Graft-vs.-lymphoma effect in various histologies of non-Hodgkin's lymphoma

Generally, there is a significantly lower risk of lymphoma relapse following allogeneic than after autologous stem cell transplant. Factors contributing to this lower risk of relapse include an absence of the use of ablative conditioning, with a tumor-free graft, and the generation of a graft-vs.-tumor (GVT) immune response. Allogeneic transplantation, however, has the possibility of graft-vs.-host disease (GVHD). The use of autologous and conventional allogeneic hematopoietic stem cell transplantation (HSCT) in follicular lymphoma, diffuse large cell lymphoma, chronic lymphocytic leukemia and multiple myeloma is discussed. Due to a 1-year transplant-related mortality of 30-40% and complications caused by GVHD, conventional, myeloablative, allogeneic transplantation is a high-risk option for low-grade lymphoproliferative disorders. Novel applications of allogeneic HSCT are described that take advantage of a GVT effect while reducing the risk of GVHD. Minimally myelotoxic pretransplant conditioning regimens allow host antigen-presenting cells to persist, enabling presentation of host minor histocompatibility antigens to donor T cells, causing a GVT response. Although complications may arise due to GVHD, non-myeloablative HSCT can be offered to patients previously ineligible for conventional high-dose treatment. A protocol developed in Seattle using a low-dose total body irradiation (TBI)-based conditioning regimen with immunosuppression using mycophenolate mofetil in combination with cyclosporin has been used in a multicenter trial. To overcome the problem of graft rejection fludarabine was later added to the protocol. A second protocol from a smaller trial used a preparative, conventional-dose regimen of fludarabine, given with cyclophosphamide. Rituximab was also given to provide synergistic action with the chemotherapy to enhance tumor control in the early post-transplant period to allow time for the establishment of the GVT effect. Following transplantation, GVHD prophylaxis was given using tacrolimus with methotrexate. A trial of a further variation of allogeneic HSCT, tandem auto/allo transplants, is described. First, high-dose therapy with autologous PBSC rescue was used to cytoreduce the disease. This was followed by a reduced-intensity or non-myeloablative allogeneic graft. This procedure was devised to take advantage of high-dose therapy and allogeneic HSCT. Results for non-myeloablative allogeneic HSCT are particularly promising in low-grade NHL and the GVT effect may augment response and delay or prevent relapse. However, for aggressive disease, non-myeloablative regimens are only indicated for patients with minimal disease, as the non-myeloablative regimens are unable to control the tumor before the generation of a GVT effect, and/or lack the ability to control rapidly proliferating disease. Patients with relapsed disease may require a higher-dose regimen or tandem transplant approach.     

Allogeneic hematopoietic stem cell transplantation for lymphoma

For patients with relapsed or refractory Hodgkin's or non-Hodgkin's lymphomas, allogeneic hematopoietic stem cell transplantation (HSCT) is a treatment option when autologous HSCT fails to achieve durable remission or is deemed inappropriate. Allogeneic HSCT can result in long-term survival even in patients with refractory lymphomas. The efficacy of allogeneic HSCT is attributed, at least in part, to an immune-mediated graft-versus-lymphoma (GVL) effect that can also be associated with significant toxicity resulting from graft-versus-host disease. However, clinical evidence of a potent GVL effect is inconsistent. Reduced-intensity conditioning before allogeneic HSCT can facilitate the use of this treatment in older patients and those at high risk. The decrease in toxicity with reduced-intensity regimens may be associated with a loss of antitumor effects. Patients with lymphoma should be selected for allogeneic HSCT on the basis of characteristics that strongly influence transplant outcomes, including histology, chemosensitivity, and donor source.     

Allogeneic lymphocytes induce tumor regression of advanced metastatic breast cancer.

PURPOSE: Allogeneic T lymphocytes can induce regression of metastatic breast cancer through an immune-mediated graft-versus-tumor (GVT) effect in murine models. To determine if a clinical GVT effect exists against metastatic breast cancer, allogeneic lymphocytes were used as adoptive cellular therapy after a reduced-intensity chemotherapy conditioning regimen and allogeneic hematopoietic stem-cell transplantation (HSCT) from human leukocyte antigen-matched siblings. PATIENTS AND METHODS: Sixteen patients with metastatic breast cancer that had progressed after treatment with anthracyclines, taxanes, hormonal agents, and trastuzumab, received allogeneic HSCT. The reduced-intensity transplant conditioning regimen consisted of cyclophosphamide and fludarabine. To distinguish an immunological GVT effect from any antitumor effect of cytotoxic chemotherapy in the transplant-conditioning regimen, allogeneic T lymphocytes were removed from the stem-cell graft and were subsequently administered late postallogeneic HSCT. Allogeneic lymphocytes containing 1 x 10(6), 5 x 10(6), and 10 x 10(6) CD3(+) cells/kg were infused on days +42, +70, and +98 post-allogeneic HSCT, respectively. RESULTS: Objective tumor regressions occurred after day +28 post-allogeneic HSCT in six patients and were attributed to allogeneic lymphocyte infusions. Two of these responding patients had disease progression post-allogeneic HSCT before subsequent tumor regression. Tumor regressions occurred concomitantly with the establishment of complete donor T-lymphoid engraftment, were associated with the development of graft-versus-host disease (GVHD), and were abrogated by subsequent systemic immunosuppression for GVHD. CONCLUSION: Allogeneic lymphocytes can induce regression of advanced metastatic breast cancer. These results indicate that an immunological GVT effect from allogeneic lymphocytes exists against metastatic breast cancer and provide rationale for further development of allogeneic cellular therapy for this largely incurable disease.     

Allogeneic hematopoetic stem-cell transplantation for patients with relapsed or refractory lymphomas: comparison of high-dose conventional conditioning versus fludarabine-based reduced-intensity regimens.

BACKGROUND: Allogeneic hematopoetic stem-cell transplantation (alloHSCT) has curative potential for poor risk lymphoma patients due to the graft-versus-lymphoma effect. High non-relapse mortality with conventional high-dose conditioning indicates the necessity for less toxic transplant strategies. PATIENTS AND METHODS: Between 1992 and 1999, 25 patients [median age 37 (20-60) years] with relapsed or refractory non-Hodgkin's lymphoma (NHL, n = 20) or Hodgkin's disease (HD, n = 5) received an alloHSCT in our institution. Patients were grafted from HLA matched (17) or mismatched (2) related, or matched unrelated donors (MUD) (6). NHL histological subtypes were lymphoblastic (6), high grade B/T-cell lymphomas (5), follicular (3), mantle cell (2) and CLL, immunocytic, composite lymphoma and panniculitic T-NHL in one patient each. Patients had received a median of four (range three to six) different therapies before alloHSCT, and 10 patients had relapsed after high-dose chemotherapy and autologous (9) or allogeneic (1) HSCT. Remission status prior to allogeneic SCT was CR1 (1), CR2 (1), relapse (11), partial remission (5) or primary refractory induction failure (7). Conventional myeloablative conditioning (cc) regimens contained total body irradiation 12 Gy (5), busulfan 16 mg/kg (7) or BCNU/VP16 (1). Twelve patients received reduced-intensity conditioning (ric) regimens with fludarabine (FLU) plus alkylating agents. Graft-versus-host disease prophylaxis consisted of cyclosporin A +/- prednisone or methotrexate. Six patients also received anti-T-lymphocyte globulin. RESULTS: Twenty-four patients engrafted. Best response after alloHSCT was complete remission in 16 of all patients [64%: 95% confidence interval (CI) 44% to 84%] and in 16 of 22 evaluable patients (73%: 95% CI 53% to 93%), partial remission in three of 25 (12%), and no change in three of 25 (12%) patients. Early death prevented response evaluation in three of 25 patients. Non-relapse mortality was 54% (95% CI 15% to 78%) in patients after cc and 17% (95% CI 0% to 41%) after FLU-based ric (P = 0.03). Six patients died due to progressive disease or relapse. Four patients with HD died, three in complete remission due to non-relapse mortality and one with progressive disease. Eleven of 25 patients are alive with a median follow up of 618 days (range 383-2815), with an overall survival of 44% (95% CI 23% to 65%) at 1 year for all patients, while eight of 12 (67%: 95% CI 35% to 98%) patients are alive after ric compared with three of 13 (23%; 95% CI 0% to 50%) after cc (P <0.02). CONCLUSIONS: AlloHSCT induces high rates of complete remission in advanced lymphoma patients, even when the tumor had relapsed after autologous HSCT. It should be considered earlier as part of the therapeutic options in poor risk patients to avoid non-relapse mortality associated with extensive pretreatment. Our novel reduced conditioning regimens show promising results, especially in heavily pretreated patients, and improve survival after allogeneic transplantation.     

Allogeneic blood stem cell transplantation after a reduced-intensity,preparative regimen: a pilot study in patients with refractory malignancies

BACKGROUND: The immune-mediated graft-versus-tumor (GVT) effect plays a therapeutic role in the treatment of patients with hematologic malignancies who undergo allogeneic hematopoietic stem cell transplantation (HSCT). More recently, it was reported that a GVT effect also occurred in patients who underwent transplantation for metastatic renal carcinoma. The authors carried out a pilot trial of allogeneic transplantation after a reduced-intensity, preparative regimen in patients with refractory malignancies, including solid tumors. The objectives of the current study were to evaluate the feasibility of this approach in terms of toxicity and engraftment and to document evidence of GVT effects. METHODS: Seventeen patients with Stage IV malignancies (7 patients with renal cell carcinoma, 3 patients with sarcoma, 2 patients with breast carcinoma, 2 patients with Hodgkin disease, 1 patient with ovarian carcinoma, 1 patient with melanoma, and 1 patient with both melanoma and renal cell carcinoma) that were not amenable to further conventional treatment were enrolled. The median patient age was 43 years (range, 10-60 years). The Eastern Cooperative Oncology Group performance status (PS) was 0-1 in 11 patients and 2-3 in 6 patients. Preparative treatment consisted of reduced-intensity chemotherapy with fludarabine (30 mg/m(2) per day for 4 consecutive days) and cyclophosphamide (30 mg/Kg per day for 2 consecutive days) prior to allogeneic HSCT from a human leukocyte antigen-identical sibling. The median number of CD34+ cells infused was 6.06 x 10(6)/kg (range, 1.5-14.0 x 10(6)/kg). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporin-A and short-term methotrexate. RESULTS: Patients who had a PS of 2-3 prior to undergoing HSCT experienced Grade 4 hematologic toxicities and Grade > or = 3 organ toxicities and died of either treatment-related complications or disease progression within 100 days from transplantation. By contrast, 10 of 11 patients who had a PS of 0-1 prior to undergoing HSCT experienced only short-lasting, Grade < or = 3 neutropenia and thrombocytopenia and no organ toxicity; 1 of 10 patients died of graft failure on Day +29 after undergoing HSCT. By Day +90, 100% donor chimerism was documented in all patients with a past history of heavy chemotherapy, whereas mixed donor chimerism was observed in the 4 patients with a past history of only 1 line of chemotherapy and/or immunotherapy prior to entering the HSCT program. Grade 2-3 acute GVHD occurred in 5 patients. Among patients with a follow-up > 100 days, 2 complete responses and 3 transitory partial responses were recorded. CONCLUSIONS: With this conditioning regimen, full donor chimerism was achieved rapidly only in patients who had received previous intensive chemotherapy. In a proportion of patients with refractory malignancies, allogeneic transplantation resulted in tumor regression. This novel therapeutic strategy may provide little benefit in patients with poor PS and rapidly progressing disease.     

An update on the role of high-dose therapy with autologous or allogeneic stem cell transplantation in mantle cell lymphoma

PURPOSE OF REVIEW: Early trials of high-dose therapy with autologous stem cell transplantation in mantle cell lymphoma were discouraging, with no clear survival advantage attributable to the procedure. Most early series were plagued by small numbers, retrospective designs, and short follow-up. Also, until recently, allogeneic stem cell transplantation was not an option for most mantle cell lymphoma patients who were too old or infirm to tolerate standard conditioning regimens. RECENT FINDINGS: New advances in allogeneic transplantation, particularly reduced-intensity conditioning regimens, have increased the availability of this procedure to patients with mantle cell lymphoma. New evidence has emerged during the last several years that suggests autologous stem cell transplantation in first complete remission may provide a survival advantage over conventional chemotherapy in patients with mantle cell lymphoma. Additionally, investigational strategies such as in vivo purging with rituximab and the use of radioimmunotherapy in conditioning regimens may further increase response rates and, hopefully, survival in mantle cell lymphoma patients. Finally, recent studies suggest the existence of a graft-versus-lymphoma effect in mantle cell lymphoma providing strong scientific rationale for the possible curative potential of allogeneic stem cell transplantation in this disease. SUMMARY: This review focuses on recent advances in allogeneic and autologous transplantation for mantle cell lymphoma. Particular emphasis is placed on the role of autologous transplantation in first complete remission, the role of in vivo purging with rituximab, the utility of radioimmunotherapy and, finally, the evolving strategy of reduced-intensity allogeneic stem cell transplantation.     

Nonmyeloablative transplantation for solid tumors: a new frontier for allogeneic immunotherapy

The failure of conventional chemotherapy to improve survival in a large percentage of patients with advanced solid tumors has prompted the development of alternative anticancer approaches. Conventional allogeneic hematopoietic stem cell transplantation (HSCT) relies on myeloablative conditioning to eradicate the underlying disease, as well as suppress the patient’s immune response, allowing engraftment of the donor’s lymphohematopoietic system. Such preparative regimens are frequently associated with serious hematologic and nonhematologic toxicities, resulting in substantial morbidity and mortality. A significant curative component of allogeneic HSCT is the immune-mediated graft-versus-tumor (GVT) effect. Nonmyeloablative preparative regimens were designed to suppress host immunity to allow for sufficient engraftment of the donor immune system for the subsequent generation of GVT effects. These relatively low-dose preparative regimens are generally well tolerated and are associated with a reduction in the risk of transplant-related mortality. Nonmyeloablative HSCT provides a safer platform to explore the efficacy of allogeneic HSCT in patients with solid tumors. Initial reports have demonstrated that GVT may occur against several different solid tumors, including renal cell carcinoma, ovarian cancer, breast cancer and others. Based on these preliminary encouraging results, further exploration of nonmyeloablative HSCT for solid tumors is clearly warranted. The development of strategies to decrease graft-versus-host disease while enhancing post-transplant antitumor immunity will hopefully be forthcoming in the near future.     

Nonmyeloablative transplantation for solid tumors: a new frontier for allogeneic immunotherapy

The failure of conventional chemotherapy to improve survival in a large percentage of patients with advanced solid tumors has prompted the development of alternative anticancer approaches. Conventional allogeneic hematopoietic stem cell transplantation (HSCT) relies on myeloablative conditioning to eradicate the underlying disease, as well as suppress the patient's immune response, allowing engraftment of the donor's lymphohematopoietic system. Such preparative regimens are frequently associated with serious hematologic and nonhematologic toxicities, resulting in substantial morbidity and mortality. A significant curative component of allogeneic HSCT is the immune-mediated graft-versus-tumor (GVT) effect. Nonmyeloablative preparative regimens were designed to suppress host immunity to allow for sufficient engraftment of the donor immune system for the subsequent generation of GVT effects. These relatively low-dose preparative regimens are generally well tolerated and are associated with a reduction in the risk of transplant-related mortality. Nonmyeloablative HSCT provides a safer platform to explore the efficacy of allogeneic HSCT in patients with solid tumors. Initial reports have demonstrated that GVT may occur against several different solid tumors, including renal cell carcinoma, ovarian cancer, breast cancer and others. Based on these preliminary encouraging results, further exploration of nonmyeloablative HSCT for solid tumors is clearly warranted. The development of strategies to decrease graft-versus-host disease while enhancing post-transplant antitumor immunity will hopefully be forthcoming in the near future.     

造血干细胞移植治疗骨髓增生异常综合征的研究进展

 人类白细胞抗原（HLA）匹配同胞供者造血干细胞移植是治疗骨髓增生异常综合征（MDS）最有效的方法,其疗效在过去十几年里有明显的提高。在缺乏同胞供者来源时,无关供者移植、脐带血移植、自体造血干细胞移植可以作为替代的治疗选择。现对MDS患者移植适应证、影响移植疗效的因素（包括年龄、移植时机、移植前诱导缓解化疗、预处理方案、造血干细胞来源等）进行综述。     

急性髓系白血病患者异基因骨髓移植后复发行同一供者二次移植一例

 目的　探索血缘HLA全相合骨髓造血干细胞移植（HSCT）后复发病例进行同一供者外周血造血干细胞二次移植（HSCT2）的可行性。方法　1例急性髓系白血病（M4）患者接受血缘HLA全相合供者骨髓移植后18个月复发,染色体检查提示为受者复发型。给予CY-TBI预处理后输注同一供者外周血HSCT2,同时降低预防移植物抗宿主病（GVHD）强度。结果　患者HSCT2后获得稳定植入,患者并发急性GVHD（肠道Ⅳ级,皮肤Ⅲ级）,完全缓解至+8月。结论　对于血缘造血干细胞供者移植后复发的患者,HSCT2同一供者HSCT是可行的。     

Acute Myeloid Leukemia: When to Transplant in First Complete Remission

Allogeneic hematopoietic stem cell transplantation (HSCT) is commonly used to treat acute myeloid leukemia (AML) because it is potentially curative when other therapies have a low likelihood of success. Although most patients with newly diagnosed AML will achieve a first complete remission (CR1) with standard induction chemotherapy, obtaining a durable remission necessarily requires either further (postremission) chemotherapy or allogeneic HSCT. The decision of which of these options to choose is complex and depends on both clinical and molecular variables as well as the availability and histocompatibility of donor stem cells. Important clinical factors include the individual patient’s age, performance status, and comorbidities. Molecular and cytogenetic factors are increasingly important in stratifying patients into favorable, intermediate, and unfavorable risk categories. Whereas patients with favorable-risk cytogenetics fare better with postremission chemotherapy, allogeneic HSCT provides superior long-term survival for most non-elderly patients with intermediate-risk or unfavorable-risk AML. Because of the expanded use of umbilical cord blood as a source of hematopoietic stem cells and the use of reduced-intensity conditioning regimens, allogeneic HSCT is an option for an increasing number of patients with AML.     

Treatment of Relapse of Acute Myeloid Leukemia After Allogeneic Hematopoietic Stem Cell Transplantation

Disease relapse remains a major cause of mortality for patients with acute myeloid leukemia (AML) undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Historically, patients who experience disease relapse after HSCT have a dismal prognosis with very few long-term survivors. There is no standard treatment for patients in this situation given the variability in patient characteristics, disease biology, complications such as graft-vs.-host disease (GVHD) and infections, donor availability, and patient choice. Here, we discuss the current options for treatment of relapsed AML after HSCT including conventional chemotherapy, novel agents, donor leukocyte infusion, second allogeneic HSCT, and emerging therapies.     

Durable clinical, cytogenetic, and molecular remissions after allogeneic hematopoietic cell transplantation for refractory Sezary syndrome and mycosis fungoides.

PURPOSE: Sezary syndrome (SS) and tumor-stage mycosis fungoides (MF) are generally incurable with currently available treatments. We conducted a retrospective study to evaluate the outcome of allogeneic hematopoietic stem-cell transplantation (HSCT) in this patient population. PATIENT AND METHODS: From August 1996 through October 2002, eight patients with advanced MF/SS underwent allogeneic HSCT at our institution. All patients were heavily pretreated, having failed a median number of seven prior therapies (range, five to 12). Clonal T-cell populations in peripheral blood or bone marrow were detectable by polymerase chain reaction analyses of T-cell receptor gamma-chain gene rearrangements in six patients and cytogenetics in three patients. The conditioning regimen included total-body irradiation and cyclophosphamide (n = 3), busulfan and cyclophosphamide (n = 1), and the reduced-intensity regimen of fludarabine and melphalan (n = 4). Allogeneic hematopoietic stem cells were obtained from HLA-matched siblings (n = 4) and unrelated donors (n = 4). RESULTS: All patients achieved complete clinical remission and resolution of molecular and cytogenetic markers of disease within 30 to 60 days after HSCT. Two patients died from transplantation-related complications; graft-versus-host disease (GVHD; n = 1) and respiratory syncytial virus pneumonia (n = 1). With a median follow-up of 56 months, six patients remain alive and without evidence of lymphoma. CONCLUSION: Our results suggest that allogeneic HSCT from both HLA-matched sibling and unrelated donors can induce durable clinical, molecular, and cytogenetic remissions in patients with advanced cutaneous T-cell lymphoma that is refractory to standard therapies.     

Stem cell transplantation for non-Hodgkin's lymphoma

Non-Hodgkin's lymphoma (NHL) includes a diverse set of conditions ranging from high-grade aggressive to more indolent low-grade disease. Hematopoietic stem cell transplantation (HSCT) has a valuable role in the management of these conditions and can provide long-term remission in selected cases. This article presents the current use of allogeneic and autologous HSCT in a number of subtypes of NHL.     

Advances in pediatric hematopoietic stem cell transplantation

Allogeneic and autologous hematopoietic stem cell transplantation (HSCT) has become a therapeutic option for an increasing number of patients with otherwise incurable leukemias, solid tumors, immunodeficiencies, hemoglobinopathies and metabolic diseases. For patients requiring an allogeneic transplant, the addition of unrelated cord blood units and partially matched family member donors as alternate stem cell sources has increased the chances that an appropriate donor can be identified. In addition, new approaches to stem cell graft engineering are yielding insights into potential cellular immune therapies, which may decrease the adverse effects of HSCT such as graft-versus-host disease (GVHD) and harness the alloimmune graft-versus-leukemia effect. Novel conditioning regimens, primarily reduced intensity and non-myeloablative regimens, allow patients with significant co-morbidities to undergo transplantation with reduced morbidity and mortality. Combinations of immune-modulatory cytokines and monoclonal antibodies with autologous and allogeneic transplantation are among the advances being explored in contemporary HSCT.     

Allogeneic Hematopoietic Stem Cell Transplantation: Does It Have a Place in Treating Hodgkin Lymphoma?

Although the majority of patients with Hodgkin lymphoma achieve sustained remission with frontline treatment, there is still a subset of patients with much less favorable prognosis. The current standard of care for Hodgkin lymphoma patients with relapsed or refractory disease is autologous stem cell transplantation. However, no randomized trial has compared autologous stem cell transplantation with allogeneic stem cell transplantation prospectively, and most studies comparing allogeneic stem cell transplantation with historical controls of autologous stem cell transplantation use a myeloablative conditioning reference group. With the more frequent use of reduced-intensity conditioning transplantation in recent studies, the role for allogeneic stem cell transplantation in Hodgkin lymphoma patients is being redefined. In contrast to other types of lymphomas, Hodgkin lymphoma patients are younger at diagnosis, which makes a curative strategy such as allogeneic stem cell transplantation particularly appealing. This review examines the role of allogeneic stem cell transplantation in Hodgkin lymphoma by looking at both retrospective and prospective analyses in the era of reduced-intensity conditioning transplantation, donor lymphocyte infusions, and biologically based treatments.     

Ganzkörperbestrahlung

The development of high-dose therapy regimens with subsequent HSCT was a breakthrough in the treatment of otherwise lethal diseases of the hematopoietic system. Initially, TBI was an essential part of the conditioning regimen prior to allogeneic transplantation. Major indications for the use of TBI are ALL, AML, CML, MDS, and non-Hodgkin’s lymphomas. Since myeloablative conditioning regimens are associated with severe side effects, in recent years several reduced-intensity regimens have been increasingly employed, especially in older patients/patients with comorbidities due to a favorable toxicity profile. The significance of these reduced-intensity concepts with/without the use of TBI and the indications are still largely unclear.     

Allogeneic stem cell transplantation for chronic myeloid leukemia resistant to tyrosine kinase inhibitors

Allogeneic hematopoietic stem cell transplantation (HSCT) is well-established as a potentially curative treatment for patients who have chronic myeloid leukemia. The success of imatinib and other tyrosine kinase inhibitors (TKI) as initial therapy has changed the treatment paradigm for this disease. Allogeneic hematopoietic transplants are now reserved for patients whose disease does not respond optimally to TKI treatment. Patients whose disease does not have an optimal response to imatinib may respond to a second-generation TKI, dasatinib or nilotinib, and many achieve major or complete molecular and cytogenetic responses. The indication for allogeneic HSCT versus continued second-line therapy is not well-defined and is the subject of ongoing study. There has been continued progress in reducing the toxicity and risks of HSCT with development of reduced-intensity regimens; transplants can be routinely performed in patients up to the age of 75 years who are in fair general medical condition. Transplantation results from unrelated donors have improved, with survival rates similar that achieved with matched siblings. Results with haploidentical and cord blood transplants have markedly improved, and should be considered for patients lacking a matched donor. Allogeneic hematopoietic transplants have the best chance to be curative in patients with chronic phase that is under hematologic control with 80% disease-free survival; patients progressing to the accelerated phase or blast crisis have a much poorer prognosis. Thus, HSCT should be considered for patients with imatinib failure. Patients receiving second-line TKI therapy must be closely monitored and referred for transplantation if a complete cytogenetic response and major molecular response is not achieved. HSCT should be performed if feasible in patients without a continued response to TKI treatment.     

Role of Hematopoietic Stem Cell Transplant in the Management of Follicular Lymphoma

Despite decades of published data regarding the application of autologous and allogeneic stem cell transplant in patients with follicular lymphoma, there remain no uniform indications for its use in this disease. Autologous transplant has been shown to lead to longer progression‐free survival times in randomized trials when compared with postremission interferon‐based chemoimmunotherapy. However, the development of rituximab and its use in frontline, salvage, and maintenance therapy complicates the decision to pursue autologous transplant, a modality developed prior to the advent of anti‐CD20 monoclonal antibodies. Allogeneic transplant offers the advantages of lymphoma‐free grafts and the immunologic graft‐versus‐lymphoma effect. These factors may confer the possibility of long‐term remission, though historically they have been accompanied by high rates of upfront morbidity and mortality, especially in heavily pretreated patients with a poor performance status or chemotherapy‐refractory disease. Advances in patient selection, human leukocyte antigen (HLA) matching, conditioning regimens, and supportive care have reduced transplant‐related mortality and the incidence of graft‐versus‐host disease. Recently published data focus on the incorporation of rituximab and radioimmunoconjugates prior to, during, and following autologous transplant. Furthermore, reduced‐intensity allogeneic stem cell transplantation has increasingly been used for relapsed follicular lymphoma patients with comorbidities or advanced age. Several recent reports suggest that reduced‐intensity regimens may provide a high likelihood of long‐term disease‐free survival for patients up to 70 years of age with a good performance status, chemotherapy‐sensitive disease, and HLA‐matched sibling donors. Such patients with relapsed disease should be referred to a transplant center that can enroll them in one of the forthcoming clinical trials that aim to confirm these outcomes.     

Allogeneic stem cell transplantation following reduced-intensity conditioning can induce durable clinical and molecular remissions in relapsed lymphomas: pre-transplant disease status and histotype heavily influence outcome.

The safety and efficacy of reduced-intensity conditioning (RIC) followed by allogeneic stem cell transplantation (SCT) for relapsed lymphomas remains unresolved. We conducted a prospective, multicentered, phase II trial. A total of 170 relapsed/refractory lymphomas received a RIC regimen followed by SCT from sibling donors. The primary study end point was non-relapse mortality (NRM). Histologies were non-Hodgkin's lymphomas (NHL) (indolent (LG-NHL), n=63; aggressive (HG-NHL), n=61; mantle cell lymphoma (MCL), n=14) and Hodgkin's disease (HD, n=32). Median follow-up was 33 months (range, 12-82). The results show that frequencies were as follows: cumulative NRM at 3 years, 14%; acute and chronic graft-versus-host disease (GVHD) 35 and 52%, respectively; 3-year overall survival (OS), 69% for LG-NHL, 69% for HG-NHL, 45% for MCL and 32% for HD (P=0.058); and 3-year relapse incidence, 29, 31, 35 and 81%, respectively (P<0.001). Relapse risk differed significantly at 3 years between follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL) (14 versus 46%, P=0.04). Molecular remission occurred in 94 and 40% (P=0.002) of patients with FL and CLL, respectively. On multivariate analysis, OS was influenced by chemorefractory disease (hazard ratio (HR)=3.6), diagnosis of HD (HR=3.5), and acute GVHD (HR=5.9). RIC allogeneic SCT is a feasible and effective salvage strategy in both indolent and aggressive NHL.