SCOTT A. MINK, JAMES O. ARMITAGE ABSTRACT. University of Nebraska Medical Center, Section of Oncology/Hematology, Omaha, Nebraska, USA

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1 High-Dose Therapy in Lymphomas: A Review of the Current Status of Allogeneic and Autologous Stem Cell Transplantation in Hodgkin s Disease and Non-Hodgkin s Lymphoma SCOTT A. MINK, JAMES O. ARMITAGE University of Nebraska Medical Center, Section of Oncology/Hematology, Omaha, Nebraska, USA Key Words. Non-Hodgkin s lymphoma Hodgkin s disease Autologous transplantation Allogeneic transplantation Review High-dose therapy Hematopoietic stem cell transplantation ABSTRACT Autologous stem cell transplantation has proven to be beneficial in selected patients with Hodgkin s disease (HD) and non-hodgkin s lymphoma (NHL). In patients with HD, transplantation appears to increase event-free survival in patients who fail to enter complete remission with initial therapy. When a patient relapses after a complete remission, transplantation is probably the best option and particularly so if the remission lasted less than 1 year. Transplantation as part of primary therapy for very highrisk patients may be beneficial, but is not standard therapy INTRODUCTION Hodgkin s disease (HD) and the non-hodgkin s lymphomas (NHL) are a heterogeneous group of malignancies. They arise from B cells, T cells, or natural killer cells in various stages of maturity, thus explaining the heterogeneity of the lymphomas. Untreated, the prognosis for these patients is poor. Almost all patients will die of their disease if not treated. With aggressive treatment, a substantial number of these patients can be cured. For HD, 7,4 new cases are expected this year in the United States and it will account for approximately 1,4 deaths [1]. These represent approximately 1% of newly diagnosed cancers in the U.S. HD is one of the most curable malignancies; overall, the cure rate is approximately 8%. Less than one-quarter of the patients will not enter a complete remission (CR) after initial therapy, and for those patients who do enter a CR, up to one-third will relapse [2]. For these patients that do relapse or fail to achieve an initial remission, a stem cell transplant may be the best treatment option. at this time. For patients with diffuse large-cell NHL, transplantation can be considered standard therapy for relapsed patients if they have chemotherapy-sensitive disease. The use of transplantation for high-risk patients in complete remission is promising, but definite recommendations cannot be made at this time. For follicular lymphomas, selected patients seem to benefit and studies are ongoing. Finally, the use of allogeneic stem cell transplantation can be useful in a select group of younger patients. The Oncologist 21;6: The NHL are much more frequent. In 2, there are expected to be at least 54,9 new cases diagnosed in the United States and 26,1 deaths [1]. The incidence of NHL has been increasing, and the explanation for this increase has not been identified [3]. For adults the potential for cure of NHL, as a group, is probably less than 3%. Some types of NHL such as the follicular lymphomas are only rarely cured. The situation is different for the diffuse large B cell lymphomas. In this group of patients, the cure rate is approximately 5% depending upon prognostic characteristics. For those patients who relapse or fail to enter remission, a bone marrow or peripheral stem cell transplant may offer the patient the best chance for a cure or long-term survival. BACKGROUND Successful allogeneic stem cell transplantation was first performed in the 196s [4] and successful autologous stem cell transplantation for lymphomas was first performed in the 197s [5]. Since then, the number of transplants performed Correspondence: Scott Mink, M.D., University of Nebraska Medical Center, Section of Oncology/Hematology, Box 98768, Omaha, Nebraska , USA. Telephone: ; Fax: ; smink@unmc.edu. Received November 2, 2; accepted for publication February 27, 21. AlphaMed Press /21/$5./ The Oncologist 21;6:

2 248 High-Dose Therapies in Lymphomas has increased dramatically. In 1998, approximately 17, allogeneic transplants and more than 3, autologous transplants were performed worldwide [6]. The increase in the numbers of transplants performed over the years is demonstrated in Figure 1 [6]. With technical improvements in all areas of transplantation, the age of patients who can be considered for transplantation has been increasing. Autologous transplantation can now be offered to a very select group of patients in their eighties. For allogeneic transplants, younger patients generally do better, but patients in their fifties are now routinely transplanted [7]. Figure 2 illustrates the number of transplants, the illnesses being transplanted, and the types of transplants being performed [6]. There are significant differences between allogeneic and autologous transplantation. Autologous transplantation is essentially a method of overcoming the marrow toxicity of high-dose therapy by the infusion of stem cells that repopulate the marrow. In allogeneic transplantation, donor cells not only repopulate the marrow, but a graft-versus-tumor effect may have a significant role in this type of transplant. The graftversus-tumor effect is an immunological reaction and T cells specific for tumor-associated antigens are believed to be responsible. The role of this effect in lymphomas is not as well established as it is in leukemia, but there is evidence it exists. In an analysis of the European Bone Marrow Transplant Registry, it was found that there was a decreased rate of recurrence in patients transplanted for lymphoma who developed chronic graft-versus-host-disease (GVHD) compared to patients without GVHD [8]. There are some basic principles that underlie the success of high-dose therapy. These principles can be applied to both allogeneic and autologous transplants. First, the tumor needs to have a steep dose-response curve. Second, active cytotoxic agents need to have a short half-life and primarily hematopoietic toxicity. Finally, there needs to be excellent supportive care to deal with treatment-related complications [9]. The preparative regimen employed is either chemotherapy or a combination of TBI and chemotherapy. The regimen utilized will depend upon past therapies and the type of malignancy. TBI is active in certain malignancies, is immunosuppressive, and usually has tolerable nonmyeloid toxicity at total dose of 1,-1,2 cgy [1]. The most useful chemotherapeutic agents are alkylating agents, etoposide, and cytarabine. These drugs have proven to be the most useful because their dose-limiting toxicity is generally hematological. The infusion of hematopoietic stem cells allows this toxicity to be overcome so that doses can be increased to levels where other organ toxicities become limiting [11]. The best preparative regimen is unknown because prospective trials comparing them are not available. n of transplants 32, 28, Autologous 24, 2, 16, 12, 8, Allogeneic 4, Year Figure 1. Annual number of blood and marrow transplants worldwide, Reprinted with permission [6]. n of transplants 4,5 4, 3,5 3, 2,5 2, 1,5 1, 5 Breast cancer Non-Hodgkin s lymphoma AML Multiple myeloma TECHNIQUES FOR AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR LYMPHOMA The traditional method for obtaining hematopoietic stem cells for autologous transplantation was multiple bone marrow aspirates while the patient was under general anesthesia. This method has largely been replaced by collection of hematopoietic stem cells from the peripheral blood. Kessinger et al. and Juttner et al. were the first investigators to report the successful use of peripheral stem cells to reconstitute marrow [12-14]. Since these initial reports, it was found that an increased number of circulating stem cells could be mobilized into the peripheral circulation using high-dose cyclophosphamide and/or hematopoietic growth factors [15-19]. In 1996, a report by Schmitz et al. [2] demonstrated that mobilized blood hematopoietic stem cells increased the rate of engraftment, decreased the need for red blood cell transfusions, increased the rate of platelet recovery, and decreased the number of days in the CML ALL Hodgkin s disease Allogeneic (total n = 5,5) Autologous (total n = 1,) MDS/other leukemia Ovarian cancer Other cancers Non-malignant disease Figure 2. Indications for blood and marrow transplantation in North America, Reprinted with permission [6].

3 Mink, Armitage 249 hospital. Approximately 9% of autologous transplants today use peripheral blood-derived stem cells [21]. An area of unknown significance in autologous transplantation is the possibility of graft contamination by tumor cells. While the use of hematopoietic stem cells obviously contaminated by tumor from autologous transplantation seems unwise, there are little data available to demonstrate an advantage for purging (i.e., in vitro attempts to eliminate tumor cells from the graft). Theoretically, there is a risk that grafts contaminated with tumor cells would increase the risk of a relapse, but there is controversy about this subject. For the NHL, evidence is available supporting the possibility that contaminating tumor cells might increase the chance for relapse. Sharp et al. demonstrated a 5-year relapse-free survival rate of 64% for patients receiving a tumor-negative peripheral stem cell transplant versus 17% for those with a contaminated graft (p <.1) [22]. Gribbon et al. demonstrated a benefit for patients with follicular lymphoma where 4 of 57 patients with uncontaminated grafts versus 26 of 57 patients with contaminated grafts had relapsed (p <.1) [23]. There are also data suggesting that purging is not beneficial. In standard chemotherapy with high-dose therapy followed by unpurged stem-cell transplantation or high-dose therapy followed by purged stem-cell transplantation (CUP trial), patients were randomized to chemotherapy, stem cell transplantation with unpurged grafts, or stem cell transplantation with purged grafts [24]. With a median follow-up of 26 months, 66% in the chemotherapy arm relapsed, while 39% in the purged group and 37% in the unpurged groups relapsed. HD Patients with HD for whom transplantation might be considered can be divided into three groups. These include patients who fail to enter a CR with initial systemic therapy, patients who relapse after attaining a CR, and patients who are at high risk for relapse and might benefit from transplantation as part of their primary therapy. For patients who do not attain a CR after induction chemotherapy, the prognosis is very poor with further conventional therapy. Data from Longo et al. demonstrate the prognosis for patients treated with conventional therapy who fail to enter a CR [25]. No patients were alive 8 years after diagnosis [25]. Bonfante et al. found 8% 8-year survival for patients failing a regimen of mechlorethamine, vincristine, procarbazine, prednisone/doxorubicine, vinblastine, bleomycin, and dacarbazine (MOPP/ABVD) [26]. Knowing that survival is dismal for patients who do not enter a CR with conventional chemotherapy, it was a logical question to ask if high-dose therapy would be of value in these patients. Yuen et al. [27] compared the results of best salvage therapy with autologous transplantation for matched patients who failed induction therapy. This was a retrospective study from Stanford that compared transplant results to historical controls. In this study, patients with resistant disease or those who had relapsed from a CR were compared to a matched control group which was given conventional chemotherapy with curative intent. There were 13 patients in the control group and 6 patients in the transplant group. At 4 years the event-free survival was 52% for a transplant versus 19% for salvage therapy, (p =.1). Overall survival was 44% for transplantation versus 38% for salvage therapy (p =.32) [27]. Additional studies have also evaluated this clinical situation and are presented in Table 1 [28-33]. It does appear that patients who have failed to enter remission with conventional therapy do derive benefit from high-dose therapy. Transplantation is an obvious consideration for patients who relapse from a chemotherapy-induced CR. The study by Yuen et al. can again be used to evaluate the role of transplantation in patients who have relapsed. For patients in the high-dose therapy group who relapsed from a CR, no difference was seen between patients who had a transplant or those who had conventional salvage therapy if their remissions lasted more than 1 year [27]. If the remission lasted less than 1 year, there was a significant difference in favor of the transplanted group. The 4-year event-free survival was 56% for transplanted patients versus 19% for conventional salvage therapy (p.1). Overall survival was 58% for transplants versus 38% for the conventional salvage group (p =.15) (Fig. 3) [27]. A randomized trial by Linch et al. [34] obtained similar results. They were not able to demonstrate a significant overall survival advantage, but they did demonstrate a 3-year event-free survival of 53% for the transplant arm versus 1% for the standard therapy arm. Several additional studies of autologous transplantation in first relapse are available and presented in Table 2 [29, 35, 36]. The data suggest that transplantation has a superior outcome if the CR lasted less than 1 year. If the remission lasted longer than 1 year, recommendations Table 1. Results of autologous transplantation after induction therapy failure for Hodgkin s disease Reference n Outcome % 5-year PFS 34% 5-year OS % 5-year PFS % 5-year PFS 6% 5-year OS % 4-year DFS % 3-year EFS 5% 3-year OS % 6-year PFS 42% 6-year OS Abbreviations: PFS = performance-free survival; EFS = event-free survival; DFS = disease-free survival; OS = overall survival.

4 25 High-Dose Therapies in Lymphomas Figure 3. Survival in patients with an initial duration of remission 12 months or less treated at relapse with either high-dose therapy and autografting (solid line, n = 25) or conventional salvage therapy (n = 35, dashed line). A) Overall survival. Log-rank p =.15. B) Event free survival. Log-rank p <.1. Reprinted with permission [27]. vary, and if the patient is in second relapse, most would offer transplant [2]. Patients who have attained a CR but have high-risk features that make them likely to relapse are potential transplant candidates. A study by Carella et al. that has been updated, evaluated patients with normal bone marrow function in the absence of bone marrow involvement, stage IV disease with two or more extra nodal locations, bulky mediastinal disease, B symptoms and an elevated lactic dehydrogenase (LDH). Twenty-two of 46 patients who attained a CR with MOPP/ABVD accepted a transplant. In patients who underwent transplantation in first remission, 77% were in unmaintained remission with a median follow-up of 86 months ( months) [37, 38]. In the nonrandomized control group, with a median follow-up of 89 months, 33% were free of disease. Results of other studies 1 looking at this question are presented in Table 3 [32, 39-41]. Because of the significant cure rate with standard-dose therapy in even high-risk patients, this approach is controversial. NHL NHL is currently the second most frequent indication for autologous hematopoietic stem cell transplantation [6]. It is not a useful treatment option for all patients with NHL, but in certain circumstances, autologous stem cell transplantation does provide patients the best opportunity for cure. When evaluating transplantation data, it is important to remember that the patient populations studied are a highly selected group [42]. In addition, it is sometimes difficult to compare studies because of different selection criteria, transplant regimens, and follow-up. Multiple trials have been performed evaluating the role of transplantation NHL, and the following trials chosen for discussion represent the best data available. There have been numerous factors identified that have significance in predicting how well patients will do with transplantation. The most predictive of these is the sensitivity of the lymphoma to chemotherapy. Philip et al. showed that A Probability (%) B Probability (%) Time (years) Time (years) Table 2. Results of autologous transplantation for Hodgkin s disease after first relapse Reference n CR <12 months PFS CR >12 months PFS p value % 57% % 47% % 85%.16 Abbreviations: CR = complete remission; PFS = progression-free survival. Table 3. Autologous transplantation for high-risk Hodgkin s disease Reference n Overall survival Event-free survival % 7-year 66% 7-year % 7-year 72% 7-year % 5-year 58% 5-year % projected 5-year 77% projected 5-year patients responses to transplantation could be predicted by their response to preceding standard-dose salvage therapy [43]. Patients with chemotherapy-responsive disease had an actuarial disease-free survival of 36%, those with resistant

5 Mink, Armitage 251 Event-free survival (%) disease had a survival of 14%, and patients with refractory disease had a survival of % [43]. Other studies have supported this finding [44-51]. Other variables have also been identified which have been found to have prognostic significance. Some of the most important factors associated with a poor outcome include an elevated LDH [47, 5], extensive previous treatment [47, 52], bulky disease [53], poor performance status [54], and high-grade histology [52, 55]. Diffuse large-cell lymphoma is the most common form of NHL, and autologous stem cell transplantation has been shown to be beneficial in some subsets with this illness. For patients with diffuse large-cell lymphoma who relapse from a CR but remain chemotherapy-responsive, autologous transplantation is the treatment of choice. The most significant study supporting transplantation is the PARMA study by Philip et al. [56]. Patients were randomized to autologous stem cell transplantation versus conventional-dose chemotherapy with dexamethasone, high-dose cytarabine, and cisplatin (DHAP) if the patient responded to two initial cycles of DHAP. The event-free survival at 5 years was 46% for the transplant arm and 12% for the conventional therapy arm (p =.1). Overall survival was 53% for transplant and 32% for the conventional therapy group (p =.38) (Fig. 4). In addition to transplant being shown to be beneficial in this group of patients, additional analysis has demonstrated that an initial remission of fewer than 12 months is an adverse prognostic indicator [57]. In the PARMA study [56], patients were classified according to the age-adjusted international prognostic index (IPI) and it was able to predict outcome in this study [58]. The age-adjusted IPI is divided into four stages according to risk of recurrence and is based on stage, LDH, and performance status for patients less than 6 years of age. Five-year predicted survival rates are 83%, 69%, 46%, and 32% for p =.1 Transplantation Conventional treatment Months after randomization Figure 4. Kaplan-Meier curves for event-free survival of patients in the transplantation and conventional treatment groups. The data are based on an intention-to-treat analysis. Tick marks represent censored data. Reprinted with permission [56]. low risk to high risk accordingly. In patients with an IPI of (i.e., low stage, normal LDH, and excellent performance status), no significant difference at relapse could be found between transplanted and conventional arms. For patients with an IPI of 1 or greater, there was a significant difference favoring the transplanted arm in progression-free survival, p <.1 [58]. The optimal approach to incorporating transplantation into the primary therapy of patients with high-risk diffuse aggressive NHL is uncertain because of conflicting results in the randomized trials performed to date [59]. A study by Haioun et al., the LNH-87 trial, had 916 eligible patients entered into the study. After induction therapy, patients were randomized to high-dose methotrexate, ifosfamide, etoposide, asparaginase, and cytarabine or to cyclophosphamide, BCNU, etoposide, and autologous stem cell transplant. Analysis originally demonstrated no difference between conventional chemotherapy and autologous transplantation arms. Final analysis of this study based on patients who were high/high-intermediaterisk patients demonstrated a significant advantage in both disease-free survival and overall survival [6]. The 8-year disease-free survival was 55% for high-dose therapy versus 39% sequential chemotherapy (p =.2) [6]. The 8-year overall survival for the high-dose therapy arm was 64% versus 49% for the sequential chemotherapy group (p =.4) [6]. These data were supported by Santini et al. who randomized 124 patients to doxorubicin, cyclophosphamide; vincristine, prednisone, and bleomycin (VACOP-B); or VACOP-B plus autologous transplantation [61]. As with the previous study, no initial survival advantage was found, but when the data were analyzed according to the age-adjusted IPI, high and highintermediate risk groups had a disease-free survival of 87% for transplant versus 48% for standard therapy (p =.8) [61]. There are also trials that have found contradictory results. Reyes et al. in the LNH93-3 trial randomized 37 patients to standard chemotherapy or autologous transplantation after an abbreviated standard-dose induction regimen. They found the 3-year event-free survival for the hematopoietic stem cell transplant group was 41% versus 54% for the standard therapy arm (p =.1). Overall survival was also in favor of standard therapy with 63% disease-free survival versus 47% in the transplanted group (p =.3) [62]. A trial by Verdonck et al. randomized 69 patients who had achieved a partial response to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) to additional CHOP or autologous bone marrow transplantation [63]. The 4-year event-free survival was 53% for the CHOP arm and 41% for the transplantation arm. Disease-free survival at 4 years was 72% for the CHOP group and 6% for transplantation [63]. At the present time, high-risk patients who achieve a CR after a full course of standard-dose chemotherapy and have a

6 252 High-Dose Therapies in Lymphomas high risk for relapse may derive the most benefit from stem cell transplantation [61, 64]. One final group of patients who may derive benefit from an autologous transplant are those who fail to enter a CR with primary induction therapy. Survival is poor for these patients with one report of a 9-month median survival [65]. A recent report by Vose et al. evaluated 184 patients with diffuse aggressive lymphomas who never achieved a CR with induction therapy and underwent autologous transplantation. These patients were all reported to the Autologous Blood and Marrow Transplant Registry [66]. This is the largest report to date on autologous transplantation in this patient population. For patients who attained a CR, the 3-year probability of survival was 68% compared to 11% for patients with a partial or no response (p <.1). The patients who seem to benefit the most from this form of therapy appear to be those with chemotherapy-sensitive disease, good performance status, age less than 55, have received only one or two chemotherapy regimens and who received involved field radiation therapy [66]. For patients with follicular lymphomas, definite conclusions about the optimal use of transplantation are difficult to draw from the available data even though numerous studies have been performed [67-74]. One problem in interpreting the results is the long natural history of follicular lymphomas. Relapses have been noted up to 9 years after a transplant [68]. This pattern of late relapses and a failure of the survival curves to plateau make it uncertain if patients are cured with transplantation. One historically controlled study from London showed that patients undergoing transplant in second remission had a better disease-free survival but not overall survival when compared to further standard chemotherapy [71]. Studies are ongoing evaluating the benefit of autologous transplantation in first remission. ALLOGENEIC TRANSPLANTATION Allogeneic hematopoietic stem cell transplantation has been evaluated in HD and NHL. The data are limited, but it appears to be a useful treatment in only a very select group of patients. There are a number of advantages and disadvantages associated with allogeneic transplantation. First, there is the need of an HLA-matched sibling donor that greatly limits the number of transplants that can be performed. The age of the patient also limits the number that can be performed because patients eligible for allogeneic transplant are generally not older than 5-6 years of age. There are also potentially serious side effects such as GVHD, delayed immune reconstitution, and graft rejection. These combine to limit the number of transplants that can be performed. There are also potential advantages associated with allogeneic transplantation. Stem cells are all from healthy donors [75] and there cannot be tumor cell contamination. There is also the potential of a graft-versus-lymphoma effect which may offer an important advantage in favor of allogeneic transplantation [76]. For patients with HD, the role of allogeneic transplantation is limited to patients who cannot have or have failed an autologous transplant [77, 78]. If the patient is young and has a donor, they may be eligible for an allogeneic transplant. The data from Gajewski et al. demonstrate the results in a study comparing allogeneic and autologous transplants [77]. Here, 1 consecutive patients who had HLA-identical sibling donors and underwent allogeneic transplantation were evaluated. The 3-year probability of disease-free survival was 15%, and the 3-year probability of survival was 21%. Milpied et al. compared 45 patients reported to the European Bone Marrow Transplant Registry who had HLA-identical sibling donors compared to a matched group who underwent autologous transplantation. They found an overall survival in favor of autologous transplantation [78]. For the autologous group, overall survival was 64% and for the allogeneic group it was 3% (p =.7) (Fig. 5) [78]. The possibilities for allogeneic transplantation in NHL are more promising. Van Besien et al. reported 113 patients who had HLA-identical sibling donors and underwent an allogeneic transplant for low-grade NHL. They found a 3-year overall survival and disease-free survival of 49%, and a treatment-related mortality of 4% [79]. Ratanatharathorn et al. compared 35 patients who had an autologous transplant to 31 who underwent an allogeneic transplant. There was no difference in progression-free survival at 14 months [8]. For allogeneic transplant, the progression-free survival was 47%, and for the autologous arm it was 24% (p =.21) [8]. Disease progression was 69% for the autologous group and 2% for the allogeneic group (p =.1) [8]. As these studies Cumulative % event free Time (years) Auto n = 17 Allo n = 17 p = Figure 5. Probability of OS in chemosensitive patients. ABMT versus allobmt. Reprinted with permission [78].

7 Mink, Armitage 253 demonstrate, there appears to be a decreased relapse rate, but toxicities seem to offset this advantage. Allogeneic transplants cannot be recommended outside of highly selected patient populations who for various reasons cannot undergo autologous transplantation [11]. There is a new method for allogeneic transplantation that may prove to be more beneficial than current approaches. This approach is referred to as nonmyeloablative allogeneic transplantation, or mini allogeneic transplantation. In this approach, nonmyeloablative chemotherapy or radiation therapy is given as a conditioning regimen followed by donor cell infusion. Occasionally a donor leukocyte infusion must be performed at a later time for full engraftment, although this usually happens over time without the infusion. The advantage of this approach appears to be less toxicity. The efficacy of this approach has not yet been determined in lymphoma, but recent reports are promising. Two reports by Khouri et al. describe this form of a transplant as promising and in need of further study [81, 82]. In their first study, 11/15 patients engrafted and 8/11 had a CR [81]. In the second study, 14/15 patients with relapsed/refractory lymphoma with aggressive disease engrafted [82]. There was a 53% CR REFERENCES 1 Greenlee RT, Murray T, Bolden S et al. Cancer Statistics, 2. CA Cancer J Clin 2;5: Bierman PJ, Armitage JO. Autologous hematopoietic cell transplantation for Hodgkin disease. In: Thomas ED, Blume KG, Forman SJ, eds. Hematopoietic Cell Transplantation, 2nd Edition. Victoria, Australia: Blackwell Science, 1999: Greer JP, Macon WR, McCurley TL. Non-Hodgkin Lymphomas. In: Lee GR, Foerster J, Lukens J et al., eds. Wintrobe s Clinical Hematology, Tenth Edition. Philadelphia: Lippincott Williams & Wilkins, 1999: Thomas ED, Blume KG. Historical markers in the development of allogeneic hematopoietic cell transplantation. 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