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mantle cell lymphomaHIGH-DOSe CyTarabINe (ara-C) IMPrOVeS OS

Peter Duggan, MD, Clinical associate Professor, Department of Medicine, university of Calgary. Leader, Tom baker Cancer Centre Hematology Tumour Group.

TRIAL SUMMARY: Longer followup brings out benefitHermine O, Hoster e, Walewski J et al. alternating courses of 3x CHOP and 3x DHaP plus rituximab followed by a high-dose ara-C containing myeloablative regimen and autologous stem cell transplantation (aSCT) increases overall survival when compared to 6 courses of CHOP plus rituxi-mab followed by myeloablative radiochemotherapy and aSCT in mantle cell lymphoma: final analysis of the MCL younger Trial of the european Mantle Cell Lymphoma Network (MCL net). aSH 2012. abstract 151.

Mantle cell lymphoma (MCL) outcome has improved during the last decades. In its first randomized trial, the MCL net demonstrated that myeloablative consolidation followed by autologous stem cell transplantation (ASCT) resulted in a significant prolongation of progression-free survival (PFS) in advanced-stage MCL (Dreyling et al. Blood 2005). Recent-Phase II studies suggest that the addition of rituximab and/or high-dose ara-C may significantly improve outcome. A Phase II trial using sequential R-CHOP (rituximab, cyclo-phosphamide, doxorubicin, vincristine and prednisone)/ R-DHAP (rituximab, dexamethasone, cytarabine and cisplatin) followed by ASCT showed an overall response rate (ORR) of 95% with a complete response (CR) rate of 61%, a median event-free survival (EFS) of 83 months and a 75% survival rate at 5 years (Delarue et al. Blood 2012). Two years ago the preliminary results of the the MCL randomized trial com-pared 6 courses of CHOP plus rituximab followed by mye-loablative radiochemotherapy (12 Gray total-body irradiation [TBI], 2x60 mg/kg cyclophosphamide) and ASCT (control arm A) vs alternating courses of 3x CHOP and 3x DHAP plus rituximab followed by a high-dose ara-C containing myeloablative regimen (10 Gray TBI, 4x1.5 g/m2 ara-C, 140 mg/m2 melphalan) and ASCT (experimental arm B). Those results showed that after a median followup of 27 months, patients in Arm B experienced a significantly better time-to-treatment failure (TTF) (49 months vs no response [NR]; p=0.0384, HR 0.68), but no overall survival differ-ence. Final results are now available, with a median followup of 51 months.

Patients had previously untreated MCL Stage II–IV up to

the age of 65 years. The primary endpoint was TTF. Stable disease after induction, progression or death from any causes were considered as treatment failures. Sample size was calcu-lated to detect a relative risk of 52% for Arm B with a power of 95%. Randomization was stopped as soon as a significant difference was observed between the two arms.

The 455 patients evaluable for the primary analysis displayed the following characteristics (A vs B): median age 54 vs 56 years, male 79% vs 79%, Stage IV 82% vs 81%, symptomatic 43% vs 31%, ECOG (Eastern Cooperative Oncology Group) status >2 4% vs 4%, elevated LDH (lactate dehydrogenase) 39% vs 35%, and MIPI (MCL International Prognostic Index) low/int/high risk 60%/25%/15% vs 64%/23%/13%, respec-tively. After induction, overall response (OR) was similar in both arms (90% vs 95%; p=0.19) but CR and unconfirmed CR (CRu) rates were significantly higher in Arm B (25% vs 36%; p=0.012 and 40% vs 54%; p=0.0003). The number of patients transplanted was similar in both arms (72% vs 73%). After transplantation OR and CR rates were comparable in both arms (98% vs 97% and 63% vs 61%). After a median followup of 51 months, TTF was longer in Arm B (46 vs 88 months; p=0.0382, HR 0.68) mainly due to a lower number of relapses after CR/CRu/partial response (n=81 vs 40). The rate of ASCT-related deaths in remission was similar in both arms (4% vs 4%). Although CR rate after ASCT was similar in both arms, remission duration (RD) after ASCT was superior in Arm B (49 vs 84 months; p=0.0001). At the time of final analysis, OS was superior in Arm B (NR vs 82 months, p=0.045). Safety after induction was comparable in both arms except for an increased grade 3/4 hematologic toxicity (hemoglobin 9% vs 30%, white blood cells 50% vs 75%, platelets 10% vs 74%), renal toxicity (creatinine Grade 1/2: 10% vs 44%, Grade 3/4: none vs 1%), and Grade 1/2 nausea and vomiting in Arm B. Toxicities of both conditioning regimens were similar.

Longer followup confirmed that high-dose ara-C in addi-tion to R-CHOP significantly increases complete response rates, TTF and, in addition, overall survival without a clinically relevant increase in toxicity. Therefore, induction regimens containing high-dose ara-C followed by ASCT should become the new standard of care in MCL patients <65 years.

Reports from the American Society of Hematology Annual Meeting

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COMMENTARY: When R-CHOP alone is used as front-line therapy for MCL, response rates of 90% or higher are seen. However, CR rates are only 25–40%. These responses are not durable, with median PFS of only 16 months.1 Dramatic improvements in outcomes have been achieved with the addition of high-dose ara-C to initial therapy, and consolida-tion with high-dose chemotherapy and ASCT.

In patients who fail to achieve a CR to R-CHOP, 84% will go on to achieve CR with the addition of 2 cycles of DHAP.2 Induction with 3 cycles of R-CHOP followed by 3 cycles of DHAP results in more complete molecular responses com-pared to 6 cycles of R-CHOP, with improvement in PFS for those with a molecular response.3 Intensive induction incor-porating high-dose cytarabine (Hyper-CVAD + methotrexate/ cytarabine) has attempted to improve induction outcomes. Single-centre data suggested an 87% CR rate for Hyper-CVAD + methotrexate/cytarabine,4 though a multicentre trial resulted in only 58% CR/CRu and 30% PR.5 Toxicity is an important issue with this regimen, with up to 29% stopping treatment early due to side effects.

A single randomized trial showed the benefit of consoli-dation with high-dose chemotherapy and ASCT following CHOP-like chemotherapy6. Median PFS was 39 months for those transplanted vs 17 months following treatment with chemotherapy alone. There was no significant difference in OS. The single-arm Nordic MCL-2 study treated patients with dose-intensive R-CHOP alternating with R-cytarabine fol-lowed by ASCT.7 The 6-year PFS and OS were 66% and 70%.

Despite the improvement in remission duration and survival achieved with the addition of high-dose cytarabine during induction and consolidation with ASCT, there is no accepted standard approach to initial therapy of young patients with MCL. This should change with the compelling results from

the MCL Younger trial presented at the 2012 ASH meeting. In this study, standard R-CHOP (Arm A) or sequential cycles of R-CHOP and R-DHAP (Arm B) was followed by myelo-ablative chemotherapy and ASCT. Although response rates following ASCT were identical in the two treatment arms, how that response was achieved did matter. Relapse rates were twice as high in Arm A as in Arm B, resulting in a 3-year improvement in remission duration for those receiving DHAP. OS was also improved (median 82 months for Arm A, not yet reached in Arm B). These results were achieved with no difference in treatment-related mortality (4% in each arm). There was however a higher rate of Grade 3/4 hematologic toxicity in the high-dose cytarabine arm (Arm B).

R-CHOP plus R-DHAP followed by high-dose chemo-therapy and ASCT should be considered the new standard of care for young, newly diagnosed MCL patients. Induction with more intensive regimens is probably unnecessary. The results of the current trial compare favourably to results seen with Hyper-CVAD + methotrexate/cytarabine,8 but with considerably less toxicity. Further advances in treatment may be seen with the use of new agents such as bendamustine in induction therapy. In elderly patients treated with chemo-therapy alone, the use of maintenance rituximab has been shown to decrease progression and improve OS.9 It is likely that similar benefit will be seen in younger patients given maintenance with rituximab or novel agents such as bortezo-mib or lenolidomide following stem cell transplant.

Disclosure: Dr. Duggan reports no conflicts of interest relevant to this article.

References1. Howard OM, Gribben JG, Neuberg DS et al.: Rituximab and CHOP induction therapy

for newly diagnosed mantle-cell lymphoma: molecular complete responses are not predictive of progression-free survival. J Clin Oncol 20, 1288-94 (2002).

2. Lefrère F, Delmer A, Levy V, et al. Sequential chemotherapy regimens followed by high-dose therapy with stem cell transplantation in mantle cell lymphoma: an update of a prospective study. Haematologica 2004;89(10):1275-76.

3. Pott C, Hoster E, Beldjord K, et al. R-CHOP/R-DHAP compared to R-CHOP induction fol-lowed by high dose therapy with autologous stem cell transplantation induces higher rates of molecular remission in MCL: results of the MCL Younger Intergroup Trial of the European MCL Network. Blood 2010;116(21):965.

4. Romaguera JE, Fayad L, Rodriguez MA, Broglio KR, Hagemeister FB, Pro B, et al. High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine. J Clin Oncol 2005;23(28):7013-23.

5. Epner EM, Unger J, Miller T, Rimzsa L, Spier C, Leblanc M, Fisher R (2007) A multi center trial of hyperCVAD+rituxan in patients with newly diagnosed mantle cell lymphoma. Blood 110:121a, abstract 387.

6. Dreyling M, Lenz G, Hoster E, van Hoof A, Gisselbrecht C, Schmits R, et al. Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs event-free survival in mantle-cell lymphoma: results of a prospective randomized trial of the European MCL Network. Blood 2005;105(7):2677-84.

7. Geisler C, Kolstad A, Laurell A, Andersen N, Pedersen LB, et al. Long-term pro-gression-free survival of mantle cell lymphoma after intensive front-line immuno-chemotherapy with in-vivo purged stem cell rescue: a non-randomized phase-2 multicenter study by the Nordic Lymphoma Group. Blood 2008;112(7):2687-93.

8. LeCasce A, Vandergrift JL, Rodriguez MA et al.: R-CHOP, followed by high dose therapy and autologous stem cell rescue (HDT/ASCR), and R-HyperCVAD have equivalent progression-free survival and are superior to R-CHOP alone in younger patients with mantle cell lymphoma: a comparative effectiveness analysis from the National Comprehensive Cancer Network (NCCN) non-Hodgkin’s lymphoma outcomes database project. Blood 2009;114, A403.

9. Kluin-Nelemans HC, Hoster E,Hermine O et al. Treatment of older patients with mantle cell lymphoma. N Engl J Med 2012; 367:520-31.

In BrIefAlready known• Mantle cell lymphoma (MCL) is an incurable

malignancy with a poor prognosis following treatment with r-CHOP alone.

• both high-dose cytarabine and aSCT have been shown to improve remission duration in MCL.

What these studies showed• The combination of r-CHOP and r-DHaP induc-

tion prior to aSCT results in longer remissions and better OS compared with pre-transplant induction with r-CHOP alone.

Next steps• Studies addressing the need for an anthracycline/

r-CHOP are ongoing.• The role of new agents in the initial management

of MCL is being explored. This includes the use of bendamustine in initial therapy, and maintenance with agents such as bortezomib and rituximab.