Is There a Role for Hemopoietic Stem-Cell Transplantation in CTCL?

The role of autologous and allogeneic stem-cell transplantation (SCT) in the treatment of cutaneous T-cell lymphoma (CTCL) is reviewed. Patients most likely to benefit are those with advanced-stage disease, multiple relapses, and short remissions; chemosensitive disease is also a prerequisite for these treatments. Autologous SCT produces high response rates in patients with peripheral T-cell lymphoma, but these are generally of short duration. This therapy is relatively safe to administer, with little transplant-related mortality. In contrast, allogeneic SCT may be highly toxic and result in transplant-related mortality, but it has the potential to produce long-lasting responses. Prospective studies of these treatments in patients with CTCL are required. Nevertheless, selected patients could be considered for allogeneic SCT, preferably early in their disease when their performance status is still good.

There are currently limited data, particularly from randomized, controlled trials, on the efficacy of many of the therapies that are used in the treatment of cutaneous T-cell lymphoma (CTCL), and stem-cell transplantation (SCT) is no exception. Indeed, there is little information from randomized, controlled trials on the use of SCT for any indication, even those in which this procedure has a well-established role. Nevertheless, there does appear to be a role for SCT in the management of some patients with CTCL. In this review, the use of both autologous and allogeneic SCT in peripheral T-cell lymphomas (PTCL) will be discussed.

Which Patients With CTCL Should Receive a Transplant?

The patients most likely to benefit from SCT are those who are currently at poor risk: those with advanced-stage disease, a low response to systemic therapies, multiple relapses, and short remissions. In particular, some patients with Sézary syndrome fall into this category-those patients with advanced disease (stages III and IV) who have a median survival of only about 2 years. For both forms of SCT, and particularly autologous SCT, to be effective, it is almost essential that patients have demonstrated some chemosensitivity and have obtained a degree of remission from previous treatments prior to transplantation. Other considerations include the patient's age, performance status, and the presence or absence of other comorbidities. In addition, for allogeneic transplants, donor availability is a factor, although this is becoming less of an issue now-for Caucasian patients, it is possible for more than 75% to find a donor through extensive registries.

Use of SCT

Data from the European Group for Blood and Marrow Transplantation (EBMT) registry show that, overall, the use of SCT has decreased in the past 3 years.[1] This is largely because it is no longer standard practice for SCT to be used in patients with solid tumors, such as breast cancer, resulting in a halving of the number of these procedures in the early 2000s.

On the other hand, the use of SCT in patients with lymphomas showed a steady increase to 2000, followed by a subsequent plateau, which probably reflects the emergence of new therapies that are allowing clinicians to use other treatment options before transplantation. In addition, with the first-line use of more efficacious therapies, fewer patients relapse and therefore fewer patients require a transplant.

Rationale for Use of Autologous SCT

Autologous SCT relies on the principle of a dose-response relationship for chemotherapy and/or radiotherapy. The use of these therapies is limited by their toxicity-particularly their toxicity to the hemopoietic stem cell- causing myelosuppression and failure of recovery of normal blood cells. By collecting and storing normal autologous hemopoietic stem cells, the dose of chemotherapy or radiotherapy can be increased and the consequent myelosuppression supported by replacement of the stored hemopoietic stem cells. It is therefore important that patients undergoing autologous SCT have chemosensitive disease. This procedure is performed in the hope of inducing or improving remissions and prolonging a patient's disease-free survival (DFS) and overall survival (OS). Autologous SCT is now the standard of care for myeloma in first remission and for many lymphomas in second remission.[1]

Autologous Transplantation in PTCL

Little information is available on the use of autologous transplantation in CTCL alone. However, some studies on PTCL have included a few patients with CTCL, as the term PTCL describes a diverse group of blood cancers that orginate from post-thymic T cells. Autologous SCT in 35 young patients with relapsed or refractory PTCL resulted in a 5-year DFS of approximately 25% and an OS of about 33%.[2] Interestingly, a plateau in DFS emerged after 3.5 years-some of the patients were showing prolonged remissions many years after autografting. This is an unusual feature of survival curves following autografts. Another study reported results for autologous SCT in 29 patients with PTCL and allograft in 7 patients.[3] Results for autologous SCT were similar to those in the previous study, with a 3-year progression-free survival (PFS) of 32% and an OS of 39%. Survival was lower for the seven patients who received allografts: PFS was 14% and OS was 29%.

When autologous SCT was used for patients with PTCL in first remission, there was an improvement in outcomes compared with the two previous studies. Among 75 young patients with advanced-stage disease and high International Prognostic Index, and who received a standard carmustine (BiCNU), etoposide, cytarabine, and melphalan (Alkeran) conditioning regimen for autograft, 5-year PFS was 65% and OS was 69%, approximately doubling the percentages reported above.[4] However, the fact that the PFS and OS are similar means that patients who did relapse were not susceptible to subsequent therapies. In another large study of autologous transplantation in patients in first remission, most (91%) showed a good response to the induction chemotherapy. However, because of its early disease progression, only 33% of patients proceeded to consolidation with SCT, and 85% of those remain in complete remission at the relatively short follow-up of 1 year.[5]

Autologous Transplantation in CTCL

Only two small studies have investigated autologous SCT in patients with CTCL. The first was published in the early 1990s and included six patients with advanced-stage mycosis fungoides who were heavily pre-treated.[6] They underwent a variety of conditioning regimens, and four also had total skin electron beam radiotherapy for disease control immediately before transplantation. The initial response rate was high, and four of the six patients experienced complete remission. Nevertheless, their PFS was short (64 days to 1 year), and three patients relapsed within the first 3 months.

The second study, in nine patients with tumor-stage mycosis fungoides, reported similar results.[7] In this study, hemopoietic stem cells were positively selected using the cell-surface antigen CD34 and underwent negative selection for contaminating T cells. After autologous SCT, one patient died at day 15 from sepsis (ie, a transplant-related death), but the eight patients who survived the procedure all reached complete remission. Again, however, there was a short median PFS of only 7 months (range: 2-14 months) and median OS was 11 months, with three patients dying within 1 year. These patients were at a late disease stage; therefore, it appears that autologous SCT had not significantly prolonged remission in most patients beyond that expected for their disease stage.

Role of Autograft in CTCL: Summary

Autologous SCT in CTCL is a relatively safe procedure, associated with few transplant-related deaths. There is also a rapid treatment response, but the response duration is short. It is possible that there may be some disease modification after relapse, so when patients do show disease progression the disease has a more indolent behavior and perhaps a better response to conventional therapies than before transplantation.[6,7] It may be possible to exploit this disease modification by considering a maintenance treatment strategy after autologous transplantation, possibly using an agent such as bexarotene (Targretin) to prolong remission and delay relapses.

Autograft vs Allograft in CTCL

There have been no randomized, comparative studies of autograft and allograft, or of SCT and conventional treatment; most of the few data that are available have been obtained retrospectively from transplant registries. In addition, the small studies that are reported are highly heterogeneous and hence difficult to compare. The disease subtypes and histology are variable, as are the disease stage, International Prognostic Index, performance status, and whether patients have chemosensitive disease at the time of transplantation. Furthermore, few patients with CTCL have been studied. It is therefore difficult to draw any inferences on treatment responses in different groups of patients.

Pooled data from the British and Australian Bone Marrow Transplant Registries 1990-2002 have allowed some assessment of SCT in patients with PTCL.[8] Data were available for 83 patients; most (n = 65) patients underwent autografting, and only a small number (n = 18) had allografts following full-intensity conditioning (these data were obtained before reduced-intensity conditioning was commonly used). The cohort included three patients with CTCL, two of whom underwent autologous SCT and one allografting. Overall, patient age was similar to that in other studies of autologous SCT (around mid-40 years of age) and considerably younger (median: 28 years) for those undergoing allografts. Most of these patients were heavily pretreated before SCT.

For patients with PTCL, the survival rates were similar to those shown in other trials (30% for both PFS and OS at 5 years). Patients with anaplastic large-cell lymphoma showed much more favorable outcomes than any of the other histologies (60% for both PFS and OS at 5 years). In addition, disease outcome was much less favorable for those with extranodal presentation (this includes cutaneous disease) than if it was nodal in origin (64% vs 29%, respectively, for PFS at 5 years; 63% vs 28%, respectively, for OS at 5 years). Possibly the most significant factor in determining outcome was whether or not a patient's disease was chemosensitive (PFS was 53% in chemosensitive disease and 38% in resistant disease; corresponding OS values were 58% and 36%, respectively). This difference was seen in both autologous and allogeneic SCT.

The difference in mortality between autologous and allogeneic SCT results primarily from the higher transplant-related mortality in patients who have undergone full-intensity allogeneic SCT. Data from a large European study in patients with chronic lymphocytic leukemia allowed a comparison of autologous and allogeneic SCT and produced data that are similar to those obtained for other malignancies.[9] Although autografting is a relatively safe procedure and there are few deaths in the first year following transplant, many patients subsequently relapse, leaving possibly one or two long-term survivors. On the other hand, full-intensity allogeneic SCT is a dangerous therapy to deliver even in the best of hands and transplant-related mortality produces a high death rate in the first year. After the first year following SCT a proportion of patients relapse, but a plateau emerges; some patients who survive beyond this time are cured. In allogeneic full-intensity SCT for chronic lymphocytic leukemia, there is the potential for cure in about 45% of patients after 5 to 6 years.

In a study of T-prolymphocytic leukemia patients, 50 were treated with alemtuzumab (CamPath) and 16 were eligible for SCT (11 autograft and 5 allograft, 2 of those with reduced-intensity conditioning).[10] Median survival for chemotherapy alone (in patients who were mostly not eligible for SCT) was 1 year, which is longer than the 6 months that would have been expected before alemtuzumab was used. In contrast, patients who received SCT had a median survival of 3 years and six patients have now reached 5 years in remission, which is a result never seen before in this disease. There is therefore a potential role in this disease for SCT, and the ideal therapy would produce the long-term advantage of allogeneic SCT without the early transplant-related mortality.

Potential Role of Allograft in CTCL

Allogeneic SCT has a potential role in CTCL because there are some patients-those with tumor-stage mycosis fungoides, for example-who have extremely poor survival prospects, and there is currently no curative therapy. Furthermore, autologous SCT has failed to produce durable remissions. Advantages of allogeneic SCT are the presence of an uncontaminated stem-cell source and, the most significant benefit of this procedure, the possibility of a graft-vs-lymphoma/leukemia (GVL) effect. Allogeneic SCT provides a means for delivering adoptive immunotherapy-allowing a new immune system, which may have some independent activity to attack the disease (GVL effect), to enter the patient's body. It is also possible to encourage further that immune effect by subsequent donor-lymphocyte infusion, to stimulate a donor immune response against host tumor cells.

A major limitation of full-intensity allogeneic SCT is the regimen-related toxicity and the associated transplant-related mortality. Graft-vs-host disease (GVHD) can also produce significant morbidity in some patients. In addition, there is a high risk of infection related to the myelosuppressive effects of the conditioning regimen and the delay in immune reconstitution. Finally, despite the favorable long-term relapse rates in allogeneic compared with autologous SCT, relapse still remains a possibility.

Reduced-Intensity Conditioning

Data from the EBMT show that there has been a large increase in the use of reduced-intensity SCT (RISCT) in the past few years, with a plateau or reduction in the use of full-intensity conditioning.[1] The rationale for the use of RISCT is the relative lack of toxicity of these regimens, which reduces the transplant-related mortality and expands patient eligibility, in terms of age, comorbidities, performance status, and previous autografts. Following allogeneic engraftment, RISCT relies on the mediation of a cure by a GVL effect, which can be further improved by donor-lymphocyte infusion.

The ideal reduced-intensity regimen involves balancing immunosuppressive effects of the treatment, which will allow donor engraftment and a GVL effect, with tumor control, which inevitably brings with it myelosuppression. The toxicity of conditioning should ideally be low, but if it is too low aggressive disease may be inadequately controlled, and a period of disease control is required until immune reconstitution can take place and the GVL effect initiates. GVHD should also be kept to a minimum, although some GVHD may reflect a good GVL effect. Thus, the ideal treatment will achieve a balance between good immune reconstitution and GVHD.

At our center we use alemtuzumab at 20 mg/d, fludarabine (Fludara) at 30 mg/m²/d, melphalan at 140 mg/m², unmanipulated peripheral blood stem cells/marrow, and cyclosporin A as GVHD prophylaxis from day-1. The advantage of alemtuzumab is that it is a highly effective immunosuppressant, allows good donor engraftment and a low GVHD, and is associated with low transplant-related mortality. Potential disadvantages of this treatment are infection, mixed chimerism-retention of some recipient cells in the marrow along with the donor cells, for 3 to 4 months after transplantation-and therefore delayed immune reconstitution and a reduced GVL effect as a result of immunosuppression.

Engraftment is good following this RISCT. In a series of 94 patients, 92 showed durable engraftment (1 died before being evaluable and 1 rejected the graft with autorecovery).[11] Neutrophil recovery was rapid, so patients often had only a few days of neutropenia, and myelosuppression was not a problem. Most (n = 71) patients had no acute GVHD, and only 4 had grade 3 or 4 GVHD.[11] Transplant-related mortality in patients with PTCL was 37% at 3 years, and in patients with chronic lymphocytic leukemia this value was 10%.[11] It seems likely that the value for patients with CTCL will fall between these two, as PTCL is a more aggressive, and chronic lymphocytic leukemia a less aggressive, disease. In chronic lymphocytic leukemia, 65% of patients were in remission at 3 years, and the value for patients with PTCL was 29%.[11]

Evidence for a GVL Effect Following RISCT

Establishment of a GVL effect is key in RISCT, as this is the prime mediator of long-term disease control. The presence of a GVL effect has been demonstrated to some extent in a study of 17 patients with PTCL.[12] Conditioning was with thiotepa/fludarabine/cyclophosphamide; 16 patients had sibling transplants, 1 an unrelated donor. Over 2 years, 14 of the 16 patients remained alive and 12 were in complete remission. This is extremely good efficacy in a group of patients with refractory/relapsed disease whose chance of being alive at 2 years with conventional treatment is less than 10%. Moreover, of the four patients who relapsed, two responded to donor-lymphocyte infusion. Thus, OS (80%) was greater than PFS (64%), indicating that some patients who relapsed could be rescued by donor-lymphocyte infusion and other modulatory therapies (Figure 1).

Efficacy of Allogeneic SCT in CTCL

Only four studies have reported the efficacy of allogeneic SCT in CTCL (Table 1).[13-16] In these studies, response rates were high and complete remission was prolonged; most of the studies were ongoing at 4 to 5 years and showed continued responses at that time. In addition, most patients were responsive to donor-lymphocyte infusion when this was tested.

The largest study involved eight patients, including three with tumor-stage mycosis fungoides and four with Sézary syndrome.[16] Following various conditioning regimens, there was 100% engraftment and 100% complete remission within 30 to 60 days. Six patients developed some GVHD, but their performance status was good (70%-100%), so this was clearly not too debilitating. Six patients are alive and in complete remission at a median of 53 months (range: 33-108 months). This is an exciting result, as it suggests that there has been a change in the natural history of CTCL following RISCT.

Conclusions

In CTCL, autologous SCT induces high response rates, but of short duration. The procedure may modulate the disease, but this is uncertain; it may well be necessary to initiate a maintenance therapy regimen to prolong survival. Allogeneic transplant is highly toxic if conventional doses of conditioning treatment are used, but with RISCT there is the possibility of durable responses and evidence of a GVL effect. There are currently few data on the use of SCT in CTCL, and prospective studies are required. Nevertheless, highly selected patients who have high disease risk and chemosensitive disease could be considered for treatment with SCT. Ideally, this procedure should be carried out early in the disease course, when patients still have a good performance status. The treatment of choice for eligible patients would be allogeneic SCT with reduced-intensity conditioning.

Disclosures:

Dr. Dearden has received speaker fees from Schering AG, Berlex Oncology, and Cephalon Europe.

References:

1. EBMT database [http://www.ebmt.org/4Registry/registry1.html].

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5. d'Amore F, Lauritzsen G, Jantunen E, et al: High-dose therapy (HDT) and autologous stem cell transplant (ASCT) as 1st line treatment in peripheral T-cell lymphomas (PTCL) (abstract 71). Ann Oncol 16(suppl 5), 2005.

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9. Esteve J, Villamor N, Colomer D, et al: Different clinical value of minimal residual disease after autologous and allogeneic stem cell transplantations for chronic lymphocytic leukaemia. Blood 99:1873-1874, 2002.

10. Krishnan B, Swansbury J, Cazin B, et al: Clinical outcome of stem cell transplantation (SCT) in patients with T-cell prolymphocytic leukaemia (T-PLL) previously treated with alemtuzumab: A multicentre experience (abstract 1127). Blood 106:328a, 2005.

11. Mackinnon S, Thomson K, Morris E, et al: Reduced intensity transplantation: Where are we now? Haematol J 5(suppl 3):S34-S38, 2004.

12. Corradini P, Dodero A, Zallio F, et al: Graft-versus-lymphoma effect in relapsed peripheral T-cell non-Hodgkin's lymphomas after reduced-intensity conditioning followed by allogeneic transplantation of hematopoietic cells. J Clin Oncol 22:2172-2176, 2004.

13. Guitart J, Wickless SC, Oyama Y, et al: Long-term remission after allogeneic hematopoietic stem cell transplantation for refractory cutaneous T-cell lymphoma. Arch Dermatol 138:1359-1365, 2002.

14. Soligo D, Ibatici A, Berti E, et al: Treatment of advanced mycosis fungoides by allogeneic stem-cell transplantation with a nonmyeloablative regimen. Bone Marrow Transplant 31:663-666, 2003.

15. Herbert KE, Spencer A, Grigg A, et al: Graft-versus-lymphoma effect in refractory cutaneous T-cell lymphoma after reduced-intensity HLA-matched sibling allogeneic stem cell transplantation. Bone Marrow Transplant 34:521-525, 2004.

16. Molina A, Zain J, Arber DA, et al: Durable clinical, cytogenetic, and molecular remissions after allogeneic hematopoietic cell transplantation for refractory Sezary syndrome and mycosis fungoides. J Clin Oncol 23:6163-6171, 2005.