Efficacy
© Journal of Clinical Oncology 2017
The combination of chlorambucil and rituximab resulted in improved ‘remission quality’ with more complete remission (CR) and partial remission (PR) events compared to either agent alone (Arm A: 85% vs Arm B: 94% vs Arm C: 78%, respectively). The combination was associated with a longer median progression free survival (PFS) (8.3 years vs not reached vs 6.9 years respectively) but no difference in overall survival (OS).r
The International Prognostic Index (IPI) score was associated with longer survival on multivariate analysis, while primary gastric involvement was associated with longer Event Free Survival (EFS), PFS and higher CR rate.r
Kaplan-Meier survival curves
© Journal of Clinical Oncology 2017
© Journal of Clinical Oncology 2017
Six small phase 2 studies have assessed the efficacy and safety of the chlorambucil plus rituximab combination.rrrrrr
Study |
Histology |
N |
Prior therapy |
CR % |
PR% |
PFS |
OS% |
% patients needed a dose reduction or delay |
Martinelli et al 2003r |
Indolent NHL (SLL, FL, MZL) |
29 (6 with MZL) |
14/29 (48%) |
63 |
26 |
Not reported |
Not reported |
10% |
Levy et al 2010r |
Gastric MALT refractory to HP7 |
12 |
Nil |
100 |
0 |
100% at 24 months |
100% at 24 months |
Not reported |
Rigacci et al 2007r |
Ocular adnexal MALT |
9 |
0 |
89 |
12 |
92% at 36 months |
100% at 25 months |
0% |
Laszlo et al 2007r |
Follicular NHL (grade I or II) |
25 |
0 |
89 |
9 |
- |
92% at 36 months |
0% |
Bauwens et al 2005r |
Mantle cell lymphoma |
14 |
12/14 were refractory |
36 |
29 |
Median 15 months |
58% at 24 months |
Not reported |
Sachanas et al 2011r |
Non blastoid Mantle cell lymphoma |
20 |
0 |
90 |
5 |
89% at 3 years |
95% at 36 months |
Not reported |
These studies (except Rigacci et al and Sachanas et al) used identical dosing schedules with an induction and consolidation phase as reported by Zucca et al.r
In MZL, these smaller phase 2 studies all show similar Overall Response Rate (ORR) (89 to 100%) and median PFS of over 24 months.
The authors felt that treatment was well tolerated with only 10-25% requiring dose reduction.
Grade 3-4 haematologic toxicity occurred in 22-30%. The incidence of febrile neutropenia was very low (0-3%). The need for GCSF and transfusion support was not reported in any of the studies. Non-haematologic toxicity is predominantly gastrointestinal (14 to 18%) and hepatic (3 to 7%).
All studies used identical response assessment protocols with CT scanning following induction and at the completion of consolidation. Importantly, best responses were seen at 6 months.r
In summary, the combination of chlorambucil and rituximab compared with chlorambucil or rituximab alone as initial treatment in MALT lymphoma appears to result in improved PFS but not OS. The regimen is well tolerated with few grade 3-4 toxicities. Importantly, 40% of patients in the study by Zucca et alr had stage 1 disease and 40% had primary gastric MALT. Radiation therapy can also be considered as a first line treatment option in these patients but has never been compared with chlorambucil and rituximab head to head. Anthracycline containing regimens are not recommended for up-front use as they are toxic and do not appear to result in improved outcomes when compared head to head with lower intensity regimens.r The combination of bendamustine and rituximab has been explored in phase 2 studiesr but never compared to chlorambucil and rituximab.