Ibrutinib as part of risk-stratified treatment for posttransplant lymphoproliferative disorder: the phase 2 TIDaL trial.

ABSTRACT: Posttransplant lymphoproliferative disorder (PTLD) is a rare complication of solid organ transplantation, and cytotoxic chemotherapy is associated with treatment-related morbidity and mortality. Current treatment takes a sequential, risk-stratified approach, and patients with low-risk disease after initial immunotherapy can avoid escalation to immunochemotherapy. TIDaL is a prospective, single-arm phase 2 trial investigating the activity and tolerability of ibrutinib combined with risk-stratified therapy for first-line treatment of PTLD. Eligible patients were adults with newly diagnosed CD20+ B-cell PTLD after solid organ transplant and performance status 0 to 2. Initial treatment comprised 49 days of ibrutinib 560 mg once daily, with 4 doses of weekly rituximab. Treatment response on interim scan and baseline International Prognostic Index were used to allocate patients to either a low-risk arm (who continued ibrutinib, alongside 4 further doses of 3-weekly rituximab) or high-risk (escalation to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] immunochemotherapy, with ibrutinib continuing in patients aged <65 years). The primary outcome was complete response on interim scan, achieved by 11 of 38 patients (29%; 95% confidence interval [CI], 15-46). This did not reach the prespecified threshold for clinically significant activity. Secondary outcomes included allocation to the low-risk arm (41% of patients), 2-year progression-free survival (58%; 95% CI, 44-76), and 2-year overall survival (76%; 95% CI, 63-91). Adverse events were mostly hematological, gastrointestinal, and infective. Although TIDaL does not support adding ibrutinib into first-line treatment of PTLD, increasing the proportion of patients who can be treated without cytotoxic chemotherapy remains an important aim of future research. This trial was registered at www.clinicaltrials.gov as #ISRCTN32667607.

Pirtobrutinib: a new hope for patients with BTK inhibitor-refractory lymphoproliferative disorders.

Patients with lymphoproliferative disorders such as chronic lymphocytic leukemia and mantle cell lymphoma (MCL) who are resistant to covalent Bruton tyrosine kinase inhibitors (cBTKis), especially if also venetoclax refractory, have an unmet therapeutic need. Pirtobrutinib, a noncovalent BTKi, achieves high response rates in patients who are refractory to cBTKi, regardless of mechanism of cBTKi resistance. This led to recent accelerated US Food and Drug Administration approval in MCL. The toxicity profile in early studies suggests suitability for use in combination approaches. We summarize existing preclinical and clinical data for pirtobrutinib.

Tabelecleucel for allogeneic haematopoietic stem-cell or solid organ transplant recipients with Epstein-Barr virus-positive post-transplant lymphoproliferative disease after failure of rituximab or rituximab and chemotherapy (ALLELE): a phase 3, multicentre, open-label trial.

BACKGROUND: Survival in Epstein-Barr virus (EBV)-positive post-transplant lymphoproliferative disease following haematopoietic stem-cell transplant (HSCT) or solid organ transplant (SOT) is poor after failure of initial therapy, indicating an urgent need for therapies for this ultra-rare disease. With recent EU marketing authorisation, tabelecleucel is the first off-the-shelf, allogeneic, EBV-specific T-cell immunotherapy to receive approval for treatment of relapsed or refractory EBV-positive post-transplant lymphoproliferative disease. We aimed to determine the clinical benefit of tabelecleucel in patients with relapsed or refractory EBV-positive post-transplant lymphoproliferative disease following HSCT or SOT. METHODS: In this global, multicentre, open-label, phase 3 trial, eligible patients (of any age) had biopsy-proven EBV-positive post-transplant lymphoproliferative disease, disease that was relapsed or refractory to rituximab after HSCT and rituximab with or without chemotherapy after SOT, and partially HLA-matched and appropriately HLA-restricted tabelecleucel available. Patients received tabelecleucel administered intravenously at 2 × 106 cells per kg on days 1, 8, and 15 in 35-day cycles and are assessed for up to 5 years for survival post-treatment initiation. The primary endpoint was objective response rate. All patients who received at least one dose of tabelecleucel were included in safety and efficacy analyses. This trial is registered with ClinicalTrials.gov, NCT03394365, and is ongoing. FINDINGS: From June 27, 2018, to Nov 5, 2021, 63 patients were enrolled, of whom 43 (24 [56%] male and 19 [44%] female) were included, 14 had prior HSCT, 29 had SOT. Seven (50%, 95% CI 23-77) of 14 participants in the HSCT group and 15 (52%, 33-71) of 29 participants in the SOT group had an objective response, with a median follow-up of 14·1 months (IQR 5·7-23·9) and 6·0 months (1·8-18·4), respectively. The most common grade 3 or 4 treatment-emergent adverse events were disease progression (in four [29%] of 14 in HSCT and eight [28%] of 29 in SOT) and decreased neutrophil count (in four [29%] of 14 in HSCT and four [14%] of 29 in SOT). Treatment-emergent serious adverse events were reported in 23 (53%) of 43 patients and fatal treatment-emergent adverse events in five (12%); no fatal treatment-emergent adverse event was treatment-related. There were no reports of tumour flare reaction, cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, transmission of infectious diseases, marrow rejection, or infusion reactions. No events of graft-versus-host disease or SOT rejection were reported as related to tabelecleucel. INTERPRETATION: Tabelecleucel provides clinical benefit in patients with relapsed or refractory EBV-positive post-transplant lymphoproliferative disease, for whom there are no other approved therapies, without evidence of safety concerns seen with other adoptive T-cell therapies. These data represent a potentially transformative and accessible treatment advance for patients with relapsed or refractory disease with few treatment options. FUNDING: Atara Biotherapeutics.

Late effects in survivors of post-transplant lymphoproliferative disease.

BACKGROUND: Treatment of post-transplant lymphoproliferative disease (PTLD) varies, with only some patients receiving chemotherapy. Concern for chemotherapy toxicities may influence treatment decisions as little is known regarding the late effects (LE) in PTLD survivors. This report characterizes LE in PTLD survivors at our institution. PROCEDURE: Pediatric patients (0-18 years old) diagnosed with PTLD from 1990 to 2020 were examined. All patients included survived 6 months after completing chemotherapy or were 6 months from diagnosis if received no chemotherapy. Treatment with anti-CD20 antibody (rituximab) alone was not considered chemotherapy. Toxicities were classified per Common Terminology Criteria for Adverse Events Version 5.0. Chi-square tests assessed differences between categorical groups, or Fischer's exact test or the Fischer-Freeman-Halton exact test for limited sample sizes. RESULTS: Of the 44 patients included, 24 (55%) were treated with chemotherapy. Twenty-four (55%) were alive at last follow-up. Chemotherapy was not associated with differences in survival (odds ratio [OR] 1.40, confidence interval [CI]: 0.42-4.63; p = .31). All patients experienced LE. Grade 3 toxicity or higher was experienced by 82% of patients with no difference in incidence (OR 1.20, CI: 0.27-5.80; p > .99) or median toxicity grade (3.00 vs. 4.00, p = .21) between treatment groups. Patients who received chemotherapy were more likely to experience blood and lymphatic toxicity (58% vs. 25%, p = .03) and cardiac toxicity (46% vs. 15%, p = .03), but less likely to have infections (54% vs. 85%, p = .03). CONCLUSIONS: Survivors of PTLD experience LE including late mortality regardless of chemotherapy exposure. Further investigation to better understand LE could optimize upfront therapy for children with PTLD and improve outcomes.

Effect of pre-emptive rituximab on EBV DNA levels and prevention of post-transplant lymphoproliferative disorder in pediatric kidney transplant recipients: A case series from the pediatric nephrology research consortium.

BACKGROUND: There are scant data on the effect of rituximab on EBV DNA levels and prevention of post-transplant lymphoproliferative disorder (PTLD) in pediatric kidney transplant recipients with EBV DNAemia. METHODS: Kidney transplant recipients with EBV DNAemia treated with rituximab to prevent PTLD between 7/1999 and 7/2019 at five pediatric centers were included. Those with confirmed PTLD at the onset of rituximab were excluded. Primary outcomes included percentage change in EBV DNAemia and occurrence of PTLD post rituximab. RESULTS: Twenty-six pediatric kidney transplant recipients were included. Median age at transplant was 4 years (IQR 2.1-10.3). EBV DNA load monitoring by qPCR was performed at 1-3 month intervals. EBV DNAemia onset occurred at a median of 73 days post-transplant (IQR 52-307), followed by DNAemia peak at a median of 268 days (IQR 112-536). Rituximab was administered at a median of 9 days post peak (IQR 0-118). Rituximab regimens varied; median dose 375 mg/m2 (IQR 375-439) weekly for 1-4 doses per course. Following rituximab, EBV DNA load decreased to <10% of baseline at 120 days in 20/26 patients; however, only 30% achieved complete resolution at last follow-up (median 2094 days post-transplant [IQR 1538-3463]). Two (7%) developed PTLD at 915 and 1713 days post rituximab. All recipients had functioning grafts. One death occurred in a child with PTLD following remission due to unrelated reasons. CONCLUSIONS: In the largest pediatric kidney transplant recipient case series with EBV DNAemia given rituximab to prevent PTLD, rituximab achieved a short-term reduction in DNA load; however, recurrent DNAemia is common.

Treatment of Monomorphic Posttransplant Lymphoproliferative Disorder in Pediatric Solid Organ Transplant: A Multicenter Review.

Posttransplant lymphoproliferative disorder (PTLD) is the most common posttransplant malignancy in children. We reviewed data from 3 Canadian pediatric centers to determine patient characteristics, treatment approaches, and outcomes for children with monomorphic PTLD. There were 55 eligible children diagnosed between January 2001 to December 2021. Forty-eight patients (87.2%) had B-cell PTLD: Burkitt lymphoma (n = 25; 45.4%) and diffuse large B-cell lymphoma (n = 23; 41.2%), the remainder had natural killer (NK)/T-cell lymphoma (n = 5; 9.1%), Hodgkin lymphoma (n = 1;1.8%), or other (n = 1;1.8%). Thirty-nine (82.1%) patients with B-cell PTLD were treated with rituximab and chemotherapy with or without a reduction in immunosuppression (reduced immune suppression). The chemotherapy used was primarily one of 2 regimens: Mature Lymphoma B-96 protocol in 22 patients (56.4%) and low-dose cyclophosphamide with prednisone in 14 patients (35%). Most patients with T/NK-cell lymphoma were treated with reduced immune suppression + chemotherapy (n = 4; 80%). For all patients with monomorphic PTLD, the projected 3-year event-free survival/3-year overall survival was 62% and 77%, respectively. Of the patients, 100% with T/NK-cell PTLD 100% progressed or relapsed and, subsequently, died of disease. For patients with B-cell PTLD, there was no significant difference in outcome between the two main chemotherapy regimens employed.

Gastric Burkitt's monomorphic post-transplant lymphoproliferative disorder after kidney transplantation: A case report.

We report on a 53-year-old Japanese man diagnosed with gastric Burkitt's monomorphic post-transplant lymphoproliferative disorder (B-PTLD) after endoscopy for gastric discomfort 28 months after the patient underwent renal transplantation in Ethiopia. Serum Epstein-Barr virus (EBV) tests were negative before transplantation, but the tumor cells collected from a gastric biopsy showed positive EBV-encoded small RNAs (EBER) at B-PTLD onset. Intensive treatment started with R(rituximab)-CHOP therapy and continued with DA-EPOCH-R therapy has been effective, and relapse has not yet occurred. Burkitt lymphoma has a poor prognosis, but B-PTLD may be effectively treated with high-dose chemotherapy. This is a rare case of gastric B-PTLD in a Japanese patient.

Regression of Necrotic Lesions after Methotrexate Withdrawal in Patients with Methotrexate-Associated Lymphoproliferative Disorders: A Retrospective CT Study.

This retrospective study investigated whether necrotic lesions detected on a computed tomography (CT) scan are more regressive than non-necrotic lesions after methotrexate withdrawal in patients pathologically diagnosed with methotrexate-associated lymphoproliferative disorders (MTX-LPD). In total, 89 lesions extracted from 24 patients on CT scans were included in the analysis. All patients had been evaluated for the presence of necrosis within lesions via CT scan upon first suspicion of MTX-LPD (baseline CT scan). The percentage lesion size reduction between the baseline and initial follow-up CT scan was calculated. The association between necrosis within lesions and size changes was estimated via linear regression analyses using both crude and adjusted models. Necrosis was significantly more common in extranodal lesions (27 out of 30 lesions, 90%) than in nodal lesions (9 out of 59 lesions, 15%, p<0.001). In the crude model, the regression of necrotic lesions was 58.5% greater than that of non-necrotic lesions; the difference was statistically significant (p<0.001). Additionally, the longest diameter of necrotic lesions at the baseline CT scan was significantly greater than that of non-necrotic lesions (p<0.001). Based on the adjusted model, necrotic lesions showed 49.3% greater regression than non-necrotic lesions (p=0.017). Necrosis detected on a CT scan was found to be an independent predictor of regression after MTX withdrawal in patients with MTX-LPD.

CAD204520 Targets NOTCH1 PEST Domain Mutations in Lymphoproliferative Disorders.

NOTCH1 PEST domain mutations are often seen in hematopoietic malignancies, including T-cell acute lymphoblastic leukemia (T-ALL), chronic lymphocytic leukemia (CLL), splenic marginal zone lymphoma (SMZL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL). These mutations play a key role in the development and progression of lymphoproliferative tumors by increasing the Notch signaling and, consequently, promoting cell proliferation, survival, migration, and suppressing apoptosis. There is currently no specific treatment available for cancers caused by NOTCH1 PEST domain mutations. However, several NOTCH1 inhibitors are in development. Among these, inhibition of the Sarco-endoplasmic Ca2+-ATPase (SERCA) showed a greater effect in NOTCH1-mutated tumors compared to the wild-type ones. One example is CAD204520, a benzimidazole derivative active in T-ALL cells harboring NOTCH1 mutations. In this study, we preclinically assessed the effect of CAD204520 in CLL and MCL models and showed that NOTCH1 PEST domain mutations sensitize cells to the anti-leukemic activity mediated by CAD204520. Additionally, we tested the potential of CAD204520 in combination with the current first-line treatment of CLL, venetoclax, and ibrutinib. CAD204520 enhanced the synergistic effect of this treatment regimen only in samples harboring the NOTCH1 PEST domain mutations, thus supporting a role for Notch inhibition in these tumors. In summary, our work provides strong support for the development of CAD204520 as a novel therapeutic approach also in chronic lymphoproliferative disorders carrying NOTCH1 PEST domain mutations, emerging as a promising molecule for combination treatment in this aggressive subset of patients.

[Clostridioides difficile infection diagnosed by nucleic acid amplification test in a patient with Epstein-Barr Virus-related T-cell lymphoproliferative disorder].

Steroid usage poses a risk of Clostridioides difficile infection (CDI), but high-dose corticosteroid treatment can lead to false-negative CD toxin test results. Moreover, CDI-induced nausea can complicate administration of oral antibiotics, which are typically the primary therapy for CDI. In the present case, a 43-year-old woman diagnosed with EBV-associated T-cell post-transplant lymphoproliferative disorder developed CDI during treatment with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP). Following five cycles of CHOP, the patient presented with nausea and diarrhea. CT scans revealed swelling in the ileocecal to transverse area of the colon. While the glutamate dehydrogenase (GDH) antigen test result was positive, the CD toxin test result was negative. However, the nucleic amplification test (NAAT) result was positive, confirming the diagnosis of CDI. Oral treatment with fidaxomicin was initially impractical due to persistent nausea. Instead, treatment began with intravenous metronidazole, and was later switched to fidaxomicin pills. Symptoms improved notably within 10 days, and the patient ultimately made a complete recovery. This case underscores the significance of exploring alternative approaches to CDI management, particularly in immunosuppressed patients.

Post-transplant lymphoproliferative disorder: Update on treatment and novel therapies.

Post-transplant lymphoproliferative disorder (PTLD) is rare and heterogeneous lymphoid proliferations that occur as a result of immunosuppression following solid organ transplant (SOT) and haematopoietic stem cell transplant (HSCT) with the majority being driven by EBV. Although some histologies are similar to lymphoid neoplasms seen in immunocompetent patients, treatment of PTLD may be different due to difference in pathobiology and higher risk of treatment complications. The most common treatment approach in SOT PTLD after failing immunosuppression reduction (RIS) takes into consideration a risk-stratified sequential algorithm with rituximab +/- chemotherapy based on phase 2 studies. In HSCT PTLD, RIS alone and chemotherapy are usually ineffective making rituximab +/- RIS as the gold standard of frontline treatment. In this review, we give an update on the treatment of PTLD beyond RIS. We highlight the most recent studies that attempted to incorporate more aggressive chemotherapy regimens and novel treatments into the traditional risk-stratified sequential approach. We also discuss the role of EBV-cytotoxic T lymphocytes in treatment of EBV-driven PTLD. Other novel agents with potential role in PTLD will be discussed in addition to the challenges that could arise with chimeric antigen receptor T-cell therapy and immune checkpoint inhibitors in this population.

Lymphoproliferative disorder during temozolomide therapy; a representative case of a formidable complication and management challenges.

BACKGROUND: Lymphoproliferative disorder represents a heterogeneous clinicopathological spectrum characterized by uncontrolled proliferation of lymphocytes. Immunodeficiency is a major trigger of its development. While induction of immunodeficiency is a well-known adverse effect of temozolomide therapy, development of lymphoproliferative disorder following temozolomide therapy has not previously been described. CASE PRESENTATION: A patient with brainstem glioma developed constitutional symptoms, pancytopenia, splenomegaly and generalized lymphadenopathy during the 2nd cycle of maintenance therapy following induction therapy with temozolomide. Epstein-Barr virus-infected lymphocytes were observed histopathologically and "other iatrogenic immunodeficiency-associated lymphoproliferative disorder" (OIIA-LPD) was diagnosed. Although discontinuation of temozolomide led to rapid remission, relapse was observed 4 months later. CHOP chemotherapy was induced, resulting in secondary remission. Vigilant follow-up for another 14 months showed radiologically stable brainstem glioma and no further recurrence of OIIA-LPD. CONCLUSIONS: This is the first report documenting OIIA-LPD during temozolomide administration. Timely diagnosis of the disease and discontinuation of the causative agent were considered to be the management of choice. Close monitoring for relapse should be continued. Finding a balance between glioma management and controlling the remission of OIIA-LPD remains to be clarified.

Primary central nervous system other iatrogenic immunodeficiency-associated lymphoproliferative disorders presenting as extraosseous plasmacytoma with a progressive clinical course: A case report and literature review.

Other iatrogenic immunosuppressive-associated lymphoproliferative disorders (OIIA-LPDs) rarely occur in the central nervous system (CNS). Additionally, they almost always present as lymphoma and withdrawal by cessation of immunosuppressive treatment. We report a case of primary CNS OIIA-LPD that presented as extraosseous plasmacytoma (EP) with a progressive clinical course in spite of immunosuppressive treatment cessation. A 78-year-old man with a history of rheumatoid arthritis (RA) presented with a month-long headache. Magnetic resonance imaging showed mass lesions in the left temporal lobe, left middle fossa, and intradural cervical spine. The left temporal lesion was resected and diagnosed as EP histologically, and OIIA-LPD presented as plasmacytoma integrally due to his history of immunosuppressive treatment using tacrolimus for RA. Despite immunosuppressive treatment cessation, OIIA-LPD lesions did not regress but, on the contrary, showed a progressive clinical course. Considering his advanced age and renal dysfunction, postoperative treatment with radiation and moderate chemotherapy using prednisolone were administrated. Subsequently, the disease state stabilized, and the patient had a Karnofsky performance status score of 90 for 6 months; however, the tumor recurred with meningeal dissemination, and he died 8 months after treatment. Types of OIIA-LPD onset as EP and its progressive clinical course resistant to cessation of immunosuppressive treatment are rare. Moreover, this OIIA-LPD disease state worsened despite its radiosensitivity. We believe the progressive clinical course of this OIIA-LPD case with its high cell proliferation is similar to Epstein-Barr virus negative plasmablastic lymphoma, which could lead to a poor outcome.

Pre-Emptive Use of Rituximab in Epstein-Barr Virus Reactivation: Incidence, Predictive Factors, Monitoring, and Outcomes.

Post-transplant lymphoproliferative disease (PTLD) is a fatal complication of hematopoietic cell transplantation (HCT) associated with the Epstein-Barr virus (EBV). Multiple factors such as transplant type, graft-versus-host disease (GVHD), human leukocyte antigens (HLA) mismatch, patient age, and T-lymphocyte-depleting treatments increase the risk of PTLD. EBV reactivation in hematopoietic cell transplant recipients is monitored through periodic quantitative polymerase chain reaction (Q-PCR) tests. However, substantial uncertainty persists regarding the clinically significant EBV levels for these patients. Guidelines recommend initiating EBV monitoring no later than four weeks post-HCT and conducting it weekly. Pre-emptive therapies, such as the reduction of immunosuppressive therapy and the administration of rituximab to treat EBV viral loads are also suggested. In this study, we investigated the occurrence of EBV-PTLD in 546 HCT recipients, focusing on the clinical manifestations and risk factors associated with the disease. We managed to identify 67,150 viral genomic copies/mL as the cutoff point for predicting PTLD, with 80% sensitivity and specificity. Among our cohort, only 1% of the patients presented PTLD. Anti-thymocyte globulin (ATG) and GVHD were independently associated with lower survival rates and higher treatment-related mortality. According to our findings, prophylactic measures including regular monitoring, pre-emptive therapy, and supportive treatment against infections can be effective in preventing EBV-related complications. This study also recommends conducting EBV monitoring at regular intervals, initiating pre-emptive therapy when viral load increases, and identifying factors that increase the risk of PTLD. Our study stresses the importance of frequent and careful follow-ups of post-transplant complications and early intervention in order to improve survival rates and reduce mortality.

[Methotrexate-related lymphoproliferative disease showing different histological findings at recurrence].

A 55-year old female patient was treated with methotrexate (MTX) and infliximab (IFX) for rheumatoid arthritis (RA). She experienced unknown fever, generalized lymphadenopathy, and liver tumors. Histological examination of the inguinal lymph node and a liver tumor resulted in the pathological diagnosis of classic Hodgkin lymphoma, with many Reed-Sternberg cells with the positivity of Epstein-Barr virus (EBV). She was diagnosed with MTX-related lymphoproliferative disorders (MTX-LPDs). She received chemotherapy after the cessation of MTX and IFX and achieved complete remission. RA showed recurrence after a while, and she was treated with steroids or other drugs. Six years after the chemotherapy, she experienced low-grade fever and anorexia. Whole computed tomography images showed an appendix tumor and enlargement of the surrounding lymph nodes. Appendectomy with the radical lymph nodes dissection was performed. The pathological diagnosis was diffuse large B-cell lymphoma, resulting in the clinical diagnosis of the relapse of MTX-LPD. EBV was negative at this point. The pathological findings of MTX-LPD may change at relapse; thus, biopsy should be considered when the relapse of MTX-LPD is suggested.

In vitro and in vivo evidence that the switch from calcineurin to mTOR inhibitors may be a strategy for immunosuppression in Epstein-Barr virus-associated post-transplant lymphoproliferative disorder.

Post-transplant lymphoproliferative disorder is a life-threatening complication of immunosuppression following transplantation mediated by failure of T cells to control Epstein-Barr virus (EBV)-infected and transformed B cells. Typically, a modification or reduction of immunosuppression is recommended, but insufficiently defined thus far. In order to help delineate this, we characterized EBV-antigen-specific T cells and lymphoblastoid cell lines from healthy donors and in patients with a kidney transplant in the absence or presence of the standard immunosuppressants tacrolimus, cyclosporin A, prednisolone, rapamycin, and mycophenolic acid. Phenotypes of lymphoblastoid cell-lines and T cells, T cell-receptor-repertoire diversity, and T-cell reactivity upon co-culture with autologous lymphoblastoid cell lines were analyzed. Rapamycin and mycophenolic acid inhibited lymphoblastoid cell-line proliferation. T cells treated with prednisolone and rapamycin showed nearly normal cytokine production. Proliferation and the viability of T cells were decreased by mycophenolic acid, while tacrolimus and cyclosporin A were strong suppressors of T-cell function including their killing activity. Overall, our study provides a basis for the clinical decision for the modification and reduction of immunosuppression and adds information to the complex balance of maintaining anti-viral immunity while preventing acute rejection. Thus, an immunosuppressive regime based on mTOR inhibition and reduced or withdrawn calcineurin inhibitors could be a promising strategy for patients with increased risk of or manifested EBV-associated post-transplant lymphoproliferative disorder.

HCV-related lymphoproliferative disorders in the direct-acting antiviral era: From mixed cryoglobulinaemia to B-cell lymphoma.

HCV has been shown to induce many B-cell lymphoproliferative disorders. B lymphocytes specialise in producing immunoglobulins and, during chronic HCV infection, they can cause manifestations ranging from polyclonal hypergammaglobulinaemia without clinical repercussions, through mixed cryoglobulinaemic vasculitis to B-cell non-Hodgkin lymphoma. This spectrum is supported by substantial epidemiological, pathophysiological and therapeutic data. Many, although not all, of the pathogenic pathways leading from one extreme to another have been decrypted. Chronic viral antigen stimulation of B lymphocytes has a central role until the final steps before overt malignancy. This has direct implications for treatment strategies, which always include the use of direct-acting antivirals sometimes alongside immunosuppressants. The role of direct-acting antivirals has been well established in patients with cryoglobulinaemia vasculitis. However, their positive impact on B-cell non-Hodgkin lymphoma needs to be confirmed in larger studies with longer follow-up.

Incidence and outcomes of post-transplant lymphoproliferative disease after 5365 solid-organ transplants over a 20-year period at two UK transplant centres.

Post-transplant lymphoproliferative disease (PTLD) is a life-threatening complication of solid-organ transplantation (SOT). We present the incidence and outcomes of PTLD in a cohort of 5365 SOT recipients over a 20-year period at two UK transplant centres. With a median follow-up of 7.7 years, 142 of 5365 patients have developed PTLD. Cumulative incidence was 18% at five years after multivisceral transplant and 1%-3% at five years following the other SOT types. Twenty-year cumulative incidence was 2%-3% following liver and heart transplantation and 10% following kidney transplantation. Median overall survival (OS) following SOT was 16 years, which is significantly reduced compared with the age-adjusted UK population. There is relatively high early mortality following diagnosis of PTLD and only patients surviving two years regained a longer-term survival approaching the non-PTLD SOT cohort. Of 90 patients with monomorphic PTLD, diffuse large B-cell lymphoma, 66 were treated with first-line rituximab monotherapy and 24 received first-line rituximab plus chemotherapy. Up-front rituximab monotherapy does not appear to compromise OS, but the number of patients dying from non-lymphoma causes before and after treatment remains high with both treatment approaches. Multivariate analysis of all 90 monomorphic PTLD patients identified an International Prognostic Index (IPI) of 3+ as the strongest pretreatment variable associating with inferior one-year OS.

T-cell immune response after mRNA SARS-CoV-2 vaccines is frequently detected also in the absence of seroconversion in patients with lymphoid malignancies.

Patients affected by lymphoid malignancies (LM) are frequently immune-compromised, suffering increased mortality from COVID-19. This prospective study evaluated serological and T-cell responses after complete mRNA vaccination in 263 patients affected by chronic lymphocytic leukaemia, B- and T-cell lymphomas and multiple myeloma. Results were compared with those of 167 healthy subjects matched for age and sex. Overall, patient seroconversion rate was 64·6%: serological response was lower in those receiving anti-cancer treatments in the 12 months before vaccination: 55% vs 81·9% (P < 0·001). Anti-CD20 antibody plus chemotherapy treatment was associated with the lowest seroconversion rate: 17·6% vs. 71·2% (P < 0·001). In the multivariate analysis conducted in the subgroup of patients on active treatment, independent predictors for seroconversion were: anti-CD20 treatment (P < 0·001), aggressive B-cell lymphoma diagnosis (P = 0·002), and immunoglobulin M levels <40 mg/dl (P = 0·030). The T-cell response was evaluated in 99 patients and detected in 85 of them (86%). Of note, 74% of seronegative patients had a T-cell response, but both cellular and humoral responses were absent in 13·1% of cases. Our findings raise some concerns about the protection that patients with LM, particularly those receiving anti-CD20 antibodies, may gain from vaccination. These patients should strictly maintain all the protective measures.

Rituximab as induction therapy in pediatric kidney transplantation: A single-center experience in four patients.

BACKGROUND: The anti-CD20 rituximab is often used in the treatment of children with steroid-resistant nephrotic syndrome or EBV-induced post-transplant lymphoproliferative disorder. This single-center series reports the use of rituximab as induction therapy in pediatric kidney transplantation. METHODS: Four children who received rituximab as induction therapy for kidney transplantation since 2016 were retrospectively analyzed. Clinical and laboratory data were extracted from medical records. RESULTS: The patients (2 boys and 2 girls) were aged from 6.1 to 11.9 years and were treated with rituximab on the day of the transplantation procedure; all the transplants came from deceased donors. In all patients, rituximab was used because of positive EBV viral loads before kidney transplantation. Viral loads remained undetectable for the first 6 months after the transplantation procedure and remained below the 4.5 log threshold thereafter. After a median follow-up of 2.3 years, none of the patients displayed rejection or de novo donor-specific antibodies; the glomerular filtration rate remained above 70 ml/min/1.73 m2 . No post-transplant lymphoproliferative disorder was observed. CONCLUSION: The results suggest that rituximab can be used as induction therapy to prevent EBV replication and its complications in case of positive viral load prior to kidney transplantation.