By C. Dean Buckner, MD – December 2005

Introduction

The application of allogeneic stem cell transplants (allo-SCT) to treat and possibly cure malignant disease has followed two guiding principles: first, the use of transplanted stem cells to permit dose-intensified treatment of malignancy by circumventing dose-limitation from marrow failure and, second, the use of the lymphoid component of the allograft to provide an immunological graft-versus-malignancy (GVM) effect. Increasing the dose-intensity of transplant regimens is often associated with a lower relapse rate in some malignancies, but this is usually off-set by an increase in transplant-related morbidity and mortality.[1]  Furthermore, many malignancies do not respond to increasing dose intensity that can be achieved without prohibitive non-marrow toxicities.

In the 1990s, following the demonstration that donor lymphocytes could induce durable remissions in leukemia patients relapsing after BMT, confidence grew in the ability of the graft-versus-leukemia (GVL) effect to eliminate and cure malignant disease.[2],[3],[4]GVL effect was almost always accompanied by clinical acute or chronic graft-versus host disease (GVHD). There has been much preclinical and clinical effort devoted to achieving a GVL effect without a GVHD effect. Although some success has been achieved in animal models, there has been limited success in clinical transplantation and GVHD continues to be a major cause of transplant-related morbidity and mortality despite the associated GVL effect.

The early experience of donor lymphocyte infusions set the stage for testing the potential of the alloimmune transplant itself to eliminate malignancy without recourse to dose-intensive preparative regimens. Such transplants required a different approach to the preparative regimen, with the main focus being to ensure engraftment using powerful immunosuppression but with no intention of significant cytoreduction of the malignancy being treated. This altered approach brought some potential advantages:(1) reducing the intensity of the regimen opened up the possibility of safely transplanting patients hitherto considered unsuitable because of a high risk of treatment-related mortality (TRM) (e.g., patients over 60 years of age, patients with debilitating co-morbidities and patients who have received prior intensive therapy such as autologous stem cell transplantation (auto-SCT); (2) the GVM effect could be logically explored in diseases such as metastatic cancers in which dose-intensive treatments have proved ineffective; (3) reduced- intensity preparative regimens were seen by some transplant teams as a means to control engraftment by initially achieving a balance between host and donor immune systems (mixed chimerism) and then introducing donor lymphocytes to treat the malignancy. Clearly there were limitations to abandoning intensive anti-malignancy treatment prior to transplant since patients with rapidly progressing malignancy would not survive long enough to benefit from the slower-acting GVM effect. Furthermore, it was not clear whether the GVM effect could work effectively against a heavy tumor load.

The development of reduced-intensity stem cell transplants (RI-SCT) thus proceeded along several lines in several pioneering centers, notably the M.D. Anderson Cancer Center in Houston (emphasis on decreasing TRM in older or debilitated patients), the Hadassah Hospital in Jerusalem (emphasis on treating debilitated patients and obtaining balanced chimerism),  the Fred Hutchinson Cancer Research Center in Seattle (emphasis on treating older patients and obtaining balanced chimerism), San Martino Hospital Genova (treatment of auto-SCT failures)  and the National Institutes of Health, Bethesda (emphasis on GVM in metastatic solid tumors).[5],[6],[7],[8],[9] Today, RI-SCT is increasingly being used worldwide to treat an ever-widening spectrum of diseases. Reduced-intensity allo-SCTs now account for more than a quarter of all allo-SCTs performed in the United States and Europe and virtually all allo-SCTs in patients over the age of 50 years.  

Reduced-Intensity Treatment Regimens

In the beginning of research into RI-allo-SCT, regimens were developed with the only concern being to apply sufficient immunosuppression to achieve engraftment. As research progressed, some of the regimens developed became more intensive as it became clear that the GVM effect of RI regimens was insufficient to eradicate disease in most patients, especially those with gross disease or refractory disease at the time of transplant.  This has led to a gradual increase in the intensity of some RI regimens but still not as intense as previous myeloablative regimens. These studies have shown that the intensity of regimens can be increased without increasing TRM.

Original Reduced-Intensity Regimens with Sole Intent of Assuring Engraftment

A number of transplant regimens were developed primarily to achieve engraftment with the least toxicity. Virtually all of these regimens utilize Fludara® (fludarabine) as the primary immunosuppressive agent along with low doses of a more cytotoxic agent such as total body irradiation (TBI), busulfan or melphalan. Anti-thymocyte globulin (ATG) is also frequently used for added immunosuppression, but the role of this agent is still controversial. Post transplant immunosuppression for the prevention of GVHD varies from center to center, but the most common regimen is the combination of cylclosporine and methotrexate with a reduction in the number of doses of methotrexate. All transplant centers use Neupogen® mobilized peripheral blood stem cell as the graft. Table 1 lists some of the more commonly used RI transplant regimens.

Table 1: Original Reduced-Intensity Transplant Regimens

Table 2: More Intensive “Reduced-Intensity” Regimens with Intent to Improve Cytoreduction

Regimens

Current Indications for Reduced Intensity Regimen Transplants

Reduced-intensity allo-SCTs have been evaluated in all the hematologic malignancies and some solid tumors. Transplants have successfully been performed on patients in their 70s, but upper age limits are determined more by the presence or absence of significant co-morbidities than by age. Thus, the risk/benefit ratio has to be determined for each individual patient. Reduced-intensity SCT has proved to be well tolerated in younger but debilitated patients with a prior history of fungal infection or who have failed an auto-SCT.  Thus, it appears RI-SCT can be applied to a wider spectrum of individuals than can conventional allo-SCT.

Outcome of Reduced-Intensity Transplants

Most transplant centers perform RI-SCT in an outpatient setting as complications in the first 30 days are minimal. Reduced-intensity regimens characteristically produce very brief and mild post-transplant cytopenias. Patients frequently require no transfusion support and neutropenic fevers are less common than following myeloablative regimens. Mucositis is absent and veno-occlusive disease (VOD) of the liver is seen only infrequently and exclusively following busulphan-containing regimens. However, there is increasing evidence that late toxicities related to GVHD are substantial with significant delayed morbidity and mortality. Very late transplant-related complications such as secondary malignancies, abnormal growth and development and gonadal dysfunction should be significantly lower in long-term survivors than following standard transplants, but this has yet to be documented.

While it is clear that RI-SCTs are better tolerated, survival following transplant is primarily dictated by the success or lack of it in controlling the original malignancy. Thus, patients with chronic lymphoid leukemia (CML), Hodgkin’s (HL) and non-Hodgkin lymphoma (NHL), acute myeloid leukemia (AML) or acute lymphoid leukemia (ALL) in remission, and early stages of myelodysplastic syndromes (MDS) have quite favorable outcomes with (where measurable) sustained molecular cures. In contrast, advanced leukemias and rapidly progressing malignancies have a high probability of treatment failure.

Results of Reduced-Intensity SCT in Specific Malignancies

Acute Myeloid leukemia (AML) and Myelodysplastic Syndromes (MDS): The European Group for Blood and Marrow Transplantation has compared outcomes of 315 patients with AML over the age of 50 years receiving RI-allo-SCTs with the outcomes of 407 similar patients treated with myeloablative regimens.[10]  Most of these patients had failed conventional chemotherapy and many were refractory to treatment. Half the patients in the RI-SCT group received a busulfan-based regimen and 25% received a low-dose TBI-based regimen. These researchers observed a higher incidence of acute GVHD, a lower incidence of TRM and a higher relapse rate following RI-SCT. There was no difference in leukemia-free survival (LFS) between the two groups. These authors suggest that these results support a prospective evaluation of RI-allo-SCT versus conventional ablative SCT in patients with AML to determine the relative effectiveness of RI-allo-SCT.

Researchers from Germany have reported that patients with AML and MDS receiving RI-SCTs for relapsed or refractory disease had a 40% 2-year LFS.[11]  They utilized a sequential treatment strategy of chemotherapy, RI-SCT and prophylactic donor lymphocyte infusions. The induction regimen was Fludara, cytarabine and amsacrine. The RI regimen was 4 Gy of TBI and 80-120 mg/kg of Cytoxan and ATG. Donors were HLA matched family members or unrelated donors, and lymphocytes were infused in the absence of GVHD. Eighty-eight percent of patients had a CR. Survival was best in those with limited chronic GVHD and those receiving a high dose of stem cells (CD34+ cells).

Researchers from M.D. Anderson Cancer Center evaluated outcomes of patients with AML and MDS receiving a RI-Allo regimen consisting of Fludara, cytarabine and idarubicin with a more ablative but still reduced-intensity regimen of Fludara plus 140 mg/m2 or 180 mg/m2 of melphalan in 94 patients.[12]  They observed a lower relapse rate following the more intensive regimen (30% vs 60%). However, there was no improvement in overall survival due to increased TRM except for patients transplanted in CR.

One study has evaluated early RI-allo-SCT in patients with AML. Researchers from Marseille, France, have reported a 76% 2-year, LFS in 33 adults (median age of 52 years) with AML treated with a RI-Allo-SCT after remission induction and consolidation.[13]  Researchers involved in this study evaluated reduced-intensity allogeneic stem cell transplants in 33 adults with a median age of 52 with the oldest patients being 60 years old. Sixty-four percent of patients were characterized as high risk for relapse. All patients had achieved a complete remission (CR) to induction therapy and had received two consolidation chemotherapy courses. Thirteen patients also received an autologous SCT following high-dose melphalan treatment for consolidation therapy. Transplant-related mortality was 9%, and 18% relapsed.  With a median follow-up of 18 months, 26 patients survive, and 24 of these have not relapsed. No patient with GVHD had a relapse while 44% without chronic GVHD relapsed. These data suggest that immunotherapy in the form of a RI-allo-SCT can be used to eradicate minimal residual disease in patients with AML in CR with acceptable toxicity. Further studies focusing on patients with a high risk of relapse will be necessary to determine the full impact of this approach.

It is unlikely that randomized trials will be performed in older patients with AML comparing the results of RI-SCT with conventional SCT because of the reluctance to use conventional SCT in older patients. Thus, for now the results of RI-SCT will have to be compared to conventional chemotherapy. 

Chronic Myeloid Leukemia (CML)

Early studies showed that sustained cytogenetic and molecular remissions of CML could be achieved following RI-SCT.[14],[15]   More recently, the European Bone Marrow Transplant (EBMT) group has reported the outcomes of 186 patients with CML who received RI-allo-SCTs.[16]  The median age was 50 years, and 64% of these patients were in chronic phase. The 100 day TRM was 6.1%. Graft-versus host disease was a major problem in these patients. As expected, patients in first or second chronic phase had better outcomes than patients transplanted in accelerated or blastic phase of CML. For patients transplanted in chronic phase overall survival at 3 years was 70%.

A small study of RI-allo-SCTs in patients with CML in chronic phase was also reported from Latin America.[17]  These researchers transplanted 24 patients early in chronic phase of CML with a median age of 41 years with the oldest being 71 years old. Overall survival at 830 days was 92%, with 2 patients dying of transplant-related causes. These data are promising for early transplantation but need to be confirmed. Reduced-intensity SCTs may not replace conventional transplants for younger patients with CML as the current results are very good. However, RI-SCTs should increase the number of older patients failing Gleevec that are treated with SCT.

Researchers from the M.D. Anderson Cancer Center have incorporated Gleevec into the pre- and post-transplant treatment regimen in recipients of reduced-intensity allogeneneic stem cell transplants.[18]  The transplant regimen consisted of Gleevec, busulfan, ATG and fludarabine. The protocol also included donor lymphocyte infusions in those without GVHD. The researchers treated 18 patients: 7 were in chronic phase with clonal evolution, 8 were in second chronic phase and the other 3 were in AP. One patient died of chronic GVHD. The researchers observed a cytogenetic CR in 13 patients and a molecular CR in 6 patients. These results suggest that this technique could be applied earlier in the disease course and may represent an alternative to donor lymphocyte infusions, as no patient in this study had it performed.

Outcomes in Patients with Myeloid Metaplasia

Researchers from the Blood and Marrow Transplantation Program, University of Illinois College of Medicine, have reported that RI-SCT is effective treatment for older patients with myelofibrosis with myeloid metaplasia.[19]  These researchers evaluated a regimen consisting of Fludara (30 mg/m2 intravenously daily for 5 days) and Alkeran (70 mg/m2 intravenously daily for 2 days) followed by transplantation of Neupogen-mobilized peripheral blood cells from HLA-identical siblings. They treated 4 older patients (median age, 56 years; range, 48-58 years) with advanced disease. All patients achieved prompt neutrophil and platelet engraftment and have experienced a significant regression of splenomegaly and bone marrow fibrosis. All patients now have normal bone marrow cellularity. With a median follow-up of 13 months (range, 11-19 months), all 4 patients are alive with stable full-donor hematopoietic chimerism. These results support the feasibility and effectiveness of reduced-intensity conditioning prior to allogeneic HSC transplantation for older patients with advanced MMM.

Chronic Lymphoid Leukemia

Researchers from M.D. Anderson Cancer Center have reported complete remissions were seen in 3 of 8 patients with CLL and 5 of 7 patients with NHL.[20]  Durable responses are possible in heavily pretreated and chemo-refractory patients.

Researchers from Italy have reported that allogeneic stem cell transplantation using a reduced intensity regimen of thiotepa, fludarabine and cyclophosphamide results in high rate of complete clinical and molecular remissions in patients with relapsed or refractory chronic lymphocytic leukemia and follicular lymphoma.[21]

This clinical trial evaluated a reduced intensity regimen followed by infusion of allogeneic stem cells in 44 patients with CLL or follicular lymphoma with a median age of 54 years (32-69). Twenty-five percent of these patients had failed an autologous transplant and 32% were considered chemo-refractory. The pertinent findings of this study are shown in Table 3.

Table 3: Reduced Intensity Regimen Followed by Allogeneic Transplant in CLL or Follicular Lymphoma

These authors concluded that molecular remissions can be achieved by reduced intensity allogeneic stem cell transplants, and that this effect is related to GVHD. They stated that in the absence of GVHD, the relapse rate was high. These data are very encouraging for this very high-risk group of patients, suggesting, at least for CLL and follicular lymphoma, that there may be a role for reduced intensity allogeneic stem cell transplants.

Researchers from the Fred Hutchinson Cancer Research Center and several other cooperating transplant centers have reported that reduced intensity allogeneic stem cell transplants were effective therapy for patients with advanced chronic lymphocytic leukemia (CLL).[22]This study looked at outcomes of 64 patients with advanced CLL, with a median age of 55 years, treated with related (n=44) or unrelated (n=20) allogeneic stem cell transplants following a reduced-intensity total body irradiation based regimen. These patients were of older age or had significant co-morbidities precluding treatment with myeloablative treatment regimens. Over 80% were resistant to fludarabine, 25% were refractory to Rituxan and 30% were refractory to alkylating agents. Table 4 summarizes the major findings of this study.

Table 4: Response of Advanced CLL Patients to Allogeneic Stem Cell Transplants

These authors reported that 8 patients received donor lymphocyte infusions for treatment of relapse or rejection. Only one of these patients is currently alive after such therapy. Data was also presented showing that cytogenetic abnormalities cleared more rapidly following transplants from unrelated donors. They also reported that of 11 patients who achieved a molecular remission only one has relapsed.

Non-Hodgkin’s Lymphoma

Researchers from the National Cancer Institute have reported that RI-Allo-SCTs result in prolonged EFS and OS in patients with non-Hodgkin’s lymphoma (NHL) who have failed chemotherapy.[23]  This clinical trial used a standardized re-induction regimen of etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin for treatment of 28 patients with relapsed or refractory disease. Re-induction therapy was followed by a RI-allo-SCT. For patients with chemosensitive disease, the median EFS and OS have not been reached. For patients with stable disease OS at 24 months was 50% with a 25% EFS. Only one patient with progressive disease after re-induction was alive at the time of this report. In multivariate analysis, response to chemotherapy was the best predictor of outcome. These data support the observations by others that response of disease is the prime predictor of outcome following reduced-intensity allogeneic stem cell transplantation. However, these authors also showed that patients with stable disease had a significant benefit from treatment, which is a new finding.

Researchers from Japan have reported the outcomes of 20 patients with relapsed NHL treated with RI-allo-SCT. Fifty percent of these patients had chemo-refractory disease.[24]Twelve of the 20 patients achieved a CR, and the one-year PFS was 70%. Long-term follow-up of a 20 patient trial by German researches showed that the two main predictors of outcome were the presence of chronic GVHD and chemo-sensitive disease.[25]  Event-free survival at 2 years was over 60% for patients with chemo-sensitive disease and most survivors had chronic GVHD.

Researchers from the M.D. Anderson Cancer Center have reported the outcomes of 20 patients treated with RI-allo-SCT following failure of an auto-SCT.[26]  Fifteen patients were treated with a regimen of Fludara, Cytoxan and Rituxan (n=15) or cisplatin (Platinol®), cytarabine and Fludara. They reported excellent results in this group of patients with a 3-year progression-free survival (PFS) of 95%. There was only one death, from fungal infection, and the only patient to relapse achieved a remission with donor lymphocyte infusions.

Researchers from the Hematologic Malignancies division from the Yale Cancer Center conducted a clinical trial to evaluate a conditioning regimen for reduced-intensity allogeneic stem cell transplants consisting of pentostatin, TBI (6 Gy) and extracorporeal photopheresis in patients who were not eligible for an ablative transplant.[27]   The regimen consisted of 2 days of extracorporeal photopheresis followed by infusional Nipent (8 mg/m2 over 48 hours) and 6 Gy TBI. Nipent is a purine analog that substituted for fludarabine, which is used as the primary immunosuppressant by most transplant centers.  Extrcorporeal photopheresis involves the administration of psoralin and exposing the blood to a UV-A light source, which selectively kills circulating T-cells. The TBI dose of 600 Gy is three times higher than the dose used at other institutions for reduced-intensity allogeneic stem cell transplants.

To date, 106 patients have been treated. Patients treated were diagnosed with NHL, AML, MDS, CML, ALL, MM and HL. Half of the patients were over the age of 50 years, 27 patients had a prior transplant, and 39 had a mismatched donor. At a median follow-up of 504 days, one-year overall survival was 67%; one-year event-free survival was 58%; acute GVHD (grades II-IV) occurred in 7% of patients with a sibling donor and 23% of patients with a mismatched donor; extensive chronic GVHD occurred in 12% of patients; full donor chimerism occurred in 90%-95% of patients by days 28-30; and the median time to engraftment was day 14.

Engraftment failure occurred in only 6 patients who were diagnosed with AML and had circulating blasts at the time of transplant. There were no episodes of severe mucositis, nausea or veno-occlusive disease of the liver (VOD). These results are of interest because of the relatively low incidence of acute and chronic GVHD and the relatively low relapse rates. One explanation for the low relapse rate is the increased dose of TBI of 6 Gy, which would have to be classified as an intermediate rather than a low-dose. The use of UV-A to kill T-cells is unique to this study and may explain the relatively low incidence of GVHD.

Hodgkin’s Lymphoma

Researchers from M.D. Anderson Cancer Center have reported the outcome of 40 patients with relapsed or refractory HL who received a RI-allo-SCT.[28]  These patients were treated with a less intensive regimen of Fludara, Cytoxan and ATG or a more intensive regimen of Fludara and melphalan. The day 100 and 18 month mortalities were 5% and 22%, respectively. Overall survival following the more intensive regimen was 73% compared to 39% for the less intensive regimen.

Multiple Myeloma

Early promising results were also reported in patients with multiple myeloma.[29]  German researchers reported 2-year survivals of 25% following allogeneic transplantation using a reduced intensity regimen for patients with multiple myeloma who have failed conventional treatment.[30]They treated a total of 22 patients with multiple myeloma who had failed previous therapies with a RI-allo-SCT followed by stem cells from related (n=7) or unrelated (n=15) donors. The median age of this group of patients was 53; the oldest was 66. Treatment-related mortality was 23%, which is approximately half of what one would anticipate from a transplant following a marrow ablative regimen. Follow-ups ranged from 8 to 36 months in this study. Two-year survival for the entire group was 25% but was better in patients with a chemo-sensitive relapse (62.5%). The two factors that were predictive of a poor outcome were chemo-refractory disease and absence of chronic graft-versus host disease.

Researchers from the University of Arkansas have treated 31 patients with multiple myeloma with a RI-allo-SCTs followed by related or unrelated stem cells.[31]Thirty of these patients had already received one or more autologous transplant utilizing high-dose melphalan. At a median follow-up of 6 months, 61% of these patients were in a complete or near complete remission. At one year the EFSl was 86% for those who had received one autograft and 31% for those who had received more than one autograft. There was a high incidence of acute and chronic graft-versus host disease in this study. 

One comparative study casts doubt on the advantages of RI-allo-SCTs in patients with multiple myeloma.[32]  Researchers affiliated with the European Group for Blood and Marrow Transplantation (EBMT) Chronic Leukemia Working Party have concluded that there is no evidence that RI-allo-SCTs are better than conventional myeloablative transplants. This analysis included 321 patients with multiple myeloma who had received RI-allo-SCTs and 196 who had received conventional transplants between 1998 and 2002. These patients were matched by age and stage of disease. The median age was 49 years, and patients had received a median of two prior regimens. Ten percent of patients had failed more than one autograft. Table 5 compares the results of conventional versus RI-allo-SCTs.

Table 5: Conventional Versus Reduced Intensity Transplants

These authors concluded that the RI-allo-SCTs may decrease immediate mortality, but there was no evidence of long-term benefit in this patient population.

Sequential auto-SCTs and RI-allo-SCTs are being explored in an attempt to improve the outcomes of patients with multiple myeloma. Researchers from the Fred Hutchinson Cancer Research Center, City of Hope National Medical Center, Stanford University, University of Colorado, the University of Leipzig, and University of Torino have reported that sequential autologous and allogeneic stem cell transplants produces complete remissions in 56% of patients with relapsed or refractory multiple myeloma.[33]  In this study, 54 patients with multiple myeloma with a median age of 52 years and a range up to 71 years were treated with high-dose melphalan followed by autologous peripheral blood stem cell infusion. Two months later this was followed by the administration of 2 Gy of TBI and an allogeneic peripheral blood stem cell transplant from an HLA compatible sibling. These authors reported that significant acute GVHD occurred in approximately 40% of patients and chronic GVHD in 46%. The ultimate complete response rate was 57% with relatively slow disease resolution reported. With a median follow-up of almost 2 years, 78% of patients were alive. The major causes of death in this study were related to acute or chronic GVHD and the overall TRM was 17%. Estimated PFS for all patients at 2 years was 55%.

Reduced-Intensity Allogeneic Transplants for Patients Failing an Autograft

Many of the patients treated with RI-allo-SCT have failed an auto-SCT. Many of the studies in relapsed or refractory patients cited in this review included patients who had failed an auto-SCT. Researchers from the Kaiser Permanente-City of Hope BMT Program have reported successful salvage of patients who relapse or develop emia (MDS/AML) after an auto-SCT.[34]  In this study, 28 patients with hematologic malignancies who had developed a recurrence or MDS/AML after an autologous stem cell transplant were treated with RI-allo-SCTs from related or unrelated donors. The primary regimen used was a combination of melphalan and fludarabine. All patients received cyclosporine and mycophenolate mofetil for prophylaxis against graft-versus host disease. They reported successful engraftment in all patients. Treatment-related mortality was still high (32%), but 46% of patients were alive at the time of this report. The probability of event-free survival at 2 years was reported to be 41%. These are remarkably good results in this very high-risk group of patients. The researchers demonstrated that allogeneic stem cell transplantation with a RI-allo-SCT offers some hope for patients who have failed an autologous stem cell transplant.

Reduced Intensity Allogeneic Transplants for Solid Tumor

Reduced intensity allo-SCTs have been evaluated in small numbers of patients with variety of solid tumors, but the only tumor that has receive wide attention is renal cell carcinoma. Results of RI-allo-SCTs for other tumors have shown responses, but none of these studies have produced meaningful results.[35]There have been no responses to melanoma, which is disappointing, since this is considered an immune response cancer.  At the present time, RI-allo-SCTs are only indicated for patients with renal cell carcinoma of the clear cell type.

Renal Cell Cancer

Dramatic effects of RI-allo-SCTs were reported early for the treatment of metastatic renal cell cancer (RCC). In a series of 19 patients, four obtained durable complete remissions and a further 6 had partial responses.[36]  Many groups have now treated renal cell carcinoma with this approach, and effectiveness is still being determined. A recent review of 100 RI-allo-SCTs concluded that the objective response rate was 23%.[37]  They also concluded that remissions only occurred after complete engraftment of donor lymphocytes. Objective responses were almost always accompanied by graft-versus host disease after withdrawal of immunosuppression and/or infusion of donor lymphocytes.

Researchers affiliated with the European Bone Marrow Transplantation Solid Tumor Working Party have reported prognostic factors for survival of patients receiving RI-allo-SCT for renal cell carcinoma.[38]  This study looked at 70 patients with advanced renal cell carcinoma who underwent RI-allo-SCT third line therapy. These researchers were able to separate patients into a high and low risk group based on Karnofsky performance status, C-reactive protein levels and lactic dehydrogenase levels.

For low risk patients the 100 day mortality was 4% compared to 43% for high risk patients. At one year, the mortality for low risk patients was 43% compared to 83% for high risk patients.  The median survival of high risk patients was 3.5 months versus 23 months for low risk patients. These authors think that patients with poor risk factors should not receive a stem cell transplant. However, they suggest that allogeneic stem cell transplants may be the best option available for low risk patients. This analysis helps to determine the role of RI-allo-SCTs for patients with renal cell carcinoma. However, it is also clear that this procedure needs to be evaluated earlier in the disease course to determine the full impact of this therapy.

Patients with Metastatic Breast Cancer

Reduced-intensity SCTs have been evaluated in 16 patients with metastatic breast cancer treated at the National Cancer Institute.[39]  Patients were treated with a T-depleted RI-allo-SCT followed by infusion of donor T-cells. Objective tumor regressions were seen in 6 patients that were associated with GVHD and complete lymphoid engraftment.

Researchers from Genoa, Italy, treated 17 patients with heavily pre-treated patients with metastatic breast cancer with a RI-allo-SCT following an auto-SCT.[40]  Engraftment occurred in 13 of these patients, and the overall response rate was 24% with 5 patients surviving (29%) for up to 3.5 years.

Although there are immune responses to RI-allo-SCTs in patients with breast cancer, this treatment will probably be of benefit only in patients treated early in their disease course who have minimal residual disease with a high probability of relapse. However, no such studies have been reported.

Colorectal Cancer

Three patients with metastatic colorectal cancer have been treated by RI-allo-SCTs by researchers in Japan.[41]  One patient achieved a PR, and two had stable disease and all developed acute and chroic GVHD. However, the responses were short lived. Japanese researchers observed a complete response in one of 6 patients with metastatic colorectal cancer treated with RI-allo-SCT.[42]

Patients With HIV-Related Malignancies

Researchers at the National Heart, Lung, and Blood Institute assessed the safety and efficacy of RI-allo-SCTs in 2 patients with HIV infection.[43]  Both patients had refractory hematologic malignancies and concomitant HIV infection. The indications for transplantation were treatment-related acute myelogenous leukemia and primary refractory Hodgkin’s disease. They evaluated a cyclophosphamide/fludarabine-based conditioning regimen. Donors were HLA-matched siblings. They also examined the possibility of efficient gene transfer of an HIV resistance vector carrying a dominant-negative mutant Rev at the level of the self-renewing stem cell.

Both patients tolerated the procedure well with minimal toxicity, and complete remissions were achieved in both patients, but patient 2 died of relapsed Hodgkin’s disease 12 months after transplantation. Patient 1 continues in complete remission with undetectable HIV levels and rising CD4 counts, and with both the therapeutic and control gene transfer vectors remaining detectable at low levels more than 2 years after transplantation.

These results suggest that nonmyeloablative allogeneic transplantation in the context of highly active anti-retroviral therapy is feasible in patients with treatment-sensitive HIV infection. These researchers speculate that a reluctance to consider allogeneic transplantation in HIV-infected patients has resulted in slow accrual to this study. Further improvements in both gene transfer technology and allogeneic transplantation may allow application to patients with progressive AIDS without an underlying hematologic malignancy. Patients with HIV-associated malignancy who have an HLA matched sibling now have a new potential therapy: allogeneic bone marrow transplantation using non-marrow ablative treatment regimens. The accrual of patients to this study was slow due to the reluctance of physicians to refer patients for experimental treatment. It is hoped that this preliminary study will enhance patient enrollment so the true benefit can be determined.

Novel Reduced-Intensity Treatment Regimens

Most of the development in RI-SCT regimens appears to be in the direction of increasing dose intensity with increased doses of TBI, melphalan and busulfan. These are in essence “add back” experiments to determine regimen-related morbidity and mortality with doses of drugs or irradiation that are somewhat reduced from truly myeloablative doses. However, researchers from Stanford University have developed a regimen that appears to separate GVHD from a GVM effect.[44]  They have reported that allogeneic stem cell transplantation following a conditioning regimen of low-dose total lymphoid irradiation (TLI) and ATG results in a low incidence of acute GVHD and a good survival in patients with lymphoid malignancies and AML. Researchers at Stanford have been evaluating the role of TLI for a number of years and have perfected a mouse model that has now been applied in the clinical setting. In this model, regulatory natural killer (NK) cells become the predominant T cell subset. Secretion of high levels of IL-4 by the host NK cells protects against GVHD following hematopoietic stem cell transplant. However, CD8+T cells remain intact. These data have now been used to plan transplant studies in patients with hematologic malignancies.

These researchers have evaluated the effectiveness of TLI and ATG in preparing patients for an allogeneic stem cell transplant. They have transplanted a total of 37 patients, 24 with lymphoid malignancies and 13 with acute leukemia, 12 of whom are at AML. Three quarters of these patients were characterized as having advanced disease, but all patients were in a partial or complete remission at the time of transplant. All patients with leukemia had less than 5% blasts. Twelve patients had failed an autologous transplant, and all were deemed unsuitable for a conventional transplant.

Stem cells were collected from the peripheral blood of related or unrelated donors following the administration of Neupogen. In the entire cohort of patients there was one grade III and one grade I acute GVHD. However, there were 9 cases of chronic GVHD. Importantly, 14 of the 22 patients with lymphoid malignances are alive and in complete remission 250 to 1069 days from transplant. Two more patients survive with partial remission. Ten of the 13 patients with acute leukemia are alive and in remission from 215 to 1041 days post-transplant. These authors concluded that TLI and ATG conditioning markedly reduced the incidence of acute GVHD while maintaining anti-tumor activity of the graft.

These are interesting and important findings that suggest this technique can be very useful in performing RI-allo-SCTs in patients with lymphoid malignancies and AML. One key aspect of this study is that patients were apparently carefully selected to have minimal disease at the time of transplant. In the case of leukemia, all patients were in bone marrow remission. It is unlikely that this approach would be effective in patients with large quantities of tumor. It will also be of interest to see if other transplant centers can confirm these data.

Conclusions

Since the last review of this subject by John Barrett in Current Topics in Oncology more that 5 years ago, there has been significant progress in the development of RI-allo-SCTs. There is no doubt that this approach has allowed more older and more debilitated patients to receive an allogeneic stem cell transplant. However, it is still not clear that RI-allo-SCTs are superior to conventional transplants in younger, fit patients. The current trend is to increase the dose-intensity of RI regimens without causing a significant increase in TRM. This trend will probably continue, especially for patients with gross and refractory malignancies. As a generality, the infusion of donor lymphocytes has not achieved its promise, primarily because of the high incidence of acute and chronic GVHD observed with current conditioning regiments. There is also the possibility that newer regimens will be developed that separate reduced GVHD without compromising a GVL effect.

References