Long-Term Thymic Function and Reconstitution of the T Cell Compartment after T Cell-Replete Haplo-Identical Allografting

INTRODUCTION Post-transplant cyclophosphamide (PTCY) has expanded the application of haploidentical stem cell transplantation (haplo-HSCT). Thymic function may play a pivotal role in long-term clinical outcomes. OBJECTIVES To evaluate the kinetics of long-term immune thymus-dependent reconstitution after PTCY haplo-HSCT. METHODS Twenty-nine patients (median age 53) underwent T-cell replete haplo-HSCT with PTCY. Blood samples were collected before conditioning and at 1, 3, 6, 12, 18, 24 months after transplantation. Analyses of CD4 and CD8 T-cell subsets by flow-cytometry were correlated by generalized linear models with Real-Time PCR quantification of signal joint T-cell receptor excision DNA circles (sjTRECs), specific marker of naive T-cells thymopoiesis. A) Naive; b) central; c) memory; and d) revertant CD4 and CD8 T-cells were defined as follows: a) CD45RA+CD62L+; b) CD45RO+CD62L+; c) CD45RO+CD27-; and d) CD45RA+/45RO+, respectively. SjTRECs real-time PCR was performed on genomic DNA (100 ng) extracted from sorted CD4 and CD8 T-cells. RESULTS Following PTCY induced T-cell depletion, a constant gradual increase in absolute numbers of all CD4 and CD8 T cell subsets and of sjTRECs copies from the first month up to two years post-transplant was observed ( Figure 1 ). Overall, at two years, CD4 and CD8 T-cell levels and sjTRECs levels were however lower than those observed in healthy donors. sjTRECs kinetics was associated with the increase in naive T-cells (overall, p CONCLUSIONS Active thymic function despite age-dependent involution, substantially contributes to T-cell reconstitution after haplo-HSCT. Chronic GVHD and older age are however significantly correlated with lower thymic activity. Overall, lower production of sjTRECs after haplo-HSCT as compared after HLA identical sibling HSCT may partly be due to a higher degree of "mismatching" of MHC molecules during thymic re-education

First-line therapy with either bortezomib-melphalan-prednisone or lenalidomide-dexamethasone followed by lenalidomide for transplant-ineligible multiple myeloma patients: a pooled analysis of two randomized trials

Bortezomib-melphalan-prednisone and continuous lenalidomide-dexamethasone represent the standard treatment of transplant-ineligible, newly diagnosed, multiple myeloma patients. To date, no randomized trial has compared bortezomib-melphalan-prednisone to lenalidomide-dexamethasone, and there is no evidence of the optimal treatment for newly diagnosed multiple myeloma, particularly in high-risk cytogenetic patients (del(17p), t(4;14) or t(14;16)). We pooled together data from newly diagnosed myeloma patients treated with bortezomib-melphalan-prednisone or lenalidomide-dexamethasone induction followed by lenalidomide maintenance 10 mg enrolled in the GIMEMA-MM-03-05 and EMN01 trials, to evaluate their efficacy in different patient subgroups, focusing on standard and high-risk cytogenetics. Overall, 474 patients were analyzed (bortezomib-melphalan-prednisone: 257 patients; lenalidomide-dexamethasone followed by lenalidomide maintenance: 217 patients). No difference in progression-free survival (Hazard Ratio: 0.96) and overall survival (Hazard Ratio: 1.08) was observed between bortezomib-melphalan-prednisone and lenalidomide-dexamethasone followed by lenalidomide in standard-risk, while a reduction in the risk of progression (Hazard Ratio: 0.54) and death (Hazard Ratio: 0.73) was seen in high-risk patients treated with bortezomib-melphalan-prednisone vs. lenalidomide-dexamethasone followed by lenalidomide. In particular, standard risk patients >75years benefited less from bortezomib-melphalan-prednisone than lenalidomide-dexamethasone followed by lenalidomide (Hazard Ratio for progression-free survival: 0.96; Hazard Ratio for overall survival: 1.81). In this non-randomized analysis, bortezomib-melphalan-prednisone and lenalidomide-dexamethasone followed by lenalidomide were equally effective in younger (≤75years), standard-risk patients, while older ones (>75years) benefited more from lenalidomide-dexamethasone followed by lenalidomide. In high-risk patients, bortezomib-melphalan-prednisone improved progression-free survival and overall survival irrespective of age. The source trials are registered at ClinicalTrials.gov (NCT01063179 and NCT01093196)

Carfilzomib induction, consolidation, and maintenance with or without autologous stem-cell transplantation in patients with newly diagnosed multiple myeloma: pre-planned cytogenetic subgroup analysis of the randomised, phase 2 FORTE trial

Background: Patients with newly diagnosed multiple myeloma and high-risk cytogenetic abnormalities (HRCA) represent an unmet medical need. In the FORTE trial, lenalidomide and dexamethasone plus carfilzomib (KRd) induction resulted in a higher proportion of patients with at least a very good partial response as compared with carfilzomib, cyclophosphamide, and dexamethasone (KCd), and carfilzomib plus lenalidomide maintenance prolonged progression-free survival compared with lenalidomide maintenance. In this prespecified analysis of the FORTE trial, we described the outcomes of enrolled patients according to their cytogenetic risk. Methods: The UNITO-MM-01/FORTE was a randomised, open-label, phase 2 trial done at 42 Italian academic and community practice centres, which enrolled transplant-eligible patients with newly diagnosed multiple myeloma aged 18-65 years. Eligible patients had newly diagnosed multiple myeloma based on standard International Myeloma Working Group criteria, a Karnofsky performance status of at least 60%, and had not received any previous treatment with anti-myeloma therapy. At enrolment, 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 autologous stem-cell transplantation (ASCT; four 28-day induction cycles with KRd, melphalan at 200 mg/m2 and ASCT [MEL200-ASCT], followed by four 28-day KRd consolidation cycles), 12 28-day KRd cycles, or KCd plus ASCT (four 28-day induction cycles with KCd, MEL200-ASCT, and four 28-day KCd consolidation cycles), using a web-based system (block randomisation, block size of 12). Carfilzomib was administered at 20 mg/m2 on days 1 and 2 of cycle 1, followed by 36 mg/m2 intravenously administered on days 8, 9, 15, and 16 of cycle 1, and then 36 mg/m2 intravenously administered for all subsequent doses on days 1, 2, 8, 9, 15, 16; lenalidomide 25 mg was administered orally on days 1-21; cyclophosphamide 300 mg/m2 was administered orally on days 1, 8, and 15; and dexamethasone 20 mg was administered orally or intravenously on days 1, 2, 8, 9, 15, 16, 22, and 23. After the consolidation phase, patients were stratified according to induction-consolidation treatment and randomly assigned (1:1; block size of 8) to maintenance treatment with carfilzomib plus lenalidomide or lenalidomide alone. Carfilzomib 36 mg/m2 was administered intravenously on days 1-2 and days 15-16, every 28 days for up to 2 years, and 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. In this preplanned analysis, we included patients enrolled in the FORTE trial with complete cytogenetic data on del(17p), t(4;14), t(14;16), del(1p), gain(1q) (3 copies), and amp(1q) (≥4 copies) assessed by fluorescence in-situ hybridisation analysis on CD138-positive sorted cells. We assessed progression-free survival, overall survival, minimal residual disease negativity, and 1-year sustained minimal residual disease negativity according to the presence of zero, one, and two or more HRCA across treatment groups. The FORTE trial is ongoing, and registered with ClinicalTrials.gov, NCT02203643. Findings: Between Feb 23, 2015, and April 5, 2017, 477 patients were enrolled, of whom 396 (83%) had complete cytogenetic data and were analysed (176 [44%] of whom were women and 220 [56%] were men). The median follow-up from first randomisation was 51 months (IQR 46-56). 4-year progression-free survival was 71% (95% CI 64-78) in patients with zero HRCA, 60% (95% CI 52-69) in patients with one HRCA, and 39% (95% CI 30-50) in patients with two or more HRCA. Compared with patients with zero HRCA, the risk of progression or death was similar in patients with one HRCA (hazard ratio [HR] 1·33 [95% CI 0·90-1·97]; p=0·15) and higher in patients with two or more HRCA (HR 2·56 [95% CI 1·74-3·75]); p<0·0001) across the induction-intensification-consolidation groups. Moreover, the risk of progression or death was also higher in patients with two or more HRCA versus those with one HRCA (HR 1·92 [95% CI 1·34-2·76]; p=0·0004). 4-year overall survival from the first randomisation was 94% (95% CI 91-98) in patients with zero HRCA, 83% (95% CI 76-90) in patients with one HRCA, and 63% (95% CI 54-74) in patients with two or more HRCA. Compared with patients with zero HRCA, the risk of death was significantly higher in patients with one HRCA (HR 2·55 [95% CI 1·22-5·36]; p=0·013) and two or more HRCA (HR 6·53 [95% CI 3·24-13·18]; p<0·0001). Patients with two or more HRCA also had a significantly higher risk of death than those with one HRCA (HR 2·56 [95% CI 1·53-4·28]; p=0·0004). The rates of 1-year sustained minimal residual disease negativity were similar in patients with zero HRCA (53 [35%] of 153] and with one HRCA (57 [41%] of 138) and were lower in patients with two or more HRCA (25 [24%] of 105). The median duration of follow-up from second randomisation was 37 months (IQR 33-42). 3-year progression-free survival from the second randomisation was 80% (95% CI 74-88) in patients with zero HRCA, 68% (95% CI 59-78) in patients with one HRCA, and 53% (95% CI 42-67) in patients with two or more HRCA. The risk of progression or death was higher in patients with one HRCA (HR 1·68 [95% CI 1·01-2·80]; p=0·048) and two or more HRCA (2·74 [95% CI 1·60-4·69], p=0·0003) than in patients with zero HRCA. Interpretation: This preplanned analysis of the FORTE trial showed that carfilzomib-based induction-intensification-consolidation regimens are effective strategies in patients with standard risk (zero HRCA) and high-risk (one HRCA) myeloma, resulting in similar rates of progression-free survival and 1-year sustained minimal residual disease negativity. Despite promising progression-free survival, patients with ultra-high-risk disease (those with 2 or more HRCA) still have an increased risk of progression and death and therefore represent an unmet medical need. Funding: Amgen and Celgene/Bristol Myers Squibb

Maintenance in myeloma patients achieving complete response after upfront therapy: a pooled analysis

Purpose: Maintenance demonstrated to improve survival in newly diagnosed multiple myeloma (NDMM) patients and the achievement of complete response (CR) is a strong predictor of survival. Nevertheless, the role of maintenance according to response after induction/consolidation has not been investigated so far. To evaluate the impact of maintenance according to response, we pooled together and retrospectively analyzed data from 955 NDMM patients enrolled in two trials (GIMEMA-MM-03-05 and RV-MM-PI-209). Methods: Primary endpoints were progression-free survival (PFS)1, PFS2 and overall survival (OS) of CR patients randomized to maintenance and no maintenance. Secondary endpoints were PFS1, PFS2 and OS in very good partial response/partial response (VGPR/PR) patients. Results: Overall, 213 patients obtained CR after induction/consolidation, 118 received maintenance and 95 no maintenance. In patients achieving CR, maintenance significantly improved PFS1 (HR 0.50, P < 0.001), PFS2 (HR 0.58, P 0.02) and OS (HR 0.51, P 0.02) compared with no maintenance; the advantage was maintained across all the analyzed subgroups according to age, International Staging System (ISS) stage, cytogenetic profile and treatment. Similar features were seen in VGPR/PR patients. Conclusion: Maintenance prolonged survival in CR and in VGPR/PR patients. The benefit in CR patients suggests the importance of continuing treatment in patients with chemo-sensitive disease. Trial registration: The two source studies are registered at ClinicalTrials.gov: identification numbers NCT01063179 and NCT00551928