NCRI phase II study of CHOP in combination with ofatumumab in induction and maintenance in newly diagnosed Richter syndrome

Abstract

Richter syndrome (RS) is associated with chemotherapy resistance and a poor historical median overall survival (OS) of 8-10 months. We conducted a phase II trial of standard CHOP-21 (cyclophosphamide, doxorubicin, vincristine, prednisolone every 21 d) with ofatumumab induction (Cycle 1: 300 mg day 1, 1000 mg day 8, 1000 mg day 15; Cycles 2-6: 1000 mg day 1) (CHOP-O) followed by 12 months ofatumumab maintenance (1000 mg given 8-weekly for up to six cycles). Forty-three patients were recruited of whom 37 were evaluable. Seventy-three per cent were aged >60 years. Over half of the patients received a fludarabine and cyclophosphamide-based regimen as prior CLL treatment. The overall response rate was 46% (complete response 27%, partial response 19%) at six cycles. The median progression-free survival was 6·2 months (95% confidence interval [CI] 4·9-14·0 months) and median OS was 11·4 months (95% CI 6·4-25·6 months). Treatment-naïve and TP53-intact patients had improved outcomes. Fifteen episodes of neutropenic fever and 46 non-neutropenic infections were observed. There were no treatment-related deaths. Seven patients received platinum-containing salvage at progression, with only one patient obtaining an adequate response to proceed to allogeneic transplantation. CHOP-O with ofatumumab maintenance provides minimal benefit beyond CHOP plus rutuximab. Standard immunochemotherapy for RS remains wholly inadequate for unselected RS. Multinational trials incorporating novel agents are urgently needed.

An update for Richter syndrome – new directions and developments

“…The median SUV max was 3.4 (range 1.5–6.3) and 3.1 (range 1.2–5.9) in newly diagnosed and relapsed CLL, respectively whilst the median SUV max with suspected or confirmed RT reached 16.5 (range 7.2–25.3) ( P < 0.001) (Papajík et al , ). These studies were consistent with the prospective results from the recent prospective CHOP‐OR (cyclophosphamide, doxorubicin, vincristine, prednisolone and ofatumumab followed by ofatumumab maintenance in newly diagnosed RS) trial (Eyre et al , ). Within this trial, of the 17 patients with measurable disease on baseline PET‐CT, the median SUV max was 18 (range 5.85–69.4).…”

“…There is no evidence at present that either of these scoring systems should be used to alter therapy at induction. The CHOP‐OR trial attempted to further validate both scoring systems and although analysis was limited by small numbers, the trend of the results were consistent with the prior published data (Eyre et al , ).…”

“…Rossi et al () found that 47.1% of RS patients displayed TP53 deletion, mutation or both. A similar proportion of patients with TP53 disruption were treated in the prospective CHOP‐OR trial (Eyre et al , ). TP53 aberrations have been described in the clonal evolution of CLL to clonally related RS.…”

“…In the CHOP‐OR trial, only two of 29 tested cases were positive for EBV by either LMP1 IHC or EBER ISH. Neither had received prior fludarabine and one was treatment‐naïve (Eyre et al , ). There is little evidence to suggest an association with EBV in typical DLBCL arising in CLL patients not exposed to prior purine analogues (Rossi et al , ).…”

Fully automated real-time PCR for EGFR testing in non-small cell lung carcinoma

“…Funding for obtaining and preparing tissue samples was provided from funds paid to ES for work on an unrelated clinical trial [32, 33]. …”