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Leukemia/Lymphoma

Stem Cell Transplantation For Non-Hodgkin’s Lymphoma 
  Submitted By: Matt  Kalaycio, M.D

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Article by Matt Kalaycio, M.D.
Director, Leukemia Program

Cleveland Clinic Foundation

Stem Cell Transplantation

For Non-Hodgkin’s Lymphoma


Introduction

The non-Hodgkin’s lymphomas (NHL) are cancers of the cells that populate lymph nodes. The NHLs are classified according to the way they look under the microscope (histology), the way they express different proteins on the their cell surface (immunophenotype), the way their chromosomes are altered (cytogenetics), and the way their cellular machinery is altered (molecular biology). Most NHLs are cancers of B-lymphocytes and are characterized by their sensitivity to chemotherapy. Unfortunately, they are not always curable with chemotherapy alone. Autologous stem cell transplant (ASCT) takes advantage of the sensitivity of NHL to chemotherapy and offers a greater potential for long-term remission, if not cure, for a substantial portion of patients who would otherwise be incurable. Allogeneic stem cell transplant has historically exploited the dose-response curve of NHL, but emerging evidence suggests that immune modulation may play as important a role in curing lymphoma as chemotherapy does.

Autologous Stem Cell Transplant

As demonstrated in Figure 1, there is a steep dose-response curve between the dose of chemotherapy and the response of NHL. In this hypothetical figure, a given dose of chemotherapy (point A) results in a certain tumor response (Point 1). Oncologists are limited in the dose range they can administer because of chemotherapy side effects to the normal bone marrow stem cells. If those side effects could be avoided, then the dose of chemotherapy could be increased (Point B). Such a dose-increase leads to a greater tumor response leading to a longer remission, if not cure.



Figure 1. Hypothetical dose-response curve for chemotherapy dose versus tumor response for NHL.



Diffuse Large B-cell Lymphoma

The concept of dose-response has been clinically proven for diffuse large B-cell lymphoma (DLCL). Patients with relapsed DLCL and responding to chemotherapy have a better 5 year survival when treated with high-dose chemotherapy and autologous stem cell transplant (ASCT) compared to those treated with chemotherapy alone (56% versus 32% respectively).1 Thus, ASCT represents the standard of care for patients with relapsed DLCL. The benefit of ASCT for earlier stages of DLCL has been more difficult to prove and remains investigational.

Follicular Lymphoma

Historically, follicular lymphomas have been considered incurable whether treated with or without ASCT. A recently published study, however, suggests that survival may be improved with ASCT compared to chemotherapy alone. In this European study, patients with relapsed follicular lymphoma that was responding to chemotherapy were randomized to further treatment with either more chemotherapy or ASCT. The patients randomized to ASCT enjoyed an improved overall survival of 71-77% compared to 46% in those treated with chemotherapy alone.2 Given the long-natural history of follicular lymphoma, and the availability of alternative treatments with high response rates, this study does not establish ASCT as the standard of care for relapsed follicular lymphoma. However, ASCT is a reasonable treatment option for selected patients.

Mantle Cell Lymphoma

Mantle cell lymphoma is a particularly difficult B-cell lymphoma to treat. Although this lymphoma responds to chemotherapy, it usually relapses quickly and is generally chemotherapy resistant when it does so. In fact, ASCT is not generally recommended for relapsed mantle cell lymphoma. However, several studies have explored the role of ASCT for mantle cell lymphoma as part of initial therapy. The results of most of these studies suggest improved survival for patients treated with ASCT compared to historical experience. In a study of intensive chemotherapy followed by ASCT for 25 patients at MD Anderson Cancer Center in Houston, Texas, the 3-year event-free survival was 72%.3 Unfortunately, no prospective, randomized trials have been completed to know with certainty whether or not ASCT is beneficial in this population of patients.

Other Lymphomas

The data for ASCT in other lymphomas like small lymphocytic lymphoma and marginal zone lymphoma is too scarce to draw conclusions from.

Allogeneic Stem Cell Transplant

The role of allogeneic transplant for lymphoma is controversial. Unlike autologous transplants, allogeneic transplants require a donor. As such, an allogeneic transplant replaces the patient’s bone marrow with somebody else’s. The new, donor marrow then reconstitutes the donor’s immune system. Since the donor’s immune system was designed to protect the donor, not the patient, the new immune system that has been grafted into the host (or patient) may recognize the host as a foreign body and try to reject the host. Unlike the situation in solid organ transplants where the greatest concern is with rejection of the donor organ, in allogeneic transplants the greatest concern is with the donor graft rejecting the host. The immune reaction of the donor graft against the host is called graft-versus-host disease (GVHD).

Depending on both donor and host characteristics, GVHD occurs in 20-50% of patients. Of those afflicted, about 50% have such severe disease that they die of it. The high mortality rate associated with GVHD has generally relegated allogeneic stem cell transplant to a position of last resort in the treatment of NHL.

New information, however, is challenging the status quo. At least some of the mortality attributed to allogeneic stem cell transplant is due to the toxic effects of the high dose of chemotherapy and radiation needed to destroy (myeloablate) the patient’s bone marrow and immune system to allow the donor marrow to grow. The toxic effects of chemotherapy and radiation also tend to worsen the severity of GVHD. If the intensity of treatment could be reduced, toxicity would be less and fewer patients should die as a result of transplant.

Reducing intensity of treatment, though, lessens the advantage of the dose-response curve in NHL. Emerging evidence, however, suggests that the dose-response curve may not be as important in allogeneic stem cell transplant as it is in ASCT. Certainly in leukemia, and to a lesser extent in NHL, patients who develop GVHD tend not to relapse.4 The donor graft seems to attack the host’s lymphoma as well as the normal tissues. The immunologic attack of the donor’s immune system against the patient’s lymphoma is termed the graft-versus-lymphoma (GVL) effect. That this effect exists is best demonstrated by the observation that the relapse rate after allogeneic transplant is much lower than the rate after ASCT.5 Indeed, recent results seem to suggest that cure is possible for a majority of patients with follicular lymphoma treated with allogeneic stem cell transplant.6

These observations provide the impetus for non-myeloablative allogeneic stem cell transplants (NMSCT), sometimes referred to as “mini-transplants.” In order to get donor marrow to replace recipient marrow the recipient’s immune system needs to be suppressed, but it does not need to be destroyed. New, immunosuppressive treatment regimens have been devised that allow donor marrow to effectively replace recipient marrow. The transplant also replaces the recipient immune system with the donor’s immune system. GVHD may result, but it is generally less severe than GVHD induced by myeloablative transplants. Encouraging early data also suggests that the GVL effect is induced. Thus, NMSCT is a new technique that reduces the toxicity of allogeneic stem cell transplant and offers the possibility of cure to some patients with NHL, particularly those with low-grade NHL like the follicular lymphomas. For example, the group at MD Anderson Cancer Center in Houston, Texas treated 20 patents with relapsed, low-grade NHL with NMSCT. With 21 months of follow-up, no relapses were reported with a probability of relapse-free survival of 84%.7

Summary

Both autologous and allogeneic stem cell transplantation are viable treatment alternatives for the non-Hodgkin’s lymphomas. The decision as to which treatment to pursue is individualized based on the type of lymphoma, the stage of disease, and the general health of the patient. Importantly, allogeneic transplant requires a donor and finding a suitable donor takes time. Early referral to a transplant center is recommended for any patient being considered for an allogeneic transplant approach. 


 


Additional Authors:  

Works Cited:  
  References

1) Philip T, Guglielmi C, Hagenbeek A, et al. Autologous bone marrow transplant as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s Lymphoma. New Engl J Med 333:1540-1545, 1995
2) Schouten HC, Qian W, Kvaloy S, Porcellini A, Hagberg H, Johnsen HE, Doorduijn JK, Sydes MR, and Kvalheim G. High-Dose Therapy Improves Progression-Free Survival and Survival in Relapsed Follicular Non-Hodgkin’s Lymphoma: Results From the Randomized European CUP Trial. J Clin Oncol 21: 3918-3927, 2003
3) Khouri IF, Romaguera J, Kantarjian H, et al. Hyper-CVAD and high-dose methotrexate/cytarabine followed by stem cell transplantation: an active regimen for aggressive mantle-cell lymphoma. J Clin Oncol 16:3803-3809, 1998.
4) Horowitz MM, Gale RP, Sondel PM. Graft-versus-leukemia reactions after bone marrow transplantation. Blood 75: 555-562, 1990.
5) Verdonck LF, Dekker AW, Lokhorst HM, et al. Allogeneic versus autologous bone marrow transplantation for refractory and recurrent low-grade non-Hodgkin’s lymphoma. Blood 90:4201- 4205, 1997.
6) Van Besien KW, Khouri IF, Giralt SA, et al. Allogeneic bone marrow transplantation for refractory and recurrent low-grade lymphoma. The case for aggressive management. J Clin Oncol 13: 1096-1102, 1995.
7) Khouri IF, Saliba RM, Giralt SA, et al. Nonablative allogeneic hematopoietic transplantation as adoptive immunotherapy for indolent lymphoma: low incidence of toxicity, acute graft-versus-host disease, and treatment-related mortality. Blood 98: 3595-3599, 2001.

 
 


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