The Transplant Centers belonging to Gruppo Italiano per il Trapianto di Midollo Osseo (GITMO) conducted a survey with the aim of evaluating the effect of SARS-CoV2 pandemic on the allogeneic ...transplant activity in Italy. The pandemic period from 1/3/2020 to 31/7/2020 was compared with the same period in 2019. Overall, in 2020 there was a 2.4% reduction in the number of allo-HCT cases compared to 2019. Interestingly, this deflection did not affect the acute leukemia cases (+5.7% in 2020). The use of peripheral blood-derived stem cells (+10.7%) and cryopreservation (97.4% of the centers) was highly adopted in 2020. Despite the sanitary emergency, almost all of the surveyed centers declared no impact of SARS-CoV2 pandemic on the transplant timing and outcomes, and the sanitary policy was positively evaluated by the majority of centers. The emergency measures ensured that only a minority of the allo-HCT patients had been infected by SARS-CoV2; however, a mortality of 42.1% among the allo-HCT patients hospitalized for COVID-19 was recorded. This survey gives us the information that the GITMO Group reacted positively to the pandemic. Thanks to the emergency strategies, the Italian allo-HCT activity continued safely, showing only a minor deflection and offering the same probability of cure to the transplanted patients.
Patients with acute graft-
-host disease (GvHD) grade I were randomized to an observation arm (n=85) or to a treatment arm (n=86) consisting of 6-methylprednisolone 1 mg/kg/day, after stratification ...for age and donor type. The primary end point was development of grade II-IV GvHD. The cumulative incidence of grade II-IV GvHD was 50% in the observation arm and 33% in the treatment arm (
=0.005). However, grade III-IV GvHD was comparable (13%
10%, respectively;
=0.6), and this was true for sibling and alternative donor transplants. Moderate/severe chronic GvHD was also comparable (17%
9%). In multivariate analysis, an early interval between transplant and randomization (<day +20) was the only negative predictor of grade III-IV GvHD. Patients in the observation arm had less infectious bacterial episodes (12
25;
=0.04), less severe infectious fungal episodes (0
3;
=0.04), and less severe adverse events (3
11;
=0.07). At five years, non-relapse mortality was 20%
26% (
=0.2), relapse-related mortality 25%
21%, and actuarial survival was 51%
41% (
=0.3) in the observation and treatment arms, respectively. In multivariate analysis, advanced disease phase, older age and an early onset of GvHD were significant negative predictors of survival, independent of the randomization arm. In conclusion, steroid treatment of acute grade I GvHD prevents progression to grade II but not to grade III-IV GvHD, and there is no effect on non-relapse mortality and survival. Patients treated with steroids are at a higher risk of developing infections and have more adverse events. (
).
We conducted a retrospective multicenter study including pediatric and adult patients with acute leukemia (AL) who received donor lymphocyte infusions (DLIs) after allogeneic hematopoietic stem cell ...transplantation (HCT) between January 1, 2010 and December 31, 2015, in order to determine the efficacy and toxicity of the immune treatment. Two hundred fifty-two patients, median age 45.1 years (1.6–73.4), were enrolled from 34 Italian transplant centers. The underlying disease was acute myeloid leukemia in 180 cases (71%). Donors were HLA identical or 1 locus mismatched sibling (40%), unrelated (40%), or haploidentical (20%). The first DLI was administered at a median time of 258 days (55–3,784) after HCT. The main indication for DLI was leukemia relapse (73%), followed by mixed chimerism (17%), and pre-emptive/prophylactic use (10%). Ninety-six patients (38%) received one single infusion, whereas 65 (26%), 42 (17%), and 49 patients (19%) received 2, 3, or ≥4 infusions, respectively, with a median of 31 days between two subsequent DLIs. Forty percent of evaluable patients received no treatment before the first DLI, whereas radiotherapy, conventional chemotherapy or targeted treatments were administered in 3, 39, and 18%, respectively. In informative patients, a few severe adverse events were reported: grade III–IV graft versus host disease (GVHD) (3%), grade III–IV hematological toxicity (11%), and DLI-related mortality (9%). Forty-six patients (18%) received a second HCT after a median of 232 days (32–1,390) from the first DLI. With a median follow-up of 461 days (2–3,255) after the first DLI, 1-, 3-, and 5- year overall survival (OS) of the whole group from start of DLI treatment was 55, 39, and 33%, respectively. In multivariate analysis, older recipient age, and transplants from haploidentical donors significantly reduced OS, whereas DLI for mixed chimerism or as pre-emptive/prophylactic treatment compared to DLI for AL relapse and a schedule including more than one DLI significantly prolonged OS. This GITMO survey confirms that DLI administration in absence of overt hematological relapse and multiple infusions are associated with a favorable outcome in AL patients. DLI from haploidentical donors had a poor outcome and may represent an area of further investigation.
What is known and objective
The aim of this survey, conducted by the Gruppo Italiano per il Trapianto di Midollo Osseo (GITMO), was to evaluate the involvement of pharmacists in the haematopoietic ...stem cell transplant (HSCT) program in Italian adult and paediatric centres.
Methods
A 63‐item online questionnaire was developed and sent to the Italian Transplant Programs on behalf of GITMO.
Results and discussion
Overall, 54.7% of the Italian HSCT centres participated in the survey (88.5% adult, 7.7% paediatric, 3.8% mixed), of which 50% were in public hospitals and 50% affiliated with public universities. Just over 80% declared that a pharmacist is involved in the HSCT centre, and 86.5% reported the presence of a documentation system to signal of adverse events, accessible by physicians, nurses and pharmacists in 57.7%. Chemotherapy drugs were centralized in the pharmacy in 98.1% of HSCT centres, while parenteral nutrition was centralized in 55.8%. The use of off‐label drugs was authorized by an internal committee and by the regional health authorities in 88.5% of the centres. On univariate analysis, few statistically significant differences were found on response frequencies between public hospitals and university centres or between HSCT centres performing only autologous stem cell transplantation versus other centres performing autologous and allogeneic stem cell transplantation.
What is new and conclusion
This survey suggests that there is good collaboration between pharmacists and physicians and nurses in Italian HSCT transplantation centres. The enhancement of pharmacists dedicated to HSCT programs could improve some problems, for example, the centralization of parenteral nutrition.
Introduction: HLA molecules play an important role for immunoreactivity in allogeneic hematopoietic stem cell transplantation (HSCT). To elucidate the effect and the potential identification of ...“permissive” and “non permissive” I and II class HLA mismatching (mm) loci on the early and long term transplant outcome, we conducted a retrospective/prospective observational analysis on 1789 patients transplanted with unmanipulated haematopoietic stem cells from a volunteer unrelated donor (URD).
Methods Between January 2012 to December 2015, 1789 adult patients with a median age of 49 years (18-70) affected by haematological malignant diseases, performed an unrelated HSCT, coordinated by the Italian Bone Marrow Donor Registry (IBMDR). All patients have been typed by high resolution (HR) HLA typing for HLA-A/B/C/DRB1/DQB1 loci, at the start of the donor's search process. Patient and donor characteristics are shown in Table 1. As conditioning regimen and GVHD prophylaxis, 71% of patients received a myeloablative conditioning and 76% a combination of anti-Thymoglobuline, Cyclosporine and Metotrexate short course. Total Body Irradiation was part of conditioning regimen in 14% of cases and PBSC was used as stem cell source in 80% of transplants. Median follow for survivors was 38 months (1-76). Regarding to the allelic compatibility, 890 (50%) of donor/recipient (D/R) pairs were 10/10 HLA matched, 677 (38%) showed 1 mm for A, B, C, DRB1 or DQB1 in 249, 141, 173, 2 and 112 cases, respectively and 222 (12%) received HSCT from a 8/10 or less HLA matched donor.
Results: Overall 90% and 79% of patients achieved PMN and PLTS engraftment within 30 and 90 days, respectively. Probabilities of 3-y Overall Survival (3-yr OS), Progression Free Survival (3-yr PFS), and Graft Relapse Free Survival (3-yr GRFS) were 52%, 42%, and 30%, respectively. The 3-y CI of Transplant Related Mortality (TRM) was 26%, with a 100-days CI of acute GVHD ≥2 of 26%, whereas the 3-yr CI of chronic GVHD was 30%, of which 10% extensive. Cox multivariate analysis showed that, compared to 10/10 HLA-matched HSCT, 9/10 and ≤8/10 HLA-matched HSCT were associated with worse outcomes in terms of OS (HR 1.16, p=0.04 and HR 1.3, p=0.007, respectively), GRFS (HR 1.2, p=0.005 and HR 1.2, p=0.07, respectively), TRM (HR 1.3, p=0.007 and HR 1.6, p<0.0001, respectively), grade 3-4 aGVHD (HR 1.8, p=0.0001 and HR 1.8, p=0.01, respectively) and cGvHD (HR 1.3, p=0.005 and HR 1.1, p=0.35, respectively). Notably, no significant differences occurred through the comparison between ≤8/10 and 9/10 matching. Univariate comparisons are shown in Figure 1. Moreover, in order to identify permissive and non permissive allelic mismatching, we analyzed the donor/recipient pairs with a single HLA mm with a frequency > 5%: the presence of A02:01 in the patient's HLA, after adjustment for HLA matching at the other loci and other clinical variables known to affect HSCT outcome, was associated with significant higher risk of TRM (HR 1.9, p= 0.03) and worst OS (HR 1.7, p=0.04). Patient's age > 49 years (p<0.0001), advanced disease stage (p<0.0001), presence of 1 or more co- morbidity according to the Sorror Hematopoietic Cell Transplant-Comorbidity Index (p=0.01) were associated with a hazard risk of 1.4, 2, 1.2 for OS and 1.6, 1.75, 1.4 for TRM. Moreover, the Italian origin of recipient and donor resulted in reduced grade 2-4 acute (HR=0.6, p=0.001) and chronic GVHD (p=0.002, HR=0.4). Finally, the Transplant Program expertise (>10 HSCT/year) is associated with reduced TRM (HR 0.8, p=0.0001), HSCT from female donor to male recipient was associated with higher risk of extensive cGvHD (HR 1.4, p=0.03), and CMV negative/negative status versus other combinations had protective effect on development of grade 3-4 aGVHD (HR 0.56, p=0.04).
Conclusions: Our large cohort data of homogeneously treated 1789 URD transplants, show that 10/10 HLA matching remains a significantly favorable prognostic factor for OS, TRM, GRFS and acute/chronic GVHD, whereas there are no significant differences between 8/10 and 9/10 matching transplants. Moreover, the HLA A02:01 as single mm seems to play a “non permissive” role. Finally the Italian origin of recipient and donor is related to a reduced development of GVHD probably due to the matching of the extended MHC haplotypes in individuals of the same geographic origin.
Rambaldi:Amgen Inc.: Consultancy; Pfizer: Consultancy; Celgene: Consultancy; Omeros: Consultancy; Roche: Consultancy; Novartis: Consultancy; Italfarmaco: Consultancy. Vago:Moderna TX: Research Funding; GENDX: Research Funding. Patriarca:Janssen: Other: Advisory role; Jazz: Other: Travel, accommodations, expenses; Medac: Other: Travel, accommodations, expenses; Celgene: Other: Advisory Role; Travel, accommodations, expenses; MSD Italy: Other: Advisory Role.
Today, allogeneic stem cell transplantation (allo-SCT) can be offered to patients up to age 70 to 72 years and represents one of the most effective curative treatments for many hematologic ...malignancies. The primary objective of the study was to collect data from the allo-SCTs performed in Italy between 2000 and 2017 in patients aged ≥60 years to evaluate the changes in safety and efficacy outcomes, as well as their distribution and characteristics over time. The Italian Group for Bone Marrow Transplantation, Hematopoietic Stem Cells and Cell Therapy (GITMO) AlloEld study (ClinicalTrials.gov identifier NCT04469985) is a retrospective analysis of allo-SCTs performed at 30 Italian transplantation centers in older patients (age ≥60 years) between 2000 and 2017 (n = 1996). For the purpose of this analysis, patients were grouped into 3 time periods: time A, 2000 to 2005 (n = 256; 12%); time B, 2006 to 2011 (n = 584; 29%); and time C, 2012 to 2017 (n = 1156; 59%). After a median follow-up of 5.6 years, the 5-year nonrelapse mortality (NRM) remained stable (time A, 32.8%; time B, 36.2%; and time C, 35.0%; P = .5), overall survival improved (time A, 28.4%; time B, 31.8%; and time C, 37.3%; P = .012), and the cumulative incidence of relapse was reduced (time A, 45.3%; time B, 38.2%; time C, 30.0%; P < .0001). The 2-year incidence of extensive chronic graft-versus-host disease was reduced significantly (time A, 17.2%; time B, 15.8%; time C, 12.2%; P = .004). Considering times A and B together (2000 to 2011), the 2-year NRM was positively correlated with the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) score; NRM was 25.2% in patients with an HCT-CI score of 0, 33.9% in those with a score of 1 or 2, and 36.1% in those with a score of 3 (P < .001). However, after 2012, the HCT-CI score was not significantly predictive of NRM. This study shows that the transplantation procedure in elderly patients became more effective over time. Relapse incidence remains the major problem, and strategies to prevent it are currently under investigation (eg, post-transplantation maintenance). The selection of patients aged ≥60 could be improved by combining HCT-CI and frailty assessment to better predict NRM.
A survey within hematopoietic stem cell transplant (HSCT) centers of the Gruppo Italiano Trapianto Midollo Osseo (GITMO) was performed in order to describe current antiemetic prophylaxis in patients ...undergoing HSCT. The multicenter survey was performed by a questionnaire, covering the main areas on chemotherapy-induced nausea and vomiting (CINV): antiemetic prophylaxis guidelines used, antiemetic prophylaxis in different conditioning regimens, and methods of CINV evaluation. The survey was carried out in November 2016, and it was repeated 6 months after the publication of the Multinational Association of Supportive Care in Cancer (MASCC)/European Society for Medical Oncology (ESMO) specific guidelines on antiemetic prophylaxis in HSCT. The results show a remarkable heterogeneity of prophylaxis among the various centers and a significant difference between the guidelines and the clinical practice. In the main conditioning regimens, the combination of a serotonin
3
receptor antagonist (5-HT
3
-RA) with dexamethasone and neurokin
1
receptor antagonist (NK1-RA), as recommended by MASCC/ESMO guidelines, increased from 0 to 15% (before the publication of the guidelines) to 9–30% (after the publication of the guidelines). This study shows a lack of compliance with specific antiemetic guidelines, resulting mainly in under-prophylaxis. Concerted strategies are required to improve the current CINV prophylaxis, to draft shared common guidelines, and to increase the knowledge and the adherence to the current recommendations for CINV prophylaxis in the specific field of HSCT.
Chronic Graft versus Host Disease (cGvHD) is still the leading cause of late mortality in transplanted patients. Among the new drugs potentially useful in patients with steroid-refractory cGVHD ...(SR-cGVHD), the Tyrosine Kinase Inhibitor (TKI) Imatinib emerged as promising agent; however in our previous experiences, patient's frailty and their reduced haematological tolerance heavily limited the daily dose of Imatinib (median dose administered was 200 mg/day). Thus we planned to evaluate in the same setting a the safety and activity of a second generation TKI, such as Nilotinib (NIL), characterized by a better haematological tolerance and that could allow to treat SR-cGVHD patients with a higher relative dosage than Imatinib, thus achieving a better efficacy. Basing on this rational we designed a phase I-II study, aimed to individuate the maximum tolerated dose ( MTD) and the activity of NIL in patients with SR-cGVHD (ClinicalTrials.gov ID: NCT01810718). Primary endpoint of the phase I study was to define the dose limiting toxicity (DLT) of NIL, defined as the occurrence of any grade≥3 toxicity during at least one month of treatment. According to the Fibonacci standard 3+3 design, we started from an initial dose of 200 mg/day of NIL, up to a maximum of 600 mg/day. The drug has been supplied free of charge by Novartis Italia, Milan. In the phase II the MTD will be used to define the efficacy of NIL in SR-cGVHD patients, with similar characteristics of the previously Imatinib-treated population. Moreover all the patients enrolled in the phase I were allowed to continue NIL at the same dose, up to a cGVHD progression, if an objective improvement (OI) was documented after 3 months of treatment. We report here the preliminary results of a pre-planned interim analysis, during the phase I study, in 12 patients with SR-cGVHD who received NIL at low dose. The main characteristics of the enrolled patients are reported in table 1. Six patients received NIL 200mg/day and 6 NIL 300 mg/day. Two patients stopped NIL within 30 days: one due to cGVHD progression, the other had asymptomatic hypertransaminasemia (>5xULN) which normalized 1 month after stopping NIL; these patients received an alternative treatment. In 3 cases severe adverse events (SAE) have been reported: 1 patient had extramedullary relapse of Acute Leukemia 8 months after start of NIL, while 2 patients have been hospitalized; one due to a transient cGVHD flare, without drug interruption, the second for a late cGVHD progression; he eventually died. The most frequent extrahematological toxicities (grade 1-2 according to CTCAE) were headache, nausea, pruritus, cramps, asthenia, constipation, while the main hematological abnormalities were represented by anemia grade 1 (5/12patients), neutropenia gr.1 (1/12 patients) and lymphocyte count increase gr.2 (1/12 patients). (tab.2) With a median F-U of 10 months (range 4-20), 10 patients are alive, while two died for cGVHD progression (7 and 9 months after the enrollment). After 3 months of treatment with NIL 6 patients (50%) achieved an OI and 4 (33%) a stable disease; all the 10 patients continued Nilotinib at the same dose until ≥6 months of treatment: after 6 months we observed 5 OI, 1 stable disease and 2 mixed responses (2 lung responses with skin failure), while in 2 the response evaluation is still ongoing. These preliminary data suggest that, like Imatinib, NIL at low doses is safe and effective in SR-cGVHD patients; up to day the MTD has not been still achieved, therefore only after the end of the phase I study we will be able to fully define the NIL activity. This study is supported by GITMO (Gruppo Italiano Trapianto di Midollo Osseo). Display omitted
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Off Label Use: Bendamustine.
•Clinical outcomes were significantly worse with 9/10 and ≤8/10 HLA matching versus 10/10 HLA matching.•Outcomes were worse with HLA-A and HLA-B mismatching versus HLA-C and HLA-DQB1 mismatching.•Two ...HLA-mismatched loci should be avoided in early or intermediate disease phases•There is indication to select Italian donor for Italian patient to reduce graft-versus-host disease.
HLA molecules are important for immunoreactivity in allogeneic hematopoietic stem cell transplantation (HSCT). The Gruppo Italiano Trapianto di Cellule Staminali e Terapie Cellulari, Italian Bone Marrow Donor Registry, and Associazione Italiana di Immunogenetica e Biologia dei Trapianti promoted a retrospective observational study to evaluate HLA matching and the impact of allelic HLA mismatching and non-HLA factors on unrelated Italian HSCT outcomes. From 2012 to 2015, 1788 patients were enrolled in the study. The average donor age was 29 years and the average recipient age was 49 years. As a conditioning regimen, 71% of the patients received myeloablative conditioning. For GVHD prophylaxis, 76% received either antithymocyte or anti-T lymphocyte globulin, cyclosporine A, and methotrexate. Peripheral blood was the stem cell source in 80%. The median duration of follow-up was 53 months. Regarding HLA matching, 50% of donor-recipient pairs were 10/10 matched, 38% had 1 mismatch, and 12% had 2 or more mismatches. A total of 302 pairs shared Italian origin. Four-year overall survival (OS), progression-free survival, GVHD-free relapse-free survival, and relapse rates were 49%, 40%, 22%, and 34%, respectively. The 4-year NRM was 27%, and the 100-day cumulative incidence of grade ≥II acute GVHD (aGVHD) was 26%. In multivariate analysis, 9/10 and ≤8/10 HLA allele-matched pairs were associated with worse OS (P = .04 and .007, respectively), NRM (P = .007 and P < .0001, respectively), and grade III-IV aGVHD (P = .0001 and .01, respectively). Moreover, the incidences of grade II-IV aGVHD (P = .001) and chronic GVHD (P = .002) were significantly lower in Italian pairs. In conclusion, 10/10 HLA matching is a favorable prognostic factor for unrelated HSCT outcome in the Italian population. Moreover, the presence of 2 HLA-mismatched loci was associated with a higher NRM (P < .0001) and grade II-IV aGVHD (P = .006) and a poorer OS (P = .001) compared with 1 HLA-mismatched locus in early or intermediate disease phases. Finally, we found that Italian donor and recipient origin is a favorable prognostic factor for GVHD occurrence.
•Fludarabine with busulfan and fludarabine with thiotepa are similarly safe and effective conditioning regimens for allogeneic transplantation in myelofibrosis.•Splenomegaly was associated with ...delayed engraftment, and disease stage was the sole independent predictor for progression-free survival.
We report a randomized study comparing fludarabine in combination with busulfan (FB) or thiotepa (FT), as conditioning regimen for hematopoietic stem cell transplantation (HSCT) in patients with myelofibrosis. The primary study endpoint was progression-free survival (PFS).
Sixty patients were enrolled with a median age of 56 years and an intermediate-2 or high-risk score in 65%, according to the Dynamic International Prognostic Staging System (DIPSS). Donors were HLA-identical sibling (n = 25), matched unrelated (n = 25) or single allele mismatched unrelated (n = 10). With a median follow-up of 22 months (range, 1 to 68 months), outcomes at 2 years after HSCT in the FB arm versus the FT arm were as follows: PFS, 43% versus 55% (P = .28); overall survival (OS), 54% versus 70% (P = .17); relapse/progression, 36% versus 24% (P = .24); nonrelapse mortality (NRM), 21% in both arms (P = .99); and graft failure, 14% versus 10% (P = .96). A better PFS was observed in patients with intermediate-1 DIPSS score (P = .03). Both neutrophil engraftment and platelet engraftment were significantly influenced by previous splenectomy (hazard ratio HR, 2.28; 95% confidence interval CI, 1.16 to 4.51; P = .02) and splenomegaly at transplantation (HR, 0.51; 95% CI, 0.27 to 0.94; P = .03). In conclusion, the clinical outcome after HSCT was comparable when using either a busulfan or thiotepa based conditioning regimen.
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