memory. The DZ and LZ differ significantly in their immune composition despite the lack of a physical barrier, yet the determinants of this polarization are poorly understood. This study provides novel insights into signals controlling asymmetric T-cell distribution between DZ and LZ regions. We identify spatially-resolved DNA damage response and chromatin compaction molecular features that underlie DZ T-cell exclusion. The DZ spatial transcriptional signature linked to T-cell immune evasion clustered aggressive Diffuse Large B-cell Lymphomas (DLBCL) for differential T cell infiltration. We reveal the dependence of the DZ transcriptional core signature on the ATR kinase and dissect its role in restraining inflammatory responses contributing to establishing an immune-repulsive imprint in DLBCL. These insights may guide ATR-focused treatment strategies bolstering immunotherapy in tumors marked by DZ transcriptional and chromatin-associated features.

Marginal zone lymphoma international prognostic index: a unifying prognostic index for marginal zone lymphomas requiring systemic treatment.

Background: Marginal zone lymphomas (MZL), comprised of three unique but related subtypes, lack a unifying prognostic score applicable to all the patients in need for systemic chemotherapy and/or immunotherapy. Methods: Patients from the prospective NF10 study (NCT02904577) with newly diagnosed MZL and receiving frontline systemic therapy at diagnosis or after observation were used to train a prognostic model. The primary endpoint was progression-free survival (PFS) from start of treatment. The model was externally validated in a pooled analysis of two independent cohorts from the University of Iowa and Mayo Clinic Molecular Epidemiology Resource and the University of Miami. Findings: We identified 501 eligible patients. After multivariable modeling, lactate dehydrogenase (LDH) above upper normal limit, hemoglobin <12 g/dL, absolute lymphocyte count <1 × 109/L, platelets <100 × 109/L, and MZL subtype (nodal or disseminated) were independently associated with inferior PFS. The proposed MZL International Prognostic index (MZL-IPI) combined these 5 factors, and we defined low (LRG, 0 factors, 27%), intermediate (IRG, 1-2 factors, 57%) and high (HRG, 3+ factors, 16%) risk groups with 5-y PFS of 85%, 66%, and 37%, respectively (c-Harrell = 0.64). Compared to the LRG, the IRG (Hazard Ratio [HR] = 2.30, 95% CI 1.39-3.80) and HRG (HR = 5.41, 95% CI 3.12-9.38) had inferior PFS. Applying the MZL-IPI to the pooled US cohort (N = 353), 94 (27%), 192 (54%), and 67 (19%) patients were classified as LRG, IRG, and HRG, respectively, and the model was validated for PFS (log-rank test p = 0.0018; c-Harrell = 0.578, 95% CI 0.54-0.62). The MZL-IPI was also prognostic for OS in both the training and the external validation sets. Interpretation: MZL-IPI is a new prognostic score for use in all patients with MZL considered for systemic treatment. Funding: The MER was supported by P50 CA97274 and U01 CA195568.

Targets and treatments in primary CNS lymphoma.

Primary central nervous system lymphoma (PCNSL) is a rare and highly aggressive lymphoma entirely localized in the central nervous system or vitreoretinal space. PCNSL generally initially responds to methotrexate-containing chemotherapy regimens, but progressive or relapsing disease is common, and the prognosis is poor for relapsed or refractory (R/R) patients. PCNSL is often characterized by activation of nuclear factor kappa B (NF-κB) due to mutations in the B-cell receptor (BCR) or toll-like receptor (TLR) pathways, as well as immune evasion. Targeted treatments that inhibit key PCNSL mechanisms and pathways are being evaluated; inhibition of Bruton's tyrosine kinase (BTK) downstream of BCR activation has demonstrated promising results in treating R/R disease. This review will summarize the evidence and potential for targeted therapeutic agents to improve treatment outcomes in PCNSL. This includes immunotherapeutic and immunomodulatory approaches and inhibitors of the key pathways driving PCNSL, such as aberrant BCR and TLR signaling.

Liquid biopsy for improving diagnosis and monitoring of CNS lymphomas: A RANO review.

BACKGROUND: The utility of liquid biopsies is well documented in several extracranial and intracranial (brain/leptomeningeal metastases, gliomas) tumors. METHODS: The RANO (Response Assessment in Neuro-Oncology) group has set up a multidisciplinary Task Force to critically review the role of blood and cerebrospinal fluid (CSF)-liquid biopsy in CNS lymphomas, with a main focus on primary central nervous system lymphomas (PCNSL). RESULTS: Several clinical applications are suggested: diagnosis of PCNSL in critical settings (elderly or frail patients, deep locations, and steroid responsiveness), definition of minimal residual disease, early indication of tumor response or relapse following treatments, and prediction of outcome. CONCLUSIONS: Thus far, no clinically validated circulating biomarkers for managing both primary and secondary CNS lymphomas exist. There is need of standardization of biofluid collection, choice of analytes, and type of technique to perform the molecular analysis. The various assays should be evaluated through well-organized central testing within clinical trials.

Axicabtagene ciloleucel treatment is more effective in primary mediastinal large B-cell lymphomas than in diffuse large B-cell lymphomas: the Italian CART-SIE study.

Axicabtagene ciloleucel showed efficacy for relapsed/refractory large B-cell lymphomas (LBCL), including primary mediastinal B-cell lymphomas (PMBCL); however, only few PMBCLs were reported. Aim was to evaluate efficacy and safety of axicabtagene ciloleucel in patients with PMBCL compared to those with other LBCL, enrolled in the Italian prospective observational CART-SIE study. PMBCLs (n = 70) were younger, with higher percentage of bulky and refractory disease, compared to other LBCLs (n = 190). Median follow-up time for infused patients was 12.17 months (IQR 5.53,22.73). The overall (complete + partial) response rate (ORR,CR + PR) after bridging was 41% for PMBCL and 28% for other LBCL, p = 0.0102. Thirty days ORR was 78% (53/68) with 50% (34) CR in PMBCL, and 75% (141/187) with 53% (100) CR in other LBCL, p = 0.5457. Ninety days ORR was 69% (45/65) with 65% (42) CR in PMBCL, and 54% (87/162) with 47% (76) CR in other LBCL; progressive disease was 21% in PMBCL and 45% in other LBCL, p = 0.0336. Twelve months progression-free survival was 62% (95% CI: 51-75) in PMBCL versus 48% (95% CI: 41-57) in other LBCL, p = 0.0386. Twelve months overall survival was 86% (95% CI: 78-95) in PMBCL versus 71% (95% CI: 64-79) in other LBCL, p = 0.0034. All grade cytokine release syndrome was 88% (228/260); all grade neurotoxicity was 34% (88/260), with 6% of fatal events in PMBCL. Non-relapse mortality was 3%. In conclusion, PMBCLs achieved significantly better response and survival rates than other LBCLs.

IELSG30 phase 2 trial: intravenous and intrathecal CNS prophylaxis in primary testicular diffuse large B-cell lymphoma.

ABSTRACT: Primary testicular diffuse large B-cell lymphoma (PTL) is characterized by high risk of contralateral testis and central nervous system (CNS) relapse. Chemoimmunotherapy with intrathecal (IT) CNS prophylaxis and contralateral testis irradiation eliminates contralateral recurrences and reduces CNS relapses. The IELSG30 phase 2 study investigated feasibility and activity of an intensified IT and IV CNS prophylaxis. Patients with stage I/II PTL who had not received treatment received 2 cycles of IV high-dose methotrexate (MTX) (1.5 g/m2) after 6 cycles of the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, every 21 days). IT liposomal cytarabine was administered on day 0 of cycles 2 to 5 of 21-day R-CHOP regimen. Contralateral testis radiotherapy (25-30 Gy) was recommended. Fifty-four patients (median age: 66 years) with stage I (n = 32) or II (n = 22) disease were treated with R-CHOP, 53 received at least 3 doses of IT cytarabine, 48 received at least 1 dose of IV MTX, and 50 received prophylactic radiotherapy. No unexpected toxicity occurred. At a median follow-up of 6 years, there was no CNS relapse; 7 patients progressed, and 8 died, with 5-year progression-free and overall survival rates of 91% (95% confidence interval [CI], 79-96) and 92% (95% CI, 81-97), respectively. Extranodal recurrence was documented in 6 patients (in 2 without nodal involvement). In 4 cases, the relapse occurred >6 years after treatment. Causes of death were lymphoma (n = 4), second primary malignancy (n = 1), cerebral vasculopathy (n = 1), unknown (n = 2). Intensive prophylaxis was feasible and effective in preventing CNS relapses. Late relapses, mainly at extranodal sites, represented the most relevant pattern of failure. This trial was registered at www.clinicaltrials.gov as #NCT00945724.

Durable response after tisagenlecleucel in adults with relapsed/refractory follicular lymphoma: ELARA trial update.

ABSTRACT: Tisagenlecleucel is approved for adults with relapsed/refractory (r/r) follicular lymphoma (FL) in the third- or later-line setting. The primary analysis (median follow-up, 17 months) of the phase 2 ELARA trial reported high response rates and excellent safety profile in patients with extensively pretreated r/r FL. Here, we report longer-term efficacy, safety, pharmacokinetic, and exploratory biomarker analyses after median follow-up of 29 months (interquartile range, 22.2-37.7). As of 29 March 2022, 97 patients with r/r FL (grades 1-3A) received tisagenlecleucel infusion (0.6 × 108-6 × 108 chimeric antigen receptor-positive viable T cells). Bridging chemotherapy was allowed. Baseline clinical factors, tumor microenvironment, blood soluble factors, and circulating blood cells were correlated with clinical response. Cellular kinetics were assessed by quantitative polymerase chain reaction. Median progression-free survival (PFS), duration of response (DOR), and overall survival (OS) were not reached. Estimated 24-month PFS, DOR, and OS rates in all patients were 57.4% (95% confidence interval [CI], 46.2-67), 66.4% (95% CI, 54.3-76), and 87.7% (95% CI, 78.3-93.2), respectively. Complete response rate and overall response rate were 68.1% (95% CI, 57.7-77.3) and 86.2% (95% CI, 77.5-92.4), respectively. No new safety signals or treatment-related deaths were reported. Low levels of tumor-infiltrating LAG3+CD3+ exhausted T cells and higher baseline levels of naïve CD8+ T cells were associated with improved outcomes. Tisagenlecleucel continued to demonstrate highly durable efficacy and a favorable safety profile in this extended follow-up of 29 months in patients with r/r FL enrolled in ELARA. This trial was registered at www.clinicaltrials.gov as #NCT03568461.

MYC rearrangements in HIV-associated large B-cell lymphomas: EUROMYC, a European retrospective study.

ABSTRACT: Large B-cell lymphoma (LBCL) carrying MYC rearrangement, alone or together with BCL2 and/or BCL6 translocations, have shown a poor prognosis when treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in the HIV population. Scanty data are available on the prevalence and prognostic impact of MYC rearrangements in HIV-associated LBCL. We conducted a retrospective study to evaluate the clinical effect of MYC rearrangement in HIV-associated LBCL. We evaluated clinical characteristics, treatment received, and outcome of LBCL in patients with HIV with MYC rearrangement (MYC+) and without MYC rearrangement (MYC-). A total of 155 patients with HIV who had received fluorescence in situ hybridization analysis for MYC were enrolled in 11 European centers: 43 with MYC+ and 112 MYC-. Among patients with MYC, 10 had double-/triple-hit lymphomas, and 33 had isolated MYC rearrangement (single-hit lymphoma). Patients with MYC+ had more frequently advanced stage, >2 extranodal site at presentation, and higher proliferative index. There were no significant differences in overall survival and progression-free survival (PFS) between the 2 groups. However, patients with MYC+ received more frequently intensive chemotherapy (iCT) (44%) than (R)CHOP alone (35%) or infusional treatment (DA-EPOCH-R and R-CDE) (19%). Among patients with MYC+, those who received iCT achieved a better outcome than patients who received nonintensive treatment (complete remission, 84% vs 52%; P = .028; 5-year PFS, 66% vs 36%; P = .021). Our retrospective results suggest that HIV-associated LBCL with MYC+ could be considered for an intensive therapeutic approach whenever possible, whereas (R)CHOP seems to give inferior results in this subset of patients in terms of complete remission and PFS.

Primary central nervous system marginal zone lymphoma.

Marginal zone lymphoma (MZL) is the most common indolent lymphoma primarily arising in the central nervous system (CNS). To date, 207 cases of primary CNS MZL (PCNSMZL) were published, mostly as single case reports or small case series. It most commonly presents as extra-axial dural-based masses, more frequently in middle-aged women, displaying an insidious onset, with a long history of symptoms preceding the diagnosis. PCNSMZL can be radiographically mistaken for meningioma. PCNSMZL consists of CD20+ , CD3- small B lymphocytes with varying degrees of plasmacytic differentiation and low proliferation index. Trisomy 3, but not MALT1 or IgH translocation, is a common genetic abnormality. Other recurrent genetic abnormalities involve TNFAIP3 and NOTCH2. Ethiopathogenesis was poorly investigated. Due to its rarity, standard of care remains to be defined; it exhibits an excellent prognosis after varied treatments, such as surgery, radiotherapy, chemotherapy or their combinations. Nevertheless, each treatment should be considered after an accurate analysis of overtreatment risk. Short follow-up is a major limitation in reported PCNSMZL cases, which restrains our knowledge on long-term results and iatrogenic sequels. This review was focussed on presentation, differential diagnoses, pathological findings, treatment options and clinical outcomes of PCNSMZL; recommendations for best clinical practice are provided.

Burden of Illness in Follicular Lymphoma with Multiple Lines of Treatment, Italian RWE Analysis.

This real-world analysis investigated patients with follicular lymphoma in Italy receiving three or more treatment lines (≥3L), focusing on therapeutic pathways with their rebounds on healthcare resource consumptions and costs. Data were retrieved from administrative databases from healthcare entities covering about 13.3 million residents. Adults diagnosed with follicular lymphoma were identified between January 2015 and June 2020, and among them 2434 patients with ≥3L of treatment during the data availability interval (January 2009 to June 2021) were included. Of them, 1318 were in 3L, 494 in 4L and 622 in ≥5L. A relevant proportion of patients (12-32%) switched to a later line within the same calendar year. At 3-year follow-up (median), 34% patients died. Total mean annual expenses were euro 14,508 in the year preceding inclusion and rose to euro 21,081 at 1-year follow-up (on average euro 22,230/patient/year for the whole follow-up), with hospitalization and drug expenses as weightiest cost items. In conclusion, the clinical and economic burden of follicular lymphoma increases along with later treatment lines. The high mortality rates indicate that further efforts are needed to optimize disease management.

Tumor-Infiltrating Normal B Cells Revealed by Immunoglobulin Repertoire Clonotype Analysis Are Highly Prognostic and Crucial for Antitumor Immune Responses in DLBCL.

PURPOSE: Tumor-infiltrating B lymphocytes (TIL-B) have demonstrated prognostic and predictive significance in solid cancers. In this study, we aimed to distinguish TIL-Bs from malignant B-cells in diffuse large B-cell lymphoma (DLBCL) and determine the clinical and biological significance. EXPERIMENTAL DESIGN: A total of 269 patients with de novo DLBCL from the International DLBCL R-CHOP Consortium Program were studied. Ultra-deep sequencing of the immunoglobulin genes was performed to determine B-cell clonotypes. The frequencies and numbers of TIL-B clonotypes in individual repertoires were correlated with patient survival, gene expression profiling (GEP) data, and frequencies of DLBCL-infiltrating immune cells quantified by fluorescent multiplex IHC at single-cell resolution. RESULTS: TIL-B abundance, evaluated by frequencies of normal B-cell clonotypes in the immunoglobulin repertoires, remarkably showed positive associations with significantly better survival of patients in our sequenced cohorts. DLBCLs with high versus low TIL-B abundance displayed distinct GEP signatures, increased pre-memory B-cell state and naïve CD4 T-cell state fractions, and higher CD4+ T-cell infiltration. TIL-B frequency, as a new biomarker in DLBCL, outperformed the germinal center (GC) B-cell-like/activated B-cell-like classification and TIL-T frequency. The identified TIL-B-high GEP signature, including genes upregulated during T-dependent B-cell activation and those highly expressed in normal GC B cells and T cells, showed significant favorable prognostic effects in several external validation cohorts. CONCLUSIONS: TIL-B frequency is a significant prognostic factor in DLBCL and plays a crucial role in antitumor immune responses. This study provides novel insights into the prognostic determinants in DLBCL and TIL-B functions with important therapeutic implications.

New hopes in relapsed refractory primary central nervous system lymphoma.

PURPOSE OF REVIEW: Patients with relapsed/refractory primary central nervous system lymphoma (rrPCNSL) have poor prognosis, with a median survival after relapse of 6.8 months. In this review, we discuss the evolving landscape and the possible future directions related to this important unmet clinical need. RECENT FINDINGS: The modern two-phase approach for newly diagnosed PCNSL based on an induction using high-dose methotrexate (HD-MTX) combinations and a subsequent consolidation, has significantly improved the outcome in this setting. However, this strategy is able to cure more or less 50% of patients. rrPCNSL patients have a very poor prognosis with a reported 5-year overall survival of 18%. Late relapses (after third year) and use of high-dose chemotherapy and autologous stem cell transplantation (HDT-ASCT) represent important factors associated with a better outcome in this setting. On the basis of the growing acquisition of knowledge on the molecular characteristics of PCNSL, the use of non-chemotherapeutic drugs such as bruton tyrosine kinase inhibitors (BTK-is), immunomodulatory drugs (IMiDs) and immune checkpoint blockers (ICBs) is increasing in the last years along with the introduction of novel approaches (CAR-T cells and blood--brain barrier disruption). However, despite high responses in some cases, durations are often short, translating in outcome results still unsatisfactory. SUMMARY: Treatment of rrPCNSL patients is challenging. As no standard of care exist in this setting, it is of paramount importance to acquire new knowledge related to this condition and start multidisciplinary collaboration in order to improve pts outcome.

Primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) is a diffuse large B cell lymphoma in which the brain, spinal cord, leptomeninges and/or eyes are exclusive sites of disease. Pathophysiology is incompletely understood, although a central role seems to comprise immunoglobulins binding to self-proteins expressed in the central nervous system (CNS) and alterations of genes involved in B cell receptor, Toll-like receptor and NF-κB signalling. Other factors such as T cells, macrophages or microglia, endothelial cells, chemokines, and interleukins, probably also have important roles. Clinical presentation varies depending on the involved regions of the CNS. Standard of care includes methotrexate-based polychemotherapy followed by age-tailored thiotepa-based conditioned autologous stem cell transplantation and, in patients unsuitable for such treatment, consolidation with whole-brain radiotherapy or single-drug maintenance. Personalized treatment, primary radiotherapy and only supportive care should be considered in unfit, frail patients. Despite available treatments, 15-25% of patients do not respond to chemotherapy and 25-50% relapse after initial response. Relapse rates are higher in older patients, although the prognosis of patients experiencing relapse is poor independent of age. Further research is needed to identify diagnostic biomarkers, treatments with higher efficacy and less neurotoxicity, strategies to improve the penetration of drugs into the CNS, and roles of other therapies such as immunotherapies and adoptive cell therapies.

Treating relapsed/refractory mature T- and NK-cell neoplasms with tislelizumab: a multicenter open-label phase 2 study.

Patients with relapsed/refractory (R/R) mature T- and natural killer (NK)-cell neoplasms lack effective treatments after failure of standard therapies. This phase 2 study evaluated the efficacy and safety of the programmed cell death protein 1 inhibitor tislelizumab in these patients. Seventy-seven patients were treated with 200 mg tislelizumab every 3 weeks. Twenty-two patients with extranodal NK-/T-cell lymphomas were enrolled in cohort 1; 44 patients with peripheral T-cell lymphoma (PTCL) were enrolled in cohort 2 (21 patients had PTCL not otherwise specified, 11 patients had angioimmunoblastic T-cell lymphoma, and 12 patients had anaplastic large-cell lymphoma). Cohort 3 comprised 11 patients with cutaneous T-cell lymphoma, of which 8 patients had mycosis fungoides (MF) and 3 had Sézary syndrome. Of the 77 patients, 76.6% had advanced-stage disease, 51.9% had refractory disease, and 49.4% received ≥3 prior systemic regimens. Promising efficacy was observed in cohort 3 (median follow-up [FU], 16.6 months; overall response rate [ORR], 45.5%; complete response [CR], 9.1%; median duration of response [DOR], 11.3 months; median progression-free survival, 16.8 months; median overall survival, not reached). Modest efficacy was observed in cohort 1 (median FU, 8.4 months; ORR, 31.8%; CR, 18.2%; median DOR, not reached) and cohort 2 (median FU, 9.3 months; ORR, 20.5%; CR, 9.1%; median DOR, 8.2 months). Most treatment-related adverse events were grade 1 or 2, and the safety profile was consistent with the known safety profile of tislelizumab. In conclusion, tislelizumab was well tolerated, achieving modest efficacy in R/R mature T- and NK-cell neoplasms, with some long-lasting remissions. This trial was registered at www.clinicaltrials.gov as #NCT03493451.

Candidate germline biomarkers of lenalidomide efficacy in mantle cell lymphoma: the Fondazione Italiana Linfomi MCL0208 trial.

In the Fondazione Italiana Linfomi MCL0208 phase 3 trial, lenalidomide maintenance (LEN) after autologous stem cell transplantation (ASCT) in mantle cell lymphoma (MCL) improved progression-free survival (PFS) vs observation (OBS). The host pharmacogenetic background was analyzed to decipher whether single-nucleotide polymorphisms (SNPs) of genes encoding transmembrane transporters, metabolic enzymes, or cell-surface receptors might predict drug efficacy. Genotypes were obtained via real-time polymerase chain reaction of the peripheral blood germ line DNA. Polymorphisms of ABCB1 and VEGF were found in 69% and 79% of 278 patients, respectively, and predicted favorable PFS vs homozygous wild-type (WT) in the LEN arm was 3-year PFS of 85% vs 70% (P < .05) and 85% vs 60% (P < .01), respectively. Patients carrying both ABCB1 and VEGF WT had the poorest 3-year PFS (46%) and overall survival (76%); in fact, in these patients, LEN did not improve PFS vs OBS (3-year PFS, 44% vs 60%; P = .62). Moreover, the CRBN polymorphism (n = 28) was associated with lenalidomide dose reduction or discontinuation. Finally, ABCB1, NCF4, and GSTP1 polymorphisms predicted lower hematological toxicity during induction, whereas ABCB1 and CRBN polymorphisms predicted lower risk of grade ≥3 infections. This study demonstrates that specific SNPs represent candidate predictive biomarkers of immunochemotherapy toxicity and LEN efficacy after ASCT in MCL.