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Nilotinib in steroid-refractory cGVHD: prospective parallel evaluation of response, according to NIH criteria and exploratory response criteria (GITMO criteria)

Olivieri, A; Mancini, G; Olivieri, J; Marinelli Busilacchi, E; Cimminiello, M; Pascale, S P; Nuccorini, R; Patriarca, F; Corradini, P; Bacigalupo, A; Angelini, S; Poloni, A; Grillo, G; Onida, F; Martino, M; Di Renzo, N; Nagler, A; Mordini, N; Bruno, B; Ciceri, F; Bonifazi, F
We conducted a phase I-II study to evaluate Nilotinib (NIL) safety and pharmacokinetics in 22 SR-cGVHD patients; we also evaluated ORR by using in parallel NIH criteria and an exploratory approach, combining objective improvement (OI) without failure criteria (GITMO criteria). Results: 22 patients were enrolled. After dose escalation up to 600 mg/day, MTD was not reached. Main toxicities were asthenia, headache, nausea, pruritus, cramps, and mild anemia. Mean and median plasma concentrations of NIL (C-NIL) were 817 (SD ± 450) and 773 ng/ml. ORR at 6 months, according to 2005 and 2014 NIH and GITMO criteria were 27.8%, 22.2%, and 55.6% respectively; close correspondence has been observed for ORR, according to 2014 NIH criteria, both assessed in a conventional way and assisted by dedicated software (CROSY). At 48 months OS was 75% while FFS, according to NIH and GITMO criteria, was 30 and 25%. In conclusion the safety profile of NIL and long-term outcome makes NIL an attractive option in SR-cGVHD. Exploratory GITMO criteria could represent an alternative tool for easy response evaluation in patients with prevalent skin and lung involvement, but require validation in a larger population; CROSY software showed excellent reliability in capturing ORR according to the 2014 NIH criteria.
PMID: 32332918
ISSN: 1476-5365
CID: 4727462

Immunomodulatory and clinical effects of daratumumab in T-cell acute lymphoblastic leukaemia [Letter]

Cerrano, Marco; Castella, Barbara; Lia, Giuseppe; Olivi, Matteo; Faraci, Danilo G; Butera, Sara; Martella, Federica; Scaldaferri, Matilde; Cattel, Francesco; Boccadoro, Mario; Massaia, Massimo; Ferrero, Dario; Bruno, Benedetto; Giaccone, Luisa
PMID: 32686081
ISSN: 1365-2141
CID: 4531892

Timing of Post-Transplantation Cyclophosphamide Administration in Haploidentical Transplantation: A Comparative Study on Behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

Ruggeri, Annalisa; Labopin, Myriam; Battipaglia, Giorgia; Chiusolo, Patrizia; Tischer, Johanna; Diez-Martin, Jean Luiz; Bruno, Benedetto; Castagna, Luca; Moiseev, Ivan Sergeevich; Vitek, Antonin; Rovira, Montserrat; Ciceri, Fabio; Bacigalupo, Andrea; Nagler, Arnon; Mohty, Mohamad
The timing of immunosuppressive therapy used in combination with post-transplantation cyclophosphamide (PTCY) in haploidentical hematopoietic stem cell transplant (haplo-HSCT) is not standardized. We evaluated the schedules of immunosuppression therapy after haplo-HSCT in 509 patients with acute leukemia receiving PTCY on days +3 and +4 along with tacrolimus (group 1; n = 215), with cyclosporine A (CSA) and mycophenolate mofetil (MMF) from day +5 (group 2; n = 170), or CSA + MMF from day 0 or 1 with PTCY on days +3 and +5 (group 3; n = 124). Compared with the other 2 groups, patients in group 3 were younger (median age, 46 years; P = .02) and more often received bone marrow (77%; P < .01) and a regimen containing thiotepa, fludarabine, and busulfan (84%; P< .01). At 2 years, overall survival was 44% was in group 1, 48% in group 2, and 59% in group 3 (P= .15); leukemia-free survival (LFS) was 43%, 46%, and 53% (P= .05); and refined graft-versus-host disease-free, relapse-free survival (rGRFS) was 33%, 39%, and 36% (P = .02). The incidence of grade II-IV acute GVHD was 25% in group 1, 39% in group 2, and 18% in group 3 (P< .01); incidence of chronic GVHD was 25%, 21%, and 24% (P= .50); relapse incidence was 36%, 37%, and 26% (P= .02); and nonrelapse mortality was 26%, 20%, and 21% (P= .35). On multivariate analysis, early start of immunosuppression therapy at day +1 followed by PTCY was associated with a better LFS (hazard ratio [HR], .58; P= .02) and improved rGRFS (HR, .62; P = .02). In this study, the timing of immunosuppression influenced the outcomes of haplo-HSCT with PTCY. An early start of CSA + MMF with PTCY administered on days +3 and +5 improves LFS and rGRFS.
PMID: 32645444
ISSN: 1523-6536
CID: 4600732

Refractory and 17p-deleted chronic lymphocytic leukemia: improving survival with pathway inhibitors and allogeneic stem cell transplantation

Farina, L; Barretta, F; Scarfò, L; Bruno, B; Patriarca, F; Frustaci, A M; Coscia, M; Salvetti, C; Quaresmini, G; Fanin, R; Onida, F; Magagnoli, M; Zallio, F; Vallisa, D; Reda, G; Ferrario, A; Corradini, P; Montillo, M
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 treatment with allogeneic stem cell transplantation (alloSCT). In this multicenter retrospective analysis of 157 patients, we compared the outcomes of patients with high-risk CLL treated with alloSCT, a B-cell receptor pathway inhibitor (BCRi), and both. Seventy-one patients were treated with BCRis, 67 patients underwent reduced-intensity conditioning alloSCT, and 19 received alloSCT with a BCRi before and/or after transplantation. Inverse probability of treatment weighting analyses were performed to compare the alloSCT and no-alloSCT groups; in the 2 groups, 5-year OS, PFS, and cumulative incidence of nonrelapse mortality (NRM) and relapse were 40% versus 60% (P = .096), 34% versus 17% (P = .638), 28% versus 5% (P = .016), and 38% versus 83% (P = .005), respectively. Patients treated with alloSCT plus BCRi had a 3-year OS of 83%. The 3-year OS and NRM by year of alloSCT, including patients treated with BCRi, were 53% and 17% in 2000 to 2007, 55% and 30% in 2008 to 2012, and 72% and 18% in 2013 to 2018. In conclusion, the combination of pathway inhibitors and alloSCT is feasible and may further improve the outcome of high-risk CLL patients.
PMID: 32653626
ISSN: 1523-6536
CID: 4727702

Netupitant-palonosetron to prevent chemotherapy-induced nausea and vomiting in multiple myeloma patients receiving high-dose melphalan and autologous stem cell transplantation [Letter]

Apolito, Vincenzo; Giaccone, Luisa; Ferrero, Simone; Larocca, Alessandra; Cavallo, Federica; Coscia, Marta; Beggiato, Eloise; Butera, Sara; Martella, Federica; Dainese, Cristina; Cetani, Giusy; Scaldaferri, Matilde; Cattel, Francesco; Boccadoro, Mario; Ferrero, Dario; Bruno, Benedetto; Cerrano, Marco
PMID: 32661577
ISSN: 1432-0584
CID: 4528042

Long-term survival of 1338 MM patients treated with tandem autologous vs. autologous-allogeneic transplantation

Costa, Luciano J; Iacobelli, Simona; Pasquini, Marcelo C; Modi, Riddhi; Giaccone, Luisa; Blade, Joan; Schonland, Stefan; Evangelista, Andrea; Perez-Simon, Jose A; Hari, Parameswaran; Brown, Elizabeth E; Giralt, Sergio A; Patriarca, Francesca; Stadtmauer, Edward A; Rosinol, Laura; Krishnan, Amrita Y; Gahrton, Gösta; Bruno, Benedetto
Contrary to tandem autologous transplant (auto-auto), autologous followed by reduced intensity conditioning allogenic transplantation (auto-allo) offers graft-versus-myeloma (GVM) effect but with higher toxicity. Trials comparing these two strategies relied on availability of HLA-matched sibling donors for arm allocation (biological randomization) and yielded conflicting results. A pooled analysis of multiple trials with extended follow up provides an opportunity to compare these strategies. We obtained individual patient data from participants of four trials comparing auto-auto vs. auto-allo after induction therapy. There were 899 patients in auto-auto and 439 in auto-allo. Median follow up of survivors was 118.5 months. Median overall survival (OS) was 78.0 months in auto-auto and 98.3 months in auto-allo (HR = 0.84, P = 0.02). OS was 36.4% vs. 44.1% at 10 years (P = 0.01) for auto-auto and auto-allo, respectively. Progression-free survival was also improved in auto-allo (HR = 0.84, P = 0.004). Risk of non-relapse mortality was higher in auto-allo (10 year 8.3% vs. 19.7%, P < 0.001), while risk of disease progression was higher in auto-auto (10 year 77.2% vs. 61.6%, P < 0.001). Median post relapse survival was 41.5 months in auto-auto and 62.3 months in auto-allo (HR = 0.71, P < 0.001). This supports the existence of durable GVM effect enhancing myeloma control with subsequent therapies.
PMID: 32286506
ISSN: 1476-5365
CID: 4600682

Impact of donor age and kinship on clinical outcomes after T-cell-replete haploidentical transplantation with PT-Cy

Mariotti, Jacopo; Raiola, Anna Maria; Evangelista, Andrea; Carella, Angelo Michele; Martino, Massimo; Patriarca, Francesca; Risitano, Antonio; Bramanti, Stefania; Busca, Alessandro; Giaccone, Luisa; Brunello, Lucia; Merla, Emanuela; Savino, Lucia; Loteta, Barbara; Console, Giuseppe; Fanin, Renato; Sperotto, Alessandra; Marano, Luana; Marotta, Serena; Frieri, Camilla; Sica, Simona; Chiusolo, Patrizia; Harbi, Samia; Furst, Sabine; Santoro, Armando; Bacigalupo, Andrea; Blaise, Didier; Angelucci, Emanuele; Mavilio, Domenico; Castagna, Luca; Bruno, Benedetto
Donor selection contributes to improve clinical outcomes of T-cell-replete haploidentical stem cell transplantation (haplo-SCT) with posttransplant cyclophosphamide (PT-Cy). The impact of donor age and other non-HLA donor characteristics remains a matter of debate. We performed a multicenter retrospective analysis on 990 haplo-SCTs with PT-Cy. By multivariable analysis, after adjusting for donor/recipient kinship, increasing donor age and peripheral blood stem cell graft were associated with a higher risk of grade 2 to 4 acute graft-versus-host-disease (aGVHD), whereas 2-year cumulative incidence of moderate-to-severe chronic GVHD was higher for transplants from female donors into male recipients and after myeloablative conditioning. Increasing donor age was associated with a trend for higher nonrelapse mortality (NRM) (hazard ratio [HR], 1.05; P = .057) but with a significant reduced risk of disease relapse (HR, 0.92; P = .001) and improved progression-free survival (PFS) (HR, 0.97; P = .036). Increasing recipient age was a predictor of worse overall survival (OS). Risk of relapse was higher (HR, 1.39; P < .001) in patients aged ≤40 years receiving a transplant from a parent as compared with a sibling. Moreover, OS and PFS were lower when the donor was the mother rather than the father. Pretransplant active disease status was an invariably independent predictor of worse clinical outcomes, while recipient positive cytomegalovirus serostatus and hematopoietic cell transplant comorbidity index >3 were associated with worse OS and PFS. Our results suggest that younger donors may reduce the incidence of aGVHD and NRM, though at higher risk of relapse. A parent donor, particularly the mother, is not recommended in recipients ≤40 years.
PMID: 32813875
ISSN: 2473-9537
CID: 4600762

Impact of total body irradiation- vs chemotherapy-based myeloablative conditioning on outcomes of haploidentical hematopoietic cell transplantation for acute myelogenous leukemia

Dholaria, Bhagirathbhai; Labopin, Myriam; Angelucci, Emanuele; Ciceri, Fabio; Diez-Martin, Jose L; Bruno, Benedetto; Sica, Simona; Koc, Yener; Gülbas, Zafer; Schmid, Christoph; Blaise, Didier; Carella, Angelo Michele; Visani, Guiseppe; Savani, Bipin N; Nagler, Arnon; Mohty, Mohamad
The optimal myeloablative conditioning (MAC) for patients undergoing haploidentical hematopoietic cell transplantation (haplo-HCT) is unknown. We studied the outcomes of total body irradiation (TBI) vs chemotherapy (CT) based MAC regimens in acute myeloid leukemia (AML) patients. The study included 1008 patients who underwent first haplo-HCT with post-transplant cyclophosphamide, following TBI (N = 89, 9%) or CT (n = 919, 91%) based MAC. Patients in the TBI cohort were younger (median age, 38 vs 47 years, P < .01) and more likely to receive BM graft (57% vs 43%, P = .01). Two-year overall chronic GVHD (cGVHD) incidence was 42% vs 27% (P < .01) and extensive cGVHD incidence was 9% vs 12% (P = .33) in TBI and CT cohorts, respectively. Graft failure was reported in two (2%) TBI- and 65 (7%) CT-MAC recipients (P = .08). Death from veno-occlusive disease was reported in one (3%) TBI and 11 (3%) CT patients who died during the study period. In the multivariate analysis, TBI was associated with increased risk for overall cGVHD (hazard ratio = 1.95, 95% confidence interval:1.2-3.1, P < .01) compared to CT-based MAC. The choice of conditioning regimen did not impact relapse incidence, leukemia-free survival, non-relapse mortality, overall survival or GVHD-relapse-free survival in multivariate analysis. In conclusion, major transplant outcomes were not statistically different between TBI-based MAC and CT-based MAC in patients with AML after haplo-HCT/PTCy.
PMID: 32656791
ISSN: 1096-8652
CID: 4600752

Organ Stiffness in the Work-Up of Myelofibrosis and Philadelphia-Negative Chronic Myeloproliferative Neoplasms

Benedetti, Edoardo; Tavarozzi, Rita; Morganti, Riccardo; Bruno, Benedetto; Bramanti, Emilia; Baratè, Claudia; Balducci, Serena; Iovino, Lorenzo; Ricci, Federica; Ricchiuto, Vittorio; Buda, Gabriele; Galimberti, Sara
To define the role of spleen stiffness (SS) and liver stiffness (LS) in myelofibrosis and other Philadelphia (Ph)-negative myeloproliferative neoplasms (MPNs), we studied, by ultrasonography (US) and elastography (ES), 70 consecutive patients with myelofibrosis (MF) (no.43), essential thrombocythemia (ET) (no.10), and polycythemia vera (PV) (no.17). Overall, the median SS was not different between patients with MF and PV (p = 0.9); however, both MF and PV groups had significantly higher SS than the ET group (p = 0.011 and p = 0.035, respectively) and healthy controls (p < 0.0001 and p = 0.002, respectively). In patients with MF, SS values above 40 kPa were significantly associated with worse progression-free survival (PFS) (p = 0.012; HR = 3.2). SS also correlated with the extension of bone marrow fibrosis (BMF) (p < 0.0001). SS was higher in advanced fibrotic stages MF-2, MF-3 (W.H.O. criteria) than in pre-fibrotic/early fibrotic stages (MF-0, MF-1) (p < 0.0001) and PFS was significantly different in the two cohorts, with values of 63% and 85%, respectively (p = 0.038; HR = 2.61). LS significantly differed between the patient cohort with MF and healthy controls (p = 0.001), but not between the patient cohorts with ET and PV and healthy controls (p = 0.999 and p = 0.101, respectively). We can conclude that organ stiffness adds valuable information to the clinical work-up of MPNs and could be employed to define patients at a higher risk of progression.
PMID: 32650390
ISSN: 2077-0383
CID: 4600742

Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease

Zeiser, Robert; von Bubnoff, Nikolas; Butler, Jason; Mohty, Mohamad; Niederwieser, Dietger; Or, Reuven; Szer, Jeff; Wagner, Eva M; Zuckerman, Tsila; Mahuzier, Bruyère; Xu, Judith; Wilke, Celine; Gandhi, Kunal K; Socié, Gérard; [Bruno, B; et al]
BACKGROUND:Acute graft-versus-host disease (GVHD) remains a major limitation of allogeneic stem-cell transplantation; not all patients have a response to standard glucocorticoid treatment. In a phase 2 trial, ruxolitinib, a selective Janus kinase (JAK1 and JAK2) inhibitor, showed potential efficacy in patients with glucocorticoid-refractory acute GVHD. METHODS:We conducted a multicenter, randomized, open-label, phase 3 trial comparing the efficacy and safety of oral ruxolitinib (10 mg twice daily) with the investigator's choice of therapy from a list of nine commonly used options (control) in patients 12 years of age or older who had glucocorticoid-refractory acute GVHD after allogeneic stem-cell transplantation. The primary end point was overall response (complete response or partial response) at day 28. The key secondary end point was durable overall response at day 56. RESULTS:A total of 309 patients underwent randomization; 154 patients were assigned to the ruxolitinib group and 155 to the control group. Overall response at day 28 was higher in the ruxolitinib group than in the control group (62% [96 patients] vs. 39% [61]; odds ratio, 2.64; 95% confidence interval [CI], 1.65 to 4.22; P<0.001). Durable overall response at day 56 was higher in the ruxolitinib group than in the control group (40% [61 patients] vs. 22% [34]; odds ratio, 2.38; 95% CI, 1.43 to 3.94; P<0.001). The estimated cumulative incidence of loss of response at 6 months was 10% in the ruxolitinib group and 39% in the control group. The median failure-free survival was considerably longer with ruxolitinib than with control (5.0 months vs. 1.0 month; hazard ratio for relapse or progression of hematologic disease, non-relapse-related death, or addition of new systemic therapy for acute GVHD, 0.46; 95% CI, 0.35 to 0.60). The median overall survival was 11.1 months in the ruxolitinib group and 6.5 months in the control group (hazard ratio for death, 0.83; 95% CI, 0.60 to 1.15). The most common adverse events up to day 28 were thrombocytopenia (in 50 of 152 patients [33%] in the ruxolitinib group and 27 of 150 [18%] in the control group), anemia (in 46 [30%] and 42 [28%], respectively), and cytomegalovirus infection (in 39 [26%] and 31 [21%]). CONCLUSIONS:Ruxolitinib therapy led to significant improvements in efficacy outcomes, with a higher incidence of thrombocytopenia, the most frequent toxic effect, than that observed with control therapy. (Funded by Novartis; REACH2 number, NCT02913261.).
PMID: 32320566
ISSN: 1533-4406
CID: 4727712