Hematopoietic Stem Cell Transplantation for Non-Hodgkin’s Lymphoma

By LEONA A. HOLMBERG, MD, PhD
Assistant Member
Clinical Research Division
Fred Hutchinson
Cancer Research Center
Assistant Professor
Department of Medicine
University of Washington
School of Medicine

F. MARC STEWART, MD
Member
Clinical Research Division
Fred Hutchinson
Cancer Research Center
Professor, Department of Medicine
University of Washington
School of Medicine
Seattle, Washington | May 1, 2003

Aggressive Non-Hodgkin's Lymphoma Autologous Transplant
It is well established that in chemotherapy- sensitive relapsed aggressive NHL, autologous HSCT results in durable remissions and is superior to conventional salvage therapy.[1,2] Mantle cell NHL, although considered an aggressive form of the disease, could probably be categorized as both indolent and aggressive. In general, it is well accepted that an autologous transplant is reasonable consolidation therapy for mantle cell patients in first complete remission. In meta-analysis, the addition of rituximab(Drug information on rituximab) has also been shown to increase overall and disease-free survival with limited follow-up, and thus, has become the standard of therapy to incorporate with an autologous transplant in mantle cell patients. The addition of radiolabeled anti- CD20 to a cyclophosphamide(Drug information on cyclophosphamide) and etoposide(Drug information on etoposide) conditioning regimen has resulted in encouraging initial response rates for patients with persistent mantle cell disease.[37] Non-Mantle Cell NHL
Upfront autologous transplant, as outlined by Cabellero et al,[38] has been studied in diffuse large cell NHL. In this study, 42% of patients received stem cell transplants in first complete response, 19% in second complete response, and 47% with active disease. Moreover, 35% had disease sensitive to chemotherapy, and 12% had chemotherapy-refractory disease. The estimated overall and disease-free survival rates at 5 years were 53% and 43%, respectively, and the transplant-associated mortality rate was 11%. By multivariate analysis, the following variables significantly affected overall and diseasefree survival rates: the number of regimens to reach first complete remission and disease status at transplant. Total-body irradiation in conditioning regimens had an adverse effect on survival and age-adjusted IPI scores also affected disease-free survival. However, in terms of transplanting non-mantle cell, aggressive NHL patients in first complete remission, the role of autologous HSCT remains controversial. Several recently published randomized studies and prospective trials have compared upfront HSCT to standard therapy in poorprognosis patients in first complete or partial remission.[39-43] These studies differed in their design and conclusions. Gianni et al[39] reported much early toxicity in the transplant arm. Although differences could not be accurately measured due to the study's crossover design, event-free survival in the initial transplant arm was 76% compared with 49% in the nontransplant arm (P = .004). Haoiun et al[40] did not at first show any differences in overall or disease-free survival, but their retrospective analysis showed that patients with an IPI score of 2 or 3 who underwent HSCT had a better outcome, with a diseasefree survival rate of 55% vs 39%, and an overall survival rate of 64% vs 49% (P = .4) at 8 years. Kluin- Nelemans et al[42] compared eight cycles of CHOP (cyclophosphamide, doxorubicin(Drug information on doxorubicin) HCl, vincristine, prednisone(Drug information on prednisone)) to six cycles of CHOP plus BEAC (carmustine [BCNU], etoposide, cytarabine(Drug information on cytarabine), cyclophosphamide) and found no difference in outcome. Most patients in the study by the European Organization for Research and Treatment of Cancer had favorable IPI scores. Other studies that contained a shortened induction regimen before transplant have failed to show an advantage. Taken together, these results would seem to suggest that patients need to receive standard induction chemotherapy for diffuse large cell NHL before an autologous transplant. Patients with poor IPI risk factors at initial diagnosis of diffuse large cell NHL may benefit from front-line HSCT. On the other hand, patients who present with favorable IPI factors should not undergo an upfront autologous HSCT, but rather, should wait until first relapse. With respect specifically to adult Burkitt's and Burkitt's-like NHL, a retrospective analysis of 117 patients in Europe showed that 70 patients received an autologous transplant in first complete remission.[44] The major factor predicting for outcome after transplant was disease status at time of transplant. The 3-year actuarial survival was 72% for patients in first complete remission, compared to 36% for patients transplanted with chemosensitive relapse and 7% for chemorefractory disease. As more dose-intense therapy has become the norm for treating newly diagnosed adult Burkitt's and Burkitt's-like NHL, a randomized study comparing outcome after transplant in first complete remission to these newer dose-intense regimens is needed. Other Autologous Transplant Strategies
Tandem autologous transplants have also been assessed to see if they will increase response rates.[45] The addition of radiolabeled antibody,[ 17-19] immunotherapy (eg, dose-intense IL-2, IL-2-incubated PBSC, IL-2 and rituximab, and rituximab alone), and antigen-specific therapy (eg, Epstein-Barr virus-driven T-cells clones) to conditioning regimens are also being studied. Biologic modifiers such as bcl-2 antisense will also be studied for maintenance therapy after an autologous transplant. Myeloablative and Nonmyeloablative Allogeneic Transplants
The role of myeloablative allogeneic transplant in aggressive NHL has limitations similar to those discussed in the indolent NHL section. The lower relapse rates but still high mortality rates associated with myeloablative regimens have limited their use to patients whose stem cells cannot be collected for an autologous transplant and patients with chemorefractory disease. Many physicians believe that a total-body irradiation-containing allogeneic myeloablative regimen for chemorefractory disease may be more effective than a chemotherapy-only regimen. The use of nonmyeloablative transplants in this setting has been less studied. Aggressive non-mantle cell NHL may not be the best candidate for nonmyeloablative therapy. Intermediate-grade NHL historically has been thought to be only moderately sensitive to an allogeneic graftvs- lymphoma effect. Allogeneic transplants have resulted in fewer relapses than an autologous or syngeneic transplant, but response to donor lymphocytes is less common and more transient in intermediate NHL. Highgrade lymphomas such as Burkitt's, Burkitt's like, and immunoblastic NHL appear to be more insensitive to a graftvs- lymphoma effect, as they grow rapidly and may lack adequate ability to cause an immune response. Thus, high-grade NHL patients will benefit more from a myeloablative allogeneic transplant than a nonmyeloablative approach and, if medically stable, should not be offered the nonmyeloablative therapy. Diffuse NHL
Diffuse NHL patients may be an appropriate group in which to study the tandem transplant approach, with an autologous transplant first for tumor control followed by a nonmyeloablative allogeneic transplant. The problem remains, however, that at least 35% of diffuse NHL patients in first relapse with chemotherapy-sensitive disease are cured with an autologous transplant. To commit these patients to the risk of developing GVHD does not seem reasonable. What is needed is a better way to determine which patients will remain in the cured group with an autologous transplant. Certain indicators are inherently useful. For example, patients who relapse and then respond to salvage therapy with a complete response are more likely to stay in remission after an autologous transplant then patients with refractory disease. Thus, a better understanding of tumor markers is needed. It is hoped that this will emerge from the many ongoing molecular studies (eg, involving microarray assays), so that we can differentiate the various diffuse NHL patients and determine who is most likely to remain in remission after an autologous transplant alone. Until then, it is more reasonable to study a strategy of offering all patients with chemotherapy-sensitive diffuse NHL a standard autologous transplant and offering patients with persistent disease after the autologous transplant (who have an HLAmatched donor) a nonmyeloablative transplant. Positron-emission tomography (PET) evaluation post-autologous transplant and PCR evaluation of bone marrow may help us determine which patients have persistent minimal disease that would benefit from a nonmyeloablative allogeneic transplant. We should not shortchange our patients and give in to the temptation to reduce the dose of the autologous transplant conditioning regimen, ie, in favor of the nonmyeloablative allogeneic approach. We do not know how to maximize the allogeneic effect in a nonmyeloablative approach. We need to study whether the use of natural killer cells, donor lymphocytes sensitized to minor HLA tumorassociated antigens, amplification of the polyclonal tumor response after an allogeneic transplant, or vaccination strategies can improve the nonmyeloablative approach. Patients who are in complete remission after an autologous transplant should be followed and offered allogeneic therapy only at the time of disease progression. Conclusions The role of HSCT in the treatment of NHL is still evolving. Basic questions about when to incorporate HSCT early in the course of the disease remain unanswered. How to increase the benefit of autologous therapy through the addition of therapies such as immunotherapy, targeted radiolabeled antibody, antibody therapy, and biologic modifiers has yet to be established. Moreover, we need to explore how to decrease the toxicity of allogeneic transplants, to better control chronic GVHD, to determine which patients will benefit from a nonmyeloablative approach, and to maximize the allogeneic graftvs- lymphoma effect.

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JOHN W. SWEETENHAM, MD
ANGELO MICHELE CARELLA, MD

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Hematopoietic Stem Cell Transplantation for Non-Hodgkin’s Lymphoma

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