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Chimeric antigen receptor (CAR) T-cell therapy is an emerging highly effective treatment for refractory haematological malignancies. Unfortunately, its therapeutic benefit may be hampered by treatment-related toxicities, including neurotoxicity. Early aggressive treatment is paramount to prevent neurological sequelae, yet it potentially interferes with the anti-cancer action of CAR T-cells. We describe four CAR T-cells infused patients who presented with reiterative writing behaviours, namely paligraphia, as an early manifestation of neurotoxicity, and eventually developed frontal predominant encephalopathy (one mild, three severe). Paligraphia may represent an early, specific, and easily detectable clinical finding of CAR T-cell therapy-related neurotoxicity, potentially informing its management.

In consideration of its significant activity, the role of FLU needs to be further evaluated in the management of pretreated and untreated patients with LG-NHL.

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The International Prognostic Score (IPS) is the most commonly used risk stratification tool for patients with advanced Hodgkin lymphoma (HL). It incorporates seven clinical parameters independently associated with a poorer outcome: male sex, age, stage IV, hemoglobin level, white blood cell and lymphocyte counts, and albumin level. Since the development of the IPS, there have been significant advances in therapy and supportive care. Recent studies suggest that the IPS is less discriminating due to improved outcomes with ABVD therapy. The aim of the present study was to asses if classic prognostic factors maintain their prognostic meaning at the time of response-adapted treatment based on interim PET scans. We evaluated the prognostic significance of IPS in the 520 advanced stage HL patients enrolled in the PET-guided, HD0801 trial in which PET2-positive patients underwent a more intense treatment with an early stem-cell transplantation after 2 cycles of ABVD. We observed that in these patients, the IPS completely loses its prognostic value together with all the single parameters that contribute to the IPS. Furthermore, neutrophils, monocytes, lymphocytes, and the ratio among them also no longer had any predictive value. We believe that the substantial improvement in survival outcomes in PET2-positive patients treated with early autologous transplantation could explain the complete disappearance of the residual prognostic significance of the IPS.

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Rituximab has been shown to improve outcome in elderly patients with DLBCL (Coiffier et al., NEJM, 2002), but there is only limited data for young low-risk patients. In an intergroup study conducted in 18 countries, untreated patients (18–60 years) with low-risk CD20+ DLBCL (IPI 0 or 1, stages II-IV and stage I with bulk) were randomized to receive 6 cycles of a CHOP-like regimen (CHEMO) or the same chemotherapy plus rituximab 375 mg/m2 given on days 1, 22, 43, 64, 85, and 106 (R-CHEMO). Radiotherapy was planned to sites of initial bulk and/or extranodal involvement. The primary endpoint was time to treatment failure (TTF). Between 05/2000 and 10/2003, 824 patients were recruited. A first planned interim analysis was performed on 326 evaluable patients in November 2003 and let the independent review committee recommend the early stopping of the MInT trial on Dec 5, 2003, with 59 patients still under chemotherapy (28 CHEMO; 31 R-CHEMO). These were censored for this analysis. We here present the first full-set analysis on 823 evaluable patients (410 CHEMO; 413 R-CHEMO) with data base status as of Aug 2nd, 2004. Patient characteristics were: median age 47 years; IPI=1: 57%; stages III/IV: 28%; elevated LDH: 29%; bulky disease: 49%. Toxicity was not different in the two arms. After a median time of observation of 22 months, R-CHEMO patients had a significantly longer TTF (p<0.00001), with estimated 2-year TTF rates of 60% (CHEMO) vs 76% (R-CHEMO). Complete remission (CR) rates of evaluable patients (CR) were significantly different (67% CHEMO vs 81% R-CHEMO, p<0.0001) as were the rates of progressive disease during treatment (15% vs 4% , p<0.00001). Similarly, overall survival was significantly different (p<0.001), with 2-year survival rates of 87% (CHEMO) and 94% (R-CHEMO), respectively. The rate of lymphoma-associated deaths was reduced by two thirds with R-CHEMO. Using a Cox proportional hazard model for the primary endpoint TTF, treatment arm (p<0.00001), bulky disease (p<0.0001) and IPI (p<0.001) were significantly associated with the risk of an event. The benefit of R-CHEMO was demonstrated for all patients irrespective of these risk factors. However, 2-year TTF after R-CHEMO in patients with bulky disease and/or IPI=1 was significantly worse (p<0.001) than in patients with IPI=0 and no bulk (71% vs 90%, respectively), proposing two novel subgroups of young low-risk patients with a favorable and less favorable outcome in the era of combined rituximab/CHOP-like chemotherapy. The combination of 6 cycles of a CHOP-like chemotherapy with rituximab sets the standard for young low-risk patients with CDD20+ DLBCL. While further improvement will be difficult to demonstrate for the favorable (IPI=0, no bulk) subgroup, it is still warranted with regard to TTF for the less favorable subgroup (IPI=1 and/or bulk).