Faculty Bibliography

Background: Cytomegalovirus (CMV) infection is one of the most common complication after allogeneic hematopoietic stem-cell transplantation (HSCT) and remains associated with significant morbidity. Letermovir is an antiviral drug approved for prevention of CMV infection in seropositive HSCT recipients (R+), inhibiting the CMVterminase complex and thus acting in a different way than other standard approved antiviral drugs. In Italy, Letermovir has been available since 2019.
Method(s):We conducted a single-center cohort observational retrospective study, analysing 107 patients at highest risk of CMV infection according to recipient positive/donor negative (R+/D-) CMV serostatus, transplanted between January 2015 and April 2020 at our Center. Patients unable to take oral therapy at day +7 from HSCT or assuming drugs for concomitant clinical conditions bringing about major pharmacokinetic interaction were excluded. Nineteen of them received primary Letermovir prophylaxis (starting within day +28, up to day +100), whereas 74 patients did not (historical control group). In both groups, patients underwent pre-emptive therapy (PET) strategy according to twice weekly monitoring of blood CMV-DNA levels through PCR analysis. We compared cumulative incidence of clinically significant CMV infection (CS-CMVi), defined as CMV reactivation (CMV-DNAemia leading to PET) or CMV tissue invasive disease at day +100 and day +200. Patients who discontinued drug assumption before day +100 or had missing endpoint data at day +100 were imputed as having a primary endpoint event, according to the drug registration trial. Survival functions were estimated by the Kaplan-Meier method and compared using log-rank test.
Result(s): Letermovir prophylaxis started at a median of 11 days (range, 5-27) after HSCT. The median duration of Letermovir administration was 89 days (range, 40-113). The only early stop was due to patient death, not related to CMV or drug toxicity. None of the 19 patients in Letermovir group experienced CMV reactivation at day +100, compared to 51 in the historical group. Of note, 83% of patients receiving prophylaxes developed graft-versus-host disease (GVHD) before CS-CMVi. Overall, at day +100 CS-CMVi occurred in 5.3% and 71.6% of patients in Letermovir group and historical control group, respectively (p <.001). A trend toward lower CS-CMVi was also observed in the Letermovir group at day +200 (63,2% vs 81,1%, p=.0956). Median time to CSCMVi was +147 and +44 days after HSCT in Letermovir group and historical control group, respectively. One patient in Letermovir group and 4 in the historical one developed CMV tissue invasive disease. No difference in mortality was observed between the two groups, even if a longer follow-up period is needed.
Conclusion(s): Our experience demonstrated the efficacy of Letermovir in a real-world setting for CMV prevention in the first 14 weeks after HSCT. Further studies are needed to establish the cost-effectiveness of Letermovir primary prophylaxis compared to PET approach, and the role of extension of Letermovir beyond day +100 in high-risk subgroup

Endothelial cell (EC) dysfunction causes a number of early and life-threatening post hematopoietic stem cell transplant (HCT) complications that result in a rapid clinical decline. The main early complications are graft-vs.-host disease (GVHD), transplant associated thrombotic microangiopathy (TA-TMA), and sinusoidal obstruction syndrome (SOS). Post-HCT endothelial dysfunction occurs as a result of chemotherapy, infections, and allogeneic reactivity. Despite major advances in transplant immunology and improvements in supportive care medicine, these complications represent a major obstacle for successful HCT. In recent years, different biomarkers have been investigated for early detection of post-transplant endothelial cell dysfunction, but few have been validated. In this review we will define GVHD, TA-TMA and SOS, summarize the current data available in HCT biomarker research and identify promising biomarkers for detection and diagnosis of early HCT complications.

A mismatched unrelated (MMUD) donor represents an alternative therapeutic option for patients who need allogeneic hematopoietic cell transplantation (allo-HCT) and do not have a human leukocyte antigen (HLA) matched donor. We studied outcomes of patients with acute leukemia transplanted from ≥2 HLA allele MMUD. The study population consisted of 465 patients. The median follow-up period was 63 and 75 months in the AML and ALL groups, respectively. The incidence of grade II-IV and grade III-IV acute (a) graft-versus-host disease (GVHD) during the first 100 days was 37% and 16%, respectively. Total and extensive chronic (c) GVHD rates at 2 years were 38% and 17%, respectively. In the entire population, the 5-year relapse incidence (RI), non-relapse mortality (NRM), leukemia-free survival (LFS), overall survival and refined GVHD-free, relapse-free survival (GRFS) was 33%, 31%, 37%, 41%, and 27%, respectively. In the multivariate analysis, HLA-DR mismatch was a poor prognostic factor, giving a significantly higher NRM [hazard ratio (HR), 1.67, p = 0.02]; poorer LFS (HR, 1.42, p = 0.03); OS (HR, 1.46, p = 0.03) and higher aGVHD grade II-IV (HR, 1.46, p = 0.05). In this study, allo-HCT from ≤6/8 HLA allele MMUD in acute leukemia patients resulted in acceptable LFS and refined GRFS. HLA-DR mismatch was a poor prognostic factor.

We have used a non-myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation for the past twenty years. During that period, changes in clinical practice have been aimed at reducing morbidity and mortality from infections, organ toxicity, and graft-versus-host disease. We hypothesized that improvements in clinical practice led to better transplantation outcomes over time. From 1997-2017, 1,720 patients with hematologic malignancies received low-dose total body irradiation +/- fludarabine or clofarabine before transplantation from HLA-matched sibling or unrelated donors, followed by mycophenolate mofetil and a calcineurin inhibitor ± sirolimus. We compared outcomes in three cohorts by year of transplantation: 1997 +/- 2003 (n=562), 2004 +/- 2009 (n=594), and 2010 +/- 2017 (n=564). The proportion of patients ≥60 years old increased from 27% in 1997 +/- 2003 to 56% in 2010-2017, and with scores from the Hematopoietic Cell Transplantation Comborbidity Index of ≥3 increased from 25% in 1997 +/- 2003 to 45% in 2010 +/- 2017. Use of unrelated donors increased from 34% in 1997 +/- 2003 to 65% in 2010-2017. When outcomes from 2004 +/- 2009 and 2010-2017 were compared to 1997 +/- 2003, improvements were noted in overall survival (P=.0001 for 2004-2009 and P <.0001 for 2010-2017), profression-free survival (P=.002 for 2004-2009 and P <.0001 for 2010 +/- 2017), non-relapse mortality (P<.0001 for 2004 +/- 2009 and P <.0001 for 2010 +/- 2017), and in rates of grades 2 +/- 4 acute and chronic graft-vs.-host disease. For patients with hematologic malignancies who underwent transplantation with non-myeloablative conditioning, outcomes have improved during the past two decades. Trials reported are registered under ClinicalTrials.gov identifiers: NCT00003145, NCT00003196, NCT00003954, NCT00005799, NCT00005801, NCT00005803, NCT00006251, NCT00014235, NCT00027820, NCT00031655, NCT00036738, NCT00045435, NCT00052546, NCT00060424, NCT00075478, NCT00078858, NCT00089011, NCT00104858, NCT00105001, NCT00110058, NCT00397813, NCT00793572, NCT01231412, NCT01252667, NCT01527045.

Cytomegalovirus (CMV) retinitis (CMVR) has been reported rarely in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). In addition, little is known about strategies for ophthalmic surveillance and adequate antiviral treatment of CMVR. A case of CMVR in an allogeneic HSCT recipient is described, including clinical signs and therapy. An adult patient received HSCT from a matched unrelated donor for treatment of a Burkitt lymphoma. Donor and recipients were both CMV positive. Starting on day +40, the patient presented multiple CMV reactivation, treated with valganciclovir, foscarnet and a combination of both. On day +160, the patient started complaining of conjunctival hyperaemia and a decrease in visual acuity. Fundoscopy revealed retinal lesions consistent with CMVR, although whole blood CMV DNAemia was negative. Aqueous humor biopsy showed the presence of CMV infection (CMV DNA 230400 UI/ml). CMVR was treated with foscarnet (180 mg i.v. and 1.2 mg intravitreal injection) combined with anti CMV immunoglobulin at 0.5 ml/kg every 2 weeks. After 4 weeks of systemic therapy, 20 weekly doses of intravitreal foscarnet and six cycles of immunoglobulins, a significant improvement of visual acuity was observed. The treatment was well tolerated with no side effect. In conclusion, our case suggests that systemic and local antiviral treatment combined with CMV-specific-IVIG, may reduce CMV load in the eye of patients with CMVR, leading to a consistent improvement of visual acuity. Systematic ophthalmologic examination should be recommended in HSCT recipients with multiple CMV reactivations and high peak CMV DNA levels.

Autologous hematopoietic stem cell transplantation (auto-HSCT) is the standard of care for patients with diffuse large B-cell lymphoma (DLBCL) who relapse/progress after first line chemoimmunotherapy. Long-term outcome of those who relapse after transplant is poor. We present the results of a retrospective study of 256 adult patients reported to the EBMT registry with DLBCL who relapsed after auto-HSCT performed between 2003 and 2013, and who received active salvage strategies. One hundred and fifty-four (60%) were male; median age was 53 years. Median time to relapse was 7 months, 65% relapsed during the first year. Overall response rate after salvage therapy was 46%. Median follow-up after first salvage therapy was 40 months (IQR 23-63 months). Overall survival (OS) at 3 years was 27% (95% CI 22-33). OS at 3 years of patients relapsing longer than 1 year after auto-HSCT was 41% (95% CI 31-53) compared with 20% (95% CI 14-24) in those who relapsed in less than 1 year. Eighty-two patients (32%) had a second HSCT, an allogeneic HSCT (allo-HSCT) in 69 cases, at a median time of 6.5 months after relapse. OS at 3 years after allo-HSCT was 36% (95% CI 25-51). In conclusion, the prognosis of patients with DLBCL that relapse after auto-HSCT is dismal. Patients who relapse in less than 1 year remain an unmet need, and should be considered for CAR T cell therapy or clinical trials. Patients who relapse after 1 year can be rescued with salvage therapies and a second HSCT. These results provide a benchmark to compare data of new prospective studies.

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.

Background/UNASSIGNED:host disease (GVHD), infection and/or bleeding. Treatment options are scarce and a CD34+ stem cell boost or a second bone marrow transplantation may be required to restore adequate haematopoiesis. Methods/UNASSIGNED: = 11) were treated with eltrombopag in a single centre. The reason for eltrombopag treatment was trilineage cytopenia in six patients, bilineage cytopenia in three patients and single lineage cytopenia in three patients. Eltrombopag was initiated at a median of 214 (range: 120-877) days after haematopoietic stem cell transplantation (HCST) and administered for a median time of 114 (range: 12 days to >490) days. In 8/12 patients eltrombopag was introduced at a dose of 75 mg/day and then increased to 150 mg/day after 1 week; 1 patient was given 50 mg eltrombopag per day, and 3 patients received 75 mg daily. Results/UNASSIGNED:In 10/12 patients eltrombopag significantly enhanced blood count values and patients became transfusion independent. Once stable haematological response was obtained, treatment was tapered until final discontinuation in 9/10 responding patients. No grade 3 or 4 toxicities were observed. At time of last follow up, 3/12 patients were dead, 2 due to disease relapse, 1 due to GVHD and pneumonia. All patients except one maintained their complete response and remain transfusion independent at a median of 858 (range: 429-1119) days. Conclusion/UNASSIGNED:These preliminary data confirm that eltrombopag is able to rescue multilineage haematopoiesis in patients with treatment-refractory cytopenias after allogeneic HSCT.