Reduced-Intensity Regimens in Allogeneic Stem-Cell Transplantation for Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia

Abstract

Autologous stem-cell transplantation is widely accepted as effective therapy for patients with relapsed aggressive B-cell non-Hodgkin lymphomas. Although 40-60% of younger patients with diffuse large cell lymphoma can expect to be cured, substantial numbers will experience a relapse. In addition, certain histologic subtypes are associated with particularly poor prognoses with combination chemotherapy alone (e.g., mantle cell lymphoma). Relatively few of these patients will experience long-term responses. Although other NHL subtypes are associated with more favorable prognoses in terms of overall survival, they are rarely cured (e.g., follicular lymphoma, chronic lymphocytic leukemia). Allogeneic transplantation has been increasingly utilized in patients with lymphoid malignancies but is associated with high toxicity. Recently, reduced-intensity conditioning regimens have shown encouraging results, attributed to graftversus-lymphoma effects. This article discusses changes in the way autologous and allogeneic transplants may be carried out in the future to treat patients with lymphoid malignancies.Recurrent non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) have a poor prognoses with conventional chemotherapy.1,2 Intensive research with novel chemotherapy regimens has been conducted, but patients with recurrent disease typically have only a transient response to salvage therapies and ultimately die of their disease. Autologous and allogeneic blood and marrow transplantations have decreased morbidity and mortality rates as a result of improvements in stem cell transplantation (SCT) procedures and supportive care. As a result, there has been an increase in the use of SCT in lymphoid malignancies. Improvements in SCT for NHL and CLLToxicity related to intense preparative regimens, graft-versus-host-disease (GVHD), and infections remain the main cause of failure after high-dose chemoradiotherapy and allogeneic SCT. The treatment-related mortality (TRM) rate of this approach has been substantial, with a 30-40% risk of death within 100 days of the transplantation. The use of recently introduced reduced-intensity and truly nonmyeloablative conditioning regimens has shifted some or all of the burden of tumor-cell kill from the conditioning regimens to the graft-versus-tumor effects. These regimens are less toxic than conventional regimens and allow for the treatment of older patients and patients with comorbid conditions.The inclusion of targeted therapies that are focused on the recipient's abnormal cells and hematopoietic system while sparing all other organs; better donor selection, with improvements in histocompatibility typing procedures; new prophylactic antifungal agents; and early detection of cytomegalovirus reactivation by sensitive methods have all contributed to the decreased TRM risk of allogeneic SCT.Unlike allogeneic SCT, autologous SCT has been associated with a TRM of < 5% but has also been associated with a higher risk of relapse related to contamination of the graft and persistence of min...

Does peritransplantation use of rituximab reduce the risk of EBV reactivation and PTLPD?

“…4 It would be interesting to see how many EBV reactivations and PTLPDs have been observed after rituximab containing conditioning regimen for B-cell malignancies from a larger database. 5 Rituximab infusion given 2 months after total lymphoid irradiation (TLI)-ATG showed excellent disease control with minimal graft-versus-host disease (GVHD) without any detrimental effects on engraftment or infection and no EBV reactivation reported. 6 The European Group for Blood and Marrow Transplantation (EBMT) Working Party on Severe Aplastic Anemia (SAA) proposed adding rituximab on day ϩ5 of their fludarabine, cyclophosphamide, low-dose total body irradiation (TBI), and ATG regimen for unrelated donor transplants in acquired SAA.…”

“…7 Rituximab, with (if GVHD is present) or without donor lymphocyte infusion (DLI), has been used for persistent disease after allo-SCT for chronic lymphocytic leukemia (CLL) with excellent results. 5,8 In addition to benefits of decreasing risk of GVHD and better disease control in patients with B-cell malignancies, one would expect lower EBV reactivation and PTLPD after these regimens. If the risk of EBV reactivation and the possible development of PTLPD is reduced in patients treated with rituximab, then we will need ask these questions: (1) How should we monitor high-risk patients treated with rituximab?…”

Impaired B-cell reconstitution in lymphoma patients undergoing allogeneic HSCT: an effect of pretreatment with rituximab?

“…[1][2][3] Advances in protective care and the introduction of non-myeloablative conditioning regimens have extended the range of patients eligible for this treatment modality. 4 Chemotherapy regimens used to treat lymphoma have also evolved.…”

Current status and future perspectives for yttrium-90 (90Y)-ibritumomab tiuxetan in stem cell transplantation for non-Hodgkin's lymphoma

“…Transplant-related mortality (TRM) is low for autologous SCT, with rates below 5%. 10 However, autologous transplantation has only limited success when performed in the refractory or progressive stages of lymphoma and in heavily pre-treated or multiply relapsed patients.…”

“…Conventional high-dose myeloablative conditioning (cyclophosphamide plus TBI or busulphan) is associated with high toxicity and TRM rates of up to 40%. 10 However, TRM associated with allogeneic SCT is steadily being reduced, particularly with the introduction of reduced-intensity conditioning (RIC) regimens. 12 RIC regimens use lower doses of chemotherapy and radiation, allowing engraftment of donor cells with reduced toxicity compared to myeloablative regimens.…”