Reduced-intensity allogeneic hematopoietic stem cell transplantation for multiple myeloma: a concise review

Reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (HSCT) can result in reliable donor engraftment, relatively low treatment-related mortality, and sustained remissions in the treatment of multiple myeloma. However, substantial cytoreduction pre-allografting is often necessary because of a variable graft-versus-myeloma effect. The use of RIC allogeneic HSCT immediately after autologous HSCT provides a temporal separation between tumor reduction by high-dose chemotherapy and the graft-versus-myeloma effect. There are currently a number of prospective trials attempting to address the issue of whether this strategy leads to decreases in relapse and/or improvement in overall survival as compared with double autologous transplants. Unfortunately, similar to autografting, relapse remains the major cause of treatment failure after RIC allogeneic HSCT. To improve treatment results with allografting, consideration should be given to incorporating immunomodulatory drugs and targeted treatments to enhance pretransplantation remission status, as posttransplantation maintenance therapy, or in combination with donor lymphocyte infusions for refractory or relapsed disease. Studies exploring these strategies are ongoing.     

异基因干细胞移植治疗多发性骨髓瘤

异基因干细胞移植是惟一可能治愈多发性骨髓瘤(MM)的临床方法.较高的移植相关死亡率(TRM)限制了清髓性异基因干细胞移植在临床的广泛应用;非清髓性异基因干细胞移植降低了TRM,但疾病复发和进展的风险却增加;自体-非清髓性异基因干细胞串联移植,在降低TRM的同时,可有效减少疾病的复发和进展.目前临床上亦存在很多可能提高MM移植疗效的新方法.     

Autologous-allogeneic tandem stem cell transplantation in patients with multiple myeloma

The decrease in treatment-related mortality by using reduced intensity conditioning and the well-proven immunological effect of the graft to multiple myeloma cells has increased the interest in using allogeneic stem cell transplantation in patients with multiple myeloma. The concept of a cytoreductive autograft followed by a dose-reduced allogeneic stem cell transplantation appears to be the most promising approach. Preliminary reports of several groups observed a treatment-related mortality at 1 year ranged from 0 - 17%. The rate of acute graft-vs.-host disease (GvHD) grade II - IV ranged from 32 - 44% and of chronic GvHD from 28 - 64%. The overall response rates for all studies ranged from 68 - 83%, including a high rate of complete remissions of 52 - 83%. The overall survival at 2 or 3 years was between 62% and 78%, and the progression-free survival between 54% and 56%. Despite the high rate of complete remissions after autologous-allogeneic tandem transplantation observed in nearly all trials, the relapse rate is quite considerable and exceeded nearly 40% at 2 years. Therefore, the reduced allogeneic treatment approach in patients with multiple myeloma has still to be improved and further preclinical and clinical research is focused on two major issues: (i) to further reduce treatment-related mortality and (ii) to enhance the remission status after transplantation, via adoptive immunotherapy inducing molecular remission and enhancing the cure rate of this approach.     

Mini-Midi-Maxi? How to harness the graft-versus-myeloma effect and target molecular remission after allogeneic stem cell transplantation.

Allogeneic stem cell transplantation in multiple myeloma after standard myeloablative conditioning induces a high rate of complete remissions, but long-term freedom from disease is achieved in 30-40% of the cases only. The therapeutic effect of allogeneic stem cell transplantation is due to cytotoxicity of high-dose chemotherapy and immune-mediated graft-versus-myeloma effect by donor T cells. Retrospective studies clearly suggest that both (a) reducing the intensity of high-dose chemotherapy by using reduced-intensity or non-myeloablative conditioning regimen or (b) reducing the immunotherapy of donor T cells by using T-cell depletion result in lower treatment-related morbidity and mortality, but also in higher rate of relapse. Therefore, this review will focus on potential strategies of how treatment-related morbidity and mortality might be kept low without an increased risk of relapse and how remission status after transplantation can be enhanced by using the newly established donor immunosystems after allografting as a platform for post-transplant treatment strategies with new drugs (thalidomide, lenalidomide, bortezomib) or immunotherapy (donor lymphocyte infusion, vaccination, tumor-specific T cells) in order to achieve remission on a molecular level, which seems to be a 'conditio sine qua non' to cure myeloma patients.     

Novel agents to improve outcome of allogeneic transplantation for patients with multiple myeloma

Over the last few decades therapy for multiple myeloma has improved remarkably. In particular, the introduction of novel agents has allowed improved response rates prior to, and after, stem cell transplantation with extension of progression-free survival in high-risk patients. Nevertheless, most patients relapse, leaving multiple myeloma an incurable disease. Despite being the only treatment option that has real curative potential, allogeneic transplantation has not shown its superiority to autologous transplantation due to its high morbidity and mortality rates. This review highlights how novel agents might help to reduce treatment-related mortality and to improve tumor control prior to and post-allogeneic stem cell transplant, which will hopefully result in significantly improved long-term disease control, and maybe a cure following this treatment modality.     

Long-term clinical and molecular remission after allogeneic stem cell transplantation (SCT) in patients with poor prognosis non-Hodgkin's lymphoma.

From 1987 to 1999 35 patients with poor prognosis non-Hodgkin's lymphoma (NHL) underwent allogeneic stem cell transplantation (SCT) at the University Hospitals of Vienna and Graz. Initial biopsy specimens were reclassified according to the Revised European-American Classification of Lymphoid Neoplasms (REAL). All patients surviving 28 days engrafted. Twenty-eight of them (93%) attained clinical remission. At the last follow-up 14 patients were alive and disease-free at a median of 5.0 (range, 2.3-12.9) years after allogeneic SCT. The actuarial overall survival is 35%. Five patients relapsed 1.8 to 27.6 months after transplant, the probability of relapse is 23%. Of the 21 deaths following SCT, seven were due to relapse/refractory disease and 14 due to transplant-related causes. The probability of treatment-related mortality is 48%. After SCT, minimal residual disease (MRD) was monitored by polymerase chain reaction (PCR) in seven patients with a BCL-2/IgH translocation and in 13 with a clonal immunoglobulin heavy chain (IgH) rearrangement. All 20 patients attained clinical remission rapidly and converted to PCR negativity. In the follow-up nine of these patients are in long-term clinical and molecular remission, six PCR-negative patients died of transplant-related causes and five patients relapsed. In summary, allogeneic stem cell transplantation has a curative potential for patients with refractory and recurrent non-Hodgkin's lymphoma. In our series long-term disease-free survival was associated with molecular disease eradication after SCT. Treatment-related mortality rate was high, thus earlier referral of selected patients to allogeneic SCT should be considered.     

Posttransplant administration of cyclophosphamide and donor lymphocyte infusion induces potent antitumor immunity to solid tumor

PURPOSE: Nonmyeloablative allogeneic stem cell transplantation (SCT) has been increasingly used for the treatment of hematologic and solid malignancies, and mature donor T cells are considered to be the main effectors of the graft-versus-tumor (GVT) activity. However, the association between degree of donor chimerism and intensity of GVT effects has not been fully elucidated. We recently proposed a unique nonmyeloablative cell therapy using posttransplant cyclophosphamide and donor lymphocyte infusion, by which a significant antitumor effect against murine renal cell carcinoma, RENCA, was induced, although the level of mixed chimerism was relatively low. In this study, we attempted to clarify a role of chimerism for in vivo antitumor effects on GVT effects in radiation-associated nonmyeloablative SCT. EXPERIMENTAL DESIGN: We assessed antitumor effects on RENCA tumors and the degree of donor chimerism after several doses of irradiation followed by allogeneic SCT and compared the results with those of cyclophosphamide-based cell therapy. RESULTS: Allogeneic SCT following sublethal irradiation (6 Gy) induced almost complete donor chimerism, whereas cyclophosphamide-based cell therapy produced low levels of donor chimerism. Nonetheless, GVT activity was much more potent in cyclophosphamide-based cell therapy than irradiation-conditioned SCT. Furthermore, cyclophosphamide-conditioned SCT induced more potent immune reconstitution with less severe graft-versus-host disease than irradiation-conditioned SCT. CONCLUSIONS: Our results indicate that a high level of chimerism is not essential for the in vivo antitumor effect of nonmyeloablative allogeneic cell therapy against solid tumor and that the recovery of peripheral lymphocytes after the initial immunosuppression might be a critical event for the elicitation of in vivo antitumor effects of that treatment modality.     

New approaches to treating malignances with stem cell transplantation

Stem cell transplantation has been successfully used to treat a wide variety of hematologic malignancies. New and exciting strategies being developed for use in conjunction with transplant will be useful in overcoming tumor resistance. It is now clear that a significant part of the antitumor effect of allogeneic stem cell transplantation is derived from the graft itself and is independent of the preparative regimen. Immune therapy derived from the donor's graft is uniquely suited for killing chemoresistant tumor cells and may prove to be an invaluable tool for decreasing the risk of relapse in patients with advanced disease. Among patients who have relapsed after allogeneic bone marrow transplantation (BMT), an immunologically based antitumor effect may be obtained simply by transfusing T cells obtained by leukopheresis of the original bone marrow donor. Referred to as donor leukocyte infusion (DLI), this technique has been used to obtain complete remissions in relapsed acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), multiple myeloma, non-Hodgkin's lymphoma, myelodysplastic syndrome (MDS), and chronic myeloid leukemia (CML). Another approach that uses the donor's graft to obtain a potent antitumor effect is the combination of nonmyeloablative BMT followed by immunotherapy with DLI. Numerous investigators are exploring ways of combining autologous BMT with immune therapy. Animal studies using tumor vaccines in conjunction with autologous transplantation offer a promising method for eliminating tumor. Patients undergoing autologous transplantation may have marrow that has been contaminated with tumor, which places them at a higher risk of relapse. Attempts have been made to eliminate contaminating tumor from the marrow by purging.     

Allogeneic haemopoietic stem cell transplantation for multiple myeloma or plasma cell leukaemia using fractionated total body radiation and high-dose melphalan conditioning

We have evaluated the outcome of allogeneic haemopoietic stem cell transplantation for multiple myeloma using a conditioning regimen comprising fractionated total body irradiation and high-dose melphalan (110 mg/m2). The study comprised 25 patients (median age 49 years) who had been transplanted by either bone marrow (n = 13) or G-CSF mobilized peripheral blood stem cells (n = 12). Overall transplant-related mortality was 30% but was lower for patients < 50 years of age at transplant (21%). The main cause of treatment-related mortality was viral infection. Of the 19 patients evaluable post-transplant, 17 have so far achieved complete remissions. Currently, with a median follow-up of 3.4 years, 18 out of 25 patients are alive, of whom 15 are in continuing complete remission (CR) and 2 in second remission after suffering localized relapses, which were treated with radiotherapy and donor leucocyte infusions. Patients transplanted after 1 line of previous therapy, < 50 years of age and receiving peripheral blood stem cells (PBSC) rather than bone marrow (BM) had a superior outcome, although there was no statistically significant factor. We conclude that allogeneic transplantation should be considered as a potentially curative option for younger patients with myeloma and that the regimen using fractionated total body irradiation and melphalan has a high CR rate and a relatively low risk of treatment-related mortality, particularly in younger patients.     

Allogeneic stem cell transplantation for patients with metastatic renal cell carcinoma

Allogeneic stem cell transplantation and donor lymphocyte infusions are currently under clinical investigation as an innovative therapeutic option for patients with metastatic renal cell carcinoma. A variety of trials have proven the clinical efficacy of allogeneic stem cell transplantation using reduced-intensity conditioning protocols and donor lymphocyte infusions, as demonstrated by the induction of objective remissions in metastatic renal cell carcinoma patients. However, despite clinical remissions, reduced-intensity conditioning protocols and donor lymphocyte infusions were associated with a high treatment-related mortality rate of approximately 17%. The disproportion between clinical efficacy and treatment-related mortality may mainly be caused by the selection of patients that had often been heavily pretreated, with a large tumor burden and rapidly progressing tumors. The improvement of efficacy with the preservation of a powerful graft-versus-tumor effect while reducing the toxicity, is the major experimental and clinical challenge of allogeneic stem cell transplantation in the treatment of metastatic renal cancer and other solid tumors. Recently, there has been a revolutionary development of molecular-targeted agents in metastatic renal cancer. These inhibitors of angiogenesis and signal-transduction pathways have demonstrated clinical efficacy and significant survival prolongation in the first- and second-line settings, while causing moderate toxicity. Some of these agents have already been approved by the US FDA and will probably replace standard cytokines, such as interferon-alpha2 and interleukin-2, in metastatic renal cancer. In the context of these innovative clinical developments, allogeneic stem cell transplantation clearly has to be regarded an investigational clinical treatment approach. Therefore, patients should only be treated at centers that are experienced in clinical trials, and patient selection remains a critical factor for a successful transplant procedure.     

Allogeneic stem cell transplantation for patients with metastatic renal cell carcinoma

Allogeneic stem cell transplantation and donor lymphocyte infusions are currently under clinical investigation as an innovative therapeutic option for patients with metastatic renal cell carcinoma. A variety of trials have proven the clinical efficacy of allogeneic stem cell transplantation using reduced-intensity conditioning protocols and donor lymphocyte infusions, as demonstrated by the induction of objective remissions in metastatic renal cell carcinoma patients. However, despite clinical remissions, reduced-intensity conditioning protocols and donor lymphocyte infusions were associated with a high treatment-related mortality rate of approximately 17%. The disproportion between clinical efficacy and treatment-related mortality may mainly be caused by the selection of patients that had often been heavily pretreated, with a large tumor burden and rapidly progressing tumors. The improvement of efficacy with the preservation of a powerful graft-versus-tumor effect while reducing the toxicity, is the major experimental and clinical challenge of allogeneic stem cell transplantation in the treatment of metastatic renal cancer and other solid tumors. Recently, there has been a revolutionary development of molecular-targeted agents in metastatic renal cancer. These inhibitors of angiogenesis and signal-transduction pathways have demonstrated clinical efficacy and significant survival prolongation in the first- and second-line settings, while causing moderate toxicity. Some of these agents have already been approved by the US FDA and will probably replace standard cytokines, such as interferon-α2 and interleukin-2, in metastatic renal cancer. In the context of these innovative clinical developments, allogeneic stem cell transplantation clearly has to be regarded an investigational clinical treatment approach. Therefore, patients should only be treated at centers that are experienced in clinical trials, and patient selection remains a critical factor for a successful transplant procedure.     

Multiple myeloma: role of allogeneic transplantation

An estimated 14,600 new cases of multiple myeloma will be diagnosed in the United States in 2002. Multiple myeloma remains an incurable disease despite significant improvements in complete response rates and overall survival through the use of autologous stem cell transplantation. Allogeneic transplantation offers the advantage of a tumor-free graft and a graft-vs-myeloma effect but has been associated with a high mortality rate from transplant-related complications-primarily graft-vs-host disease (GVHD). As immunotherapy for patients with relapsed myeloma, donor lymphocyte infusion has resulted in response rates of over 50%, but many of these responses are not durable. In addition, donor lymphocyte infusion is associated with a significant risk of moderate-to-severe GVHD. In an attempt to decrease the high transplant-related mortality of conventional allogeneic transplants and to employ the proven efficacy of immunoreactive donor T lymphocytes, the use of nonmyeloablative transplants or "mini-transplants" is increasing. This approach has succeeded in significantly reducing transplant-related mortality but still may not be sufficient in producing long-term remissions or cures in myeloma patients. A combination of an autologous transplant (to achieve maximal cytoreduction) and a mini-transplant with donor lymphocyte infusion (for the immunoablative effect of alloreactive T lymphocytes) followed by maintenance therapy (thalidomide [Thalomid], steroids, cytokines, vaccines) for long-term immunomodulation is being investigated as a potential cure for this challenging disease.     

Long-term results favor allogeneic over autologous hematopoietic stem cell transplantation in patients with refractory or recurrent indolent non-Hodgkin's lymphoma.

BACKGROUND: The aim of this study was to compare the outcomes of high-dose therapy (HDT) and allogeneic versus autologous hematopoietic stem cell transplantation (SCT) in patients with refractory or recurrent indolent non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: From January 1991 to March 2000, 112 patients underwent HDT followed by either autologous (68 patients) or allogeneic (44 patients) SCT for refractory or recurrent indolent NHL. Prior conventional chemotherapy had failed in all patients. RESULTS: The two groups were similar with respect to age at transplantation, gender, histological subtypes, number of chemotherapy regimens received before transplantation and International Prognostic Index scores. The median time from diagnosis to transplantation was longer in the autologous than in the allogeneic SCT group (46 versus 27 months, P = 0.002). In the allogeneic SCT group the median follow-up time was 53 months (range 21-113), and the overall survival (OS) and disease-free survival (DFS) rates were 49% and 45%, respectively. After a median follow-up time of 71 months (range 22-109), in the autologous SCT group, the OS and DFS rates were 34% and 17%, respectively. Patients who underwent autologous SCT were more likely to have chemosensitive disease (P <0.001) and were more likely to be in complete remission at the time of transplantation (P = 0.001) than those who underwent allogeneic SCT. However, the probability of disease progression was significantly higher in the autologous SCT group than in the allogeneic SCT group (74% versus 19%, P = 0.003). CONCLUSIONS: Patients who undergo HDT with allogeneic SCT for refractory or recurrent indolent NHL have lower relapse rates but higher treatment-related mortality rates than patients who undergo autologous SCT. However, with the development of non-myeloablative preparative regimens, which can decrease treatment-related mortality, patients with recurrent indolent NHL should be considered for controlled trials of allogeneic transplantation if they have a human leukocyte antigen-identical donor.     

Nonmyeloablative stem cell transplantation for lymphoma

High-dose chemotherapy and allogeneic stem cell transplantation is a potentially curative therapy for younger patients with non-Hodgkin's lymphoma (NHL). The benefits of this therapy, however, are largely offset by the high rate of treatment-related mortality, exceeding 40% in many studies. Risks increase with comorbidities, advanced age, histocompatibility, and disease-related prognostic factors. Given the potential efficacy of graft-versus-malignancy effects against many lymphoid malignancies, we evaluated an alternative strategy utilizing less toxic, nonmyeloablative conditioning regimens to allow engraftment of donor cells, and then exploit the graft-versus-lymphoma (GVL) effects of allogeneic transplantation as the primary therapy. This strategy involved fludarabine-based preparative regimens +/- high-dose rituximab, graft-versus-host disease (GVHD) prophylaxis for 6 months, and donor lymphocyte infusion (DLI) only for progressive or nonresponding disease. Results from these trials confirm the full potential on nonmyeloablative transplantation for patients with NHL.     

Allogeneic and autologous transplantation for chronic lymphocytic leukemia.

Autologous and allogeneic transplantation are increasingly used in the management of patients with chronic lymphocytic leukemia. Many questions regarding patient selection, efficacy and outcome are unresolved, hence a review of the literature through Medline search. Autologous transplantation for CLL has been used mainly in selected patients under the age of 60. Conditioning typically involves total body irradiation (TBI). Bone marrow and more recently peripheral blood stem cells are used. Treatment-related mortality in most series is less than 10%. Molecular remissions after autologous transplantation are common, and clinical remissions can be prolonged in some patients. Randomized studies are needed to establish whether autologous transplantation confers a survival benefit over standard chemotherapy approaches. Allogeneic transplantation has a considerable treatment-related mortality, but durable remissions sometimes occur in patients with advanced disease. The use of non-myeloablative 'mini-transplants' has been investigated as a method to reduce treatment-related mortality, but prolonged follow-up will be required to establish the cure rate obtained with this procedure. Autologous and allogeneic transplantation are promising treatment modalities. Further refinements of transplant techniques and properly designed prospective studies are necessary to establish the role of stem cell transplantation in the overall management of CLL.     

Bone marrow transplantation for multiple myeloma: where we are today

Multiple myeloma is incurable with standard chemotherapy. Autologous transplantation appears to offer a modest survival advantage over standard dose chemotherapy, but most patients subsequently relapse. Through the induction of graft-versus-tumor activity, allogeneic bone marrow transplantation can lead to long-term disease-free survival, and cure in some patients with myeloma. Transplant-related mortality after allogeneic bone marrow transplantation is high. Many patients are ineligible for this approach because of advanced age, comorbid illnesses, and extensive previous chemotherapy. Ongoing investigations endeavor to reduce regimen-related mortality through nonmyeloablative preparative regimens while maintaining immunologic antitumor activity through donor lymphocytes, which have significant graft-versus-myeloma activity. Early reports demonstrate lower rates of transplant related mortality; however, graft-versus-host disease rates are high and can preclude the administration of graded donor lymphocyte infusions, which may optimize the therapeutic index of graft-versus-host reactivity.     

A reduction of recipient regulatory T cells by cyclophosphamide contributes to an anti-tumor effect of nonmyeloablative allogeneic stem cell transplantation in mice

We have recently established a unique model system of nonmyeloablative allogeneic stem cell transplantation (SCT) for treatment of murine solid tumors, based on cyclophosphamide‐induced tolerance. An injection of allogeneic donor spleen cells and bone marrow cells (BMC) followed by cyclophosphamide treatment induced a stable mixed chimerism with long lasting tolerance to the allografts. A donor lymphocyte infusion (DLI) in the cyclophosphamide‐induced tolerant mice exerted strong anti‐tumor effects on an MBT‐2 murine bladder tumor, MBT‐2 via their graft versus tumor (GVT) activity. In the present study, we determined whether a cyclophosphamide‐induced reduction of naturally occurring regulatory T cells (Tregs) was associated with the anti‐tumor activity in our nonmyeloablative SCT system. The number of recipient CD4+ CD25+ Foxp3+ Tregs significantly decreased 3 days after an intraperitoneal injection of cyclophosphamide in C3H/HeN mice that had been injected with spleen cells and BMC of donor AKR/J mice, compared with the number of CD4+ CD25+ Foxp3‐ T cells. An adoptive transfer of CD4+ CD25+ T cells from naïve C3H/He x AKR/J F1 mice into recipient mice 1 day after DLI significantly suppressed the expansion and IFN‐γ production of host‐reactive donor CD4+T cells and hampered the MBT‐2 anti‐tumor activity when compared with the transfer of CD4+ CD25‐ T cells. These results indicated that cyclophosphamide‐induced reduction of recipient Tregs is associated with retardation of tumor progression via the expansion of host‐reactive donor T cells and IFN‐γ production after DLI in our nonmyeloablative SCT system.     

Allogeneic versus autologous bone marrow transplantation for refractory and recurrent low-grade non-Hodgkin's lymphoma: updated results of the Utrecht experience.

This study was conducted to compare the results of myeloablative therapy followed either by autologous stem cell transplantation (SCT) or allogeneic SCT for poor-risk low-grade non-Hodgkin's lymphoma. Eighteen patients received autologous SCT and 15 patients received allogeneic SCT. All autologous patients had chemosensitive disease while this was the case in only 8 allogeneic patients. Besides, 14 of 15 allogeneic patients still had overt lymphoma infiltration of the marrow, when SCT took place. Despite these unfavorable characteristics, all allogeneic patients achieved complete remission (CR) with this procedure and, until now, none has relapsed. In contrast, 14 of 18 autologous patients achieved CR with SCT but 11 (79%) relapsed. Four allogeneic patients (27%) had a treatment-related death, whereas this did not occur with autologous SCT. The 3-year probabilities of relapse, overall survival, and event-free survival were 0%, 70% (95% CI, 38-87%), and 70% (95% CI, 38-87%) respectively for allogeneic SCT and 78% (95% CI, 57-93%), 33% (95% CI, 13-54%), and 22% (95% CI, 7-43%) respectively for autologous SCT. The differences in relapse and event-free survival were highly significant, p = 0.0002 and p= 0.015, respectively. These data show that allogeneic SCT leads to prolonged disease-free survival in patients with advanced poor-risk low-grade lymphoma which rarely occurs after autologous SCT. There is substantial evidence for a graft-versus-low-grade lymphoma effect.     

Alemtuzumab-based reduced-intensity conditioning allogeneic transplantation for myeloma and plasma cell leukemia - a single-institution experience

BackgroundReduced-intensity conditioning allogeneic transplantation for myeloma is associated with lower non-relapse mortality and higher relapse rates in comparison with myeloablative conditioning transplants.Patients and MethodsWe have retrospectively audited 19 patients with myeloma or primary plasma cell leukemia who received allogeneic transplantation with a uniform alemtuzumab-based reduced-intensity conditioning protocol. These patients had not been treated with bortezomib or lenalidomide before transplantation.ResultsThe treatment-related mortality at 1 year was (4/19) 21% with low incidence of graft-versus-host disease (6%) and 2-year progression-free survival and overall survival rates of 35% and 42%, respectively.ConclusionProgression-free survival in this cohort of patients is comparable to previously published data of reduced-intensity conditioning allogeneic transplantation in myeloma. However, there is no plateau observed on the survival curves with a significant transplant-related mortality of 21%. Therefore, alemtuzumab-based allogeneic transplantation cannot be recommended as standard practice outside of clinical trials for treatment of myeloma.     

Nonmyeloablative allogeneic hematopoietic stem cell transplantation for metastatic breast cancer

Previously, there was very little interest in investigating allogeneic hematopoietic stem cell transplantation (alloHSCT) in breast cancer because of the significant morbidity and mortality associated with this procedure, as well as the disappointing results observed in clinical trials with high-dose chemotherapy and autologous hematopoietic stem cell transplantation in advanced breast cancer. However, the development of nonmyeloablative (reduced-intensity) conditioning regimens, which have less treatment-related mortality but preserve the T cell-mediated graft-versus-tumor (GVT) effect, has led to the investigation of nonmyeloablative alloHSCT in diseases that had not previously been considered for conventional alloHSCT, including metastatic breast cancer. Laboratory data demonstrate that T cell-mediated responses to breast cancer that inhibit tumor growth are possible and provide the rationale to pursue allogeneic adoptive cellular therapy as a strategy to eliminate breast cancer. Early reports of nonmyeloablative alloHSCT indicate that a clinical GVT effect against breast cancer does exist. The responses appear to be dependent on the development of complete donor lymphoid chimerism, and responses may be delayed. The results from these initial trials must be interpreted cautiously. It is unlikely that nonmyeloablative alloHSCT by itself will result in complete eradication of metastatic breast cancer; however, it may serve as a therapeutic platform to enhance the effects of currently available immunotherapies (eg, trastuzumab administration) and complement existing cytotoxic therapies. Well-designed studies will be necessary to determine the clinical efficacy of nonmyeloablative alloHSCT as adoptive cellular therapy in metastatic breast cancer.