Reduced-intensity conditioning for allogeneic haematopoietic stem cell transplantation in relapsed and refractory Hodgkin lymphoma: impact of alemtuzumab and donor lymphocyte infusions on long-term outcomes

The introduction of reduced-intensity conditioning (RIC) has enabled the role of allogeneic transplantation to be re-evaluated in Hodgkin lymphoma (HL). While T-cell depletion reduces graft-versus-host disease (GvHD), it potentially abrogates graft-versus-tumour activity and increases infective complications. We compared the results in 67 sibling donor transplantations following RIC in multiply relapsed patients from two national phase II studies conditioned with fludarabine/melphalan. One used cyclosporine/alemtuzumab (MF-A, n = 31), the other used cyclosporine/methotrexate (MF, n = 36) as GvHD prophylaxis. There was a small excess of chemorefractory cases in the MF cohort (P = NS). MF-A resulted in significantly lower incidences of non-relapse mortality, acute and chronic GvHD, but no significant excess of relapse/progression. Post donor lymphocyte infusion (DLI) disease responses occurred in 8/14 (57%) and 6/11 (55%) patients in the MF-A and MF groups, respectively. Current progression-free survival (CPFS) was superior with MF-A (univariate analysis), with durable responses to DLI contributing to the favourable outcome (43% vs. 25%, P = 0.0356). Disease status at transplantation significantly influenced overall survival (P = 0.0038) and CPFS (P = 0.0014), retaining significance in multivariate analyses, which demonstrated a trend towards improved CPFS with T-cell depletion (P = 0.0939). These data suggest that alemtuzumab significantly reduced GvHD without resulting in a deleterious impact on survival outcomes following RIC in HL, and that durable responses to DLI may be more common following the inclusion of alemtuzumab in the conditioning protocol.     

Reduced-intensity allogeneic transplantation in patients with refractory or progressive Hodgkin's disease after high-dose chemotherapy and autologous stem cell infusion

BACKGROUND: We analysed the feasibility and efficacy of allogeneic stem cell transplantation (allo-SCT) with reduced-intensity conditioning (RIC) in patients with refractory or progressive Hodgkin's disease (HD) after high-dose chemotherapy (HDCT). PATIENTS AND METHODS: Fourteen patients with HD received allo-SCT with RIC: eleven patients had a human leucocytes antigen-identical related donor and three a matched unrelated donor. Six had chemoresistant disease and eight had chemosensitive one at the time of transplantation. All patients received a fludarabine-based RIC. RESULTS: All patients engrafted and full donor chimerism was achieved in all patients. Grade II acute graft-vs.-host disease (GvHD) developed in six of the 14 patients (43%). Chronic GvHD developed in eight of the 13 patients (61%). There was neither early nor late treatment-related mortality (TRM). With a median follow-up of 21 months (range 3-74), 10 of the 14 patients were alive (71%). Estimated overall survival at 1 and 2 yr was 93% and 73%, respectively, for the whole population, 83% and 44% respectively for patients with chemoresistant disease and 100% for those with chemosensitive disease. Estimated progression-free survival at 1 yr was 36%; 62.5% for chemosensitive patients and 0% for those with chemoresistant disease. CONCLUSIONS: In conclusion, allo-SCT with fludarabine-based RIC is a feasible procedure, without TRM in HD patients relapsed and refractory after HDCT. Even if several questions are still open, this approach should proposed for these poor prognosis patients.     

Reduced-intensity conditioning regimen with thiotepa and fludarabine followed by allogeneic blood stem cell transplantation in haematological malignancies

The aim of this study was to investigate thiotepa (TT) and fludarabine (Fluda) as a preparative regimen for allogeneic peripheral stem cell transplant in patients not eligible for a standard myeloablative regimen due to comorbidities and/or poor performance status. TT was given at a dose of 10 mg/kg over 2 days and Fluda at 125 mg/m(2) over 5 days. In all, 21 patients (14 male, seven female; 10 acute leukaemia, eight myelodysplastic syndrome, two non-Hodgkin's lymphoma, one Hodgkin's disease) were treated. The median age was 51 years (range 30-55 years). All patients achieved full donor-type chimaerism. Adverse events included mild nausea and vomiting in two patients and a slight increase of serum amylase in three. A total of 13 patients received RBC transfusions (median 6 U, range 1-23), and all received platelets (median 4 U, range 1-27). Four patients died of nonrelapse causes and five of relapse. The 1-year probabilities of transplant-related mortality and relapse were 19 and 29%, respectively. In total, 12 patients remain in complete remission (median follow-up: 786 days). The 3-year overall survival probability was 58%. We conclude that this regimen is feasible and well tolerated.     

Autologous stem cell transplantation for high-risk Hodgkin's disease: improvement over time and impact of conditioning regimen

BACKGROUND AND OBJECTIVE: High-dose chemo/radiotherapy with autologous stem cell support is increasingly being used in Hodgkin's disease (HD) patients who do not respond to or who relapse after conventional chemotherapy. In this work we analyze the results of 56 consecutive high-risk HD patients autografted in our institution and the role of possible prognostic factors. DESIGN AND METHODS: There were 34 males and 22 females with a median age of 31 years. At transplantation, 24 patients (43%) were in complete remission and 32 (57%) were autografted while with active disease. Twenty-nine patients were autografted before January 1993. Bone marrow was used as the source of stem cells in 40 patients (71%) and peripheral blood (PB) in 16 (29%). Forty-five patients received chemotherapy-based conditioning regimens (40 CBV and 5 BEAM) while the remaining 11 received cyclophosphamide (Cy) and total body irradiation (TBI). RESULTS: Two bone marrow transplantation (BMT) recipients did not engraft. Hematologic recovery was significantly faster in patients transplanted with PB progenitor cells. Early transplant-related mortality (early TRM) (before day 100 after transplantation) was 9%; it was higher in patients transplanted before January 1993 than in patients transplanted afterwards (14% vs 4%) and in patients receiving TBI (18% vs 7%), although these differences did not reach statistical significance. Overall TRM (before and after day 100) was 14%. TBI-containing regimens significantly increased overall TRM (36% and 9%, p = 0.03). Actuarial 3.5-year overall survival (OS), event-free survival (EFS) and progression-free survival (PFS) were 57%, 58% and 65%, respectively. On multivariable analysis, TBI containing regimens and transplantation before 1993 significantly reduced OS and EFS. INTERPRETATION AND CONCLUSIONS: Our results confirm that high-dose therapy followed by autologous stem cell transplantation is associated with sustained PFS in a remarkable proportion of patients with HD unlikely to be cured with standard chemotherapy. Results improved over time and TBI containing regimens had a negative effect on post-transplant outcome.     

Low transplant-related mortality with allogeneic stem cell transplantation in elderly patients

Historically, age >60 years was considered a contraindication for allogeneic stem cell transplantation (allo-SCT). In recent years, elderly (>60 years) patients have become eligible for allo-SCT due to the application of reduced intensity conditioning (RIC). The present report summarizes our cumulative experience in a cohort of 17 elderly patients (age 60-67, median 62.5 years) with hematological malignancies treated with 18 allo-SCT procedures, mostly nonmyeloablative. In all, 14 patients received fludarabine and busulfan/busulfex regimen, three patients were conditioned with the fludarabine and low-dose TBI and one patient received busulfan alone. All patients displayed tri-lineage engraftment. The time to recovery of absolute neutrophil count >/=0.5 x 10(9)/l was 9-27 days (median 14 days). The time interval to platelet recovery >/=20 x 10(9)/l was 3-96 days (median 11 days). Veno-occlusive disease occurred only in 3/18 procedures and subsided with conventional treatment. Nonfatal transplant-related complications occurred in 6/18 (33.3%) procedures including: renal failure, arrhythmia, CNS bleeding, cystitis, typhlitis and gastrointestinal bleeding. Transplant-related mortality occurred in 6/18 (33.3%) episodes. Of the 17 patients, 12 (12/18 episodes) were discharged. Five of 17 (29%) patients survived (median follow-up 11 m, range 8-53 m). Our data suggest that RIC-allo-SCT may be safely applied in the elderly, suggesting that allogeneic immunotherapy may become an important tool for treatment of hematological malignancies without an age limit.     

Reduced-intensity preparative regimen and allogeneic stem cell transplantation for advanced solid tumors

In this prospective multicenter program, we investigated allogeneic stem cell transplantation (ASCT) from HLA-identical siblings following reduced-intensity conditioning (RIC) regimen for patients with refractory metastatic solid tumors (STs). Fifty-seven patients, of whom 39 had a progressive disease (PD) at time of ASCT, received an RIC ASCT combining fludarabine, antithymocyte globulin (ATG), and busulfan. Patients were analyzed in terms of engraftment, transplant-related mortality (TRM), disease response, and outcome. In this setting, RIC was associated with rapid engraftment and low overall TRM (9% [95% confidence interval (CI), 1%-16%]). The cumulative incidence of objective responses (ORs) reached 14% (95% CI, 6%-30%) with this being significantly higher in patients without PD (44% [95% CI, 21%-67%] versus 0; P <.0001) at time of ASCT. Achievement of OR translated into a significantly better overall survival (OS). In multivariate analysis, OS was significantly influenced by disease status at time of ASCT (odds ratio, 4.88; P <.001) and chronic graft-versus-host disease (GVHD) occurrence (odds ratio, 2.86; P <.01). Overall, these results showed that OR can occur after RIC ASCT for resistant ST with a relatively low TRM and potential benefit especially in patients with slowly progressive disease. Further studies are warranted in patients with less advanced ST.     

Second allogeneic peripheral blood stem cell transplantation with fludarabine-based low-intensity conditioning regimen for relapsed myelodysplastic syndrome after allogeneic bone marrow transplantation

We describe the case of a 51-year-old patient with relapsed myelodysplastic syndrome after allogeneic bone marrow transplantation (BMT), who underwent allogeneic peripheral blood stem cell transplantation (PBSCT) after conditioning with a novel regimen consisting of fludarabine, busulfan, and antithymocyte globulin. The second PBSCT was performed early, at 3 months after the initial allogeneic BMT, but it was well tolerated and complete hematologic remission was documented. The patient did not experience any early transplantation-related organ toxicity but died from opportunistic infection 6 months after the second transplantation. Our experience suggests that this novel regimen may induce remission and could be offered to patients relapsing after the first transplantation; however, the fludarabine-containing regimen might be accompanied by profound immunosuppression.     

Autologous transplantation in relapsed and refractory Hodgkin's disease

Abstract:  The current data support the use of high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) as standard procedure for the majority of patients with Hodgkin's disease (HD) relapsing or progressing after combination chemotherapy. Prognostic factors reflecting unfavourable prognostic features of the disease as well as resistance to conventional salvage therapy have been identified. Preliminary data suggests a high efficacy of high-dose sequential chemotherapies in these patients. An ongoing randomized trial is comparing standard HDCT versus sequential HDCT in patients with relapsed HD.     

Reduced-intensity conditioning regimen preserves thymic function in the early period after hematopoietic stem cell transplantation

OBJECTIVE: To compare T-cell reconstitution in two groups of patients submitted to allogeneic stem cell transplantation (SCT): those receiving reduced-intensity conditioning (RIC, n = 24) and those receiving myeloablative conditioning (MA, n = 27). METHODS: Fifty-one consecutive patients undergoing SCT were evaluated. Serial assessments of lymphocyte subsets and T cell receptor excision circles (TRECs) levels were performed using multiparametric flow cytometry and real-time PCR, respectively. RESULTS: During the first 6 months posttransplant, total and na?ve CD4(+) T cell counts were higher after RIC-SCT than after MA-SCT (total CD4(+): p = 0.04, p = 0.08, and p = 0.058; na?ve CD4(+): p = 0.14, p = 0.05, and p = 0.01 at 1, 3, and 6 months, respectively). In both groups of patients, TRECs levels were low or undetectable in the first 3 months after SCT and progressively increased during the study. However, a higher proportion of patients with detectable levels of TRECs was observed in RIC-SCT at 1 and 3 months and more patients in this group reached normal levels of TRECs at 6 months post-SCT. In the multivariate analysis, including factors such as type of donor (sibling vs unrelated), dose of CD34(+) cells infused with the graft, patient age, and graft-vs-host disease (GVHD), the most important factor influencing TRECs recovery in the early period after SCT was the type of conditioning regimen. CONCLUSIONS: In this study, the pattern of immune reconstitution after RIC-SCT was different from that of MA-SCT and was characterized by higher posttransplant na?ve CD4(+) T cell counts and TRECs levels in the early period after transplant.     

Clinical outcome of allogeneic hematopoietic stem cell transplantation with FLAG sequential busulfan/cyclophosphamide conditioning regimen for refractory/relapsed acute myeloid leukemia

正Objective To investigate the therapeutic effects of allogeneic hematopoietic stem cell transplantation (alloHSCT) with FLAG sequential busulfan/cyclophosphamide (Bu/Cy) conditioning regimen for refractory/relapsed acute myeloid leukemia.Methods From February2012 to June 2017, 21 patients with refractory/relapsed acute myeloid leukemia underwent allo-HSCT with FLAG     

Reduced-intensity conditioning reduces the risk of severe infections after allogeneic peripheral blood stem cell transplantation

We compared the occurrence of severe infections following 71 reduced-intensity conditioning (RIC) allogeneic peripheral blood stem cell transplants (PBSCT) and 123 standard myeloablative PBSCT (MINI and STAND groups, respectively) from HLA-identical siblings. The probability of 1-year infection-related mortality (IRM) was 19% in the STAND group and 10% in the MINI group (log-rank, P = 0.3). On multivariate analysis the only significant variable associated with a higher risk of IRM was the development of moderate-to-severe GVHD (P = 0.005). The probability of developing CMV infection was 39% in the STAND group and 21% in the MINI group (P = 0.03) (43% and 21%, respectively, in seropositive donor/recipient pairs, P = 0.01), and the probability of developing CMV disease was 9.5% and 1%, respectively (P = 0.05) (11% and 1%, respectively, in seropositive donor/recipient pairs, P = 0.03). Multivariate analysis of CMV infection identified four variables associated with a higher risk: CMV positive serostatus (P = 0.05), STAND transplant group (P = 0.02), the development of moderate-to-severe GVHD (P < 0.001) and a dose of CD34(+) cells infused below 6 x 10(6)/kg (P = 0.01). Invasive fungal infections and pneumonias of unknown origin did not differ between groups, and neither did other severe non-CMV viral infections and bacterial infections. Our results suggest that RIC allogeneic PBSCT may decrease the risk of dying from an opportunistic infection and reduces the occurrence of CMV infection and disease. Overall, the development of GVHD (acute or chronic) is an important risk factor for these complications. Other infections continue to pose a significant threat to recipients of RIC allografts, stressing that prophylactic and supportive measures are an important aspect in their care.     

Reduced-intensity conditioning followed by allogeneic hematopoietic cell transplantation in myeloid diseases

Within the past years, reduced or modified doses of chemotherapy or radiotherapy have been widely studied for conditioning before allogeneic hematopoietic cell transplantation in patients with myeloid leukemia not eligible for conventional transplantation. The main goal was to reduce the substantial treatment-related mortality in this patient population while preserving the potential curative graft-versus-leukemia effect. This review summarizes results of published trials using reduced-intensity conditioning (RIC) in patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myeloid leukemia (CML), and myelofibrosis. In most of the published trials conditioning contained fludarabine (90–180 mg/m²) in combination with busulfan (4×10 mg/kg), melphalan (90–140 mg/m²), or 2–5 Gy total body irradiation (TBI). Peripheral blood hematopoietic stem cells from related or unrelated donors were used as graft source in most of the studies. Post-transplantation immunosuppression consisted of cyclosporine combined with methotrexate or mycophenolate mofetil. Although the majority of the patients were above the age of 50 years, early treatment-related mortality was rather low. Nevertheless, the rate of clinically significant graft-versus-host disease (GVHD) seemed to be comparable to conventional transplants in most of the protocols. The outcome differed between trials, but diagnosis and disease status pre-transplant significantly influenced outcome. In summary, this approach is feasible and provides access to the curative potential of allogeneic stem cell transplantation for patients with higher age or comorbidities. Since the majority of the reports included heterogeneous patient populations, mostly with a short follow-up, more and specifically randomized studies are needed to define the role of RIC before allogeneic hematopoietic cell transplantation.     

Immune reconstitution following allogeneic stem cell transplantation in recipients conditioned by low intensity vs myeloablative regimen

We have investigated the immune status of patients with hematologic malignancies treated with a low intensity conditioning in preparation for allogeneic stem cell transplantation. Conditioning consisted of fludarabine, anti-T lymphocyte globulin and low-dose busulfan, followed by infusion of allogeneic blood stem cells. This protocol resulted in rapid engraftment and complete replacement of host with donor hematopoietic cells. Immunological parameters of these patients were compared to those patients who were conditioned by an aggressive myeloablative regimen. Distribution of cell surface markers of lymphocyte subsets from both groups of patients was similar, but different from that of normal control cells. Reduced intensity or non-myeloablative conditioning prior to allogeneic stem cell transplantation (NST), hardly lowered the normal T cell-dependent mitogenic response even during the early period following transplant, while the myeloablative treatments resulted in a suppressed mitogenic reaction and in slow immune recovery. Reactivity of non-MHC restricted cytotoxic T cells was also at a normal level in patients who were treated with NST. We conclude that stem cell engraftment following reduced conditioning may result in early reconstitution of immune responses assessed in vitro. We hypothesize that clinical application of NST may lead to faster development of effective immune responses against residual host-type malignant and abnormal non-malignant hematopoietic cells, although the role of fludarabine on post-transplant infections remains to be investigated in a larger cohort of patients.     

Strategies to reduce transplant-related mortality after allogeneic stem cell transplantation in elderly patients: Comparison of reduced-intensity conditioning and unmanipulated peripheral blood stem cells vs a myeloablative regimen and CD34+ cell selection

OBJECTIVES: The aim of this study was to compare two approaches used to reduce transplant-related mortality (TRM) after allogeneic peripheral blood stem cell transplantation (allo-PBSCT) in elderly patients. PATIENTS AND METHODS: Data from 50 patients, 45 years of age or older, consecutively treated with an HLA-identical sibling allo-PBSCT at the Hospital de Sant Pau were analyzed. We have compared the outcome of patients treated with conventional myeloablative regimens and CD34(+)-selected cells (CD34(+) group; n=23) with those receiving reduced-intensity conditioning regimens, consisting of fludarabine (150 mg/m(2)) plus an alkylating agent, followed by unmanipulated grafts (RIC group; n=27). Patient characteristics were well balanced between the two groups, although patients in the RIC group were slightly older. RESULTS: The incidence of acute graft-vs-host disease (GVHD) was similar in both groups. The 1-year cumulative incidence of extensive chronic GVHD was 38% in the RIC group and 17% in the CD34(+) group (p=0.2). After a median follow-up of 28 months, there were no differences in the relapse rate. Patients in the RIC group had a lower TRM, with a cumulative incidence of 7% vs 30% at 6 months and 15% vs 39% at 1 year (p=0.05). The Kaplan-Meier estimates of PFS at 2 years was 67% in the RIC group and 43% in the CD34(+) group (p=0.09) and the OS was 69% vs 43% (p=0.05), respectively. CONCLUSION: CD34(+) cell selection reduced the risk of extensive cGVHD but was associated with a higher TRM. Although the number of patients is limited, our study suggests that this approach should be restricted to relatively young patients, as better outcomes can be achieved in elderly patients using RIC strategies.     

Infections after allogeneic hematopoietic stem cell transplantation with a nonmyeloablative conditioning regimen

Hematopoietic cell transplantation (HCT) following nonmyeloablative conditioning (NMSCT) may be associated with a reduced risk of infection compared to standard allogeneic HCT. We retrospectively analyzed incidence and risk factors of infection in 62 patients undergoing NMSCT with low-dose TBI +/- fludarabine and postgrafting CsA and MMF. The proportion of patients with any infection was 77%, but the majority of infectious events occurred beyond day 30. Donor other than sibling, older age, early disease and male gender were significant risk factors. The incidence of bacteremia was 55% at 1 year and the number of bacteremic episodes was 0.9 per patient (0.08 before day 30). The risk of bacteremia increased with older age and the use of a donor other than an HLA-identical sibling, but not with neutropenia. The incidence of infections other than bacteremia correlated with the use of corticosteroids. The risk of CMV infection increased with high-risk CMV serology, and risk of CMV disease with high-risk CMV serology, older age, first transplantation and a diagnosis of lymphoma. In conclusion, after NMSCT, infections are not frequent in the first 30 days post transplant but careful long-term monitoring is necessary thereafter.