Allogeneic peripheral blood stem cell transplantation using a fludarabine-based low intensity conditioning regimen for malignant lymphoma

Relapse is a serious complication following high-dose therapy and autologous bone marrow transplantation (ABMT) for malignant lymphoma (ML). Allogeneic transplantation (alloSCT) is a therapeutic option. However, it is associated with a high incidence of transplant-related organ toxicity and mortality. We recently reported fast engraftment and minimal transplant-related toxicity, using fludarabine-based conditioning with reduced amounts of chemotoxic drugs prior to alloSCT. We now present our experience with 23 heavily treated high risk ML patients who underwent matched alloSCT following the same low intensity conditioning. The patients (20 male, three female) were aged 13-63 years. Nineteen had NHL and four HD (resistant disease 12, partial remission 11). Five were post ABMT. Twenty-two patients had fully matched sibling donors, and one a fully matched unrelated donor. Engraftment was fast. There was no rejection or non-engraftment. Organ toxicity was moderate with no liver or renal toxicity >grade II. Four patients developed >grade II graft-versus-host disease (GVHD). Seven patients died - four of grade III-IV GVHD and severe infections, two of bacterial sepsis, one of pulmonary failure. Ten patients are alive after 22.5 (15-37) months. Survival and disease-free survival at 37 months are both 40%. Probability of relapse is 26%. These encouraging results suggest that alloSCT following fludarabine-based low intensity conditioning in high-risk patients merits further evaluation. Bone Marrow Transplantation (2000).     

Allogeneic blood stem cell transplantation following non-myeloablative conditioning for hypereosinophilic syndrome

A male patient with hypereosinophilic syndrome (HES) underwent an allogeneic blood stem cell transplantation from a female donor following non-myeloablative conditioning consisting of a 2 Gy dose of TBI and fludarabine 30 mg/m(2) intravenously on three days. Before transplantation 100% of the mitotic bone marrow cells of the patient showed a clonal karyotype abnormality. Three months after the transplantation eosinophilia had resolved and a chromosome analysis revealed normal female karyotype. The present study shows that stem cell transplantation after non-myeloablative conditioning may have curative potential for HES.     

Allogeneic stem cell transplantation using non-myeloablative conditioning regimens: results of the Mexican approach

We have used a novel method to conduct non-myeloablative stem cell transplantation (NST), making the following changes in previous methods: Use of the cheapest conditioning drugs, tailored number of apheresis sessions in the donors, elimination of ganciclovir and IgG, outpatient conduction when possible, diminished number of transfusions of blood products and diminished number of donor lymphocyte infusions. With this method, we have prospectively conducted 70 allografts in patients with different diseases: Chronic myelogenous leukemia, acute myelogenous leukemia, acute lymphoblastic leukemia, myelodysplasia, thalassemia major, relapsed Hodgkins disease, Blackfan-Diamond syndrome and aplastic anemia. In them, the median granulocyte recovery time to 0.5 x 10(9)/L was 11 d, whereas the median platelet recovery time to 20 x 10(9)/L was 12 d. Twenty patients did not need red blood cell transfusions and 17 did not need platelet transfusions. In 55 individuals (78%), the procedure could be completed fully on an outpatient basis. Follow-up times range between 30 and 800 d.: Four patients failed to engraft and recovered endogenous hemopoiesis; 16 patients (23%) developed acute graft versus-host disease (GVHD) whereas 28 (49%) developed chronic GVHD. Thirty two patients (47%) have died: 21 with a relapsing disease and seven as a result of GVHD; the median post-trasplant survival (SV) was 420 d., whereas the 12-mo. SV was 42%. The 100-day mortality was 3.8% and the transplant-related mortality was 14.2%. The median cost of the allografts was 18,000.00 US dollars. This method could be particularly adequate in developing countries, where very few individuals can afford the cost of a conventional bone marrow transplantation procedure.     

The treatment of multiple myeloma with an allogeneic peripheral blood stem cell transplantation using a non-myeloablative conditioning regimen

Between November 1998 and October 1999 authors treated five multiple myeloma patients with an allogeneic peripheral blood stem cell transplantation from HLA-identical sibling using a non-myeloablative conditioning regimen. The median age at the time of transplantation was 58 (range: 47-65) years. In all patients one (n = 3) or two (n = 2) autologous peripheral blood stem cell transplantations were already performed. Conditioning was performed with fludarabine, oral busulfan and anti-T-lymphocyte globulin. All patients engrafted from 13 to 18 (median: 17) days from transplantation. The duration of neutropenia (absolute neutrophiles count < 500/microl) and thrombocytopenia (platelets < 20,000/microl) ranged between 4 and 19 (median: 18) and between 13 and 18 (median: 17) days, respectively. In the period of posttransplant pancytopenia two patients developed mild gastrointestinal mucositis and two pulmonary complications (bronchopneumonia and dyspnoe of unknown etiology). Two patients had grade III-IV acute graft-versus-host disease (GvHD), none had extensive chronic GvHD. Two patients received prophylactic donor-lymphocytes infusions 200 and 225 days from transplantation. One of them developed grade III acute GvHD. All patients responded. One achieved complete and four partial remission of the disease. One patient died 111 days from transplantation due to bronchopneumonia, four are alive and well, in the stable disease, 35, 36, 51 and 52 weeks after transplantation. It can be concluded that allogenic peripheral blood stem cell transplantation using a non-myeloablative conditioning regimen is an effective way of the multiple myeloma treatment with an acceptable toxicity.     

Allogeneic hematopoietic stem cell transplantation following reduced-intensity conditioning regimen in children: a single-center experience

This single-center retrospective study reported the outcome of 19 children treated with a reduced-intensity conditioning (RIC) regimen prior to allogeneic stem cell transplantation (allo-SCT), for hematologic malignancies (n = 17), bone marrow failure (n = 1), and neuroblastoma (n = 1). Children were ineligible for standard myeloablative conditioning because of severe comorbidities (n = 9), a previous auto or allo-SCT (n = 7) or a prior history of extensive chemotherapy (n = 3). All patients underwent a fludarabine-based RIC regimen, and received grafts from matched-related donors (n = 5), match-unrelated donors (n = 6), or unrelated cord blood (UCB, n = 8). In this series, two patients treated with UCB failed to engraft and 63% achieved full donor chimerism at day 100 after allo-SCT. With a median follow-up of 537 d (range, 115-4136), treatment-related mortality was 16% and overall survival was 47%. The principal cause of death was disease relapse (n = 7). Acute graft versus host disease (GVHD) occurred in 53% of patients, while only 10% developed extensive chronic GVHD. Overall, results from this series suggest that RIC allo-SCT can be a valid alternative treatment option in unfit children with malignant hematological diseases. Prospective studies are needed to enlarge pediatric experience in this domain and better identify those children more suitable for a RIC allo-SCT approach.     

Allogeneic hematopoietic stem cell transplantation with reduced intensity conditioning for a child with recurrent anaplastic large cell lymphoma

Anaplastic large cell lymphoma (ALCL) is chemosensitive, but recurrence is frequently observed. Allogeneic hematopoietic stem cell transplantation (HSCT) has recently been reported to be effective against recurrent disease, suggesting a graft-versus-lymphoma effect. We present a 3-year-old child with recurrent ALCL who underwent HSCT from an HLA-1-locus mismatched cord blood unit following reduced intensity conditioning with fludarabine, melphalan, and low-dose thoraco-abdominal irradiation. Engraftment was uneventful, but grade III acute graft-versus-host disease was observed. He is well and free of disease 25 months after HSCT, which implies that reduced intensity conditioning may allow a sufficient graft-versus-lymphoma effect against ALCL while lessening treatment-related toxicities.     

Allogeneic stem cell transplantation in follicular lymphoma

Myeloablative allogeneic transplantation in follicular lymphoma has been found to be particularly effective in patients with relapsed disease and an inadequate bone marrow reserve or massive bone marrow involvement. Allogeneic transplantation carries the promise of long-term disease control by graft-versus-lymphoma immunity but is associated with a 30%-40% risk of transplant-related mortality. Nonmyeloablative stem cell transplantation exploits the graft-versus-lymphoma effect without the attendant toxicity of myeloablative conditioning. The results of several recent reports suggest that it has a high likelihood of resulting in long-term disease-free survival in patients up to 70 years of age with a good performance status, chemotherapy-sensitive disease, and HLA-matched sibling donors. At The University of Texas MD Anderson Cancer Center, the standard NST conditioning regimen for patients with follicular lymphoma is fludarabine, cyclophosphamide, and rituximab. This regimen results in a transplantation-related mortality rate of 10%, and 85% of patients are alive without disease at 8 years. In this article, we discuss the current issues in NST for follicular lymphoma, including chemosensitivity, conditioning intensity, graft-versus-host disease, donor lymphocyte infusion's role, and ongoing strategies to treat refractory disease.     

A non-myeloablative conditioning regimen in allogeneic stem cell transplantation from related and unrelated donors in elderly patients

We describe our experience with the use of a single non-myeloablative preparative regimen in stem-cell transplantation (NST) in 37 heavily pretreated patients > or =55 years. The conditioning regimen consisted of fludarabine, low-dose busulfan, and antithymocyte globulin. Acute graft-versus-host disease (GVHD) grade III-IV and chronic GVHD developed in 15.6% and 44.4% of cases, respectively. With a median follow-up period of 22 (range 3-113) months, the 1-year overall survival and disease-free-survival were 55% and 53%, respectively, while the overall non-relapse mortality was 35%. In conclusion, reduced intensity stem cell transplantation is feasible and effective in patients > or =55 years. Age per se, should no longer be considered as a contra-indication to stem cell transplantation.     

Allogeneic transplantation using non-myeloablative transplant regimens

Reduced intensity (non-myeloablative) stem cell transplant (NST) preparative regimens are being increasingly used to exploit the curative potential of allogeneic stem cell transplantation without the morbidity and mortality associated with conventional transplantation. Growing confidence in the power of the allogeneic graft-versus-malignancy (GVM) effect makes such an approach attractive. Lower intensity transplants increase the degree of mixed chimerism, both in T cell and myeloid cell lineages. Currently a variety of NST treatment approaches are being developed and in this chapter their safety profile and the immunological characteristics of the mixed chimeric state are described. Results of NST in specific disease categories are still limited but the NST approach appears to have promise in the treatment of both haematological and non-haematological malignancies because of the benefit of low toxicity coupled with a strong graft-versus-malignancy effect. NST regimens are also being explored in high-risk patients with non-malignant disorders. However, at present, there is insufficient data to determine whether NST should replace standard myeloablative transplants in specific disease groups. With their low toxicity, NST are well placed as platforms for future developments in transplant immunology to avoid GVHD and enhance the allograft effect against malignant diseases.     

Decreased transfusion requirements in patients given stem cell allografts using a non-myeloablative conditioning regimen: a single institution experience

We report our experience of allogeneic peripheral blood stem cell transplantation using non-myeloablative conditioning regimens delivered and supported on an outpatient basis. A group of 44 patients underwent 47 allograft procedures using peripheral blood stem cells. Approximately one third of the individuals did not require red blood cells transfusions: the median of transfused red blood cells units was 1 (range 0-10). In addition one out of three did not require platelet transfusions either, the median of platelet transfusions being 1 (range 0-6). In fourteen allografts (30%) neither red blood cells nor platelet transfusions were used. An inverse correlation was found between the number of CD34 cells infused and the PRBC and PLT transfusion requirements, those patients receiving high numbers of CD34 cells needing fewer transfusions of both PRBC and platelets. The possibility of conducting allografts without transfusion of blood products in some patients may result in a decrease in both cost and the risks stemming from exposure to human blood derivatives.     

Successful father-to-son stem cell transplantation in a child with hemophagocytic lymphohistiocytosis using a reduced-intensity conditioning regimen

OBJECTIVE: Hemophagocytic lymphohistiocytosis (HLH) is an uncommon disorder, usually lethal without allogeneic stem cell transplantation (SCT). MATERIALS AND METHODS: We report a 9-month-old boy, the first child of consanguineous parents, diagnosed with HLH and neurological involvement demonstrated by magnetic resonance imaging (MRI), who received an allogeneic SCT from his HLA genetically matched father. Transplant was performed after a reduced-intensity conditioning (RIC) regimen consisting of cyclophosphamide, fludarabine, and melphalan. Graft vs. host disease (GVHD) prophylaxis included cyclosporine a and methotrexate. RESULTS: An absolute neutrophil count of 0.5 x 10(9)/L was documented on day +20 and a platelet count >20 x 10(9)/L was shown by day 33. Full donor chimerism was showed on day +175. A follow-up brain MRI was reported normal. Twenty months after SCT, the child shows no evidence of HLH or GVHD activity, and has a normal psychomotor development. CONCLUSION: Given the reduced toxicity of SCT with RIC, it could represent an attractive transplant method for children with HLH, in whom myeloablation plays no role in disease eradication, and in whom mixed chimerism may be enough to cure the disease.     

Allogeneic stem cell transplantation for severe acquired aplastic anaemia using a fludarabine-based preparative regimen

We reviewed our experience in the treatment of 13 patients with severe acquired aplastic anaemia, using a newly developed non-myeloablative regimen consisting of fludarabine (total dose 180 mg/m2), cyclophosphamide (total dose 120 mg/kg), and antithymocyte globulin (total dose 40 mg/kg). All except one patient received multiple transfusions and had failed prior immunosuppressive treatment. Twelve out of 13 patients achieved sustained engraftment. One patient was not evaluable for engraftment because of early death on day +10. None of the patients developed graft failure. Mucositis of mild-to-moderate severity was the only observed regimen-related toxicity. The cumulative incidence of acute graft-versus-host disease (GvHD) grade II-IV and III-IV was 8.3% and 0%, respectively. With a median follow-up period of 45 months, the 5-year overall survival probability was 84%. Eight out of 11 surviving patients have been followed for more than 1 year and only one developed limited chronic GvHD. All patients enjoy a normal life style, with a Karnofsky score of 100%, and all except three, followed for 3, 5 and 6 months respectively, are free of any immunosuppressive medication. The results of this study look promising, while prospective clinical trials may be required to confirm the benefits of this regimen as an alternative to existing protocols.     

Allogeneic bone marrow transplantation for refractory mantle cell lymphoma

 We report about a 28-year-old woman with relapsed mantle cell lymphoma (MCL, centrocytic lymphoma according to the Kiel classification) refractory to salvage chemotherapy. The patient underwent allogeneic bone marrow transplantation from a HLA-identical brother after myeloablative chemotherapy consisting of busulfan, etoposide, and cyclophosphamide. The patient experienced hepatic toxicity (grade I), mucositis (grade II) according the Bearman scale, and graft versus host disease of the skin (grade II) and showed stable engraftment with complete chimerism on day 15 after bone marrow transplantation. Eight years after transplantation, the patient is still disease free and in good condition without any late side effects. This report suggests a curative potential of allogeneic stem cell transplantation in MCL. Received: 23 December 1999 / Accepted: 28 March 2000     

Allogeneic hematopoietic stem cell transplantation in a patient with HIV-negative recurrent plasmablastic lymphoma: A case report

Introduction:No standard guideline has been established for the treatment of plasmablastic lymphoma (PBL) and prognosis remains extremely poor, given that patients relapse early after chemotherapy and show resistance to commonly used cytostatic drugs.Patient concerns:We present the case of a 52-year-old HIV-negative man who presented with a mass at the left sternoclavicular joint. He had no significant comorbidities and no latent immunosuppression.Diagnosis:The largest lymph node measured was 36 × 19 mm. An excisional biopsy showed diffuse proliferation of large lymphoid cells which were positive for CD38 and CD138, but negative for CD20. He was diagnosed with stage IV PBL with a low IPI.Interventions:The patient was treated with four cycles of induction therapy with bortezomib, epirubicin and dexamethasone. He achieved complete remission. But 3 months after receiving consolidated autologous hematopoietic stem cell transplantation, he relapsed. Allogeneic hematopoietic stem cell transplantation was performed on the patient.Outcomes:The patient achieved remission again and there were no serious complications after allogeneic hematopoietic stem cell transplantation. This patient was followed up once every three months, and to date, he has been disease-free for more than 4 years.Conclusion:The survival of recurrent PBL after autologous hematopoietic stem cell transplantation is very poor. Salvage allogeneic hematopoietic stem cell transplantation may bring long-term survival opportunities for those patients. Further clinical studies are needed to explore the role of allogeneic hematopoietic stem cell transplantation in refractory and recurrent PBL.     

Allogeneic haemopoietic stem cell transplantation for non-Hodgkin's lymphoma

This chapter outlines the rationale for allogeneic haemopoietic stem cell transplantation in non-Hodgkin's lymphoma and pertinent results from published studies. Trials comparing allogeneic with autologous transplantation are discussed, as are disease-specific results for low-grade (including transformed), mantle cell and high-grade (Burkitt's and lymphoblastic) subtypes of the disease. Allogeneic transplantation for non-Hodgkin's lymphoma in the paediatric population, the use of unrelated donors, allografting after failed autologous or allogeneic transplantation, the graft-versus-lymphoma effect, the use of donor leukocyte infusions and non-myeloablative allografts are considered.