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Romidepsin-CHOEP followed by high-dose chemotherapy and stem-cell transplantation in untreated Peripheral T-Cell Lymphoma: results of the PTCL13 phase Ib/II study
Chiappella, A., Dodero, A., Evangelista, A., Re, A., Orsucci, L., Usai, S. V., Castellino, C., Stefoni, V., Pinto, A., Zanni, M., et al
Leukemia. 2023
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Editor's Choice
Abstract
The standard treatment for young patients with untreated PTCLs is based on anthracycline containing-regimens followed by high-dose-chemotherapy and stem-cell-transplantation (HDT + SCT), but only 40% of them can be cured. Romidepsin, a histone-deacetylase inhibitor, showed promising activity in relapsed PTCLs; in first line, Romidepsin was added with CHOP. We designed a study combining romidepsin and CHOEP as induction before HDT + auto-SCT in untreated PTCLs (PTCL-NOS, AITL/THF, ALK-ALCL), aged 18-65 years. A phase Ib/II trial was conducted to define the maximum tolerated dose (MTD) of Ro-CHOEP, and to assess efficacy and safety of 6 Ro-CHOEP as induction before HDT. The study hypothesis was to achieve a 18-month PFS of 70%. Twenty-one patients were enrolled into phase Ib; 7 dose-limiting toxicities were observed, that led to define the MTD at 14 mg/ms. Eighty-six patients were included in the phase II. At a median follow-up of 28 months, the 18-month PFS was 46.2% (95%CI:35.0-56.7), and the 18-month overall survival was 73.1% (95%CI:61.6-81.7). The overall response after induction was 71%, with 62% CRs. No unexpected toxicities were reported. The primary endpoint was not met; therefore, the enrollment was stopped at a planned interim analysis. The addition of romidepsin to CHOEP did not improve the PFS of untreated PTCL patients.
PICO Summary
Population
Adults aged 18-65 years with untreated peripheral T-cell lymphomas, aged 18-65 years from 26 centres in Italy (n=86)
Intervention
Romidepsin + CHOP (Ro-CHOEP) induction prior to auto-SCT
Comparison
None
Outcome
At a median follow-up of 28 months, the 18-month progression-free survival was 46.2% (95%CI:35.0-56.7), and the 18-month overall survival was 73.1% (95%CI:61.6-81.7). The overall response after induction was 71%, with 62% CRs. No unexpected toxicities were reported. The primary endpoint was not met; therefore, the enrollment was stopped at a planned interim analysis.
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High Levels of Circulating Tumor Plasma Cells as a Key Hallmark of Aggressive Disease in Transplant-Eligible Patients With Newly Diagnosed Multiple Myeloma
Bertamini, L., Oliva, S., Rota-Scalabrini, D., Paris, L., Morè, S., Corradini, P., Ledda, A., Gentile, M., De Sabbata, G., Pietrantuono, G., et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2022;:Jco2101393
Abstract
PURPOSE High levels of circulating tumor plasma cells (CTC-high) in patients with multiple myeloma are a marker of aggressive disease. We aimed to confirm the prognostic impact and identify a possible cutoff value of CTC-high for the prediction of progression-free survival (PFS) and overall survival (OS), in the context of concomitant risk features and minimal residual disease (MRD) achievement. METHODS CTC were analyzed at diagnosis with two-tube single-platform flow cytometry (sensitivity 4 × 10(-5)) in patients enrolled in the multicenter randomized FORTE clinical trial (ClinicalTrials.gov identifier: NCT02203643). MRD was assessed by second-generation multiparameter flow cytometry (sensitivity 10(-5)). We tested different cutoff values in series of multivariate (MV) Cox proportional hazards regression analyses on PFS outcome and selected the value that maximized the Harrell's C-statistic. We analyzed the impact of CTC on PFS and OS in a MV analysis including baseline features and MRD negativity. RESULTS CTC analysis was performed in 401 patients; the median follow-up was 50 months (interquartile range, 45-54 months). There was a modest correlation between the percentage of CTC and bone marrow plasma cells (r = 0.38). We identified an optimal CTC cutoff of 0.07% (approximately 5 cells/µL, C-index 0.64). In MV analysis, CTC-high versus CTC-low patients had significantly shorter PFS (hazard ratio, 2.61; 95% CI, 1.49 to 2.97, P < .001; 4-year PFS 38% v 69%) and OS (hazard ratio, 2.61; 95% CI, 1.49 to 4.56; P < .001; 4-year OS 68% v 92%). The CTC levels, but not the bone marrow plasma cell levels, affected the outcome. The only factor that reduced the negative impact of CTC-high was the achievement of MRD negativity (interaction P = .039). CONCLUSION In multiple myeloma, increasing levels of CTC above an optimal cutoff represent an easy-to-assess, robust, and independent high-risk factor. The achievement of MRD negativity is the most important factor that modulates their negative prognostic impact.
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Carfilzomib with cyclophosphamide and dexamethasone or lenalidomide and dexamethasone plus autologous transplantation or carfilzomib plus lenalidomide and dexamethasone, followed by maintenance with carfilzomib plus lenalidomide or lenalidomide alone for patients with newly diagnosed multiple myeloma (FORTE): a randomised, open-label, phase 2 trial
Gay, F., Musto, P., Rota-Scalabrini, D., Bertamini, L., Belotti, A., Galli, M., Offidani, M., Zamagni, E., Ledda, A., Grasso, M., et al
The Lancet. Oncology. 2021
Abstract
BACKGROUND Bortezomib-based induction followed by high-dose melphalan (200 mg/m(2)) and autologous stem-cell transplantation (MEL200-ASCT) and maintenance treatment with lenalidomide alone is the current standard of care for young and fit patients with newly diagnosed multiple myeloma. We aimed to evaluate the efficacy and safety of different carfilzomib-based induction and consolidation approaches with or without transplantation and of maintenance treatment with carfilzomib plus lenalidomide versus lenalidomide alone in newly diagnosed multiple myeloma. METHODS UNITO-MM-01/FORTE was a randomised, open-label, phase 2 trial done in 42 Italian academic and community practice centres. We enrolled transplant-eligible patients with newly diagnosed multiple myeloma aged 65 years or younger with a Karnofsky Performance Status of 60% or higher. Patients were stratified according to International Staging System stage (I vs II/III) and age (<60 years vs 60-65 years) and randomly assigned (1:1:1) to KRd plus ASCT (four 28-day induction cycles with carfilzomib plus lenalidomide plus dexamethasone [KRd], melphalan at 200 mg/m(2) and autologous stem-cell transplantation [MEL200-ASCT], followed by four 28-day KRd consolidation cycles), KRd12 (12 28-day KRd cycles), or KCd plus ASCT (four 28-day induction cycles with carfilzomib plus cyclophosphamide plus dexamethasone [KCd], MEL200-ASCT, and four 28-day KCd consolidation cycles). Carfilzomib 36 mg/m(2) was administered intravenously on days 1, 2, 8, 9, 15, and 16; lenalidomide 25 mg administered orally on days 1-21; cyclophosphamide 300 mg/m(2) administered orally on days 1, 8, and 15; and dexamethasone 20 mg administered orally or intravenously on days 1, 2, 8, 9, 15, 16, 22, and 23. Thereafter, patients were stratified according to induction-consolidation treatment and randomly assigned (1:1) to maintenance treatment with carfilzomib plus lenalidomide or lenalidomide alone. Carfilzomib 36 mg/m(2) was administered intravenously on days 1-2 and 15-16 every 28 days for up to 2 years; lenalidomide 10 mg was administered orally on days 1-21 every 28 days until progression or intolerance in both groups. The primary endpoints were the proportion of patients with at least a very good partial response after induction with KRd versus KCd and progression-free survival with carfilzomib plus lenalidomide versus lenalidomide alone as maintenance treatment, both assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02203643. Study recruitment is complete, and all patients are in the follow-up or maintenance phases. FINDINGS Between Feb 23, 2015, and April 5, 2017, 474 patients were randomly assigned to one of the induction-intensification-consolidation groups (158 to KRd plus ASCT, 157 to KRd12, and 159 to KCd plus ASCT). The median duration of follow-up was 50·9 months (IQR 45·7-55·3) from the first randomisation. 222 (70%) of 315 patients in the KRd group and 84 (53%) of 159 patients in the KCd group had at least a very good partial response after induction (OR 2·14, 95% CI 1·44-3·19, p=0·0002). 356 patients were randomly assigned to maintenance treatment with carfilzomib plus lenalidomide (n=178) or lenalidomide alone (n=178). The median duration of follow-up was 37·3 months (IQR 32·9-41·9) from the second randomisation. 3-year progression-free survival was 75% (95% CI 68-82) with carfilzomib plus lenalidomide versus 65% (58-72) with lenalidomide alone (hazard ratio [HR] 0·64 [95% CI 0·44-0·94], p=0·023). During induction and consolidation, the most common grade 3-4 adverse events were neutropenia (21 [13%] of 158 patients in the KRd plus ASCT group vs 15 [10%] of 156 in the KRd12 group vs 18 [11%] of 159 in the KCd plus ASCT group); dermatological toxicity (nine [6%] vs 12 [8%] vs one [1%]); and hepatic toxicity (13 [8%] vs 12 [8%] vs none). Treatment-related serious adverse events were reported in 18 (11%) of 158 patients in the KRd-ASCT group, 29 (19%) of 156 in the KRd12 group, and 17 (11%) of 159 in the KCd plus ASCT group; the most common serious adverse event was pneumonia, in seven (4%) of 158, four (3%) of 156, and five (3%) of 159 patients. Treatment-emergent deaths were reported in two (1%) of 158 patients in the KRd plus ASCT group, two (1%) of 156 in the KRd12 group, and three (2%) of 159 in the KCd plus ASCT group. During maintenance, the most common grade 3-4 adverse events were neutropenia (35 [20%] of 173 patients on carfilzomib plus lenalidomide vs 41 [23%] of 177 patients on lenalidomide alone); infections (eight [5%] vs 13 [7%]); and vascular events (12 [7%] vs one [1%]). Treatment-related serious adverse events were reported in 24 (14%) of 173 patients on carfilzomib plus lenalidomide versus 15 (8%) of 177 on lenalidomide alone; the most common serious adverse event was pneumonia, in six (3%) of 173 versus five (3%) of 177 patients. One patient died of a treatment-emergent adverse event in the carfilzomib plus lenalidomide group. INTERPRETATION Our data show that KRd plus ASCT showed superiority in terms of improved responses compared with the other two treatment approaches and support the prospective randomised evaluation of KRd plus ASCT versus standards of care (eg, daratumumab plus bortezomib plus thalidomide plus dexamethasone plus ASCT) in transplant-eligible patients with multiple myeloma. Carfilzomib plus lenalidomide as maintenance therapy also improved progression-free survival compared with the standard-of-care lenalidomide alone. FUNDING Amgen, Celgene/Bristol Myers Squibb. TRANSLATION For the Italian translation of the abstract see Supplementary Materials section.
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Multicenter Phase II Study on Haploidentical Bone Marrow Transplantation Using a Reduced-Intensity Conditioning Regimen and Posttransplantation Cyclophosphamide in Patients with Poor-Prognosis Lymphomas
Castagna, L., Dodero, A., Patriarca, F., Onida, F., Olivieri, A., Russo, D., Giordano, L., Majolino, I., Bramanti, S., Mariotti, J., et al
Transplantation and cellular therapy. 2021;27(4):328.e1-328.e6
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Editor's Choice
Abstract
Allogeneic stem cell transplantation from haploidentical donors using unmanipulated bone marrow and posttransplantation cyclophosphamide has been largely employed to cure high-risk lymphomas. However, the increased incidence of relapse associated with the use of a nonmyeloablative conditioning regimen is still considered a concerning issue. The aim of our study was to prospectively evaluate the efficacy and feasibility of a reduced-intensity conditioning regimen, including thiotepa, cyclophosphamide, and fludarabine, in high-risk lymphoma patients. This was a prospective multicenter study. We enrolled 49 patients, of whom 47 were evaluable. Graft source (bone marrow) and graft-versus-host disease (GVHD) prophylaxis were the same for all patients. The primary endpoint was the proportion of patients free of disease progression at 1 year. The primary endpoint was met, as 29 out of 47 patients were alive and free of disease at 1 year (1-year progression-free survival, 60%). Forty-five recipients engrafted and achieved full donor chimerism at day 100. The cumulative incidences (CIs) of ANC engraftment at 30 days and platelet engraftment at 60 days were 89% and 83%, respectively. Two patients experienced graft failure. The CIs of day 100 grades 2 to 4 acute GVHD and 2-year moderate-to-severe chronic GVHD were 26% and 16%, respectively. With a median follow-up of 47.5 months (range, 22 to 74), the 4-year progression-free survival and overall survival were 54% and 64%, respectively. The 4-year CI of relapse was 28%, and the 4-year nonrelapse mortality was 15%. Thiotepa-based reduced-intensity conditioning was well tolerated with encouraging survival in a cohort of patients with poor-prognosis lymphoma. Both the incidence of relapse and nonrelapse mortality were acceptable.
PICO Summary
Population
Patients with high-risk lymphoma (n=47)
Intervention
Haploidentical stem cell transplantation with a reduced intensity conditioning regimen, including thiotepa, cyclophosphamide, and fludarabine
Comparison
None
Outcome
The primary endpoint was met, as 29 out of 47 patients were alive and free of disease at 1 year (1-year progression-free survival, 60%). Forty-five recipients engrafted and achieved full donor chimerism at day 100. The cumulative incidences (CIs) of ANC engraftment at 30 days and platelet engraftment at 60 days were 89% and 83%, respectively. Two patients experienced graft failure. The CIs of day 100 grades 2 to 4 acute GVHD and 2-year moderate-to-severe chronic GVHD were 26% and 16%, respectively. With a median follow-up of 47.5 months (range, 22 to 74), the 4-year progression-free survival and overall survival were 54% and 64%, respectively. The 4-year CI of relapse was 28%, and the 4-year nonrelapse mortality was 15%.
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5.
Addition of Rituximab in Reduced Intensity Conditioning Regimens for B-Cell Malignancies Does Not Influence Transplant Outcomes: EBMT Registry Analyses Following Allogeneic Stem Cell Transplantation for B-Cell Malignancies
Tomaszewska, A., Jagasia, M., Beohou, E., van der Werf, S., Blaise, D., Kanfer, E., Milpied, N., Reményi, P., Ciceri, F., Bourhis, J. H., et al
Frontiers in immunology. 2020;11:613954
Abstract
Rituximab (R) is increasingly incorporated in reduced intensity conditioning (RIC) regimens for allogeneic hematopoietic cell transplantation (alloHCT) in patients with B-cell malignancies, not only to improve disease control, but also to prevent graft-versus-host disease (GVHD). There are no randomized prospective data to validate this practice, although single center data and the CIBMTR analysis have shown promising results. We aimed at validation of these findings in a large registry study. We conducted a retrospective analysis using the EBMT registry of 3,803 adult patients with B-cell malignancies undergoing alloHCT (2001-2013) with either rituximab (R-RIC-9%) or non-rituximab (RIC-91%) reduced intensity regimens respectively. Median age and median follow up were 55 years (range 19.1-77.3) and 43.2 months (range 0.3-179.8), respectively. There was no difference in transplant outcomes (R-RIC vs RIC), including 1-year overall survival (69.9% vs 70.7%), 1-year disease-free survival (64.4% vs 62.2%), 1-year non-relapse mortality (21% vs 22%), and day-100 incidence of acute GVHD 2-4° (12% vs 12%). In summary, we found that addition of rituximab in RIC regimens for B-cell malignancies had no significant impact on major transplant outcome variables. Of note, data on chronic GVHD was not available, limiting the conclusions that can be drawn from the present study.
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Refractory and 17p-deleted chronic lymphocytic leukemia: improving survival with pathway inhibitors and allogeneic stem cell transplantation
Farina, L., Barretta, F., Scarfo, L., Bruno, B., Patriarca, F., Frustaci, A. M., Coscia, M., Salvetti, C., Quaresmini, G., Fanin, R., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Abstract
Refractory/early relapsed and 17p deletion/p53 mutation (del(17p)/TP53mut)-positive chronic lymphocytic leukemia (CLL) has been conventionally considered a high-risk disease, potentially eligible for allogeneic stem cell transplantation (alloSCT). In this multicenter retrospective analysis of 157 patients, we compared the outcomes of high-risk CLL treated with alloSCT or B-cell receptor pathway inhibitors (BCRis) or both. Seventy-one patients were treated with BCRis, 67 patients underwent reduced intensity alloSCT, and 19 received alloSCT with BCRis before and/or after transplant. An inverse probability of treatment weighting analyses were performed to compare alloSCT versus no-alloSCT groups: 5-year OS, PFS, and cumulative incidence of NRM and relapse were 40%/60% (p=0.096), 34%/17% (p=0.638), 28%/5% (p=0.016), and 38%/83% (p=0.005), respectively. Patients treated with alloSCT+BCRis showed a 3-year OS of 83%. Three -year OS and NRM by year of alloSCT, including patients treated with BCRis, were 53% and 17% in 2000-2007, 55% and 30% in 2008-2012 and 72% and 18% in 2013-2018. In conclusion, the combination of pathway inhibitors and alloSCT is feasible and may further improve the outcome of high-risk CLL patients.
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PTCy-based haploidentical vs matched related or unrelated donor reduced-intensity conditioning transplant for DLBCL
Dreger, P., Sureda, A., Ahn, K. W., Eapen, M., Litovich, C., Finel, H., Boumendil, A., Gopal, A., Herrera, A. F., Schmid, C., et al
Blood advances. 2019;3(3):360-369
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Abstract
This study retrospectively compared long-term outcomes of nonmyeloablative/reduced intensity conditioning (NMC/RIC) allogeneic hematopoietic cell transplantation (allo-HCT) from a haploidentical family donor (haplo-HCT) using posttransplant cyclophosphamide (PTCy) with those of matched sibling donor (MSD) and matched unrelated donor (MUD) with or without T-cell depletion (TCD+/TCD-) in patients with relapsed diffuse large B-cell lymphoma (DLBCL). Adult patients with DLBCL who had undergone their first NMC/RIC allo-HCT between 2008 and 2015 were included. Recipients of haplo-HCT were limited to those receiving graft-versus-host disease (GVHD) prophylaxis with PTCy. GVHD prophylaxis in MSD was limited to calcineurin inhibitor (CNI)-based approaches without in vivo TCD, while MUD recipients received CNI-based prophylaxis with or without TCD. Outcome analyses for overall survival (OS) and progression-free survival (PFS), nonrelapse mortality (NRM), and disease relapse/progression were calculated. A total of 1438 patients (haplo, 132; MSD, 525; MUD TCD+, 403; and MUD TCD-, 378) were included. Patients with haplo donors were significantly older, had a better performance status and had more frequently received total body irradiation-based conditioning regimens and bone marrow grafts than MSD and MUD TCD+ or TCD-. 3-year OS, PFS, NRM and relapse/progression incidence after haplo-HCT was 46%, 38%, 22%, and 41%, respectively, and not significantly different from outcomes of matched donor transplants on multivariate analyses. Haplo-HCT was associated with a lower cumulative incidence of chronic GVHD compared with MSD, MUD TCD+/TCD-. NMC/RIC haplo-HCT with PTCy seems to be a valuable alternative for patients with DLBCL considered for allo-HCT but lacking a matched donor.
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First salvage treatment with bendamustine and brentuximab vedotin in Hodgkin lymphoma: a phase 2 study of the Fondazione Italiana Linfomi
Broccoli, A., Argnani, L., Botto, B., Corradini, P., Pinto, A., Re, A., Vitolo, U., Fanti, S., Stefoni, V., Zinzani, P. L.
Blood cancer journal. 2019;9(12):100
Abstract
Effective salvage options inducing high complete metabolic response (CMR) rates without significant toxicity are needed for Hodgkin lymphoma (HL) patients failing induction treatment and who are candidate to autologous stem cell transplantation (ASCT). Brentuximab vedotin (BV) and bendamustine are active monotherapies in the relapsed/refractory setting and their combination (the BBV regimen) possibly enhances their activity. This single-arm multicenter phase 2 study investigated the efficacy and safety of BBV as first salvage therapy in 40 patients with relapsed/refractory HL. Thirty-eight patients were evaluable for efficacy: 30 (78.9%) had a CMR and 2 (5.3%) a partial response, leading to an overall response rate (ORR) of 84.2%. The ORR in the primary refractory subset was 75.0%, among relapsed patients it was 94.4%. Thirty-five patients could mobilize peripheral blood stem cells and 33 underwent ASCT. At a median follow-up of 23 months, the estimated 3-year overall survival and progression-free survival are 88.1% and 67.3%. During therapy, only 3 grade IV cases of neutropenia occurred and resolved within a week. No grade 4 extrahematologic toxicities were reported; skin reactions were however rather frequent (65%). These results suggest that the BBV regimen exhibits promising efficacy and a manageable toxicity in a challenging subpopulation of HL patients.
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Allogeneic transplantation for relapsed and refractory Hodgkin lymphoma: long-term outcomes and graft-versus-host disease-free/relapse-free survival
Spina, F., Radice, T., De Philippis, C., Soldarini, M., Di Chio, M. C., Dodero, A., Guidetti, A., Viviani, S., Corradini, P.
Leukemia & lymphoma. 2018;:1-9
Abstract
This monocentric retrospective study included 70 consecutive relapsed/refractory Hodgkin lymphoma (RR-HL) patients receiving reduced-intensity allogeneic stem cell transplantation (alloSCT). We evaluated overall and progression-free survival (OS, PFS), graft-versus host disease/relapse-free survival (GFRS), and chronic GVHD-free OS (cGVHD-free OS) defined as OS without moderate-to-severe cGVHD. Patients had a median age of 33 years (range, 18-60 years), 23% had refractory disease (SD/PD). Donors were HLA identical (39%), unrelated (30%), or haploidentical (31%). Median follow-up was 6.2 years. Five-year OS was 59% and PFS was 49%. NRM was 16% at 1 year. 44% of patients had cGVHD, and 14% moderate-to-severe cGVHD at last follow-up. GFRS and cGVHD-free OS were 26 and 48% at 5 years. In multivariate analysis, resistant disease at alloSCT impacted survival and GFRS. In conclusion, disease response before alloSCT impacts survival and GFRS. GVHD outcomes may help comparing the long-term effects of the new salvage treatments that bridge patients to alloSCT.
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Brentuximab vedotin for recurrent Hodgkin lymphoma after allogeneic hematopoietic stem cell transplantation: A report from the EBMT Lymphoma Working Party
Bazarbachi, A., Boumendil, A., Finel, H., Mohty, M., Castagna, L., Blaise, D., Peggs, K. S., Afanasyev, B., Diez-Martin, J. L., Corradini, P., et al
Cancer. 2018
Abstract
BACKGROUND The treatment of patients with Hodgkin lymphoma (HL) who develop disease progression after undergoing allogeneic stem cell transplantation (allo-SCT) remains challenging. METHODS The authors assessed outcomes in 184 adult patients with HL who developed disease recurrence or progression after a matched related or unrelated allo-SCT at European Society for Blood and Marrow Transplantation-participating centers between 2010 and 2014. RESULTS Eighty patients who received brentuximab vedotin (BV) salvage therapy were compared with 104 patients who did not. Patients in the BV group were younger (median age of 30 years vs 34 years) and were more likely to receive pretransplant BV (65% vs 46%) or posttransplant donor lymphocyte infusion (66% vs 33%). The 2 groups otherwise were comparable. Patients in the BV group received a median of 6 doses of posttransplant BV, resulting in a complete remission rate of 29%, a partial response rate of 45%, and a stable disease rate of 26%. Response to BV after allo-SCT did not appear to be affected by receipt of pretransplant BV. Despite a longer median follow-up for surviving patients in the BV group (33 months vs 23 months; P<.001), approximately 34% of the original BV cohort were alive and in CR at the time of last follow-up versus 18% in the group that did not receive BV (P=.003). The use of BV before donor lymphocyte infusion was found to be associated with the highest probability of being alive and in CR (40%) at the time of last follow-up. Salvage BV appeared to have no effect on chronic graft-versus-host disease or 1-year overall survival from the time of disease recurrence after allo-SCT (76% vs 67%). CONCLUSIONS BV is a safe and effective salvage therapy for patients with HL who develop disease recurrence or progression after undergoing allo-SCT, even after prior exposure to BV.