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A phase II trial evaluated safety, feasibility and efficacy of a sequential tandem approach combining myeloablative BEAM chemotherapy and autologous stem cell transplantation (ASCT) with myeloablative radioimmunotherapy (HD-RIT), with (131)I-anti-CD20 antibody ((131)I-rituximab), followed by a second ASCT in patients with relapsed or refractory CD20+ B-cell lymphoma. According to protocol, 16 patients with relapsed (n = 14) and refractory (n = 2) CD20+ B-cell lymphoma received salvage therapy with rituximab and Dexa-BEAM, followed by BEAM (HD chemotherapy) and high-dose myeloablative radioimmunotherapy 2-6 months after BEAM. Nine of 16 patients received HD-RIT; seven patients were excluded before HD-RIT because of toxicity or progressive disease. Disease histologies were follicular lymphoma (FL) grades 1 and 2 (n = 4), transformed follicular (FL 3b; n = 6), diffuse large B-cell (DLBCL; n = 4), mantle cell (n = 1) and marginal zone lymphoma (n = 1). After a median follow-up of 50.4 months for OS and 39.7 months for progression-free survival (PFS), estimated 4-year OS and PFS were 67% and 64%, respectively. The estimated 4-year OS and PFS for patients with FL were 80% and 78%, respectively. Toxicity was significant, including one fatal outcome due to pneumonitis. Tandem transplants consisting of HD chemotherapy followed by HD-RIT with (131)I-coupled anti-CD20 are manageable and effective but toxic treatment modalities for relapsed poor prognosis CD20+ B-NHL.

Purpose: Salvage chemotherapy followed by high-dose therapy and autologous stem-cell transplantation (ASCT) is the standard treatment for relapsed diffuse large B-cell lymphoma (DLBCL). Salvage regimens have never been compared; their efficacy in the rituximab era is unknown., Patients and Methods: Patients with CD20(+) DLBCL in first relapse or who were refractory after first-line therapy were randomly assigned to either rituximab, ifosfamide, etoposide, and carboplatin (R-ICE) or rituximab, dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP). Responding patients received high-dose chemotherapy and ASCT., Results: The median age of the 396 patients enrolled (R-ICE, n = 202; R-DHAP, n = 194) was 55 years. Similar response rates were observed after three cycles of R-ICE (63.5%; 95% CI, 56% to 70%) and R-DHAP (62.8%; 95 CI, 55% to 69%). Factors affecting response rates (P < .001) were refractory disease/relapse less than versus more than 12 months after diagnosis (46% v 88%, respectively), International Prognostic Index (IPI) of more than 1 versus 0 to 1 (52% v 71%, respectively), and prior rituximab treatment versus no prior rituximab (51% v 83%, respectively). There was no significant difference between R-ICE and R-DHAP for 3-year event-free survival (EFS) or overall survival. Three-year EFS was affected by prior rituximab treatment versus no rituximab (21% v 47%, respectively), relapse less than versus more than 12 months after diagnosis (20% v 45%, respectively), and IPI of 2 to 3 versus 0 to 1 (18% v 40%, respectively). In the Cox model, these parameters were significant (P < .001)., Conclusion: In patients who experience relapse more than 12 months after diagnosis, prior rituximab treatment does not affect EFS. Patients with early relapses after rituximab-containing first-line therapy have a poor prognosis, with no difference between the effects of R-ICE and R-DHAP.

Feasibility, safety, and efficacy of a 4-course high-dose chemotherapy (HDT) protocol including autologous stem cell transplantation (SCT) after courses 2, 3, and 4 was investigated in 110 patients, aged 18 to 60 years, with primary diagnosis of aggressive NHL (aNHL), and lactic dehydrogenase (LDH) levels above normal. At dose level 1 (DL1), course 1 consisted of cyclophosphamide 1500 mg/m2, doxorubicin (Adriamycin) 70 mg/m2, vincristine 2 mg, etoposide 450 mg/m2, and prednisone 500 mg. With courses 2 and 3 cyclophosphamide and etoposide were escalated to 4500 mg/m2 and 600 mg/m2, respectively. With course 4 cyclophosphamide and etoposide were given at 6000 mg/m2 and 1000 mg/m2, respectively. At DL2 etoposide was further increased to 600, 960, 960, and 1480 mg/m2 with courses 1 to 4, respectively. Therapy as per protocol was completed by 81.8% of patients. Overall survival at 5 years was 67.2%, freedom from treatment failure (FFTF) was 62.1%, and treatment-related mortality was 4.5%. There was a trend to better FFTF at DL2 compared to DL1 (66.9% versus 54.2%). Repetitive HDT with escalated CHOP plus etoposide is feasible and effective treatment of patients with aNHL. DL2 of this therapy is being used in an ongoing phase 3 study.

Summary: Background: Allogeneic stem-cell transplantation has had limited success for patients with refractory and relapsed aggressive B-cell or T-cell lymphoma. We investigated the effect of adding rituximab to standard prophylaxis for graft-versus-host disease after transplantation and estimated overall survival when using a lymphoma-directed myeloablative conditioning regimen. Methods: We did this randomised, open-label, phase 2 study at seven German transplantation centres. We enrolled patients with aggressive B-cell or T-cell lymphoma and primary refractory disease, early relapse (<12 months after first-line treatment), or relapse after autologous transplantation. Conditioning with fludarabine (125 mg/m2), busulfan (12 mg/kg oral or 9·6 mg/kg intravenous), and cyclophosphamide (120 mg/kg) was followed by allogeneic stem-cell transplantation. Patients were randomly assigned (1:1) to receive rituximab (375 mg/m2 on days 21, 28, 35, 42, 175, 182, 189, and 196) or not. Allocation was done with a centralised computer-generated procedure; patients were stratified by histological subtype (B-cell vs T-cell lymphoma) and donor match (HLA-identical vs non-identical). Neither investigators nor patients were masked to allocation. The primary endpoints were the incidence of acute graft-versus-host disease grade 2–4 in each treatment group and overall survival at 1 year in both groups combined. All analyses were done for the intention-to-treat population. The study is registered with ClinicalTrials.gov, number NCT00785330. Findings: Between June 16, 2004, and March 24, 2009, we screened 86 patients and enrolled 84; 42 were randomly assigned to each group. The cumulative incidence of grade 2–4 acute graft-versus-host disease was 46% (95% CI 32–62) in the rituximab group and 42% (95% CI 29–59) in the no rituximab group (hazard ratio [HR] 0·91, 95% CI 0·52–1·60; p=0·74). Overall survival at 1 year for the whole study population was 52% (95% CI 41–62). Grade 4 haematological toxic effects and grade 3 alopecia occurred in all patients. The most common non-haematological grade 5 toxic effects were pneumonia (nine in the no rituximab group vs ten in the rituximab group) and other infections (seven vs four). Interpretation: The lymphoma-directed myeloablative conditioning regimen developed here is promising for patients with refractory and relapsed aggressive B-cell and T-cell lymphomas. However, the addition of rituximab did not affect the incidence of graft-versus-host disease or overall survival. Funding: Hoffmann-La Roche, Amgen, Astellas Pharma. [ABSTRACT FROM AUTHOR]

A phase II trial evaluated safety, feasibility and efficacy of a sequential tandem approach combining myeloablative BEAM chemotherapy and autologous stem cell transplantation (ASCT) with myeloablative radioimmunotherapy (HD-RIT), with I-anti-CD20 antibody (I-rituximab), followed by a second ASCT in patients with relapsed or refractory CD20+ B-cell lymphoma. According to protocol, 16 patients with relapsed ( n = 14) and refractory ( n = 2) CD20+ B-cell lymphoma received salvage therapy with rituximab and Dexa-BEAM, followed by BEAM (HD chemotherapy) and high-dose myeloablative radioimmunotherapy 2-6 months after BEAM. Nine of 16 patients received HD-RIT; seven patients were excluded before HD-RIT because of toxicity or progressive disease. Disease histologies were follicular lymphoma (FL) grades 1 and 2 ( n = 4), transformed follicular (FL 3b; n = 6), diffuse large B-cell (DLBCL; n = 4), mantle cell ( n = 1) and marginal zone lymphoma ( n = 1). After a median follow-up of 50.4 months for OS and 39.7 months for progression-free survival (PFS), estimated 4-year OS and PFS were 67% and 64%, respectively. The estimated 4-year OS and PFS for patients with FL were 80% and 78%, respectively. Toxicity was significant, including one fatal outcome due to pneumonitis. Tandem transplants consisting of HD chemotherapy followed by HD-RIT with I-coupled anti-CD20 are manageable and effective but toxic treatment modalities for relapsed poor prognosis CD20+ B-NHL. [ABSTRACT FROM AUTHOR]

Waldenström's macroglobulinaemia (WM) is an incurable lymphoproliferative disorder. The purpose of this study was to investigate the role of autologous peripheral blood stem cell transplantation (ASCT) for the treatment of WM. Seven patients (untreated or after first-line therapy) with symptomatic WM underwent two or three cycles of Dexa-BEAM chemotherapy + G-CSF with stem cell harvesting and proceeded to total body irradiation and high-dose cyclophosphamide followed by reinfusion of ex-vivo B-cell-depleted stem cells. Engraftment was prompt, and procedure-related deaths did not occur. A strong reduction or normalization of BM infiltration and serum IgM levels occurred in all evaluable patients, but immunofixation electrophoresis revealed persistent paraproteinaemia in five of them. With 3–30 months of follow-up, all patients are alive without clinical or serological signs of disease progression. This pilot trial shows for the first time that high-dose radiochemotherapy with purged stem cells is effective and may improve the course of patients with WM. In the majority of cases, however, complete eradication of the disease does not appear to be possible with ASCT alone. [ABSTRACT FROM AUTHOR]

Background: Acute myeloid leukemia (AML) is both more common and with more biologically aggressive phenotype in the elderly. Allogenic stem cell transplantation (allo-SCT) is the best treatment option in fit patients. Either HLA-matched unrelated donor (MUD) or haploidentical (Haplo) donor are possible alternative for patients in need. Methods: We retrospectively compared non-T-cell-depleted Haplo (n = 250) to 10/10 MUD (n = 2589) in AML patients ≥ 60 years. Results: Median follow-up was 23 months. Disease status at transplant differs significantly between the two groups (p < 10−4). Reduced intensity conditioning (RIC) was administrated to 73 and 77% of Haplo and MUD, respectively (p = 0.23). Stem cell source was the bone marrow (BM) in 52% of the Haplo and 6% of MUD (p < 10−4). Anti-thymocyte globulin (ATG) was most frequently used in MUD (p < 10−4) while post-Tx cyclophosphamide (PT-Cy) was given in 62% of Haplo. Engraftment was achieved in 90% of the Haplo vs 97% of MUD (p < 10−4). In multivariate analysis, no significant difference was found between Haplo and MUD for acute (a)graft versus host disease (GVHD) grade II–IV, relapse incidence (RI), non-relapse mortality (NRM), leukemia free survival (LFS), graft-versus-host-free-relapse free survival (GRFS), and overall survival (OS). Extensive chronic (c)GVHD was significantly higher for MUD as compared to Haplo (HR 2, p = 0.01, 95% CI 1.17–3.47). A propensity score analysis confirmed the higher risk of extensive cGVHD for MUD without differences for other outcomes. Conclusions: Allo-SCT from both Haplo and MUD are valid option for AML patients ≥ 60 years of age with similar results. Transplantation from MUD was associated with higher extensive cGVHD. Our findings suggest that Haplo is a suitable and attractive graft source for patients≥ 60 with AML in need of allo-SCT. [ABSTRACT FROM AUTHOR]

In this retrospective analysis we evaluated the outcome of 313 patients aged ≥ 70 years in the registry of the European Group for Blood and Marrow Transplantation with myelodysplastic syndrome (MDS; n = 221) and secondary acute myeloid leukemia (n = 92) who underwent allogeneic hematopoietic stem cell transplantation (HSCT) from related (n = 79) or unrelated (n = 234) donors. Median age at HSCT was 72 years (range, 70 to 78). Conditioning regimen was nonmyeloablative (n = 54), reduced intensity (n = 207), or standard intensity (n = 52). Allogeneic HSCT for MDS patients ≥ 70 years was increasingly performed over time. Although during 2000 to 2004 only 16 patients received HSCT, during 2011 to 2013 the number of transplantations increased to 181. The cumulative incidence of nonrelapse mortality at 1 year and relapse at 3 years was 32% and 28%, respectively, with a 3-year overall survival rate of 34%. Good performance, determined by Karnofsky performance status, and recipients' seronegativity for cytomegalovirus was associated with 3-year estimated overall survival rates of 43% ( P  = .01) and 46% ( P  = .002), respectively. Conditioning intensity did not impact survival. After careful patient selection, allogeneic HSCT can be offered to patients older than 70 years with MDS. [ABSTRACT FROM AUTHOR]

Major histocompatibility complex class I polypeptide-related sequence A (MICA) is a highly polymorphic ligand of the activating NKG2D receptor on natural killer (NK) cells, γδ-T cells, and NKT cells. MICA incompatibilities have been associated with an increased graft-versus-host disease (GVHD) incidence, and the MICA-129 (met/val) dimorphism has been shown to influence NKG2D signaling in unrelated hematopoietic stem cell transplantation (uHSCT). We investigated the effect of MICA matching on survival after uHSCT. We sequenced 2172 patients and their respective donors for MICA. All patients and donors were high-resolution HLA-typed and matched for 10/10 (n = 1379), 9/10 (n = 636), or 8/10 (n = 157) HLA alleles. Within each HLA match group, cases matched and mismatched for MICA and MICA-129 were analyzed for the end points overall survival (OS), disease-free survival (DFS), nonrelapse mortality (NRM), relapse-incidence (RI), and GVHD. Mismatches at the MICA locus as well as MICA-129 increased with the number of HLA mismatches (MICA mismatched 10/10, 9.2% [n=127]; 9/10, 22.3% [n=142]; 8/10, 38.2% [n=60]; MICA-129 mismatched 10/10, 3.9% [n=54]; 9/10, 10.2% [n=65]; 8/10, 17.2% [n=27]). Adverse OS was observed in the 10/10 match group if MICA-129 was mismatched (10/10, hazard ratio [HR], 1.77; confidence interval [CI], 1.22-2.57; P5.003). MICA-129 mismatches correlated with a significantly worse outcome for DFS in the 10/10 HLA match group (HR, 1.77; CI, 1.26-2.50; P 5 .001). Higher rates of aGVHD were seen in MICA-129 mismatched cases. Our results indicate that MICA-129 matching is relevant in uHSCT. Prospective typing of patients and donors in unrelated donor search may identify mismatches for MICA-129, and compatible donor selection may improve outcome for this small but high-risk subgroup. [ABSTRACT FROM AUTHOR]