Several guidelines including the European Society of Medical Oncology (ESMO 2014) recommend a high dose cytarabine (HD-ARA-C) containing regimen followed by dose intensification with autologous stem cell transplantation (ASCT) for younger patients with mantle cell lymphoma (MCL).r Such recommendations are based on the findings of several studies that have demonstrated the superiority of HD-ARA-C containing regimens over CHOP-like regimens alone.
The phase 2 Nordic MCL2 trialr was one of the largest studies to initially explore this approach with dose-intensified induction immunochemotherapy with rituximab (R) + cyclophosphamide, vincristine, doxorubicin, prednisolone (maxi-CHOP), alternating with R + high dose cytarabine followed by BEAM or BEAC ASCT. This resulted in progression free survival of 70% at 6 years. The GELA group performed a phase II studyr utilising 3 cycles of CHOP21 (rituximab on cycle 3 only), then 3 cycles of R-DHAP followed by ASCT. At a median follow up of 67 months, the median EFS was 83 months. Median OS was not reached and the 5 year OS was 75%.
The MCL Younger study (of the European MCL Network) a phase 3 trial comparing 3 alternating courses of R-CHOP and R-DHAP with 6 cycles of R-CHOP prior to each arm receiving ASCT.r This study confirmed the results of earlier studies (in randomised fashion) that addition of HD-ARA-C significantly increases CR rates and OS compared to R-CHOP alone (see below).
It is noted that some Australian groups substitute the R-DHAC for R-DHAP, since R-DHAC may be associated with reduced nephrotoxicity. The eviQ reference committee believes that this approach is reasonable, though it does introduce uncertainty as to outcomes. If this substitution is to be considered, there should be an appropriate discussion with the patient prior to administration. Comparable outcomes of a series of Australian patients (>60 years old) receiving alternating R-CHOP/R-DHAC has been presented internationally (conference abstract), lending weight to the feasibility of this approach.r
It should be noted also that there is a specific autologous transplant conditioning regimen that follows the R-CHOP/R-DHAP sequence in the MCL younger study (10 Gy TBI fractionated on D-7 to -5, cytarabine 1.5 g/m2 BD D-4 and D-3, then melphalan 140 mg/m2 D-2). Therefore, if an alternative conditioning regimen, such as BEAM is planned, then this will again produce uncertainty as to outcomes, which should be discussed with patients prior.
There is current debate as to whether first line ASCT is required to consolidate these intensive approaches, particularly with novel treatment options increasingly available,r however this will require further study.
Efficacy
The MCL Younger trialr evaluated 497 patients with MCL stage II-IV younger than 65 comparing R-CHOP (arm A) only versus alternating R-CHOP/R-DHAP (arm B). 234/249 patients in arm A and 232/248 in arm B were included in final analysis (total 466). Median age was 55 years.
After induction, CR/CRu rates were significantly higher in arm B (39% vs 55%; p=0.0005), though overall response (OR) was similar in both arms (90% vs 94%; p=0.14). 85% and 84% were transplanted in each arm. After ASCT, CR rates (included unconfirmed CR) was similar at 76% in arm A and 83% in arm B.
At a median of 6.1 years, time to treatment failure was longer in Arm B (9.1 years vs 6.1 years; p=0.038). It is noted at the time of analysis that overall survival was not significantly different between the two groups (5 year rate 69% versus 76%, p0.12).
Toxicity
The R-DHAP containing regimen is associated with greater toxicities when compared to R-CHOP alone. Transplant related mortality was similar in each arm (3.4%). At 5 years the incidence of secondary MDS/AML was 0.4% in control versus 2.4% in the R-DHAP containing group. Other tumours were seen in 4.8% (control) versus 4.3%.
| |
R-CHOP only (%) |
Alternating R-CHOP/R-DHAP (%) |
| Grade 3/4 anaemia |
8 |
29 |
| Grade 3/4 febrile neutropenia |
8 |
17 |
| Grade 3/4 thrombocytopenia |
9 |
73 |
| Grade 1/2 renal toxicity |
10 |
43 |