Mini-review Stem cell transplantation for mantle cell lymphoma - Nature

Bone Marrow Transplantation (2001) 28, 813–820  2001 Nature Publishing Group All rights reserved 0268–3369/01 $15.00 www.nature.com/bmt

Mini-review Stem cell transplantation for mantle cell lymphoma: should it ever be used outside clinical trials? JW Sweetenham University of Colorado Health Sciences Center, Denver, CO, USA

Summary: The outlook for patients with mantle cell lymphoma is poor. The reported median survival in most published series is only 3 to 4 years, and even the most favorable prognostic groups have median survival rates of only 5 years, with no evidence of cure. The use of autologous and allogeneic stem cell transplantation in this disease has increased dramatically in recent years. Despite encouraging reports from single centers and registries, the impact of stem cell transplantation on the outcome for mantle cell lymphoma is unclear. Optimal first-line regimens for mantle cell lymphoma have yet to be defined, and it is therefore difficult to place the role of first remission transplantation in an appropriate context. Prospective randomized trials have been difficult to design and conduct in the absence of a well-defined ‘standard’ treatment. The role of stem cell transplantation as a salvage strategy is also unknown, although available data suggest that it does not improve survival in heavily pre-treated patients. In the absence of clear evidence for a survival advantage for patients receiving stem cell transplants for mantle cell lymphoma, entry into clinical trials should be a priority. Bone Marrow Transplantation (2001) 28, 813–820. Keywords: mantle cell lymphoma; stem cell tranplantation; autologous; allogeneic

The use of stem cell transplant (SCT) strategies for patients with mantle cell lymphoma (MCL) is increasing. A total of 287 autologous transplants for MCL have been reported to the Autologous Blood and Marrow Transplant Registry of North America (ABMTR) since 1990, 177 of which have been performed since 1998. An increasing number of single institution and registry-based studies of SCT for MCL have been reported over the last 5 years,1–11 and early reports of allogeneic SCT have also been published recently.12–15 The number of cases reported in publications or to registries probably represents only a fraction of the total number of transplant procedures being performed for this disease. This Correspondence: Dr JW Sweetenham, University of Colorado Health Sciences Center, Division of Medical Oncology – F704, 4200 East 9th Avenue, Denver, CO 80262, USA

rapid increase in transplant activity in MCL is probably due to two major factors. Firstly, the diagnostic criteria and clinical characteristics of MCL have been more clearly characterized over the last 5 years resulting in its recognition as a distinct entity in the REAL/WHO classification16,17 – cases previously assigned to other ‘indolent’ categories of non-Hodgkin’s lymphoma (NHL) are now recognized as MCL. Secondly, the poor prognosis for patients with MCL treated with ‘conventional’-dose chemotherapy has been reported in multiple series.18–31 The reported median overall survival for patients with this disease is only 3 to 4 years, with less than 15% of patients alive at 5 years. As a result, many centers have investigated the use of high-dose therapy in an attempt to overcome the apparent chemo-refractoriness of this disease. There is no widely accepted ‘standard’ first-line therapy for MCL. Anthracycline-based combination chemotherapy regimens such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) are widely used, as well as fludarabine-containing combinations, and ‘dose-intensive’ third-generation NHL regimens. The use of monoclonal antibodies, either alone or combined with chemotherapy, has been reported recently,32–34 and studies of radiolabeled monoclonal antibodies are also in progress. Although encouraging results have been reported for SCT, its role in patients with MCL is unknown. It is not clear whether the apparently favorable results of SCT are a consequence of improved therapy or patient selection. The optimal timing of SCT, either as salvage therapy, or a component of first-line treatment is also unclear, as are the effectiveness of ex vivo manipulation of the stem cell product, the appropriate high-dose regimen, and the potential role of allogeneic SCT, or non-myeloablative allogeneic SCT. Well-designed clinical trials will be required to address many of these uncertainties. In the meantime, is there any evidence to support the use of SCT for patients with MCL except in the context of such a trial? Clinical features and prognostic factors in MCL Characteristic clinical features of MCL include a median age at diagnosis of 60 to 65 years, male predominance, and advanced disease at presentation. Over 70% of patients present with stage IV disease. Bone marrow, peripheral blood and splenic involvement are common, as is extrano-

Stem cell transplantation for mantle cell lymphoma JW Sweetenham

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dal disease, especially involving the gastrointestinal tract. Various prognostic factors have been identified for MCL. The most commonly identified adverse factors are summarized in Table 1. The predictive value of many of these factors has been inconsistent in different series. However, several of these studies have also demonstrated the predictive value of the International Prognostic Index (IPI) for patients with MCL.38 This has been confirmed in a report from the non-Hodgkin’s Lymphoma Classification Project (NHLCP).39 Median overall survival (OS) was 5 years for patients with none or one adverse factors, 3 years for those with two or three factors and only 15 months for those with four or five risk factors (P ⬍ 0.001). The use of prognostic factors to stratify patients for different therapies has been limited in MCL, since even the ‘favorable’ risk patients have only a 5 year median OS, with no evidence of a plateau on the survival curve. However, these prognostic factors are helpful in interpreting data reported for SCT.

Results of high-dose therapy and autologous stem cell transplantation High-dose therapy and autologous SCT has been used as salvage therapy, and as a component of first-line therapy for patients with MCL. The published series are mostly retrospective, and have included patient populations which are heterogeneous with respect to extent and nature of prior therapy, status at the time of SCT, type of high-dose regimen, source of stem cells and ex vivo manipulation of stem cell products.1–11,40,41 In addition, some retrospective studies have not included central histologic review. Reproducible diagnostic criteria for MCL have only recently been established and the consistency of diagnosis for MCL without modern diagnostic techniques is poor.42 Whether all of the patients included in the earlier reports would meet present day criteria for the diagnosis of MCL is unknown. Results from the largest studies of high-dose therapy and SCT for previously treated patients are summarized in

Table 1

Adverse prognostic factors in mantle cell lymphoma

Adverse factor

Reference

Age ⬎65 Stage IV disease ECOG performance status ⬎1 LDH above normal Bone marrow involvement Splenomegaly Extranodal involvement International prognostic index (⬎2 risk factors) Non-anthracycline chemotherapy Blastoid histologic subtype Mitotic index (⬎2–2.5 mitoses/high power field) P53 mutations Cyclin D1 overexpression

21, 23 21, 28 29 23, 28, 29 21 23, 29 29 23, 29

Bone Marrow Transplantation

21, 23, 28, 29 19, 27, 29 27, 29 35, 36 37

Table 2. Most of the patients included in these series have received autologous SCT, although a minority have undergone allogeneic SCT. However, none of the studies shows a significant difference in outcome according to type of transplant. Although duration of follow-up has varied substantially between these studies, there is an apparent trend for inferior results in those series which have included a higher proportion of patients undergoing autologous SCT after multiple previous chemotherapy regimens. In the study from the University of Nebraska Medical Center, extent of prior therapy was the only factor with prognostic significance in multivariate analysis.10 Two year event-free survival (EFS) for patients who had received less than three prior therapies was 45% compared with 0 for those receiving more than three prior therapies. Similar results were reported in the recent combined study from Stanford and City of Hope, in which status at the time of autologous SCT (CR1 vs ⬎CR1) was the only factor with predictive value in multivariate analysis.41 Three year EFS was 88% for patients undergoing ASCT in first CR, compared with 41% for those in subsequent CR. Results of this, and other studies which have specifically reported outcomes for patients receiving high-dose therapy and SCT in first CR are summarized in Table 3. The early study by Stewart et al1 reported a poor outcome for 14 patients receiving autologous SCT in first CR. The reason for this is unclear, although it may be related to the relatively low-dose intensity of the initial induction therapy. Particularly favorable results have been reported from the MD Anderson Cancer Center for patients receiving initial intensive induction chemotherapy with HyperCVAD and high-dose cytarabine and methotrexate, followed by SCT.9 In this study, 3 year EFS and OS rates were 72% and 92%, respectively, for previously untreated patients, compared with 17% and 25% in those patients who had received prior therapy. Comparison of these patients with 25 historical control patients who had received CHOP-like chemotherapy without proceeding to SCT showed a markedly superior EFS and OS in the transplant group. However, the remission status of the historical control group at completion of CHOP-like chemotherapy is not available, and it is therefore unclear whether they represent a truly comparable group to those receiving SCT after HyperCVAD. Interpretation of the effectiveness of SCT after HyperCVAD is also complicated by the fact that of the total of 45 patients who entered the HyperCVAD program, only 34 underwent transplantation. The results of this study were reported on an intention to treat basis, and the added effectiveness of SCT combined with intensive induction therapy is therefore difficult to assess from this series. The major conclusions that can be drawn from the results of all of these studies are as follows: • The outcome after autologous SCT in patients who have received more than three prior chemotherapy regimens is very poor. Few long-term survivors have been reported and there is no rationale for the use of high-dose therapy and autologous SCT in these patients, who should be offered experimental therapy. • There is a trend for better outcome in patients undergoing


Table 2

815

Results of selected series of autologous SCT (ASCT) for MCL – previously treated patients

Author/ Reference

Number of patients and status at ASCT

Transplant regimen

EFS/PFS

OS

Comments

TBI-based

24% at 3 years

24% at 3 years

1st CR patients (n ⫽ 6) had 53% 3 year OS Registry study Central histologic review of all cases 5 year OS for patients in 1st CR was 61% with ‘suggestion of plateau in survival curve at 4 years’

Ketterer et al4

16 (6 in 1st CR)

Vandenberghe et al40

150 (135 either in CR or chemosensitive relapse. 50 had only 1 prior regimen) 22 patients had allogeneic BMT (see Table 4)

Various

30% at 2 years

48% at 2 years

Malone et al41

29 (2nd or subsequent CR)

Cy/TBI/VP16 or CBV

41% at 3 years

59% at 3 years

47% had anti-B cell antibody purging

Freedman et al8

28 (8 in 1st CR or PR)

Cy/TBI

31% at 4 years

62% at 4 years

Vose et al10

40 (5 in 1st CR)

Various

36% at 2 years

65% at 2 years

All marrows purged with multiple anti-B cell antibodies No separate analysis for 1st CR patients

Milpied et al7

18 (12 in 1st PR)

TBI based or BEAM

48% at 4 years

80% at 4 years

Non-significant trend for improved OS in 1st PR patients

Blay et al6

18 (6 in 1st CR)

Various

75% at 2 years

91% at 2 years

No difference in outcome for patients in 1st CR compared with remaining patients

Khouri et al9

20

HyperCVAD/ Cytarabine/MTX Cy/TBI

17% at 3 years

25% at 3 years

4 patients underwent allogeneic transplantation

Table 3

Results of selected series of autologous SCT (ASCT) for MCL – patients transplanted in first complete remission

Author/ Reference

Number of patients and status at ASCT

Transplant regimen

EFS/PFS

OS

Comments

Stewart et al1

14 (all previously untreated)

CAP/BOP induction various high-dose regimens

8% at 5 years

23% at 5 years

Malone et al41

16 (1st CR)

Cy/TBI/VP1 6 or CBV

88% at 3 years

94% at 3 years

47% had anti-B cell antibody purging

Khouri et al9

25

HyperCVAD/Cytarabine/ MTX Cy/TBI

72% at 3 years

92% at 3 years

4 patients underwent allogeneic transplantation

‘early’ rather than ‘late’ autologous SCT. However, this observation is, to some extent, self-fulfilling – patients undergoing high-dose therapy earlier in the course of their disease are likely to experience longer survival than those transplanted after one or more relapses. • Although the reported outcomes for patients receiving high-dose therapy and autologous SCT in first remission are superficially encouraging, it is possible that selection bias is a factor in the apparently superior survival in these patients. For example, in the series by Khouri et al,9 Malone et al,41 Vose et al10 and Vandenberghe et al,40 all of which report favorable outcomes for previously untreated patients, the median age of the patient population was between 47 and 56 years – 10 to 15 years lower than the median survival for the entire population of patients with MCL. Unfortunately, few of the published series have given sufficient details of IPI risk group to allow comparison with patients who have not

undergone autologous SCT in first remission. The NHLCP study demonstrated a 3 year OS of approximately 85% for patients with MCL with none or one IPI risk factors treated with ‘conventional’-dose first-line therapy.39 This is very similar to the OS reported in several of the series using first remission SCT. Since studies of intensive induction chemotherapy protocols with SCT are likely to include similar low risk patients, the reported phase II studies do not provide strong evidence that first remission SCT improves outcome in this disease. Two important prospective trials in progress may help to clarify the effectiveness of early autologous SCT in MCL. The German Low Grade Lymphoma Study Group is conducting a randomized study with the EORTC, GELA and HOVON groups. In this study, newly diagnosed patients with MCL are initially treated with an anthracyclineBone Marrow Transplantation


816

containing induction regimen, and then randomized to intensified chemotherapy with DexaBEAM (dexamethasone, carmustine, etoposide, cytarabine, melphalan) followed by cyclophosphamide/total body irradiation (TBI) and autologous SCT, or to continued ‘conventional’-dose chemotherapy followed by maintenance interferon. The group at MD Anderson Cancer Center have modified the original HyperCVAD/high-dose cytarabine/high-dose methotrexate protocol by the addition of rituximab, and are conducting a phase II study of this regimen without subsequent stem cell transplantation. Preliminary results from this study have shown an overall response rate of 97% in 37 evaluable patients.43 With a median of 8 months followup two patients (5%) had relapsed. This compares with a relapse rate of 4% in the previous series of patients who had undergone SCT as well. Updated results from this study will hopefully be reported soon, but these data suggest that patients who receive an initial intensive chemotherapy regimen may not benefit from consolidation with SCT in first remission. Finally, a joint analysis from the registries of the EBMT and IBMTR, which is currently in progress, may provide new data from a large patient population undergoing autologous and allogeneic SCT which may help to guide the design of subsequent randomized trials. Stem cell purging in MCL Since bone marrow and peripheral blood involvement are frequent in MCL, the role of ex vivo stem cell manipulation has been investigated by several groups. None of the clinical series reviewed above has included sufficient patient numbers to be able to identify a survival or EFS difference according to whether or not ex vivo manipulation of stem cells was performed. Jacquy et al44 demonstrated that the use of chemotherapy/G-CSF mobilization protocols in MCL increased the number of t(11;14) bearing cells in the peripheral blood by at least one log compared with steady-state peripheral blood in 10 of 12 informative patients. This suggests a possible rationale for ex vivo manipulation. However, in a study of patients with MCL undergoing autologous bone marrow transplantation at the Dana Farber Cancer Institute, Andersen et al45 reported that the use of immunologic purging of marrow with multiple anti-B cell antibodies, plus complement-mediated cell lysis eradicated PCR-detectable MCL in only two of 19 informative patients. MCL cells may therefore be relatively resistant to ex vivo purging. The clinical effectiveness of ex vivo manipulation of the stem cell product is currently being prospectively assessed in a phase II study from the Nordic Lymphoma Group. In this study, previously untreated patients with MCL are treated with intermediate-dose CHOP induction chemotherapy, followed by autologous SCT in responding patients. Stem cell products are ‘purged’ using either positive or negative selection techniques, or both. The efficacy of the purging technique is assessed by PCR for t(11;14) bearing cells, or for Ig gene rearrangement. This study will therefore assess the impact of purging at the molecular and clinical level. Importantly, this study will prospectively assess the significance of PCR-detectable minimal residual


disease in the blood and bone marrow of all patients, as well as in their stem cell products. The use of rituximab as a method of ‘in vivo purging’ of peripheral blood and marrow was initially reported in patients with follicular lymphoma.46 A recent report from Magni et al47 suggests that this might also be effective in patients with MCL. High-dose regimens As shown in Table 2, TBI-based regimens have been widely used in MCL in comparison with chemotherapyonly regimens. Although some retrospective analyses have suggested that the use of TBI-containing regimens is associated with improved EFS and OS,6,7 there has been no prospective confirmation of this. However, most centers recommend the use of TBI in this disease. Allogeneic stem cell transplantation in mantle cell lymphoma As with autologous SCT, there has been a recent rapid increase in allogeneic transplant activity for MCL. A total of 118 patients with MCL undergoing allogeneic SCT have been reported to the IBMTR, of whom 115 have been transplanted since 1995. Despite this, relatively few studies have been published to date. Several of the series summarized in Tables 2 and 3 have included a small number of patients receiving allogeneic SCT, although none of these series has reported different outcomes for patients receiving allogeneic compared with autologous stem cells. However, the high frequency of bone marrow and peripheral blood involvement in MCL, as well as the reported resistance of MCL cells to purging techniques provides a rationale for the use of allogeneic SCT in this disease. Evidence for a graft-versus-lymphoma effect in lymphoid malignancies includes the apparent effectiveness of modulation of immunosuppressive therapy,48 clinical responses to donor lymphocyte infusions,49 and the effectiveness of non-myeloablative conditioning regimens with allogeneic SCT.50 Many reports of allogeneic SCT for lymphoma have included small numbers of patients with MCL, but do not allow specific conclusions about this disease. A few case reports of the use of allogeneic SCT in MCL have also been published recently.12–14,51–54 These studies have included patients undergoing full allogeneic transplantation, non-myeloablative transplant strategies, and the use of donor lymphocyte infusions (DLIs), and have included some patients who have relapsed after autologous SCT. Some of the evidence of a graft-versus-lymphoma effect from these studies is summarized in Table 4. Khouri et al15 have reported a study of 16 patients with MCL undergoing allogeneic SCT, including five previously untreated patients receiving HyperCVAD/cytarabine/methotrexate induction, and 11 previously treated patients. Two of these patients received non-myeloablative conditioning. With a median follow-up of 24 months, the actuarial OS and FFS were 55%. For those patients with chemosensitive


Table 4

817

Results of allogeneic transplantation for mantle cell lymphoma

Author/ Reference

Number of patients

Nature of allogeneic transplant

EFS/FFS

OS

1 (relapsed after autologous SCT) 1

Full allogeneic SCT

N/A

N/A

Continued clinical and molecular CR at 1 year

Full allogeneic SCT

N/A

N/A

In continuous clinical CR at 8 years

2 (relapsed after autologous SCT)

Full allogeneic SCT

N/A

N/A

Both in continuous clinical CR at 2 years

Sohn et al51

12

Full allogeneic SCT

12% EFS at 3 years

23% at 3 years

Median age ⫽ 45 years

Adkins et al52

1

Full allogeneic SCT

N/A

N/A

Continued CR at 1 year

Molina et al53

6

Full allogeneic SCT

N/A

N/A

All achieved CR, of whom 2 have relapsed. One responded to subsequent DLI

1 (relapsed after autologous SCT)

Full allogeneic SCT followed by stepwise DLI

N/A

N/A

‘Slow’ CR by day 112, continuous CR at day 615

Khouri et al15

16

Full allogeneic SCT in 14, nonmyeloablative allogeneic SCT in 2

55% EFS at 2 years

55% OS at 2 years

‘Slow’ molecular CRs achieved in some patients consistent with GvL (see text)

Vandenberghe et al40

22

Full allogeneic SCT

50% at 2 years

62% at 2 years

Corradini et al12

Kroger et al13 Martinez et al14

Sohn et al54

disease at the time of transplantation, the corresponding figures were both 90% – very similar to the results reported by the same group using autologous SCT after HyperCVAD. Although the overall results of this study do not suggest an improved outcome after allogeneic SCT, certain anecdotal observations in this study support the existence of a graft-versus-lymphoma effect in this disease. Seven patients had a detectable bcl-1 or Ig gene rearrangement by PCR in blood or bone marrow at the time of transplant. Within 4 months of transplant, four of these patients were in molecular remission, and one of the remaining patients converted from PCR positive to negative by 7 months post transplant. The single relapse observed in this study was in a patient who failed to engraft, providing further evidence of a possible graft-versus-lymphoma effect. Despite the low relapse rate in this study, six patients died from transplant-related complications, resulting in an overall survival comparable with patients receiving autologous SCT. Many of the other studies summarized in Table 4 provide evidence for a graft-versus-lymphoma effect in MCL, based on responses to DLI, or ‘slow’ responses observed after the onset of clinical GVHD. Whether the use of non-myeloablative conditioning and/or stepwise DLI will produce a clinically relevant graft-versus-lymphoma effect with lower regimen-related mortality remains the subject of prospective studies. Conclusions Stem cell transplantation cannot be considered to have a proven role in MCL. The apparently encouraging results

Comments

Comparable results with autologous SCT reported in same study

from retrospective registry and single institution series may be due to patient selection rather than improved therapy. There is no justification for autologous SCT in patients who have failed multiple lines of therapy. Results from several studies show a very poor outcome in patients who have received more than three prior regimens. The role of autologous SCT in first remission is unproven and should not be considered as standard therapy. Randomized trials are required to assess the role of SCT in this situation. One such study is in progress in Europe, but new trials should certainly be initiated – the apparent effectiveness of regimens such as HyperCVAD alone and in combination with rituximab may establish these therapies as appropriate control arms in new comparative trials. As other new treatment modalities such as radio-labeled monoclonal antibodies and idiotypic vaccination gain more use in MCL, this may also modify the design of future trials of first remission SCT. Until an accepted ‘standard’ first-line therapy emerges for MCL, it will be difficult to design an appropriate trial to test the efficacy of first remission SCT. In the meantime, entry of patients into phase II trials of new approaches is preferable to the use of SCT ‘off study’. The role of allogeneic SCT in MCL is also unclear and unproven. Continued prospective phase II studies of this approach are necessary, with appropriate study endpoints which should include assessments of molecular as well as clinical remission. In the absence of any current evidence that overall survival is superior for patients receiving allogeneic vs autologous SCT for this disease, there is no justification for allogeneic transplantation except as part of a clinical trial. Bone Marrow Transplantation


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Table 5 Future approaches in stem cell transplantation for mantle cell lymphoma

2 Intensive induction/pre-transplant chemotherapy regimens ⫾ monoclonal antibodies Monoclonal antibodies as ‘in vivo purge’ Radiolabeled monoclonal antibody-based high-dose regimens Non-myeloablative SCT Post-transplant immunotherapy: Monoclonal antibodies Donor lymphocyte infusion Idiotypic vaccination

Patients whose disease has relapsed after one or two previous regimens have a poor prognosis with conventionaldose salvage therapy, and the data reviewed above suggest that this group may have an improved outcome after SCT. Randomized trials in this group are unlikely, and SCT may be considered in this group, although there is no evidence that it is curative, and these patients should also be entered into phase II clinical trials of novel treatments in preference to ‘routine’ transplantation. New treatment approaches are needed to improve the outlook for patients with MCL. Several new approaches, summarized in Table 5, may ultimately improve the activity of SCT in this disease. The use of radiolabeled monoclonal antibodies has already been reported in the context of SCT. Press et al55 have reported results of the use of 131I-tositumomab with etoposide and cyclophosphamide with autologous SCT in a phase I/II trial in 52 patients with relapsed B cell NHL, six of whom had MCL. Results in this group were favorable in comparison to historical controls who had received external beam TBI as a pre-transplant regimen, and merit further investigation. Approaches which maximize the potential benefit of graft-versus-lymphoma including non-myeloablative SCT and DLI are also being explored. The use of pre-and post-transplant immunotherapy, including the use of monoclonal antibodies or idiotypic vaccination strategies56 are also under investigation in some subtypes of NHL, and are likely to be extended to MCL. Stem cell transplantation may ultimately prove to be beneficial for some patients with this disease. However, since the median age at onset is 60 to 65 years of age, it may only be applicable to the minority of patients who are relatively young at presentation. Its effectiveness can only be assessed through the conduct of well-designed clinical trials. Entry into such trials should be a priority.

3 4 5

6

7

8

9

10 11 12

13 14

15

Acknowledgements

16

The author wishes to acknowledge the assistance of the Statistical Center of the International Bone Marrow Transplant Registry and the Autologous Blood and Marrow Transplant Registry who provided details of transplant activity in mantle cell lymphoma, and Dr Hillard M Lazarus for his critical review of this manuscript.

17 18

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