Allogeneic hematopoietic cell transplantation (allo-HCT) is indicated for patients with relapsed or refractory Hodgkin lymphoma (HL). Although long-term disease control can be achieved, relapse is ...still frequent. The programmed cell death protein 1 (PD-1) pathway-blocking antibody nivolumab has shown substantial therapeutic activity and an acceptable safety profile in patients with relapsed or refractory HL who did not receive allo-HCT. However, PD-1 blocking strategy can increase the risk of graft-versus-host disease (GVHD) in murine models. We retrospectively assessed the efficacy and toxicity of nivolumab as a single agent in 20 HL patients relapsing after allo-HCT. GVHD occurred in 6 patients (30%) after nivolumab initiation. All 6 patients had prior history of acute GVHD. The patients with nivolumab-induced GVHD were managed by standard treatment for acute GVHD. Two patients died as a result of GVHD, 1 of progressive disease and 1 of complications related to a second allo-HCT. Overall response rate was 95%. At a median follow-up of 370 days, the 1-year progression-free survival rate was 58.2% (95% CI, 33.1%-76.7%) and the overall survival rate was 78.7% (95% CI, 52.4%-91.5%). Among 13 patients still in response, 6 received a single dose of nivolumab and 7 remain on nivolumab. Compared with standard options for this indication, our results show that nivolumab is effective with an acceptable safety profile.
•PD-1 blockade with nivolumab provides durable disease control after allo-HCT.•PD-1 blockade with nivolumab after allo-HCT is associated with 30% acute GVHD.
Patients with relapsed/refractory Hodgkin lymphoma (R/R HL) experience high response rates upon anti-PD1 therapy. In these patients, there is limited data about the optimal duration of treatment and ...the risk of relapse after anti-PD1 discontinuation. We have previously reported the outcome of 11 patients with R/R HL who discontinued anti-PD1 therapy after achieving a complete response (CR) upon nivolumab1 . These patients experienced favorable outcome as only 2 of them had relapsed after a median follow-up of 21.2 months from discontinuation. Despite the low relapse rate observed in that study, physicians may be worried about the possibility to further rescue these heavily pre-treated patients in case of relapse after anti-PD1 discontinuation. Notably, it is still unknown whether these patients will remain sensitive to a 2nd course of anti-PD1.
T-cell specificity can be redirected against tumor antigens either ex vivo using engineered chimeric antigen receptor (CAR) T-cells or in vivo by bridging natural T-cells and tumor cells with ...bispecific T-cell engager (TCE) antibodies. Currently, four CAR T-cells have been approved by the FDA for the treatment of B-cell lymphomas, including diffuse large B cell lymphomas (DLBCL), mantle cell lymphoma (MCL), and follicular lymphoma (FL). No TCE have yet been approved for the treatment of B-cell lymphomas. However, at least four of them are in clinical development and show promising activity. Here, we review the most recent advances of CAR T-cells and TCE in the treatment of B-cell lymphomas.
Summary
Composite and sequential lymphomas involving both classical Hodgkin lymphoma (CHL) and primary mediastinal B‐cell lymphoma (PMBCL) are rare phenomena. Beyond the relevant biological interest ...raised by these cases, treatments and outcome data are poorly covered in the recent literature. This retrospective analysis describes the pathological and clinical characteristics of 10 composite and 15 sequential cases included after a central pathological review. At diagnosis, 70% of the composite lymphomas presented a disseminated and extranodal disease. Among the 15 sequential lymphomas, 12 were CHL at first occurrence and three were PMBCL. Based on their clinical evolution, these sequential lymphomas could be divided into early (i.e., diagnosis of second lymphoma within a year) and late (i.e., a second lymphoma occurrence occurring after a long period of complete remission). All composite cases were alive in complete remission after a median follow‐up of 34 months. If the early sequential lymphoma presented a particularly poor outcome with a median overall survival shorter than one year, the late cases were efficiently salvaged. Further molecular studies are needed to describe the underlying biology of these rare diseases, possibly representing the extreme of tumour cell plasticity found in grey‐zone lymphoma.
BackgroundParaneoplastic syndromes (PNS) are autoimmune disorders specifically associated with cancer. There are few data on anti-PD-1 or anti-PD-L1 immunotherapy in patients with a PNS. Our ...objective was to describe the outcome for patients with a pre-existing or newly diagnosed PNS following the initiation of anti-PD-1 or anti-PD-L1 immunotherapy.MethodsWe included all adult patients (aged ≥18) treated with anti-PD-1 or anti-PD-L1 immunotherapy for a solid tumor, diagnosed with a PNS, and registered in French pharmacovigilance databases. Patients were allocated to cohorts 1 and 2 if the PNS had been diagnosed before vs. after the initiation of immunotherapy, respectively.FindingsOf the 1304 adult patients screened between June 27th, 2014, and January 2nd, 2019, 32 (2.45%) had a PNS and were allocated to either cohort 1 (n = 16) or cohort 2 (n = 16). The median (range) age was 64 (45–88). The tumor types were non-small-cell lung cancer (n = 15, 47%), melanoma (n = 6, 19%), renal carcinoma (n = 3, 9%), and other malignancies (n = 8, 25%). Eleven (34%) patients presented with a neurologic PNS, nine (28%) had a rheumatologic PNS, eight (25%) had a connective tissue PNS, and four (13%) had other types of PNS. The highest severity grade for the PNS was 1–2 in 10 patients (31%) and ≥ 3 in 22 patients (69%). Four patients (13%) died as a result of the progression of a neurologic PNS (encephalitis in three cases, and Lambert-Eaton syndrome in one case). Following the initiation of immunotherapy, the PNS symptoms worsened in eight (50%) of the 16 patients in cohort 1.InterpretationOur results show that PNSs tend to be worsened or revealed by anti-PD-1 or anti-PD-L1 immunotherapy. Cases of paraneoplastic encephalitis are of notable concern, in view of their severity. When initiating immunotherapy, physicians should carefully monitor patients with a pre-existing PNS.
Chimeric antigen receptor T cells (CAR T cells) can induce prolonged remission in a substantial subset of patients with relapse/refractory lymphoma. However, little is known about patients' life ...after CAR T‐cell therapy. We prospectively assessed the multidimensional recovery of lymphoma patients in remission, before leukapheresis, before CAR T‐cell infusion, and 3, 6, and 12 months thereafter. Validated tools were used to measure lymphoma‐related and global health‐related quality of life (HRQoL; Functional Assessment of Cancer Therapy‐Lymphoma FACT‐Lym and EQ‐5D‐5L), cognitive complaint (FACT‐Cognition), fatigue (FACIT‐Fatigue subscale), psychological status (Hospital Anxiety and Depression Scale, Post‐Traumatic Check List Scale), and sexuality (Relationship and Sexuality Scale). Beyond 12 months of remission, we also surveyed physical, professional, sexual, and general life status. At 3, 6, and 12 months, 53, 35, and 23 patients were evaluable, respectively. Improvement in lymphoma‐related HRQoL was clinically relevant at 3, 6, and 12 months with a mean change from baseline of 10.9 (95% confidence interval CI: 5.8; 16.1), 12.2 (95% CI: 4.2; 20.1), and 11.72 (95% CI: 2.06; 21.38), respectively. Improvement in global HRQoL, fatigue, and anxiety was clinically relevant, but 20%–40% of patients experienced persistent fatigue, psychological distress, and cognitive complaints over time. Beyond 12 months after CAR T cells, 81.8% of 22 evaluable patients were satisfied with their daily life. Physical activity, professional, sexual, and global well‐being had returned to prediagnosis levels in nearly half of the patients. We found an improvement in HRQoL after CAR T‐cell therapy including anxiety, depression, sexual satisfaction, and general well‐being. However, not all patients recover a “normal life.” Further research is needed to determine which patients are at risk of quality‐of‐life impairment to improve recovery after CAR T‐cell infusion.
Introduction International guidelines regarding the management of immune effector cell-associated neurotoxicity syndrome (ICANS) recommend several paraclinical assessments, including MRI, lumbar ...puncture (LP) and EEG based on ICANS grade. However, the impact of these paraclinical investigations has not yet been evaluated. Methods Here, we aimed to analyze the role of MRI, LP and EEG in the management of ICANS in a cohort of real-life patients treated with CAR T-cells at the University Hospital of Rennes, France. The primary endpoint was to assess the therapeutic modifications induced by each paraclinical investigation. The secondary endpoints were to assess the specific abnormalities and differential diagnoses founded on MRI, LP and EEG. We also performed subgroup analysis for each ICANS grade. Results Between August 2018 and January 2023, 190 consecutive patients were treated with CAR T-cells. A total of 91 (48%) patients developed an ICANS including 25 grade 1 (13%), 32 grade 2 (17%), 21 grade 3 (11%) and 12 grade 4 (6%). MRI was performed in 71 (78%) patients with ICANS. The most common result was a normal MRI, corresponding to 80 % of MRI. One of the most frequent abnormal result was aspecific hypersignal, which occurred in 4 (6%) patients with ICANS. Notably, there was no oedema depicted on MRI, even in the most severe ICANS grade 4. Overall, 3 MRI (4% of all MRI) generated therapeutic modification (Figure 1). Two MRI which described strokes in patients with ICANS grade 3 led to initiation or increase of APT therapy. One patient with ICANS grade 1 received APT as MRI described a stroke event but reclassified as normal a posteriori. Lumbar puncture was performed in 43 (47%) patients. A high rate of LP was abnormal in our cohort (86%). There were 3 preemptive therapeutic modifications for unconfirmed infection (7%) (Figure 1). Two LP led to probabilistic antivirals introduction (aciclovir) in patient with ICANS grade 1 and 2 because of lymphocytic meningitis. One LP led to probabilistic antifungals introduction (voriconazole) in patient with ICANS grade 3 for a suspected Aspergillus spp. meningitis, which was not confirmed after infectious disease physician's expertise. Systematic EEG performed in 51 (56%) patients requested without clinical signs of epilepsy were analyzed. Only 18% of EEG were normal (Table 1). The most common finding was encephalopathy in 45% of patients. Notably, 6 EEG (12%) reported seizure or status epilepticus in patients with no abnormal movements. Finally, 8 EEG (16%) led to therapeutic modification in the entire cohort (Figure 1). All EEG which found seizure or status epilepticus led to an increase in AE prophylaxis by levetiracetam or introduction of a new AE (mainly phenytoin). Discussion The therapeutic impact varied between paraclinical investigations. On one hand, systematic EEG based on ICANS grade only was often followed by therapeutic modification (16% of cases). On the other hand, systematic LP was never associated with relevant therapeutic modification, even in case of severe ICANS, and this broad LP policy resulted in initiation of antimicrobial agents for unconfirmed infections in three patients (7%). Moreover, the need for systematic MRI assessment is also questionable, as only 4% of MRI led to a therapeutic modification and no MRI found oedema, which is one of the main concerns of treating physicians managing severe ICANS. Our study shows that EEG is the paraclinical assessment with the greatest therapeutic impact while MRI and LP appear to have a limited therapeutic impact. Our results emphasize the role of EEG in the current guidelines, but questions the need for systematic MRI and LP, which might be left to the discretion of the treating physician.
Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) have both demonstrated impressive clinical activity in relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL). In this ...study, we analyzed the outcome of 809 patients with R/R DLBCL after two or more previous lines of treatment who had a commercial chimeric antigen receptor (CAR) T cells order for axi-cel or tisa-cel and were registered in the retrospective French DESCAR-T registry study ( NCT04328298 ). After 1:1 propensity score matching (n = 418), the best overall response rate/complete response rate (ORR/CRR) was 80%/60% versus 66%/42% for patients treated with axi-cel compared to tisa-cel, respectively (P < 0.001 for both ORR and CRR comparisons). After a median follow-up of 11.7 months, the 1-year progression-free survival was 46.6% for axi-cel and 33.2% for tisa-cel (hazard ratio (HR) = 0.61; 95% confidence interval (CI), 0.46-0.79; P = 0.0003). Overall survival (OS) was also significantly improved after axi-cel infusion compared to after tisa-cel infusion (1-year OS 63.5% versus 48.8%; HR = 0.63; 95% CI, 0.45-0.88; P = 0.0072). Similar findings were observed using the inverse probability of treatment weighting statistical approach. Grade 1-2 cytokine release syndrome was significantly more frequent with axi-cel than with tisa-cel, but no significant difference was observed for grade ≥3. Regarding immune effector cell-associated neurotoxicity syndrome (ICANS), both grade 1-2 and grade ≥3 ICANS were significantly more frequent with axi-cel than with tisa-cel. In conclusion, our matched comparison study supports a higher efficacy and also a higher toxicity of axi-cel compared to tisa-cel in the third or more treatment line for R/R DLBCL.
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