Review Stem cell transplantation for mantle cell lymphoma - Nature

Bone Marrow Transplantation (2005) 36, 655–661 & 2005 Nature Publishing Group All rights reserved 0268-3369/05 $30.00

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Review Stem cell transplantation for mantle cell lymphoma: if, when and how? TL Kiss1,5, P Mollee2,5, HM Lazarus3 and JH Lipton4 1

Hematology-Oncology, Hopital Maisonneuve Rosemont, University of Montreal, Montreal, Quebec, Canada; 2Hematology, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia; 3Comprehensive Cancer Center of Case Western Reserve University Hospitals of Cleveland, Cleveland, OH, USA; and 4Allogeneic Blood and Marrow Transplant Program, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada

Summary: Although the prognosis for mantle cell lymphoma (MCL) patients has improved in recent years, the outlook for those with advanced or recurrent disease remains poor. High-dose chemotherapy and autografting performed early in responding patients appears to be a method to extend progression-free survival (PFS) and overall survival (OS). The use of monoclonal antibody therapy added into the initial therapy and in the peritransplant period may improve on these results. Myeloablative allogeneic transplant appears to be a modality capable of providing curative therapy, but is plagued by a high treatment-related mortality, especially in older patients. Reduced-intensity conditioning allografting have fewer problems associated with the initial phase of transplant and hence may be preferred for those patients for whom an allograft is considered but have comorbid conditions or age issues that preclude a full allograft. Long-term results are lacking and the side effects associated with chronic GVHD may be as significant and debilitating. Trials designed to look at newly diagnosed patients with MCL examining the outcomes after planned autologous and allogeneic transplant as part of the initial management are needed to confirm the role of these various modalities in the overall therapy of this poor-outcome lymphoma. Bone Marrow Transplantation (2005) 36, 655–661. doi:10.1038/sj.bmt.1705080; published online 11 July 2005 Keywords: mantle cell lymphoma; autologous; allogeneic; nonmyeloablative stem cell transplantation

Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin’s lymphoma (NHL) frequently associated with a t(11;14)(q13;q34) translocation that juxtaposes BCL1 with the immunoglobulin heavy chain gene, yielding upregulated cyclin D1.1 The biologic properties, diagnosis, and manage-

Correspondence: Dr JH Lipton, Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario, Canada M5G 2M9; E-mail: [email protected] 5 Contributed equally to this review. Received and accepted 1 June 2005; published online 11 July 2005

ment of MCL have been reviewed extensively.1,2 Although conventional CHOP-like therapy, fludarabine-based therapy and more recently, anti-CD20-based therapies have shown increasing responses, the majority of patients and in particular, those with advanced disease, will relapse. Stem cell transplant offers the options of trying to incorporate dose intensification with or without a putative graft-versus-lymphoma (GvLy) effect into the management of such patients, often building on the maximum response observed with new pre-transplant regiments and attempting to extend the response duration or even cure.3,4 The goal of this review is to summarize the outcome of these attempts.

Autologous stem cell transplantation in MCL Single-center trials A number of single-center trials in the 1990s have been reported initially with discouraging results.5–11 Ketterer et al5 reported 16 patients with MCL who received highdose chemotherapy followed by autologous stem cell support, six treated first line and 10 in chemotherapysensitive relapse. Disease-free survival (DFS) and overall survival (OS) at 3 years were 24%, with a median survival after diagnosis of 29 months. Stewart et al6 reported on 14 patients with MCL treated with intense anthracycline containing chemotherapy and on nine patients with recurrent MCL treated with autologous stem cell transplant. OS and failure free survival (FFS) of chemotherapy patients after 5 year were 23 and 8%, 2 year FFS of transplant patients was 34%. Improved results were reported by a number of European groups in 1998. Milpied et al7 reported on results of 18 MCL patients, 17 receiving unpurged autologous BMT and one allogeneic BMT. In all, 10 were in first partial response, the remaining in more advanced phase of disease. Preparation consisted of TBI plus chemotherapy in 13 and BEAM in five patients. DFS and OS were estimated at 48 and 80% at 4 years. TBI containing preparation led to better results and there was a trend to improved results for those patients transplanted in PR1. A larger series of 28 patients with progressive disease, only eight in first complete remission (CR) and all others multitreated and or with relapsed disease, bone marrow infiltration present in 57%, was reported.8 The cyclophosphamide/TBI preparation was well tolerated with no

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treatment-related deaths. Bone marrow was purged with anti-B cell antibodies. DFS and OS were estimated at 4 years at 31 and 62%. No plateau was observed at a median follow-up of 24 months. The Nebraska group published their results of autologous transplantation in 40 patients who underwent their transplant between 1991 and 1998 followed for a median of 24 months.12 The 2 year OS and event-free survival (EFS) were 65 and 36%, respectively. In multivariate analysis, the only factor associated with poor EFS was the number of prior chemotherapy regimens. Patients who had more than three prior chemotherapy regimens had an EFS of 0% as compared to 45% at 2 years for those who had received fewer than three treatment regimens.

Registry (observational database) and multicenter trials As interest was growing to use high-dose therapy with stem cell support in MCL, international registries pooled resources to analyze outcomes. The European Blood and Marrow Transplant (EBMT) and Autologous Blood and Marrow Transplant (ABMTR) Registries pooled their data and performed a retrospective analysis on the outcome of 195 patients with MCL who had received an autologous transplant between 1988 and 1998.13 The median follow-up was 3.9 years with OS at 2 and 5 years, 76 and 50% and progression-free survival (PFS) 55 and 33%. Multivariate analysis showed improved outcome for patients transplanted in CR1. No difference was seen in outcomes using chemotherapy alone vs chemotherapy and radiation as part of the preparative regimen. Comparison with historical controls suggested in this large study that autologous transplantation improves outcomes in patients with MCL as compared to nontransplant controls. Similar results were seen in a French study14 with 24 patients with MCL receiving an autologous transplant. With a median followup of 34 months, an EFS and OS at 3 years of 55 and 68%, respectively were noted. No disease or treatment specific parameters influenced outcome in this study. Several groups have developed multicenter trials to examine the influence of timing of transplant on treatment results;15–17 patients in first CR have better results than patients receiving transplant as salvage or at a later stage of disease. The European MCL network designed a prospective randomized trial comparing consolidation with myeloablative radiochemotherapy followed by autologous stem cell transplantation to interferon maintenance in first remission patients.18 Patients received CHOP or CHOPRituximab as initial treatment for four to six cycles. Those achieving CR or PR were randomized to mobilization with DexaBEAM followed by autologous stem cell transplantation using Cyclophosphamide/TBI as preparation or to two additional courses of consolidation with DexaBEAM and interferon maintenance. In total, 122 patients were evaluable 62 proceeded to transplant and 60 received interferon maintenance. Median duration of PFS was superior in the transplant arm with 39 months vs 17 months (P ¼ 0.01), whereas OS at 3 years was not different suggesting feasibility and a potential benefit for early autologous transplantation. Bone Marrow Transplantation

HyperCVAD therapy Khouri et al19,20 used intensive upfront chemotherapy with the HyperCVAD regimen followed by early autologous stem cell transplantation. Encouraging results on 33 patients were reported. Median follow-up was 49 months and OS and DFS at 5 years were estimated to be 77 and 43%. A subset of patients with low tumor load and low b-2 microglobulin blood concentration had particularly favorable outcomes, which were statistically significantly superior to patients who had more advanced disease.

Rituximab therapy More recently rituximab has been used in combination with autologous stem cell transplantation. This agent has been incorporated either as part of the induction treatment,21 as strategy for in vivo purging of autologous stem cells prior to transplantation,22–24 or also as immunotherapy after autograft.25–27 An Italian study reported on 28 untreated MCL patients younger than 61 years of age.22 These subjects were treated with three cycles of standard dosedebulking chemotherapy followed by high-dose rituximabsupplemented chemotherapy using cyclophosphamide, cytarabine, melphalan and mitoxantrone. Rituximab was given prior to apheresis, prior to stem cell infusion and also after stem cell infusion. A total of 24/27 patients alive after transplant remain in CR at a median follow-up time of 35 months. OS and EFS were 89 and 79%, respectively. These results compared with OS and EFS of 42 and 18% observed in 35 age-matched historic controls treated with standard dose chemotherapy at the same centers. Another smaller study combining rituximab followed by high-dose therapy and autologous transplantation confirmed these results.23 Rituximab therapy used as consolidation after autologous stem cell transplantation has been reported in 30 patients (20 with follicular lymphoma, 10 with MCL).25 In all, 25 patients were censored and were evaluable for minimal residual disease at an actuarial EFS of 81% at 4 years. PCR negativity was observed in 22% of patients before autologous transplant, in 53% post transplant, 72% after rituximab therapy and in all patients at 6 months after autograft. Outcomes of 20 newly diagnosed MCL patients treated on a prospective trial of autograft and post transplant rituximab therapy were compared with the outcome of 40 matched historic control patients treated using standard combination chemotherapy.26 PFS and OS were superior in the transplant group at 3 years with PFS of 89 vs 29% (Po0.00001) and OS of 88 vs 65% ( ¼ 0.052). Freedman et al24 reported on 28 patients with MCL who underwent high-dose chemoradiotherapy (cyclophosphamide/TBI) and an anti-B-cell monoclonal antibody purged autologous BMT. In all, 19 of 28 patients relapsed after a median time of 21 months. These unsatisfactory results may be related to the fact that most of these patients were heavily pretreated and only nine were transplanted in first CR/PR.


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Use of radiolabeled monoclonal antibody therapy Encouraging results have been noted using a combination of radiolabeled anti-CD20 monoclonal antibody therapy and autologous stem cell transplant. In total, 16 advanced disease MCL patients (relapsed or refractory) were treated with 131I labeled anti-CD20 antibody (tositumomab) delivering 20–25 Gy to normal organs.28 Autologous stem cell transplantation was performed 10 days later. OS at 3 years was estimated at 93% and PFS at 61%. Seven refractory disease MCL patients who had relapsed after an autologous stem cell transplant were treated with an 131I labeled chimeric anti-CD20 antibody (C2B8) followed by stem cell support.29 Five patients remain in CR; two patients have relapsed, one at 3 months and the other at 26 months after treatment.

Conclusions regarding autotransplant in MCL Autologous stem cell transplantation appears to improve outcomes over conventional treatment; however, no large conclusive comparative studies are available. Outcomes after autograft appear superior in patients treated while in a minimal disease state or in first CR and in patients who have not received multiple prior chemotherapy regimens. Intense pretransplant regimens like HyperCVAD improve results in selected patients. The addition of rituximab therapy to the autograft regimen appears to provide an additional benefit in terms of outcome although this finding may also be true with nontransplant treatment regimens. Radiolabeled anti-CD20 antibodies should be explored further and patients not considered eligible for allogeneic transplantation or experimental treatment protocols should be evaluated for autologous transplantation early in their disease course. Patients who have not obtained a CR despite exposure to multiple chemotherapy regimens should not be considered candidates for autologous stem cell transplantation.

Allogeneic SCT (AlloSCT) in MCL There are fewer reports assessing the role of alloSCT when compared to autograft in MCL. This observation relates to MCL being a relatively uncommon and only recently described disease. The median age at diagnosis of 65 years makes standard alloSCT unsuitable for most patients. In addition, early reports of alloSCT demonstrated substantial treatment-related mortality (TRM) in this patient population.30 Nonetheless, alloSCT remains a potentially attractive therapeutic modality due to potential GvLy effects, and the avoidance of marrow contamination by tumor and post transplant tMDS/AML that are associated with autologous transplantation.

GvLy effect in MCL Lymphoma is a biologically heterogeneous disease. Convincing evidence to support a significant GvLy effect in histologically aggressive lymphomas is lacking,31 while a GvLy effect in indolent lymphomas (particularly follicular

lymphomas) is reasonably well documented.32 Owing to its distinctive biology and natural history, a GvLy effect in MCL cannot be inferred from such effects in indolent or aggressive disease but needs to be assessed from reports of patients with MCL undergoing alloSCT. Even though the literature in this area is limited, there is emerging evidence to support a GvLy effect in MCL. These data include: reduced relapse rates after allografts, both in comparison to historic controls and to autografts;33–36 disease response to withdrawal of immunosuppression;37 delayed progressive post transplant improvement in clinical or molecular remission status in the absence of antilymphoma therapy;33,38,39 and clinical responses to donor lymphocyte infusions (DLI).33,40,41 In contrast, there is a substantial relapse rate after alloSCT reported in an EBMT registry study42 and similar relapse rates noted between auto- and allo-SCT in a report from the Johns Hopkins Cancer Center.43 The lack of any plateau in the survival curves reported in an IBMTR registry study35 also poses questions regarding the potency of any GvLy effect to overcome the almost inevitable risk of relapse in patients with MCL.

Myeloablative AlloSCT Several recent publications reporting the use of myeloablative alloSCT have expanded our understanding of this approach in MCL. Studies analyzing cohorts of more than five patients are detailed in Table 1. The median age at transplant has been 45–50 years, several years less than the median age of patients with MCL. The age of patients undergoing transplantation no doubt contributes to the high TRM that has been reported in some series. Often such patients have advanced disease with multiply relapsed or refractory lymphoma, while fewer patients are transplanted in first remission. The small patient numbers and variety of conditioning regimens in these reports make interpretation of the data difficult. The largest experience comes from registry studies of the EBMT44 and IBMTR,35 both of which have been presented as preliminary communications. Vandenberghe et al44 analyzed the outcomes of 22 MCL patients and found a 2-year EFS and OS of 50 and 62%, respectively. The median follow-up was too short to establish any curative potential of alloSCT. Armitage35 presented the IBMTR experience of 212 patients (188 matched-related donors and 28 unrelated or haploidentical donors). In first remission, 16% of patients were transplanted, 38% in relapse or second remission and 46% were never in remission. At a median follow-up of 12 months (range, 3–106 months), EFS was poor with 2-year OS approximately 40%. There was no plateau in the EFS curve, even for patients transplanted in first remission. These registry data suggested that MCL remained incurable using conventional alloSCT although follow-up was relatively short. Contrasting results were presented in the two small series with the longest follow-up. The City of Hope experience of 13 patients at a median follow-up of 4.75 years found a 3-year PFS of 53% with infrequent late relapses.36 The Princess Margaret Hospital also detailed six patients at a median follow-up in excess of 4 years.34 Remarkably, there was no TRM and only one late, isolated testicular relapse in six Bone Marrow Transplantation


Bone Marrow Transplantation

NRM ¼ nonrelapse mortality; EFS ¼ event-free survival; DFS ¼ disease-free survival; OS ¼ overall survival; NA ¼ not available; FFP ¼ freedom from progression. a Both autologous stem cell transplant (autoSCT) and allogeneic stem cell transplant (alloSCT).

AlloSCT has increased NRM but lower relapse vs autoSCT o20% at 2 years B40% at 2 years 50 years 212 (+553 auto)

CR1 16%Never in CR 46%Relapse/CR2 38%

NA

NA

Refractory disease for EFS and OSa

One patient in ongoing remission at 11 years

0 14% at 3 years NA 100% at 4 years 100% at 4 years 53% at 3 years 51% at 3 years 50% at 2 years 62% at 2 years 0% NA NA 48.3 years 47 years 6 13 (+64 auto) 22 (+150 auto)

4% refractory 55 years 19 (+38 auto)

a

Berdeja et al45 Updated in Kasamon et al43 Rifkind et al34 Popplewell et al36 Vandenberghe et al13/ EBMT Armitage35/IBMTR

No refractory 23% refractory NA

10 of 19

B37% at 3 years

?

20% at 3 years

1 year FFP 90% vs 44% for chemosensitive vs refractory disease Refractory disease prognostic for worse EFS 1 late relapse at 51 months a

NA 1 23% at 3 years 55% at 3 years Seven of 12 12% at 3 years Six of 16 55% at 3 years 25% refractorya 5 refractory 47 yearsa 52 years 12 (+16 auto) 16 Sohn et al30 Khouri et al33

OS EFS/DFS NRM Median age Disease status at transplant N Author

Table 1

Selected studies (45 patients) of conventional allogeneic stem cell transplantation in mantle cell lymphoma

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Comment

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patients, all of whom who underwent transplant for relapsed disease. One patient remains in remission 11 years after transplant. Thus, for select patients, prolonged DFS and possibly cure can be achieved after alloSCT. The importance of chemosensitivity in determining outcome after alloSCT for MCL has been demonstrated repeatedly across most studies.33,35,44,45 Those subjects refractory to salvage chemotherapy at the time of transplant generally have an EFS of less than 25%, although it may be appreciably worse in some cases due to both increased rates of relapse and increased TRM. This pattern is not dissimilar to that seen with autograft, suggesting that there is only a limited role for alloSCT to overcome MCL chemoresistance. Conclusive evidence that conventional alloSCT offers a cure for MCL is still lacking, although small numbers of patients who are experiencing prolonged DFS are appearing. TRM associated with this procedure should preclude its use in first remission, but myeloablative alloSCT still may play a role in MCL patients who have chemotherapy sensitive relapsed disease.

Nonmyeloablative AlloSCT Many MCL patients are considered too old to be able to tolerate myeloablative conditioning; nonmyeloablative alloSCT represents a mechanism of delivering GvLy effect with less toxicity. Several recent reports examining this approach are detailed in Table 2. The largest experience, from the EBMT,42 recently was updated46 and reported on the outcome of 144 patients undergoing nonmyeloablative alloSCT in which a variety of different preparative regimens were employed. Patients had received a median of two prior chemotherapy regimens and 42% previously had undergone an autograft. In all, 100 had chemosensitive MCL, 22 were refractory and 22 were untested at the time of transplant. At a median followup of 9 months, 2-year TRM was 50% and at 2 years they noted a relapse rate of 57% and PFS and OS of 26 and 31%, respectively. Patients with chemoresistant disease had a particularly poor outcome. Recently, three institutions have reported their experience with nonmyeloablative alloSCT in MCL. Khouri et al38 analyzed 18 patients conditioned predominantly with fludarabine, cyclophosphamide and high-dose rituximab. In all, 16 patients had chemosensitive MCL after HyperCVAD/high-dose methotrexate þ cytarabine/rituximab salvage chemotherapy. At a median follow-up of 26 months 2-year PFS was 82% with only three relapses reported. While such a preparative regimen is likely to have significant activity even in multiply relapsed patients, these data suggest that a GvLy effect was operative. Two patients received DLI resulting in one sustained complete response and one partial response lasting for 1 year. Maris et al39 reported 33 patients undergoing nonmyeloablative alloSCT using fludarabine/low-dose TBI conditioning. This group of patients had advanced disease with a median of four lines of previous chemotherapy, a prior autograft in 42 and 39% demonstrating chemorefractory MCL at the time of transplant. At a median follow-up of 2 years, the 2-year nonrelapse mortality was 24% and relapse


49 years Robinson et al42/ EBMT Updated in Robinson et al46

NRM ¼ nonrelapse mortality; EFS ¼ event-free survival; DFS ¼ disease-free survival; OS ¼ overall survival; NA ¼ not available; DLI ¼ donor lymphocyte infusion; TRM ¼ treatment-related mortality; Cisplat ¼ cisplatin; Flu ¼ fludarabine; AraC ¼ cytarabine; Mel ¼ melphalan; Mab ¼ monoclonal antibody; TBI ¼ total body irradiation.

57% at 2 years Chemorefractory disease adversely prognostic for TRM, OS and relapse 31% at 2 years 26% at 2 years Various

Refractory in 22

50% at 2 years

60% at 3 years 50% at 3 years NA

10 (+78 other lymphoma) 144 Morris et al41

53.5 years Maris et al39

33

Campath/Flu/Mel

Refractory in one

20% at 3 years

64% at 2 years 39% refractory

24% at 2 year

60% at 2 years

16% at 2 years Chemosensitivity not predictive of relapse 50% at 3 years

One sustained response to DLI 3 86% at 3 years 82% at 3 years 56.5 years Khouri et al20

18

Cisplat/Flu/AraC n¼5 Flu/Cy/Mab n ¼ 13 Flu/TBI

Refractory in two

1

OS EFS/PFS NRM Disease status at transplant Conditioning Median age N Author

Table 2

Selected studies (45 patients) of conventional allogeneic stem cell transplantation in mantle cell lymphoma

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Comment

659

rate 16%; 2-year EFS and OS were 60 and 64%, respectively. Interestingly, chemosensitivity at the time of transplant did not predict for poor outcome in contrast to most other studies. Finally, Morris et al41 assessed 10 patients undergoing nonmyeloablative alloSCT using a Campath-based preparative regimen. Nine of 10 patients had chemosensitive MCL and four had a prior autologous stem cell transplant. At a median follow-up of 3 years, nonrelapse mortality was 20% and 3-year PFS and OS were 50 and 60%, respectively. Half of the patients relapsed; two of these five patients received DLI and one responded. Of the four patients transplanted in CR, three remain without demonstrable disease and all four are alive. The experience with nonmyeloablative alloSCT in MCL is accumulating. This approach appears feasible, although the high nonrelapse mortality in the EBMT series should prompt a caution in more widespread application of the technique. There appears to be evidence for a GvLy effect in the nonmyeloablative setting although it remains to be seen whether this feature is sufficiently potent to impact on OS.

Summary MCL remains a disease with significant therapeutic challenges. Available treatment modalities require further improvement. Autologous and allogeneic stem cell transplantation can improve DFS of patients as compared to conventional treatment at the cost of significant TRM and toxicity. Results of autologous stem cell transplants are improved when performed early in the course of patient’s disease and in patients who are in remission. The addition of anti-CD20 antibodies such as rituximab or radiolabeled antibodies to an autologous stem cell transplant appears to improve further upon patient outcome. Rituximab-containing induction regimens can improve CR and overall response rates; however, responses are mostly short lived47,48 suggesting that consolidation with further treatment be it transplantation or experimental options is reasonable. HyperCVAD as part of an aggressive upfront chemotherapy program followed by autologous transplantation can improve outcomes in selected patients. Allografting leads to long-term survival in selected patients, however, at the cost of significant toxicity and should be explored in suitable patients with chemotherapy sensitive disease. Although allogeneic reduced intensity transplantation in this setting currently lacks long-term data, this modality should continue to be explored.

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