Long term follow-up of clinical trials in lymphoid malignancies (CLL/LGL/MM)

During EHA 2025, Prof Dr Krzysztof Giannopoulos, hematologist at the Medical University of Lublin in Poland chaired a much-anticipated oral abstract session featuring long-term updates of 5 randomized-controlled, clinical trials evaluating new treatment options across different lymphoid malignancies.

In a first of these studies, cyclophosphamide was compared to methotrexate as a first line treatment for patients with large granular lymphocyte (LGL) leukemia. The study indicated a complete response rate of 12% with methotrexate as compared to 24% with cyclophosphamide. Corresponding objective response rates (ORR) were 32% and 74%, respectively. No difference was seen between the two treatment arms in terms of toxicity. As such, these findings identify cyclophosphamide as the standard of care first line treatment for patients with LGL leukemia.¹

The session also included the results of the final analysis of the phase III GAIA/CLL13 study. Previously, this trial showed a superior progression-free survival (PFS) for venetoclax-obinutuzumab (GV) and GV + ibrutinib (GIV) compared to chemoimmunotherapy (CIT) and venetoclax-rituximab (RV) in fit, treatment-naive CLL patients without a TP53 mutation. After a median follow-up of 63.8 months, the PFS continued to be superior for GV and GIV compared to CIT and RV. In addition, GIV now also showed a significantly longer PFS compared to GV (HR[97.5%CI: 0.61[0.41-0.91], p=0.0046). Estimated 5-year PFS rates were reported at 50.7%  with CIT, 57.4% with RV, 69.8% with GV and 81.3% with GIV. Importantly, the longer PFS obtained with GIV compared to the standard GV regimen should be balanced against the higher toxicity encountered with this regimen and the impact on the quality of life of patients. However, for certain high-risk patients, adding ibrutinib to GV may be a valid treatment choice.²

The three other studies that were discussed in the session focussed on the treatment of multiple myeloma (MM). A first of these presentations provided long-term remission and survival data of the CARTITUDE-1 trial, evaluating ciltacabtagene autoleucel (cilta-cel) in patients with heavily pretreated relapsed/refractory MM. Of the 97 patients who were treated in this study, 32 (33.0%) remained alive and free of progression for ≥5 years after the cilta-cel infusion, without further MM treatment. As such, these long-term data provide the first evidence that cilta-cel may be curative in patients with relapsed/refractory MM.³

In the ATLAS study, the combination of carfilzomib with lenalidomide and dexamethasone (KRd) was compared to lenalidomide (R) alone as maintenance therapy after an autologous stem cell transplantation (ASCT) for patients with newly-diagnosed MM. In the KRd group, patients with standard-risk cytogenetics and measurable residual disease (MRD) negativity at 10^-5 after cycle 6 were switched to R maintenance after cycle 8. The remaining patients continued KRd up to 36 cycles and then switched to R alone. Interestingly, the PFS proved to  was superior for KRd vs R, with 4-year PFS rates of 67.5%  and 38.0%, respectivey (median PFS: 72.8 vs. 37.3 months; HR[95%CI]: 0.46 [0.30- 0.70]; p=0.0002). The delayed disease progression obtained with KRd maintenance also translated into a significantly better OS, with 4-year OS rates of 84.3% and 79.2% with KRd and R, respectively (median not reached vs. 82.2 months; HR[95%CI]: 0.49[0.26-0.90]; p=0.023). In conclusion, these findings identify extended KRd maintenance as a potential new standard of care in transplant-eligible, newly-diagnosed MM patients.⁴

In the randomized, phase II FORTE trial 474 newly diagnosed MM patients were randomized into one of three induction–intensification–consolidation arms: KRd followed by an ASCT, KRd for 12 cycles without an ASCT or KCd followed by an ASCT. Subsequently, patients entered a second randomization between maintenance therapy with KR or R alone. Long-term follow-up data of this trial revealed a median PFS of about 8 years with KRd-ASCT, confirming the superiority of this regimen over KRd12 (HR:  0.59; 0=0.002) and KCd-ASCT (HR: 0.63; p=0.006). In the maintenance phase, the addition of K to R for up to 24 months resulted in a signficantly better PFS (4-year PFS rate: 75% vs. 66%; HR: 0.66; p= 0.04).⁵