Advertisement
help button home button The Oncologist
HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow eLetters: Submit a response to this article
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article link to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Mink, S. A.
Right arrow Articles by Armitage, J. O.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Mink, S. A.
Right arrow Articles by Armitage, J. O.
The Oncologist, Vol. 6, No. 3, 247-256, June 2001
© 2001 AlphaMed Press

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

Correspondence: Scott Mink, M.D., University of Nebraska Medical Center, Section of Oncology/Hematology, Box 987680, Omaha, Nebraska 68164-7680, USA. Telephone: 402-559-6210; Fax: 402-559-6520; e-mail: smink{at}unmc.edu.


   ABSTRACT
Top
 Abstract
Introduction
 Background
 Techniques for Autologous...
 HD
 NHL
 Allogeneic Transplantation
 Summary
 References
 
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 high-risk patients may be beneficial, but is not standard therapy 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.

Key Words. Non-Hodgkin's lymphoma • Hodgkin's disease • Autologous transplantation • Allogeneic transplantation • Review • High-dose therapy • Hematopoietic stem cell transplantation


   INTRODUCTION
Top
 Abstract
 Introduction
Background
 Techniques for Autologous...
 HD
 NHL
 Allogeneic Transplantation
 Summary
 References
 
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, 7,400 new cases are expected this year in the United States and it will account for approximately 1,400 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 80%. 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.

The NHL are much more frequent. In 2000, there are expected to be at least 54,900 new cases diagnosed in the United States and 26,100 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 30%. 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 50% 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
Top
 Abstract
 Introduction
 Background
Techniques for Autologous...
 HD
 NHL
 Allogeneic Transplantation
 Summary
 References
 
Successful allogeneic stem cell transplantation was first performed in the 1960s [4] and successful autologous stem cell transplantation for lymphomas was first performed in the 1970s [5]. Since then, the number of transplants performed has increased dramatically. In 1998, approximately 17,000 allogeneic transplants and more than 30,000 autologous transplants were performed worldwide [6]. The increase in the numbers of transplants performed over the years is demonstrated in Figure 1Go [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 2Go illustrates the number of transplants, the illnesses being transplanted, and the types of transplants being performed [6].



View larger version (12K):
[in this window]
[in a new window]
  		Figure 1. Annual number of blood and marrow transplants worldwide, 1970-1997. Reprinted with permission [6].

 


View larger version (21K):
[in this window]
[in a new window]
  		Figure 2. Indications for blood and marrow transplantation in North America, 1997. Reprinted with permission [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 graft-versus-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 1,000-1,200 cGy [10]. 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.


   TECHNIQUES FOR AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR LYMPHOMA
Top
 Abstract
 Introduction
 Background
 Techniques for Autologous...
HD
 NHL
 Allogeneic Transplantation
 Summary
 References
 
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. [20] 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 hospital. Approximately 90% 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 < 0.01) [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 < 0.00001) [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
Top
 Abstract
 Introduction
 Background
 Techniques for Autologous...
 HD
NHL
 Allogeneic Transplantation
 Summary
 References
 
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 103 patients in the control group and 60 patients in the transplant group. At 4 years the event-free survival was 52% for a transplant versus 19% for salvage therapy, (p = 0.01). Overall survival was 44% for transplantation versus 38% for salvage therapy (p = 0.32) [27]. Additional studies have also evaluated this clinical situation and are presented in Table 1Go [28-33]. It does appear that patients who have failed to enter remission with conventional therapy do derive benefit from high-dose therapy.


View this table:
[in this window]
[in a new window]
  		Table 1. Results of autologous transplantation after induction therapy failure for Hodgkin's disease
 
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 <= 0.01). Overall survival was 58% for transplants versus 38% for the conventional salvage group (p = 0.15) (Fig. 3Go) [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 10% for the standard therapy arm. Several additional studies of autologous transplantation in first relapse are available and presented in Table 2Go [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 vary, and if the patient is in second relapse, most would offer transplant [2].




View larger version (14K):
[in this window]
[in a new window]
  		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 = 0.15. B) Event free survival. Log-rank p < 0.01. Reprinted with permission [27].

 

View this table:
[in this window]
[in a new window]
  		Table 2. Results of autologous transplantation for Hodgkin's disease after first relapse
 
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 (34-114 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 looking at this question are presented in Table 3Go [32, 39-41]. Because of the significant cure rate with standard-dose therapy in even high-risk patients, this approach is controversial.


View this table:
[in this window]
[in a new window]
  		Table 3. Autologous transplantation for high-risk Hodgkin's disease
 

   NHL
Top
 Abstract
 Introduction
 Background
 Techniques for Autologous...
 HD
 NHL
Allogeneic Transplantation
 Summary
 References
 
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 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 disease had a survival of 14%, and patients with refractory disease had a survival of 0% [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, 50], 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 = 0.001). Overall survival was 53% for transplant and 32% for the conventional therapy group (p = 0.038) (Fig. 4Go). 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].



View larger version (16K):
[in this window]
[in a new window]
  		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].

 
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 60 years of age. Five-year predicted survival rates are 83%, 69%, 46%, and 32% for low risk to high risk accordingly. In patients with an IPI of 0 (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 < 0.0001 [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-intermediate-risk patients demonstrated a significant advantage in both disease-free survival and overall survival [60]. The 8-year disease-free survival was 55% for high-dose therapy versus 39% sequential chemotherapy (p = 0.02) [60]. The 8-year overall survival for the high-dose therapy arm was 64% versus 49% for the sequential chemotherapy group (p = 0.04) [60]. 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 high-intermediate risk groups had a disease-free survival of 87% for transplant versus 48% for standard therapy (p = 0.008) [61].

There are also trials that have found contradictory results. Reyes et al. in the LNH93-3 trial randomized 370 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 = 0.01). Overall survival was also in favor of standard therapy with 63% disease-free survival versus 47% in the transplanted group (p = 0.003) [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 60% 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 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 < 0.0001). 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
Top
 Abstract
 Introduction
 Background
 Techniques for Autologous...
 HD
 NHL
 Allogeneic Transplantation
Summary
 References
 
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 50-60 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, 100 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 30% (p = 0.007) (Fig. 5Go) [78].



View larger version (10K):
[in this window]
[in a new window]
  		Figure 5. Probability of OS in chemosensitive patients. ABMT versus alloBMT. Reprinted with permission [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 40% [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 [80]. For allogeneic transplant, the progression-free survival was 47%, and for the autologous arm it was 24% (p = 0.21) [80]. Disease progression was 69% for the autologous group and 20% for the allogeneic group (p = 0.001) [80]. As these studies 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 and a 13% partial response in this group of patients with a median follow-up of 6 months.


   SUMMARY
Top
 Abstract
 Introduction
 Background
 Techniques for Autologous...
 HD
 NHL
 Allogeneic Transplantation
 Summary
References
 
Autologous stem cell transplantation has proven to be beneficial in selected patients with HD and NHL. In patients with HD, transplantation appears to increase event-free survival in patients who fail to enter CR with initial therapy. When a patient relapses after a CR, 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 high-risk patients may be beneficial, but is not standard therapy 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 CR 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.


   REFERENCES
Top
 Abstract
 Introduction
 Background
 Techniques for Autologous...
 HD
 NHL
 Allogeneic Transplantation
 Summary
 References
 

  1. Greenlee RT, Murray T, Bolden S et al. Cancer Statistics, 2000. CA Cancer J Clin 2000;50:7-33.[Abstract]
  2. 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, 1999:952-962.
  3. 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, 1999:2447-2537.
  4. Thomas ED, Blume KG. Historical markers in the development of allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 1999;5:341-346.[CrossRef][Medline]
  5. Appelbaum FR, Herzig GP, Ziegler JL et al. Successful engraftment of cryopreserved autologous bone marrow in patients with malignant lymphoma. Blood 1978;52:85-95.[Abstract/Free Full Text]
  6. Rizzo JD. New summary slides show current trends in BMT. Autologous Blood and Marrow Transplant Registry Newsletter 1998;5:4-10.
  7. Vose JM, Kessinger A, Bishop MR et al. Bone marrow transplantation. In: Abeloff MD, Armitage JO, Lichter AS, eds. Clinical Oncology, Second Edition. New York: Churchill Livingstone, 2000:482-493.
  8. Chopra R, Goldstone AH, Pearce R et al. Autologous versus allogeneic bone marrow transplantation for non-Hodgkin's lymphoma: a case-controlled analysis of the European Bone Marrow Transplant Group Registry data. J Clin Oncol 1992;10:1690-1695.[Abstract/Free Full Text]
  9. Blume KG, Thomas ED. A review of autologous hematopoietic cell transplantation. Biol Blood Marrow Transplant 2000;6:1-12.[Medline]
  10. Yahalom J. Strategies for the use of total-body irradiation as systemic therapy in hematologic malignancies. In: Armitage JO, Antman KH, eds. High-Dose Cancer Therapy: Pharmacology, Hematopoietins, Stem Cells, Third Edition. Philadelphia: Lippincott Williams & Wilkins, 2000:77-107.
  11. Chakraverty RK, Goldstone AH, McMillan AK et al. High-dose therapy for the treatment of non-Hodgkin's lymphoma. In: Armitge JO, Antman KA, eds. High-Dose Cancer Therapy: Pharmacology, Hematopoietins, Stem Cells. Third Edition. Philadelphia: Lippincott Williams & Wilkins, 2000:775-795.
  12. Kessinger A, Armitage JO, Landmark JD et al. Reconstitution of human hematopoietic function with autologous cryopreserved circulating stem cells. Exp Hematol 1986;14:192-196.[Medline]
  13. Kessinger A, Armitage JO, Landmark JD et al. Autologous peripheral hematopoietic stem cell transplantation restores hematopoietic function following marrow ablative therapy. Blood 1988;71:723-727.[Abstract/Free Full Text]
  14. Juttner CA, To LB, Ho JQ et al. Early lympho-hemopoietic recovery after autografting using peripheral blood stem cells in acute non-lymphoblastic leukemia. Transplant Proc 1988;20:40-42.[Medline]
  15. Siena S, Bregni M, Brando B et al. Circulation of CD34+ hematopoietic stem cells in the peripheral blood of high-dose cyclophosphamide-treated patients: enhancement by intravenous recombinant human granulocyte-macrophage colony-stimulating factor. Blood 1989;74:1905-1914.[Abstract/Free Full Text]
  16. To LB, Shepperd KM, Haylock DN et al. Single high doses of cyclophosphamide enable the collection of high numbers of hemopoietic stem cells from the peripheral blood [see comments]. Exp Hematol 1990;18:442-447.[Medline]
  17. Sheridan WP, Begley CG, Juttner CA et al. Effect of peripheral-blood progenitor cells mobilised by filgrastim (G-CSF) on platelet recovery after high-dose chemotherapy [see comments]. Lancet 1992;339:640-644.[CrossRef][Medline]
  18. Shpall EJ, Wheeler CA, Turner SA et al. A randomized phase 3 study of peripheral blood progenitor cell mobilization with stem cell factor and filgrastim in high-risk breast cancer patients. Blood 1999;93:2491-2501.[Abstract/Free Full Text]
  19. Brown RA, Adkins D, Goodnough LT et al. Factors that influence the collection and engraftment of allogeneic peripheral-blood stem cells in patients with hematologic malignancies. J Clin Oncol 1997;15:3067-3074.[Abstract]
  20. Schmitz N, Linch DC, Dreger P et al. Randomised trial of filgrastim-mobilised peripheral blood progenitor cell transplantation versus autologous bone-marrow transplantation in lymphoma patients [see comments] [published erratum appears in Lancet 1996;347:914]. Lancet 1996;347:353-357.[CrossRef][Medline]
  21. Bierman PJ, Armitage JO. Autologous hematopoietic stem cell transplantation for non-Hodgkin's lymphoma. In: Atkinson K, ed. Clinical Bone Marrow and Blood Stem Cell Transplantation, Second Edition. Cambridge: Cambridge Press, 2000:211-239.
  22. Sharp JG, Kessinger A, Mann S et al. Outcome of high-dose therapy and autologous transplantation in non-Hodgkin's lymphoma based on the presence of tumor in the marrow or infused hematopoietic harvest. J Clin Oncol 1996;14:214-219.[Abstract]
  23. Gribben JG, Freedman AS, Neuberg D et al. Immunologic purging of marrow assessed by PCR before autologous bone marrow transplantation for B-cell lymphoma [see comments]. N Engl J Med 1991;325:1525-1533.[Abstract]
  24. Schouten HC, Kvaloy S, Sydes M et al. The CUP trial: a randomized study analyzing the efficacy of high dose therapy and purging in low-grade non-Hodgkin's lymphoma (NHL). Ann Oncol 2000;11:91-94.[Abstract/Free Full Text]
  25. Longo DL, Duffey PL, Young RC et al. Conventional-dose salvage combination chemotherapy in patients relapsing with Hodgkin's disease after combination chemotherapy: the low probability for cure. J Clin Oncol 1992;10:210-218.[Abstract]
  26. Bonfante V, Santoro A, Vivian S et al. Outcome of patients with Hodgkin's disease failing after primary MOPP-ABVD [see comments]. J Clin Oncol 1997;15:528-534.[Abstract/Free Full Text]
  27. Yuen AR, Rosenberg SA, Hoppe RT et al. Comparison between conventional salvage therapy and high-dose therapy with autografting for recurrent or refractory Hodgkin's disease. Blood 1997;89:814-822.[Abstract/Free Full Text]
  28. Sweetenham JW, Taghipour G, Linch DC et al. Thirty percent of adult patients with primary refractory Hodgkin's disease (HD) are progression free at 5 years after high dose therapy (HDT) and autologous stem cell transplantation (ASCT): data from 290 patients reported to the EBMT. Blood 1996;88:486a.
  29. Chopra R, McMillan AK, Linch DC et al. The place of high-dose BEAM therapy and autologous bone marrow transplantation in poor-risk Hodgkin's disease. A single-center eight- year study of 155 patients. Blood 1993;81:1137-1145.[Abstract/Free Full Text]
  30. Reece DE, Barnett MJ, Shepherd JD et al. High-dose cyclophosphamide, carmustine (BCNU), and etoposide (VP16-213) with or without cisplatin (CBV ± P) and autologous transplantation for patients with Hodgkin's disease who fail to enter a complete remission after combination chemotherapy. Blood 1995;86:451-456.[Abstract/Free Full Text]
  31. Yahalom J, Gulati SC, Toia M et al. Accelerated hyperfractionated total-lymphoid irradiation, high-dose chemotherapy, and autologous bone marrow transplantation for refractory and relapsing patients with Hodgkin's disease. J Clin Oncol 1993;11:1062-1070.[Abstract/Free Full Text]
  32. Moreau P, Fleury J, Bouabdallah R et al. Early intensive therapy with autologous stem cell transplantation (ASCT) in high-risk Hodgkin's disease (HD): report of 158 cases from the French registry (SFGM). Blood 1996;88:486a.
  33. Gianni AM, Siena S, Bregni M et al. High-dose sequential chemo-radiotherapy with peripheral blood progenitor cell support for relapsed or refractory Hodgkin's disease—a 6-year update. Ann Oncol 1993;4:889-891.[Abstract/Free Full Text]
  34. Linch DC, Winfield D, Goldstone AH et al. Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin's disease: results of a BNLI randomised trial. Lancet 1993;341:1051-1054.[CrossRef][Medline]
  35. Bierman PJ, Anderson JR, Freeman MB et al. High-dose chemotherapy followed by autologous hematopoietic rescue for Hodgkin's disease patients following first relapse after chemotherapy. Ann Oncol 1996;7:151-156.[Abstract/Free Full Text]
  36. Reece DE, Connors JM, Spinelli JJ et al. Intensive therapy with cyclophosphamide, carmustine, etoposide ± cisplatin, and autologous bone marrow transplantation for Hodgkin's disease in first relapse after combination chemotherapy [see comments]. Blood 1994;83:1193-1199.[Abstract/Free Full Text]
  37. Carella AM, Carlier P, Congiu A et al. Autologous bone marrow transplantation as adjuvant treatment for high-risk Hodgkin's disease in first complete remission after MOPP/ABVD protocol. Bone Marrow Transplant 1991;8:99-103.[Medline]
  38. Carella AM, Prencipe E, Pungolino E et al. Twelve years experience with high-dose therapy and autologous stem cell transplantation for high-risk Hodgkin's disease patients in first remission after MOPP/ABVD chemotherapy. Leuk Lymphoma 1996;21:63-70.[Medline]
  39. Sureda A, Mataix R, Hernandez-Navarro F et al. Autologous stem cell transplantation for poor prognosis Hodgkin's disease in first complete remission: a retrospective study from the Spanish GEL-TAMO cooperative group. Bone Marrow Transplant 1997;20:283-288.[CrossRef][Medline]
  40. Delain M, Cartron G, Bout M et al. Intensive therapy with autologous stem cell transplantation as first-line therapy in poor-risk Hodgkin's disease and analysis of predictive factors of outcome. Leuk Lymphoma 1999;34:305-313.[Medline]
  41. Fleury J, Legros M, Colombat P et al. High-dose therapy and autologous bone marrow transplantation in first complete or partial remission for poor prognosis Hodgkin's disease. Leuk Lymphoma 1996;20:259-266.[Medline]
  42. Surbone A, Armitage JO, Gale RP. Autotransplantation in lymphoma: better therapy or healthier patients? [editorial]. Ann Intern Med 1991;114:1059-1060.
  43. Philip T, Armitage JO, Spitzer G et al. High-dose therapy and autologous bone marrow transplantation after failure of conventional chemotherapy in adults with intermediate-grade or high-grade non-Hodgkin's lymphoma. N Engl J Med 1987;316:1493-1498.[Abstract]
  44. Colombat P, Gorin NC, Lemonnier MP et al. The role of autologous bone marrow transplantation in 46 adult patients with non-Hodgkin's lymphomas. J Clin Oncol 1990;8:630-637.[Abstract]
  45. Weisdorf DJ, Haake R, Miller WJ et al. Autologous bone marrow transplantation for progressive non-Hodgkin's lymphoma: clinical impact of immunophenotype and in vitro purging. Bone Marrow Transplant 1991;8:135-142.[Medline]
  46. Lazarus HM, Crilley P, Ciobanu N et al. High-dose carmustine, etoposide, and cisplatin and autologous bone marrow transplantation for relapsed and refractory lymphoma. J Clin Oncol 1992;10:1682-1689.[Abstract/Free Full Text]
  47. Vose JM, Anderson JR, Kessinger A et al. High-dose chemotherapy and autologous hematopoietic stem-cell transplantation for aggressive non-Hodgkin's lymphoma [see comments]. J Clin Oncol 1993;11:1846-1851.[Abstract/Free Full Text]
  48. Wheeler C, Strawderman M, Ayash L et al. Prognostic factors for treatment outcome in autotransplantation of intermediate-grade and high-grade non-Hodgkin's lymphoma with cyclophosphamide, carmustine, and etoposide. J Clin Oncol 1993;11:1085-1091.[Abstract/Free Full Text]
  49. Mills W, Chopra R, McMillan A et al. BEAM chemotherapy and autologous bone marrow transplantation for patients with relapsed or refractory non-Hodgkin's lymphoma. J Clin Oncol 1995;13:588-595.[Abstract/Free Full Text]
  50. van Besien K, Tabocoff J, Rodriguez M et al. High-dose chemotherapy with BEAC regimen and autologous bone marrow transplantation for intermediate grade and immunoblastic lymphoma: durable complete remissions, but a high rate of regimen-related toxicity. Bone Marrow Transplant 1995;15:549-555.[Medline]
  51. Ladenstein R, Pearce R, Hartmann O et al. High-dose chemotherapy with autologous bone marrow rescue in children with poor-risk Burkitt's lymphoma: a report from the European Lymphoma Bone Marrow Transplantation Registry. Blood 1997;90:2921-2930.[Abstract/Free Full Text]
  52. Petersen FB, Appelbaum FR, Hill R et al. Autologous marrow transplantation for malignant lymphoma: a report of 101 cases from Seattle. J Clin Oncol 1990;8:638-647.[Abstract]
  53. Rapoport AP, Lifton R, Constine LS et al. Autotransplantation for relapsed or refractory non-Hodgkin's lymphoma (NHL): long-term follow-up and analysis of prognostic factors. Bone Marrow Transplant 1997;19:883-890.[CrossRef][Medline]
  54. Phillips GL, Fay JW, Herzig RH et al. The treatment of progressive non-Hodgkin's lymphoma with intensive chemoradiotherapy and autologous marrow transplantation. Blood 1990;75:831-838.[Abstract/Free Full Text]
  55. Weaver CH, Petersen FB, Appelbaum FR et al. High-dose fractionated total-body irradiation, etoposide, and cyclophosphamide followed by autologous stem-cell support in patients with malignant lymphoma. J Clin Oncol 1994;12:2559-2566.[Abstract/Free Full Text]
  56. Philip T, Guglielmi C, Hagenbeek A et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma [see comments]. N Engl J Med 1995;333:1540-1545.[Abstract/Free Full Text]
  57. Guglielmi C, Gomez F, Philip T et al. Time to relapse has prognostic value in patients with aggressive lymphoma enrolled onto the Parma trial. J Clin Oncol 1998;16:3264-3269.[Abstract]
  58. Blay J, Gomez F, Sebban C et al. The International Prognostic Index correlates to survival in patients with aggressive lymphoma in relapse: analysis of the PARMA trial. Parma Group. Blood 1998;92:3562-3568.[Abstract/Free Full Text]
  59. Shipp MA, Abeloff MD, Antman KH et al. International Consensus Conference on High-Dose Therapy with Hematopoietic Stem Cell Transplantation in Aggressive Non-Hodgkin's Lymphomas: report of the jury. J Clin Oncol 1999;17:423-429.[Free Full Text]
  60. Haioun C, Lepage E, Gisselbrecht C et al. Survival benefit of high-dose therapy in poor-risk aggressive non-Hodgkin's lymphoma: final analysis of the prospective LNH87-2 protocol—a groupe d'Etude des lymphomes de l'Adulte study. J Clin Oncol 2000;18:3025-3030.[Abstract/Free Full Text]
  61. Santini G, Salvagno L, Leoni P et al. VACOP-B versus VACOP-B plus autologous bone marrow transplantation for advanced diffuse non-Hodgkin's lymphoma: results of a prospective randomized trial by the non-Hodgkin's Lymphoma Cooperative Study Group. J Clin Oncol 1998;16:2796-2802.[Abstract]
  62. Reyes F, Lepage E, Morel P et al. Failure of first-line inductive high-dose chemotherapy (HDC) in poor-risk patients (PTS) with aggressive lymphoma: updated results of the randomized LNH93-3 study. Blood 1997;90:594a.
  63. Verdonck LF, van Putten WL, Hagenbeek A et al. Comparison of CHOP chemotherapy with autologous bone marrow transplantation for slowly responding patients with aggressive non-Hodgkin's lymphoma [see comments]. N Engl J Med 1995;332:1045-1051.[Abstract/Free Full Text]
  64. Haioun C, Lepage E, Gisselbrecht C et al. Benefit of autologous bone marrow transplantation over sequential chemotherapy in poor-risk aggressive non-Hodgkin's lymphoma: updated results of the prospective study LNH87-2. Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 1997;15:1131-1137.[Abstract/Free Full Text]
  65. Cabanillas F, Hagemeister FB, McLaughlin P et al. Results of MIME salvage regimen for recurrent or refractory lymphoma. J Clin Oncol 1987;5:407-412.[Abstract]
  66. Vose J, Zhang M-J, Rowlings P et al. Autologous transplantation for diffuse aggressive non-Hodgkin's lymphoma in patients never achieving remission: a report from the autologous blood and marrow transplant registry. J Clin Oncol 2001;19:406-413.[Abstract/Free Full Text]
  67. Freedman AS, Ritz J, Neuberg D et al. Autologous bone marrow transplantation in 69 patients with a history of low-grade B-cell non-Hodgkin's lymphoma. Blood 1991;77:2524-2529.[Abstract/Free Full Text]
  68. Fouillard L, Gorin NC, Laporte JP et al. Feasibility of autologous bone marrow transplantation for early consolidation of follicular non-Hodgkin's lymphoma. Eur J Haematol 1991;46:279-284.[Medline]
  69. Colombat P, Donadio D, Fouillard L et al. Value of autologous bone marrow transplantation in follicular lymphoma: a France Autogreffe retrospective study of 42 patients. Bone Marrow Transplant 1994;13:157-162.[Medline]
  70. Schouten HC, Colombat P, Verdonck LF et al. Autologous bone marrow transplantation for low-grade non-Hodgkin's lymphoma: the European Bone Marrow Transplant Group experience. EBMT Working Party for Lymphoma. Ann Oncol 1994;5:147-149.[Abstract/Free Full Text]
  71. Rohatiner AZ, Johnson PW, Price CG et al. Myeloablative therapy with autologous bone marrow transplantation as consolidation therapy for recurrent follicular lymphoma. J Clin Oncol 1994;12:1177-1184.[Abstract/Free Full Text]
  72. Cervantes F, Shu XO, McGlave PB et al. Autologous bone marrow transplantation for non-transformed low-grade non-Hodgkin's lymphoma. Bone Marrow Transplant 1995;16:387-392.[Medline]
  73. Bastion Y, Brice P, Haioun C et al. Intensive therapy with peripheral blood progenitor cell transplantation in 60 patients with poor-prognosis follicular lymphoma. Blood 1995;86:3257-3262.[Abstract/Free Full Text]
  74. Bierman PJ, Vose JM, Anderson JR et al. High-dose therapy with autologous hematopoietic rescue for follicular low-grade non-Hodgkin's lymphoma. J Clin Oncol 1997;15:445-450.[Abstract/Free Full Text]
  75. Phillips GL, Reece DE. HLA-identical sibling hematopoietic stem cell transplantation for the non-Hodkgin's lymphomas and Hodgkin's disease. In: Atkinson K, ed. Clinical Bone Marrow and Blood Stem Cell Transplantation, Second Edition. Cambridge: Cambridge Press, 2000:500-514.
  76. Horowitz MM, Gale RP, Sondel PM et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood 1990;75:555-562.[Abstract/Free Full Text]
  77. Gajewski JL, Phillips GL, Sobocinski KA et al. Bone marrow transplants from HLA-identical siblings in advanced Hodgkin's disease. J Clin Oncol 1996;14:572-578.[Abstract/Free Full Text]
  78. Milpied N, Fielding AK, Pearce RM et al. Allogeneic bone marrow transplant is not better than autologous transplant for patients with relapsed Hodgkin's disease. European Group for Blood and Bone Marrow Transplantation. J Clin Oncol 1996;14:1291-1296.[Abstract/Free Full Text]
  79. van Besien K, Sobocinski KA, Rowlings PA et al. Allogeneic bone marrow transplantation for low-grade lymphoma. Blood 1998;92:1832-1836.[Abstract/Free Full Text]
  80. Ratanatharathorn V, Uberti J, Karanes C et al. Prospective comparative trial of autologous versus allogeneic bone marrow transplantation in patients with non-Hodgkin's lymphoma. Blood 1994;84:1050-1055.[Abstract/Free Full Text]
  81. Khouri IF, Keating M, Körbling M et al. Transplant-lite: induction of graft-versus-malignancy using fludarabine- based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies [see comments]. J Clin Oncol 1998;16:2817-2824.[Abstract]
  82. Khouri IF, Giralat S, Saliba R et al. "Mini"-allogeneic stem cell transplanationa for relapsed/refractory lymphomas with aggressive histologies. Proc Am Soc Clin Oncol 2000;19:47a.
Received November 2, 2000; accepted for publication February 27, 2001.




This article has been cited by other articles:


Home page
 Ann OncolHome page
A. Gondos, F. Bray, T. Hakulinen, H. Brenner, and the EUNICE Survival Working Group
Trends in cancer survival in 11 European populations from 1990 to 2009: a model-based analysis
Ann. Onc., March 1, 2009; 20(3): 564 - 573.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
K. A. Goodman, E. Riedel, V. Serrano, S. Gulati, C. H. Moskowitz, and J. Yahalom
Long-Term Effects of High-Dose Chemotherapy and Radiation for Relapsed and Refractory Hodgkin's Lymphoma
J. Clin. Oncol., November 10, 2008; 26(32): 5240 - 5247.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Pathol.Home page
T Mitterlechner, M Fiegl, H Muhlbock, W Oberaigner, S Dirnhofer, and A Tzankov
Epidemiology of non-Hodgkin lymphomas in Tyrol/Austria from 1991 to 2000
J. Clin. Pathol., January 1, 2006; 59(1): 48 - 55.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow eLetters: Submit a response to this article
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article link to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Mink, S. A.
Right arrow Articles by Armitage, J. O.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Mink, S. A.
Right arrow Articles by Armitage, J. O.

HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
THE ONCOLOGIST STEM CELLS CME ALPHAMED PRESS JOURNALS