Peripheral-blood autologous stem-cell transplantation (ASCT) in patients with HIV-related lymphoma (HIV-Ly) has been reported as a safe and useful procedure. Herein we report the European Group for ...Blood and Marrow Transplantation experience on patients with HIV-Ly undergoing ASCT.
This was a retrospective, multicentric, registry-based analysis.
Since 1999, 68 patients from 20 institutions (median age, 41 years; range, 29 to 62 years) were included, diagnosed with non-Hodgkin's lymphoma (NHL; n = 50) or Hodgkin's lymphoma (n = 18). At the time of ASCT, 16 patients were in first complete remission (CR1); 44 patients were in CR more than 1, partial remission, or chemotherapy-sensitive relapse (chemo-S); and eight patients had chemotherapy-resistant disease. The median number of CD34(+) cells infused was 4.5 x 10(6)/kg (range, 1.6 to 21.2 x 10(6)/kg). Median time to neutrophil and platelet engraftment were 11 days (range, 8 to 36 days) and 14 days (range, 6 to 455 days), respectively, with a cumulative incidence (CI) at 1 year of 95.6% and 87%, respectively. CI of nonrelapse mortality (NRM) was 7.5% at 12 months after ASCT, mainly because of bacterial infections. CI of relapse was 30.4% at 24 months, statistically related with not being in CR at ASCT (relative risk RR = 3.6), NHL histology other than diffuse large B-cell lymphoma (RR = 3.4), and use of more than two previous treatment lines (RR = 3). At a median follow-up of 32 months (range, 2 to 81 months), progression-free survival (PFS) was 56%. Patients not in CR or with refractory disease at ASCT had poorer PFS (RR = 2.4 and 4.8, respectively).
Similarly to HIV-negative patients with lymphoma, ASCT is a useful treatment for patients with HIV-Ly and is associated with low NRM, mainly when performed in early stages and chemo-S disease.
Thanks to the recent developments in transplant procedures, an increasing number of patients with acute myeloid leukemia (AML) with a poor Karnofsky Performance Status (KPS) score are currently ...offered an allogeneic hematopoietic stem cell transplantation (allo-HCT). Nevertheless, little data is available about outcome of this fragile population.
We report here the results of a retrospective study designed to evaluate outcome of patients with AML undergoing allo-HCT with KPS score ≤80%. The analysis included patients with AML aged ≥18 years, undergoing allo-HCT in first remission between 2000 and 2018, with a KPS score at the time of transplant between 50% and 80%. Patients who received manipulated grafts or had incomplete data about cytogenetics were excluded. Conditioning intensity was defined according to EBMT definitions.
A total of 2,963 patients were identified. Median age at transplant was 55 years (18-77 years). Median year of transplant was 2014. The KPS score was =80% in 85% of the patients and <80% in 15% of the patients. Cytogenetic risk was good, intermediate or poor in 6%, 68% and 26% of the patients, respectively. Donor type was sibling (MSD), matched (10/10 UD), mismatched (9/10 UD) unrelated, haploidentical (haplo) or cord blood (CB) in 47%, 35%, 8%, 6% and 4% of patients, respectively. Conditioning was myeloablative (MAC) or reduced-intensity (RIC) in 42% and 58% of patients. Stem cell source was PBSC or BM in 84% and 14% of the patients. Anti-thymocyte globulin (ATG) was administered to 55% of the patients.
Cumulative incidence of grade II-IV and III-IV acute GVHD (aGvHD) was 26% and 8%, respectively. The 2-year cumulative incidence of chronic GVHD (cGvHD) and severe cGVHD was 38% and 18%. Non-relapse mortality (NRM) and relapse incidence (RI) at 2 years were 19% and 27%, respectively. Notably, in the subgroup of patients with KPS <80% NRM rate was as high as 27%. At 2 years, leukemia-free survival (LFS), overall survival (OS) and GVHD-free, relapse-free survival (GRFS) rates were 54%, 59% and 41%, respectively.
On multivariate analysis, transplant from a MSD was associated with a reduced risk of aGvHD (10/10 UD HR 1.8, 9/10 UD HR 2.4, haplo HR 1.9, CB HR 3.4, p<10-4, MSD as reference) and NRM (10/10 UD HR 1.4, 9/10 UD HR 2.4, haplo HR 1.8, CB HR 2, p<10-3, MSD as reference) as compared to all other donor types (Table 1). Transplant from 10/10 UD was associated with lower GRFS (HR 1.2, p=0.03), while 9/10 UD predicted inferior LFS, OS and GRFS (HR 1.6, 1.7, and 1.5, respectively, p<0.001) as compared to MSD. Patients with KPS score of 80% had significantly lower NRM and improved survival as compared to patients with KPS score <80% (NRM: HR 0.6, p<10-4; OS: HR 0.7, p<10-4). Other factors independently associated with improved OS were younger age, female sex, good or intermediate risk cytogenetics and de-novo AML. Notably, administration of ATG was associated with reduced risk of developing grade II-IV aGVHD (HR 0.7, p<10-4), cGVHD (HR 0.6, p<10-4), severe cGVHD (HR 0.5, p<10-4) and predicted improved GRFS (HR 0.8, p<0.01).
In order to compare outcome following MAC and RIC conditioning the analysis was restricted to patients receiving transplant from MSD or UD. Patients with a KPS score =80% or <80% were analyzed separately. In the group of patients with a KPS score of 80%, a RIC regimen was associated with higher RI (HR 1.4, p<0.01), higher incidence of severe cGVHD (HR 1.6, p<0.001), and inferior GRFS (HR 1.3, p<0.001) as compared to MAC. NRM was not significantly different following RIC or MAC in this population. In contrast, in patients with a KPS score <80%, RIC was associated with lower NRM (HR 0.3, p<0.0001) and better LFS (HR 0.6, p<0.01), OS (HR 0.5, p<0.0001) and GRFS (HR 0.6, p<0.01) as compared to MAC.
In conclusion, allo-HCT is feasible in patients with acute myeloid leukemia in first remission and KPS score <80%, with acceptable NRM and survival rates. As for the conditioning regimen, in patients with a KPS score of 80% a MAC regimen was associated with lower relapse rate, similar NRM and better GRFS as compared to RIC, while in patients with a KPS score lower than 80% RIC was associated with reduced NRM and improved OS as compared to MAC. In addition, transplant from a MSD predicted a reduced risk of NRM and aGVHD as compared to other donor types. Notably, 9/10 UD was associated with significantly inferior survival as compared to MSD. Finally, administration of ATG correlated with reduced acute and chronic GVHD and improved GRFS.
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Labopin:Jazz Pharmaceuticals: Honoraria. Kröger:Sanofi-Aventis: Research Funding; Celgene: Honoraria, Research Funding; DKMS: Research Funding; JAZZ: Honoraria; Medac: Honoraria; Neovii: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Riemser: Research Funding. Socie:Alexion: Consultancy. Blaise:Pierre Fabre medicaments: Honoraria; Jazz Pharmaceuticals: Honoraria; Sanofi: Honoraria; Molmed: Consultancy, Honoraria. Byrne:Ariad/Incyte: Honoraria, Speakers Bureau. Esteve:Astellas: Consultancy, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Roche: Consultancy; Pfizer: Consultancy. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.
Cyclosporine A (CsA) alone or in combination with mycophenolate mofetil (MMF) has been used as graft-versus-host-disease (GvHD) prophylaxis since the early development of reduced intensity ...conditioning (RIC). The association of CsA+MMF, while commonly used after transplantation from a matched unrelated donor (MUD), has never been tested in a large randomized prospective trial.
We retrospectively investigated the outcomes of adult patients with AML in complete remission (CR) undergoing a MUD transplant using CsA+MMF or CsA alone as GvHD prophylaxis, transplanted between 2007-2017 and registered with the ALWP of the EBMT.
Of the 497 patients who were evaluated, 183 received CsA alone and 314 received CsA+MMF. The median age at transplant was similar, being 59 (range, 20-75) years in the CsA group and 60 (range, 21-75) years in the CsA+MMF group. All patients underwent a RIC regimen with fludarabine and busulfan and received anti-thymocyte globulin as part of the conditioning. The median follow-up was 33 (range, 18-60) months in the CsA group and 34 (range, 18-75) months in the CsA+MMF group. Disease status at transplant was first complete remission (CR1) for 81% (n=149) in CsA group and 86% (n=268) in CsA+MMF group (p=NS). Poor risk cytogenetics was reported for 19% of patients who received GvHD prophylaxis with CsA alone and for 15% of patients receiving CsA+MMF (p=NS). Peripheral blood stem cells (PBSC) was the graft source in 93% of patients receiving CsA alone and in 96% of patients who received CsA+MMF (p=0.17). Female to male mismatch was present in 13% and 15% of patients in the CsA goup and CsA+MMF group respectively, (p=NS). All but 2 patients engrafted. The 100 day cumulative incidence (CI) of grade II-IV and grade III-IV GvHD were 30% and 10%, respectively. The 2-year CI chronic GvHD was 35% and CI of extensive cGvHD was 15%. The 2-year CI of non-relapse mortality (NRM) and relapse were 19% and 25%, respectively. Of the 81 patients who died in the CsA group, disease recurrence (n=31), GvHD (n=20) and infection (n=17) were the most common causes of death. One hundred twenty seven patients died in the CsA+MMF group; cause of death was relapse for 53, GvHD for 28 and infection for 28 of them. The 2-year GVHD-free relapse-free survival (GRFS), leukemia- free survival (LFS), and overall survival (OS) were 45%, 56% and 60%, respectively.
On multivariate analysis (MVA), no statistically significant differences were found among the two GvHD prophylaxis groups with respect to relapse, NRM, LFS, OS, acute and chronic GvHD.
A positive cytomegalovirus serology of the donor was associated with higher NRM HR=2.03, p<0.001 and higher cGvHD HR=1.44, p=0.03 and a lower OS HR 1.66, p<0.001, LFS HR=1.69, p=0.001 and GRFS HR=1.75, p<0.001.
In a subgroup analysis of patients in CR1 who received PBSC, (CsA alone, n=138; CsA+MMF, n=257), no differences were detected between the two groups for relapse, NRM, LFS, OS, or aGvHD, but patients who received CsA alone tended to have a higher cGvHD (41% vs 33%, p=0.05). However, on MVA, although the risk of cGvHD was lower in the CsA+MMF group, this finding was not statistically significant HR=0.67, p=0.08. Adverse cytogenetics was an independent risk factor for relapse HR=2.22, p<0.001.
In this study, we observed comparable outcomes in patients with AML in CR1 who underwent MUD transplantation and RIC with CsA+MMF or CsA alone as GvHD prophylaxis. This suggests that both strategies may be considered valid approaches. Additional randomized trials are needed to further assess which patients could benefit from the addition of MMF in GvHD prophylaxis.
Blaise:Pierre Fabre medicaments: Honoraria; Molmed: Consultancy, Honoraria; Sanofi: Honoraria; Jazz Pharmaceuticals: Honoraria. Socie:Alexion: Consultancy. Chevallier:Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria; Incyte: Consultancy, Honoraria. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.
Background: Providing achievement and sustainability of deep molecular responses (DMR), patients (pts) taking tyrosine kinase inhibitors (TKI) against CML may discontinue therapy. The STOP 2G-TKI ...observational study showed that dasatinib and nilotinib could be safely stopped and prior suboptimal response or resistance to imatinib was an adverse prognostic factor for treatment-free remission (TFR). We present updated results with a specific focus on the risk of relapse using post-baseline information during follow-up.
Methods: Adult CML pts treated with dasatinib or nilotinib without a history of allogeneic stem cell transplantation (ASCT) or progression to advanced phase stopped TKI provided that: (1) BCR-ABL transcripts were of the major type, (2) total TKI treatment duration was ≥36 months, (3) uMR4.5 had been achieved and maintained for ≥24 months (undetectable BCR-ABL with ≥32000 copies of ABL). Relapse was defined by loss of major molecular response (MMR: BCR-ABL IS >0.1%) on a single occasion and triggered TKI reintroduction. The primary objective was TFR at 12 months. After TKI discontinuation, BCR-ABL transcripts were monitored monthly during the first 6-12 months, every 3 months during the 2nd year and then every 3-6 months. Data as of July 1, 2019 are reported in 104 pts (median follow-up 55 months (range: 6-70)).
Results: Median age at inclusion was 56 years (range: 21-82) and 65.4% of pts were female. Sokal risk score was low in 49%, intermediate in 31%, high in 16% and unknown in 4%. 2G-TKIs were given after imatinib intolerance in 47% of pts, suboptimal response or resistance to imatinib in 22%, lack of DMR on imatinib in 3% and as 1st line treatment in 28%. Median duration of TKI, 2G-TKI and uMR4.5 was 74 months (range: 36-163), 49 months (range: 19-112) and 31 months (range: 24-72), respectively.
Overall, 43 pts (41%) lost MMR within a median time of 5 months (range: 1-59). Overall 60-month TFR was 56% (95% CI, 45.8-66.3) but TFR probabilities increased up to 64% (95% CI: 53.3-74.8), 76.7% (95% CI, 65.9-87.5), 86.2% (95% CI; 76.3-96.2), and 92.1% (95% CI: 83.4-100) for pts still in MMR at 3, 6, 12 and 18 months, respectively (Figure 1).
Prior suboptimal response or resistance to TKI was confirmed as the strongest adverse baseline prognostic factor with a 60-month TFR rate of 29.8% (95% CI; 10.8-48.7) (median TFR 12 months) versus 63.6% (95% CI; 52.1-75.2) (median not reached) in pts without such history (logrank p=0.0012). This was explained by significantly higher risk of early relapses (within 6 months but not later) in pts with prior suboptimal response or resistance to TKI (cumulative incidence of relapses by 6 months 47.8% (95% CI; 31.2-73.2) versus 20.9 (95% CI; 13.7-32) in other pts (p=0.00879)).
Landmark analyses at specific time points were performed to study the prognostic value of molecular responses categories after TKI discontinuation. All pts in MMR but not deeper at 3 months relapsed by month 9 (median time to relapse 4 months) while pts in ≥MR4 (BCR-ABL IS ≤0.01%) had 12- and 60-months probabilities of 86.8% (95% CI; 79.1-94.4) and 74.9% (95% CI: 64-85.7), respectively (logrank p<10-4). All pts but 1 in MMR but not deeper at 6 months relapsed (median time to relapse 12 months) while pts in ≥MR4 had 12- and 60-months probabilities of 95% (95% CI; 89.6-100) and 87.5% (95% CI: 78.7-96.2), respectively (logrank p<10-4).
Forty three pts restarted treatment including 1 who lost MR4.5 but not MMR and 42 who lost MMR. When treatment was reintroduced, 42 pts were in CHR and all regained MMR after a median time of 3 months (range: 1-11). The remaining pt lost MMR but not CHR 5 month after 1st line nilotinib cessation and was found in sudden myeloid blast crisis at the month 6 TKI reintroduction visit. No BCR-ABL mutation was found but an inversion of chromosome 3 at karyotyping analysis. The pt underwent ASCT after chemotherapy + ponatinib and is alive in remission 29 months later.
Conclusion: 2G-TKI may be successfully stopped in CML pts with long-lasting MR4.5. Those without a history of suboptimal response or resistance have greatest chances of success. Sudden blast crisis is rare but unpredictable. Post-TKI discontinuation estimates of TFR change overtime. Together with that of molecular response type at specific time points, they represent important dynamic prognostic measures of outcome. They may also help individualizing molecular monitoring programs after TKI cessation.
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Rea:Incyte Biosciences: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Nicolini:Sun Pharma Ltd: Consultancy; Incyte Biosciences: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Rousselot:Pfizer: Research Funding; Incyte: Research Funding. Etienne:Pfizer: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Guerci:INCYTE: Consultancy, Honoraria. Legros:Pfizer: Honoraria, Research Funding; BMS: Honoraria; Novartis: Honoraria; Incyte Biosciences: Honoraria, Research Funding. Coiteux:Pfizer: Honoraria; BMS: Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Mahon:Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau.
Noninfectious manifestations—allergy, autoimmunity/inflammation, lymphoproliferation, and malignancies—are known to exist in many primary immunodeficiency diseases (PID) and to participate in ...prognosis.
To obtain a global view on their occurrence, we retrieved data from a retrospective cohort of 1375 patients included in the French National Reference Center for Primary Immune Deficiencies (CEREDIH) for whom we had a 10-year follow-up since inclusion in the registry.
These patients were followed for 10 years (2009-2018) by specialized centers in university hospitals. This study showed that 20.1% of patients without prior curative therapy (n = 1163) developed at least 1 manifestation (event) encompassing 277 events.
Autoimmune/inflammatory events (n = 138) and malignancies (n = 85) affected all age classes and virtually all PID diagnostic groups. They were associated with a risk of death that occurred in 195 patients (14.2%) and were found to be causal in 43% of cases. Malignancies (odds ratio, 5.62; 95% confidence interval, 3.66-8.62) and autoimmunity (odds ratio, 1.9; 95% confidence interval, 1.27-2.84) were clearly identified as risk factors for lethality. Patients who underwent curative therapy (mostly allogeneic hematopoietic stem cell transplantation, with a few cases of gene therapy or thymus transplantation) before the 10-year study period (n = 212) had comparatively reduced but still detectable clinical manifestations (n = 16) leading to death in 9.4% of them.
This study points to the frequency and severity of noninfectious manifestations in various PID groups across all age groups. These results warrant further prospective analysis to better assess their consequences and to adapt therapy, notably indication of curative therapy.
L’incompatibilité ABO n’est pas une contre-indication à la greffe de Cellules Souches Hématopoïétiques (CSH). Les traitements appliqués au greffon - désérythrocytation dans les incompatibilités ABO ...majeures ou déplasmatisation dans les incompatibilités ABO mineures - permettent de réduire le risque d’hémolyse et de mauvaise reconstitution érythrocytaire (érythroblastopénie). Les anticorps dirigés contre des antigènes non-ABO (ex. anti-RH ou anti-JK) sont aussi impliqués dans les hémolyses post-allogreffe immédiates ou retardées. Ils peuvent être présents avant la greffe chez le donneur ou le receveur du fait d’antécédents transfusionnels ou obstétricaux, mais peuvent aussi apparaître après la greffe, à la suite de transfusions de concentrés plaquettaires. Il existe un autre mécanisme pouvant expliquer l’apparition d’anticorps en post-allogreffe. Il s’agit du syndrome du lymphocyte passager (PLS) initialement décrit dans les incompatibilités ABO mineures. Les lymphocytes B du donneur contenus dans le greffon sont transférés chez le receveur et produisent des anticorps dirigés contre les antigènes érythrocytaires du receveur. De nombreux cas de PLS post-greffe d’organes (foie, rein, poumon) ou de CSH ont été décrits dans la littérature. Nous présentons un cas de PLS post-greffe de CSH dont la particularité est une immunisation tardive (anti-E+anti-c) détectée 8 mois après la greffe alors que le délai d’apparition moyen des anticorps dans le PLS est de 1 à 3 semaines après la greffe.
Background
Three different scoring systems have been developed to assess pre‐transplant comorbidity in allogeneic hematopoietic stem cell transplantation (Allo‐HSCT): the Hematopoietic Cell ...Transplantation‐Specific Comorbidity Index, the Comorbidity/Age index, and the Augmented Comorbidity/Age index. All were devised to predict overall survival (OS) and disease‐free survival (DFS) survivals and non‐relapse mortality (NRM) in patients receiving HLA‐matched Allo‐HSCT, but their performance has scarcely been studied in the haploidentical Allo‐HSCT setting with post‐transplant cyclophosphamide, a procedure in constant expansion worldwide.
Methods
To address this issue, their impact on survivals and NRM was examined in a cohort of 223 patients treated with haploidentical Allo‐HSCT in four different centers.
Results
With a median follow‐up of 35.6 months, 3‐year OS, DFS, and NRM were 48.1% ± 4%, 46.3% ± 4%, and 30.0% ± 3%, respectively. No impact was found for any of the three comorbidity scores in univariate analysis. In multivariate analyses, the only three factors associated with lower OS were DRI (p < 0.001), an older age of recipients (≥55 years old, p = 0.02) and of donors (≥40 years old, p = 0.005). Older donor age was also associated with lower DFS and higher NRM.
Conclusion
The comorbidity scores do not predict survivals nor NRM in haploidentical Allo‐HSCT with PTCY, suggesting that pre‐transplant comorbidities should not be a contra‐indication to this procedure.
Three different scoring systems have been developed to assess pre‐transplant comorbidity in allogeneic hematopoietic stem cell transplantation: the Hematopoietic Cell Transplantation‐Specific Comorbidity Index, the Comorbidity/Age index, and the Augmented Comorbidity/Age index, but their performance has scarcely been studied in the haploidentical stem cell transplantation setting with post‐transplant cyclophosphamide, a procedure in constant expansion worldwide. To address this issue, their impact was examined in a cohort of 223 patients from four French centers treated with haploidentical stem cell transplantation. No impact was found for any of the three comorbidity scores in this study, suggesting that pre‐transplant comorbidities should not be a contra‐indication to this procedure.
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