Results Of Allogeneic Transplantation Research Articles

Results of Allogeneic Transplantation As First Line Rescue Therapy in Patients with Multiple Myeloma Relapsing to a Prior Autograft: Role of Conditioning Regimen

INTRODUCTIONThe availability of new and effective drugs in multiple myeloma has modified the standard management of these patients. Accordingly, allogeneic stem cell transplantation (alloSCT) is not routinely used upfront except in very specific subgroups of high risk patients. In spite of this data, the number of alloSCT has increased along the last years, most patients undergoing alloSCT beyond first relapse. AIMIn the current study we analyze the outcome of alloSCT as second line therapy among patients who have relapsed to a first line which included autologous stem cell transplantation (autoSCT) and we have compared their outcomes depending on the type of conditioning. PATIENTS AND METHODSWe selected 573 patients transplanted from 1991 to 2014 included in the EBMT data registry who received alloSCT within the first year after having relapsed to first line treatment including autoSCT. One hundred and two patients received myeloablative conditioning (MAC), 284 reduced intensity conditioning (RIC), 120 non-myeloablative (NMA) and 67 underwent tandem auto-alloSCT (Auto-allo). Patients characteristics are summarized in table 1. RESULTSWith a median follow-up of 47 months, median overall survival (OS) was 22.2 months with 39.6% and 31% patients surviving at 3 and 5 years, respectively. Variables which significantly influenced on OS in multivariable analysis were: type of conditioning [HR for MAC 1.68, (95% CI =1.16-2.44), p=0.006] , age [HR 1.02, (95% CI =1.01-1.04), p=0.001], disease status at transplant [HR for less than PR 1.56, (95% CI =1.07-2.28), p=0.01] and time from first relapse to SCT [HR 0.95, (95% CI =0.91-0.99), p=0.02 ]. Time from first autoSCT to relapse influenced on OS in univariate but not in multivariable analysis. Median Progression free survival (PFS) was 8.1 months with 17% and 12% patients being free of progression at 3 and 5 years after alloSCT. Variables which significantly influenced on PFS in multivariable analysis were: type of GVHD prophylaxis [HR for use of alemtuzumab 1.46, (95% CI =1.03-2.07), p=0.03], disease status at transplant [HR for less than PR 1.67, (95% CI =1.19-2.33), p=0.002 ], time from first autoSCT to relapse [HR 0.99, (95% CI =0.98-0.99), p=0.03 ] and time from first relapse to SCT [HR 0.95, (95% CI =0.92-0.98), p=0.009].For patients younger than 53 years old, who underwent RIC or NMA alloSCT>9 months after relapse with GVHD prophylaxis other than alemtuzumab median OS and PFS were 80 and 17 months, respectively. CONCLUSSIONAllogeneic stem cell transplantation allows to obtain remarkable median OS and PFS when used as rescue therapy after a relapse to first line treatment which includes autoSCT. Use of approached other than MAC within the conditioning and alemtuzumab as GVHD prophylaxis allows to obtain the better outcomes. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

HLA Ligandome Analysis in Multiple Myeloma Reveals Novel Naturally Presented Myeloma-Associated Antigens Showing Stable Expression Under Proteasome Inhibitor Therapy

Results of allogeneic transplantation and reports that multiple myeloma (MM) cells can act as antigen presenting cells, but also the favorable immune effector-to-target cell ratio in the minimal residual disease (MRD) setting suggest that MM, which previously was considered to be weakly immunogenic, may be targeted effectively by T cell based immunotherapy. Following conventional therapy, peptide-based immunotherapy might offer a low side-effect opportunity to extend time to disease progression and possibly eradicate MRD. Therefore we aim to develop a multi-peptide vaccine for the immunotherapy of MM patients based on naturally processed and presented HLA ligands.In a first step we analyzed HLA surface expression on MM cells, which constitutes a prerequisite for effective T cell recognition. In MM patients (n=20), HLA class I expression was found to be heterogeneous with a mean of 415,000 ± 55,000 molecules on malignant cells. This expression was significantly (p<0.005, unpaired t-test) higher than that on autologous healthy B cells (200,000 ± 20,000), T cells (165,000 ± 15,000) and hematopoietic progenitor cells (205,000 ± 30,000). In addition, HLA class I expression on primary MM cells was also found to be significantly higher than that on plasma cells of healthy volunteers (HV, n=15) (290,000 ± 25,000, p<0.05). Mean HLA-DR expression on myeloma cells (25,000 ± 7,000) was significantly lower compared to HLA class I expression (p<0.0001) without significant difference compared to expression levels on autologous bone marrow cells as well as normal plasma cells of HVs (40,000 ± 5,000).Using the approach of direct isolation and identification of naturally presented HLA peptides by affinity chromatography and mass spectrometry, we identified more than 15,000 different HLA class I ligands from 8 primary MM samples, 2 plasma cell leukemia samples and 5 myeloma cell lines (MCLs). Comparative mapping of MM HLA ligandomes and the ligandomes of 40 HVs (30 blood and 10 bone marrow samples) revealed 15 ligandome-derived tumor-associated antigens (LiTAAs) represented by 36 corresponding HLA peptides (LiTAPs), showing exclusive representation in >30% of myeloma samples. Among them we identified 3 novel HLA peptides derived from Multiple Myeloma SET domain(MMSET), which is an established driver of myeloma cell proliferation, stimulating the expression of c-myc.We further studied the effect of the second-generation proteasome inhibitor carfilzomib on HLA surface expression and HLA ligandome composition. Notably, a slight albeit not significant increase in mean HLA class I expression was observed after 24h (t24) and 48h (t48) of carfilzomib treatment in MCL (n=5, fold change t24=1.4, pt24=0.37, fold change t48=1.6, pt48=0.25) as well as in primary myeloma cells in vitro (n=7, fold change t24=1.2, pt24=0.21, fold change t48=1.1, pt48=0.46). No significant loss or down regulation of HLA class I expression on MM cells was observed in ex vivo analysis of primary samples obtained from 2 myeloma patients before therapy and after 4 weeks of carfilzomib treatment.In order to analyze the impact of proteasome inhibition on the composition of the HLA class I ligandome we incubated MCLs (U266, MM.1S) with carfilzomib and performed quantitative mass spectrometry at baseline as well as at t24 and t48. On U266, 4.6% (4.0%) and 4.4% (8.6%) of total identified peptides (n=2444) were significantly up- or down regulated after 24h/48h of treatment with carfilzomib, respectively, whereas on MM.1S (n=1693) 1.6% (12.4%) and 10.8% (18.0%) were significantly regulated after 24h/48h. Focusing on the LiTAPs presented on these MCLs, 76.5% (88.2%) on U266 and 83.3% (66.7%) on MM.1S remained stably expressed after incubation with carfilzomib. Further analyses evaluating overall changes in peptide motifs and the occurrence of novel, cryptic peptides after carfilzomib treatment are ongoing.Taken together our data demonstrate that myeloma cells are valid targets for T cell based immunotherapy and provide a panel of novel, naturally presented myeloma-associated antigens, which exhibit stable presentation under proteasome inhibitor therapy. DisclosuresNo relevant conflicts of interest to declare.

The Impact Of European Leukemia Net (ELN) Genetic Classification On The Outcome Of Allogeneic Stem Cell Transplantation (ALLOHCT) For Acute Myeloid Leukemia (AML) In First Complete Remission

IntroductionThe improvements in genetic characterization of AML allowed the ELN to propose a prognostic classification into 4 categories: Favorable, Intermediate I, Intermediate II and Adverse. Several groups have tested the outcome of AML patients based on these genetic subgroups in registries and databases from prospective trials. Since ALLOSCT recommendations are being established based on the ELN risk categories, we considered of interest to investigate whether these also have an impact on the results of allogeneic transplants. This could be helpful to identify the patients that may benefit the most from ALLOHCT in the first complete remission (CR1). ObjectivesTo investigate whether the ELN genetic groups of AML have any impact on the results of ALLOHCT performed in CR1. To identify the patients who are best candidates for transplantation, based on the ELN categories as well as in other characteristics. MethodsPatients were transplanted between 1990 and 2012. In all cases, treatment prior to transplant had consisted of anthracycline based induction and intermediate-dose cytarabine consolidation according to the CETLAM AML-88, AML-94, AML-99 and AML-03 trials. Upper age limit for transplantation was 60 years until 2002 and 70 years thereafter. Most patients above 50 years received either CD34 selected grafts or reduced intensity conditioning. GVHD prophylaxis after transplant was usually based on cyclosporine and prednisone or methotrexate. The main characteristics of patients and transplants were included in the exploratory analysis of variables influencing survival; those with a p- value up to 0.1 were incorporated as covariates to the multivariable model. ResultsOne hundred ninety two patients in CR1 received an ALLOHCT from HLA-identical siblings (n=140), adult unrelated donors (n=26) or umbilical cord blood (n= 26). Age distribution of the patients was as follows: 16-35 years-old (y-o) n=65 (34%), 36-50 y-o n= 55 (29%), 51-60 y-o n= 54 (28%), >60 y-o n=18 (9%). Twenty-three patients (12%) were classified as in the favorable ELN category, 54 (28%) in the intermediate I, 41 (21%) in the intermediate II and 74 (39%) in the adverse. One-hundred fifty-seven patients (82%) had achieved CR1 after a single course of chemotherapy. Conditioning was myeloablative (MA) in 139 (72%) patients and reduced-intensity (RIC) in 53 (28%). In 76 cases of the MA regimens total body irradiation was included.Thirty-eight patients (20%) died due to transplant complications other than relapse and 47 (24%) experienced a leukemia recurrence. Overall survival (OS) and leukemia-free survivals at 8-years were 55±4% and 53±4%, respectively. Multivariate analysis of factors influencing OS included as covariates age at diagnosis of AML, ELN categories, courses to CR1 and conditioning regimen (MA versus RIC), since they had a p-value <0.1 in the univariate comparisons. The variables with independent on OS impact were age (p=0.01), courses to CR (p=001) and ELN classification (p=0.01). OS at 8 years in the favorable, intermediate I, intermediate II and adverse categories were 69±10%, 53±8%, 69±7% and 42±6%, respectively. In patients from the adverse ELN category, independent factors influencing OS in the multivariate analysis of this subgroup were age (16-60 y-o vs>60, p=0.01) and courses to CR (1 vs more, p=0.03). ConclusionsThe ELN genetic categories have impact on OS of AML patients who receive an ALLOHCT in CR1. The results were very good in the favorable category and, most important, in intermediate II patients. Even patients in the adverse category had a substantial probability of long-term survival. This is remarkable, since the outcome of patients with adverse genetic features when treated with CT only is very poor. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

The results of allogeneic transplants in patients with malignant lymphoma-a retrospective analysis of data from the Czech National Registry

We processed data of 79 patients (pts) with malignant lymphoma from the National Registry of haematopoietic stem cell transplants conducted between 1997 and 2006. The haematopoietic stem cell donor in 48 pts was an HLA matched relative, and in 30 pts an unrelated volunteer. Sixty (77%) pts were transplanted with reduced intensity conditioning (RIC), eleven (23%) pts with myeloablative conditioning (MC). Acute graft-versus-host disease (aGVHD) was recorded in 26 (33%) pts. Chronic GVHD was diagnosed in 19 (36%) of the 53 assessable pts. Transplant-related mortality (TRM) in the first 100 days, 1 year and 3 years for the whole group was 26%, 33% and 33%. Twenty (26%) of the pts relapsed. During the median follow-up of 26 months the overall survival (OS) was 44%, the progression free survival (PFS) was 54% and cumulative incidence of relapse was 45%. Pts with chemoresistant disease had significantly worse results (OS at 3 years 22% vs. 56%, p=0.002). We did not find any correlation between the incidence of GVHD and the frequency of relapse. Similarly, we did not observe any difference in survival between patients following MC vs. RIC. Survival of pts transplanted from related donors did not differ statistically from unrelated donors. Key words: Lymphoma, allogeneic, transplantation, GVHD.

Advances in therapy of multiple myeloma

To summarize the results of treatment of multiple myeloma in the era of novel agents. Recent publications comparing autologous stem cell transplantation (ASCT) with conventional chemotherapy in the era of 'old' drugs have shown that the contribution of ASCT in the treatment of multiple myeloma has been modest. Five trials comparing single vs. double ASCT showed an increased progression-free survival in three of them, whereas the overall survival was significantly prolonged in one. The benefit would be only for patients failing to achieve very good partial response with the first transplant. The results of allogeneic transplantation with reduced-intensity conditioning, particularly after debulking with an ASCT, are encouraging. On the contrary, the impact of pretransplant induction regimens with novel agents (thalidomide, bortezomib and lenalidomide) on the posttransplant outcome is being investigated in several large phase III trials. For elderly patients, the combination of 'old' therapies with thalidomide, bortezomib or lenalidomide has resulted in the melphalan-prednisone-thalidomide, melphalan-prednisone-Velcade, melphalan-prednisone-Revlimid and lenalidomide/dexamethasone regimens, which are highly effective. ASCT has resulted in a modest contribution in the treatment of multiple myeloma. Hopefully, its impact will be increased with the incorporation of novel agents in the pretransplant induction regimens. The combination of thalidomide, bortezomib or lenalidomide with melphalan-prednisone or with dexamethasone has resulted in highly effective regimens for patients not eligible for high-dose therapy/stem cell transplantation.

Syngeneic Hematopoietic Stem-Cell Transplantation for Non-Hodgkin’s Lymphoma: A Comparison With Allogeneic and Autologous Transplantation—The Lymphoma Working Committee of the International Bone Marrow Transplant Registry and the European Group for Blood and Marrow Transplantation

To compare results of syngeneic, allogeneic, and autologous hematopoietic stem-cell transplantation for non-Hodgkin's lymphoma (NHL). The databases of the International Bone Marrow Transplant Registry (IBMTR) and the European Group for Blood and Marrow Transplantation were used to identify 89 NHL patients who received syngeneic transplants. These patients were compared with NHL patients identified from the IBMTR and the Autologous Blood and Marrow Transplant Registry who received allogeneic (T-cell depleted and T-cell replete) and autologous (purged and unpurged) transplants. No significant differences in relapse rates were observed when results of allogeneic transplantation were compared with syngeneic transplantation for any histology. T-cell depletion of allografts was not associated with a higher relapse risk, but was associated with improved overall survival for patients with low-grade and intermediate-grade histology. Patients who received unpurged autografts for low-grade NHL had a five-fold (P =.008) greater risk of relapse than recipients of syngeneic transplants, and recipients of unpurged autografts had a two-fold (P =.0009) greater relapse risk than patients who received purged autografts. Among low-grade NHL patients, the use of purging was associated with significantly better disease-free survival (P =.003) and overall survival (P =.04) when compared with patients who received unpurged autografts. These analyses failed to find evidence of a graft-versus-lymphoma effect, but do provide indirect evidence to support the hypothesis that tumor contamination may contribute to lymphoma relapse, and that purging may be beneficial for patients undergoing autologous hematopoietic stem-cell transplantation for low-grade NHL.

Allogeneic transplantation in malignant lymphoma

Allogeneic transplantation of bone marrow and peripheral blood stem cells is a frequently discussed therapeutic option in the treatment of malignant lymphoma. By analysing the results of our own transplant program in patients with advanced lymphoma we tried to evaluate indications for allogeneic transplantations. Data from lymphoma patients treated at the Klinikum Grosshadern between 1985 and 2001 were analysed retrospectively. 56 patients were included. 24 patients had low grade Non-Hogdkin's lymphoma (NHL) (follicular lymphoma: n = 8, mantle cell lymphoma: n = 6) or chronic lymphocytic leukemia (CLL: n = 10), 16 patients had high grade NHL (immunoblastic/lymphoblastic: n = 5; large cell/diffuse: n = 5) and 8 patients suffered from Hodgkins's disease. Median age was 41 years, 34 patients were transplanted from an HLA-identical sibling, 19 from an HLA-id. unrelated donor and three from an HLA-mismatched related donor. 30 patients received bone marrow and 26 peripheral blood stem cells. 22 pat. were treated with an intensive 12 Gy TBI containing conditioning regimen, whereas 34 patients were treated with a dose-intensity reduced conditioning procedere. 25 patients are alive between 2 month and 15 years after transplantation. Overall survival after 2 years is 48 % for patients with low grade NHL (incl. CLL), 9.3 % for patients with high grade lymphoma and 25 % for patients with Hodgkin's disease. 1-year-transplant-related mortality (TRM) was 33.9 % in all patients. Dose-intensity-reduced conditioning was not able to reduce TRM. Allogeneic bone marrow or stem cell transplantation is able to induce long lasting complete remissions in patients with heavily pretreated malignant lymphoma. Results of allogeneic transplantation are encouraging in patients with follicular and other low grade lymphoma. However transplant-related toxicity is high. At present the impact of reducing the intensity of conditioning is not yet clear.

Progress in haematopoietic stem cell transplantation for multiple myeloma.

High-dose myeloablative treatment followed by autologous haematopoietic stem cell transplantation has significantly improved survival of patients younger than 65 years of age with multiple myeloma as compared with conventional chemotherapy. However, all patients seem to relapse and molecular remissions are rare. Results of allogeneic transplantation, still hampered by high transplant-related mortality, have improved dramatically over the last 5-6 years and this is an option for patients younger than 50-55 years old. The relapse rate is lower than with autologous transplantation and molecular remissions are frequent. Some patients are still in complete haematological remission more the 10 years following transplantation. Autologous transplantation followed by nonmyeloablative allogeneic transplantation is on trial and may be a way to eventually cure a fraction of younger patients with multiple myeloma.

Autologous and allogeneic transplantation for multiple myeloma at a single centre.

We report the results of a consecutive series of patients who underwent autologous (auto) (40), allogeneic (allo) (22) or syngeneic transplantation (2) for multiple myeloma (MM) at our centre. Median age at diagnosis was 45.5 (auto) and 43 (allo) years. Most patients had stage 2 (27% auto; 27% allo) or stage 3 (62% auto; 50% allo) disease and 73% demonstrated chemosensitivity prior to transplant. Median time from diagnosis to transplant was 18.6 months (auto) and 16.4 months (allo). Standard conditioning regimens were used. Median time to neutrophil engraftment was 11 days (7-18) (auto) and 18 days (13-24) (allo) and median time to platelet engraftment was 11 days (6-60) and 18 days (13-105), respectively. Ninety-day mortality was 5% (auto) and 27% (allo). Median follow-up was 15 months (6-48) (auto) and 42 months (24-52) (allo). Three-year progression-free survival (PFS) was 17 +/- 10% (auto) and 22 +/- 9% (allo) and 3-year overall survival (OS) was 74 +/- 11% (auto) and 32 +/- 10% (allo). Autologous transplantation for MM is a safe procedure with good OS although disease progression following transplant is frequent. Allogeneic transplantation has a high procedure-related mortality and PFS comparable to autologous transplantation but OS is poor. The early mortality and high OS of autologous transplantation in MM compares favourably with both the results of allogeneic transplantation and published results of standard therapy in this retrospective analysis.