Outpatient autologous hematopoietic stem cell transplantation for patients with relapsed follicular lymphoma

Autologous stem cell transplantation (ASCT) has emerged as a viable option for the treatment of relapsed follicular non-Hodgkin’s lymphoma. We report on the outpatient experience of 60 patients who underwent ASCT for this condition. The median age was 51 years (30–65). Pre-transplantation conditioning regimens consisted of either etoposide/melphalan/TBI, CBV or BEAM. Patients participated in this transplant program for a median of 20.5 days (14–78), and 58.4% of the total program days were spent in the outpatient setting. Six patients were well enough to be treated solely as outpatients. Ninety percent of patients required at least one inpatient admission (median 7 days), and 70% of first inpatient transfers occurred within the first week following transplant and always before day +12. There were no predictors for prolonged inpatient stays. Febrile neutropenia and gastrointestinal toxicity were the main reasons for inpatient transfers. No outpatient required an urgent admission to the ICU or died in the outpatient setting. The treatment-related mortality at days 30 and 100 was 0 and 1.7%, respectively. The overall and progression-free survivals at 5 years were 65.7 and 56.1%, respectively. Outpatient ASCT with total body irradiation is feasible, safe, and effective for patients with relapsed follicular lymphoma.     

Brentuximab vedotin enables successful reduced-intensity allogeneic hematopoietic cell transplantation in patients with relapsed or refractory Hodgkin lymphoma

Brentuximab vedotin induces an overall response rate of 75% in patients with relapsed/refractory Hodgkin lymphoma, but its impact on future allogeneic transplantation (allo-HCT) is not known. We retrospectively examined the records of 18 patients with relapsed/refractory Hodgkin lymphoma who were treated on brentuximab vedotin clinical trials to evaluate the efficacy and safety of subsequent reduced-intensity allo-HCT. Seventeen patients had previous autologous transplant; 6 were in complete remission, and 8 were in partial remission before allo-HCT with 12 grafts from unrelated or mismatched donors. The 1-year overall survival was 100%, progression-free survival was 92.3%, and nonrelapse mortality was 0% (median follow-up, 14 months). The incidence of acute GVHD was 27.8% and chronic GVHD was 56.3%. Brentuximab vedotin before reduced-intensity allo-HCT does not appear to adversely affect engraftment, GVHD, or survival and may provide sufficient disease control to enable reduced-intensity allo-HCT.     

Second allogeneic stem cell transplantation using nonmyeloablative conditioning for patients who relapsed or developed secondary malignancies following autologous transplantation

OBJECTIVE: Second allogeneic stem cell transplants for hematological malignancies are associated with a high incidence of transplant-related mortality due to the cumulative incidence of toxicity of the high-dose chemoradiotherapy traditionally used as an essential component of the conditioning. We have demonstrated previously that nonmyeloablative conditioning for primary allogeneic transplants from both sibling and unrelated donors results in minimal transplant-related toxicity and excellent stem cell engraftment. This study explores the possibility of using nonmyeloablative conditioning to minimize transplant-related toxicity in patients who have undergone second allogeneic transplants. PATIENTS AND METHODS: Twelve high-risk, heavily treated patients-five with acute myelogenous leukemia (AML); five with non-Hodgkin's lymphoma (NHL); one with Burkitt's lymphoma, and one with acute lymphoblastic leukemia (ALL)-underwent second allogeneic nonmyeloablative stem cell transplantation (NST) from human leukocyte antigen (HLA)-matched donors, 29 (median) (range 3-57) months following their first transplantation procedure. The conditioning consisted of fludarabine 30 mg/m(2) daily for 6 days, busulfan 4 mg/kg daily for 2 days, and anti-T-lymphocyte globulin 10 mg/kg daily for 4 days. Anti-graft-vs-host disease (anti-GVHD) prophylaxis consisted of cyclosporine A alone, 3 mg/kg. RESULTS: Engraftment was observed in all recipients, with complete and stable chimerism. None of the patients developed veno-occlusive disease of the liver or multi-organ failure. Five very high-risk patients with NHL (n = 3), Burkitt's lymphoma (n = 1), and AML (n = 1) relapsed 2 to 6 months post-transplant, and four of them died. Six patients appear to be disease-free after median follow-up of 23 months. One additional patient died from grade IV hemorrhagic cystitis. Actuarial survival and disease-free survival at 34 months are 56% and 50% respectively, with 95% confidence interval (25-78%). CONCLUSION: These results suggest that nonmyeloablative conditioning significantly reduces transplant-related toxicity, thus making a second transplant feasible.     

Cyclophosphamide, etoposide and carboplatine plus non-cryopreserved autologous peripheral blood stem cell transplantation rescue for patients with refractory or relapsed non-Hodgkin's lymphomas

A simplified schedule of high-dose chemotherapy consisting of cyclophosphamide (60 mg/kg/day for 2 days), etoposide (15 mg/kg/day for 2 days) and carboplatine (400 mg/m(2)/day for 2 days), together with autologous non-cryopreserved peripheral blood stem cells was used for treatment of relapsed (29 patients) and refractory (three patients) patients with non-Hodgkin's lymphoma (NHL). The use of such granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cells (PBSC) after high-dose myeloablative therapy resulted in a rapid, complete and sustained hematopoietic recovery. The median time to achieve an absolute neutrophil count greater than 0.5 x 10(9)/l was 12 days (range 8-17 days). The median time to self-sustained platelet count greater than 20 x 10(9)/l was 14 days (range 7-19 days). Fifteen of the 32 patients (49%) were alive and disease free at a median follow-up of 18 months (range 10-96 months) for all surviving patients. The estimated 2-year overall survival (OS) and disease free survival (DFS) for all patients were 50 and 43%, respectively. Twelve patients died of relapse or progressive disease, two patients died of infection and one patient died of cardiac cause. The median time to relapse was 12 months (5-27) from PBSC infusion. High-dose chemotherapy with short-duration chemotherapy and non-cryopreserved bone marrow (BM) is an effective and safe treatment modality for patients with relapsed or resistant NHL.     

Bortezomib plus dexamethasone treatment followed by reduced-intensity allogeneic stem cell transplantation for multiple myeloma refractory to high-dose chemotherapy with autologous transplantation

We present two long-term survivors after allogeneic transplantation with reduced-intensity conditioning regimen following relapse after autologous stem cell transplantation (ASCT) for multiple myeloma (MM). The first case was a 47-year-old male with IgG MM treated with 2 courses of high-dose melphalan along with ASCT and thalidomide, resulting in a minimal response. He then received 2 courses of bortezomib plus dexamethasone (BD) regimen, which was discontinued due to peripheral neuropathy. Allogeneic peripheral stem cell transplantation (PBSCT) from a sibling donor was performed after pretreatment with fludarabin (125 mg/m(2)) and melphalan (100 mg/m(2)). Engraftment was observed on day 11 and monoclonal IgG had disappeared 5 months after transplantation. The patient has been in complete remission for more than two and a half years with moderate chronic graft-versus-host disease (GVHD). The second case was a 51-year-old male who relapsed after ASCT for IgA MM. After 3 courses of BD treatment, irradiation to lumbar plasmacytoma, and thalidomide therapy, he received allogeneic PBSCT from a related donor after the same reduced intensity conditioning as performed in case 1. A complete response was observed 6 months after PBSCT. The patient has remained relapse-free for two years without GVHD. BD treatment followed by allogeneic stem cell transplantation with reduced intensity conditioning is supposed to be one of the most powerful strategies for patients showing relapse after ASCT.     

Brentuximab vedotin for the treatment of patients with relapsed or refractory Hodgkin lymphoma after autologous stem cell transplantation

Brentuximab vedotin (BV) is the first approved novel agent for salvage treatment of relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL) after autologous stem cell transplantation (ASCT). In this study, a literature-based analysis was undertaken to assess, via an indirect treatment comparison, the comparative efficacy of BV to salvage chemotherapy as treatment for R/R cHL patients following ASCT. This comparative effectiveness research was undertaken to support a reimbursement submission for BV to the Australian Pharmaceutical Benefits Advisory Committee. Retrospective analysis of individual patient data from four data sources demonstrated that the use of BV as first salvage treatment in cHL patients relapsing or progressing post-ASCT achieved improvements in both clinical response and overall survival. More specifically, BV was associated with an incremental improvement of 22% in overall response rate compared to salvage chemotherapy. Five-year overall survival and progression-free survival rates were 92·2% [95% confidence interval (CI): 85·5–99·3%] and 32·2% (95% CI: 19·1–54·6%) respectively for BV, compared to 30·5% (95% CI: 22·2–42·0%) and 3·2% (95% CI: 1·1–8·9%) respectively for salvage chemotherapy. The encouraging results from this conservative analysis have the potential to support informed clinical management and funding decisions for the first salvage of cHL patients demonstrating recurrence after ASCT.     

High-dose treosulfan in patients with relapsed or refractory high-grade lymphoma receiving tandem autologous blood stem cell transplantation

This phase I/II study evaluated high-dose treosulfan in patients with high-grade lymphoma. In all, 21 patients (median age 51, 25-60 years) with primary refractory disease (n=3) or early (n=11) or late (n=7) relapse received DexaBEAM and one course etoposide for cytoreduction and PBPC mobilization. Subsequently, 16 patients received 30 g/m2 treosulfan and 140 mg/m2 melphalan, followed by autologous transplantation. Nine patients received a 2nd high-dose treatment (HDT) with 30 g/m2 treosulfan and 750 mg/m2 thiotepa. Recovery time to >1/nl leukocytes and >25/nl thrombocytes was 8.9 (range 8-11) and 11.9 (8-16) days after 1st and 9.6 (7-13) and 13 (9-19) days after 2nd HDT. Reversible grade 3 or 4 nonhematologic toxicities included mucositis (n=7), infection (n=7) and one episode of re-entry tachycardia. Two treatment-related deaths occurred after 2nd HDT. Since three dose-limiting toxicities occurred among nine patients receiving tandem HDT, 30 g/m2 of treosulfan was considered MTD in this setting. Patients with late compared to early relapse or refractory disease had a higher probability of CR (6/7 vs 3/14 patients, P=0.017) and overall survival (71 vs 21%, P<0.05, 24-49 months follow-up). In conclusion, high-dose treosulfan as major therapy component induces sustained complete remissions in relapsed high-grade lymphoma with acceptable toxicity.     

High-dose chemotherapy using BEAM without autologous rescue followed by reduced-intensity conditioning allogeneic stem-cell transplantation for refractory or relapsing lymphomas: a comparison of delayed versus immediate transplantation

Patients with refractory/relapsing lymphoma are rarely cured by chemotherapy. High-dose chemotherapy (HDC) for tumor debulking followed by reduced-intensity conditioning (RIC) hematopoietic stem-cell transplantation (HSCT) has been advocated as a concept. We previously treated 10 patients (group A) with BEAM chemotherapy followed by delayed RIC HSCT at day 28. We now report on the subsequent 11 patients receiving BEAM followed immediately by fludarabine/total body irradiation and allogeneic HSCT (group B), and compare the outcome to group A patients. Non-hematological toxicity before engraftment was comparable, only gut toxicity was higher in group B. Days in aplasia, days on antibiotics and length of hospital stay were significantly longer in group A. Cumulative incidence of acute (GvHD) >or=grade II and incidence of chronic GvHD were lower in group B. At last follow-up, seven patients in group A were alive, with six of them in complete remission. In group B, nine patients were alive, seven of them in complete remission. No significant difference in estimated 3-year overall survival was seen. These data challenge the initial concept of debulking first and delaying allogeneic RIC HSCT. Allogeneic HSCT with standard BEAM conditioning is a valid alternative for patients with resistant/relapsed lymphoma, which might be considered earlier in the disease course.     

Current indications for reduced-intensity allogeneic stem cell transplantation

Stem cell transplantation preceded by reduced-intensity conditioning (RIC) is based on the use of immunosuppressive agents as the sine qua non to ensure donor cell engraftment. It is a curative option for select patients suffering from haematological and non-haematological malignancies. The most beneficial results are observed when a full donor engraftment is achieved with 'tolerable' graft-vs-host disease (GVHD). To date, a vast amount of clinical data has been published, but in an uncontrolled manner. This review summarizes the currently known outcome of allogeneic transplants with RIC, with every disease category analysed separately. Unresolved problems include the optimal combination of immunosuppressive agents, the degree of infectious complications, and GVHD that may appear in some patients. Directions to overcome these complications are discussed. Despite the paucity of controlled clinical data, the current indications for RIC allogeneic transplantation are summarized based on the best-available phase II data.     

Outcomes after alemtuzumab-containing reduced-intensity allogeneic transplantation regimen for relapsed and refractory non-Hodgkin lymphoma

We report the outcomes after reduced-intensity conditioning allogeneic stem cell transplantation (RIT) for non-Hodgkin lymphoma (NHL) in 88 patients (low-grade NHL [LG-NHL], n = 41; high-grade NHL [HG-NHL], n = 37; mantle cell lymphoma [MCL], n = 10). Thirty-seven patients had previously received autografts, and 21 were in complete remission (CR) at transplantation. Conditioning therapy consisted of alemtuzumab, fludarabine, and melphalan. Sixty-five patients received peripheral blood stem cells (PBSCs) from HLA-identical siblings, and 23 received bone marrow (BM) from matched unrelated donors. Prophylaxis for graft-versus-host disease (GVHD) consisted of cyclosporin A. Grade III-IV acute GVHD developed in 4 patients, and chronic GVHD developed in 6 patients. With a median follow-up of 36 months (range, 18-60 months), the actuarial overall survival (OS) rates at 3 years were 34% for HG-NHL, 60% for MCL, and 73% for LG-NHL (P < .001). The 100-day and 3-year transplant-related mortality (TRM) rates for patients with LG-NHL were 2% and 11%, respectively, and were better (P = .01) than they were for patients with HG-NHL (27% and 38%, respectively). The actuarial current progression-free survival (PFS) rate at 3 years, including the rate for patients who achieved remission after donor lymphocyte infusion (DLI) for progression, was 65% for LG-NHL, 50% for MCL, and 34% for HG-NHL (P = .002). Twenty-one patients underwent DLI for matched related donor (MD)-persistent disease or relapse, and 15 underwent DLI for mixed hematopoietic chimerism. Patients who experienced relapses of LG-NHL and chronic lymphocytic leukemia (CLL) achieved excellent PFS with extremely low TRM and GVHD, even when matched related donors were unavailable.     

Successful treatment with reduced-intensity stem cell transplantation in a case of relapsed refractory central nervous system lymphoma

A 33-year-old male with refractory relapsed central nervous system lymphoma underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) from an HLA-identical sibling after reduced-intensity conditioning chemotherapy. The preparative regimen for allo-HSCT consisted of fludarabine and busulfan. Cyclosporine (CsA) and short-term methotrexate were used as prophylaxis for acute graft-versus-host disease (GVHD). Although CsA was quickly reduced to induce a graft-versus-lymphoma (GVL) effect, no symptoms of GVHD and GVL effect were evident. Donor lymphocyte infusion (DLI) was performed on day +40 following transplantation. The patient developed acute GVHD (grade III) after DLI, and lymphoma regression was observed after the occurrence of GVHD. Four months after transplantation, complete remission was achieved with extensive chronic GVHD, and the patient continues to be disease free at 15 months after transplantation.     

Impact of hematopoietic stem cell transplantation in patients with relapsed or refractory mantle cell lymphoma

Rituximab has been shown to improve outcomes in patients with B-cell lymphoma. However, patients with relapsed or refractory (R/R) mantle cell lymphoma (MCL) still have a poor prognosis, and the choice between high-dose therapy with autologous hematopoietic cell transplantation (HCT) and allogeneic HCT remains controversial in these patients. We retrospectively analyzed the risk factors for outcomes in 162 R/R MCL patients who received autologous (n?=?111) or allogeneic (n?=?51) HCT between 2004 and 2014. The median overall survival (OS) rates were 48 and 65 months in the autologous and allogeneic HCT groups, respectively (P?=?0.20). Significant risk factors for overall survival in R/R MCL patients after autologous HCT were >?60 years of age at HCT (P?=?0.017), higher score of HCT-specific comorbidity index at HCT (P?=?0.033), and receiving MCEC (ranimustine?+?carboplatin?+?etoposide?+?cyclophosphamide) regimen (P?=?0.017), while higher performance status at HCT (P?=?0.011) and longer interval from diagnosis to HCT (P?=?0.0054) were risk factors after allogeneic HCT. Strategies that carefully select R/R MCL patients for autologous HCT may allow the identification of individuals suitable for allogeneic HCT.     

Age-adjusted International Prognostic Index predicts autologous stem cell transplantation outcome for patients with relapsed or primary refractory diffuse large B-cell lymphoma

Second-line chemotherapy followed by high-dose therapy (HDT) with autologous stem cell transplantation (ASCT) cures less than half of the patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Prognostic models capable of predicting outcome are essential. In 3 sequential clinical trials, conducted from January 1993 to August 2000, we treated 150 patients with relapsed or primary refractory DLBCL with ifosfamide, carboplatin, and etoposide (ICE) chemotherapy followed by HDT/ASCT for patients with chemosensitive disease. We evaluated the age-adjusted International Prognostic Index at the initiation of second-line therapy (sAAIPI) as a predictor of progression-free survival (PFS) and overall survival (OS). At a median follow-up of 4 years, the PFS and OS are 28% and 34% by intention to treat and 39% and 45% for only those patients with chemosensitive disease. Three risk groups with different PFS and OS were identified by the sAAIPI: low risk (0 factors), 70% and 74%; intermediate risk (1 factor), 39% and 49%; and high risk (2 or 3 factors), 16% and 18% (P <.001 for both PFS and OS). The sAAIPI also predicts the PFS and OS for patients with ICEchemosensitive disease: low risk, 69% and 83%; intermediate risk, 46% and 55%; and high risk, 25% and 26% (P <.001 PFS and OS). The sAAIPI predicts outcome for patients with relapsed or primary refractory DLBCL in both intent-to-treat and chemosensitive populations. This powerful prognostic instrument should be used to evaluate new treatment approaches and to compare results of different regimens.     

Favorable outcome of allogeneic hematopoietic stem cell transplantation for relapsed or refractory acute promyelocytic leukemia in childhood

The optimal therapy for children with relapsed or refractory acute promyelocytic leukemia (APL) is unclear. We therefore reviewed our institutional outcomes for children undergoing allogeneic hematopoietic stem cell transplantation (HSCT) for advanced APL. Between 1986 and 2003, 12 allogeneic HSCTs (five related donor, seven unrelated donor) were performed for 11 patients (median age, 13 years) with relapsed (n = 8) or refractory (n = 3) APL. All patients engrafted, after a median of 18.5 days. Grade B-D acute graft-versus-host disease (GVHD) developed after five transplants (42%; 90% CI, 18-68%), and the cumulative incidence of chronic GVHD was 45% (90% CI, 19-71%). The cumulative incidence of overt relapse post-HSCT was 10% (90% CI, 0-28%). The overall 5-year survival was 73% (90% confidence interval (CI), 51-95%), with a median post-HSCT follow-up of 64 months. The Lansky/Karnofsky performance scores are 100% in six of eight survivors. In view of the low risk of subsequent relapse and favorable survival suggested by other reports and our own experience, we continue to recommend allogeneic HSCT for children with advanced APL for whom a suitably HLA-matched donor is identified.