Risk Factors for Early Cytomegalovirus Reactivation and Impact of Early Cytomegalovirus Reactivation on Clinical Outcomes after T Cell-Replete Haploidentical Transplantation with Post-Transplantation Cyclophosphamide.

Risk factors for cytomegalovirus (CMV) reactivation and the impact of CMV reactivation on patient outcomes have been extensively investigated after matched related or unrelated donor transplantation, but little is known in the setting of haploidentical stem cell transplantation (Haplo-SCT) with post-transplantation cyclophosphamide (PT-Cy), in which recipients are considered more severely immunocompromised. We retrospectively analyzed a cohort of 554 consecutive patients undergoing Haplo-SCT with PT-Cy at 3 different centers. Early CMV reactivation (occurring within the first 120 days post-transplantation) occurred in 242 patients, for an estimated cumulative incidence of 44%. Among those patients, 74 (30%) had recurrent CMV and 20 (8%) had CMV disease. On multivariable analysis, positive recipient CMV serostatus (hazard ratio [HR] >2.5; P < .001), disease histology (lymphoid versus myeloid: HR, 0.66; P = .003) and increasing recipient age (HR, 1.01; P = .015) were independent predictors of CMV reactivation. At a 4-month landmark analysis, CMV reactivation was associated with higher 1-year and 5-year cumulative incidence of nonrelapse mortality (NRM) relative to patients without reactivation: 13% versus 5% and 22% versus 9%, respectively (P < .001). On multivariable analysis, CMV reactivation was an independent negative predictor of NRM (HR, 2.69; P < .001) and was close to statistically significant for overall survival (HR, 1.38; P = .062). Our results suggest that CMV reactivation plays an important role at determining NRM. Because patient CMV serostatus is the main predictor of CMV reactivation, it should be considered when evaluating strategies for preventing CMV reactivation. 2022 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Feasibility and Efficacy of a Pharmacokinetics-Guided Busulfan Conditioning Regimen for Allogeneic Stem Cell Transplantation with Post-Transplantation Cyclophosphamide as Graft-versus-Host Disease Prophylaxis in Adult Patients with Hematologic Malignancies.

Busulfan (Bu) is an alkylating agent routinely used for conditioning regimens before allogeneic stem cell transplantation (allo-SCT). Bu shows wide pharmacokinetic (PK) variability among patients. Patients can have a higher systemic exposure (expressed as area under the curve [AUC]) with an increased risk of toxicity or a lower AUC with a higher probability of graft rejection and/or disease relapse. After i.v. administration, an optimal Bu therapeutic window (AUC target of 16,000 to 24,000 µM·minute) has been identified. The use of PK-guided Bu dosing leads to improved overall survival (OS) and progression-free survival (PFS) compared with fixed-dose administration in a variety of hematologic diseases. The aim of this study was to evaluate the outcomes and feasibility of a reduced-toxicity conditioning (RTC) regimen comprising thiotepa, Bu, and fludarabine (TBF) with therapeutic drug monitoring of Bu in patients with hematologic disorders. We report on 41 adult patients with myeloid or lymphoid malignancies who underwent an allo-SCT with a PK-guided Bu-based RTC regimen between January 2019 and October 2020. Patients received a total Bu dose to achieve a target AUC of 16,000 µM·minute in combination with Flu and thiotepa. The median time to absolute neutrophil count recovery and transfusion-independent platelet count recovery was 23 days (range, 15 to 42 days) and 29 days (range, 14 to 97 days), respectively. The cumulative incidence (CI) of nonrelapse mortality was 7% at 100 days and 13% at 1 year. Grade 3 liver toxicity was observed in 6 patients. One patient developed sinusoidal obstruction syndrome at day +27. Grade 3 mucositis occurred in 18 patients. Looking at grade ≥3 infections, the CI was 29% at 30 days, 34% at 60 days, 44% at 100 days, and 56% at 1 year. The 180-day CI of grade II-IV acute graft-versus-host disease (GVHD) was 15%, and the 1-year CI of overall chronic GVHD was 20%. With a median follow-up of alive patients of 14.4 months (range, 3.2 to 24 months), the CI of relapse at 1 year was 6%. The 1-year PFS was 81%, and 1-year OS was 84%. In conclusion, these data support the efficacy of PK-guided Bu dose in the context of a TBF conditioning regimen and the feasibility of therapeutic dosage monitoring of i.v. Bu for patients with hematologic diseases. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Nonmyeloablative Conditioning Regimen Including Low-Dose Total Marrow/Lymphoid Irradiation Before Haploidentical Transplantation with Post-Transplantation Cyclophosphamide in Patients with Advanced Lymphoproliferative Diseases.

Low-dose total body irradiation (TBI) has long been used in nonmyeloablative conditioning (NMAC) regimens before allogeneic stem cell transplantation from haploidentical donors (haplo-SCT). More recently, the use of total marrow lymphoid irradiation (TMLI) instead of TBI in conditioning is increasing. This study aimed to evaluate outcomes in a cohort of patients treated with low-dose TMLI in terms of engraftment, full donor chimerism status, graft-versus-host disease (GVHD), and extrahematologic toxicities, and to compare these outcomes with those in a cohort of patients receiving conventional TBI-containing conditioning. This retrospective single-center study included 100 patients with advanced hematologic malignancies who underwent haplo-SCT. Between 2009 and 2011, the NMAC regimen consisted of cyclophosphamide, fludarabine, and low-dose TBI (2 Gy), and after 2011, TBI was replaced with TMLI (2 Gy). Patients received post-transplantation cyclophosphamide, calcineurin inhibitor, and mycophenolate mofetil as GVHD prophylaxis. For all patients, the median time to absolute neutrophil count (ANC) recovery to >0.5 × 109/L was 21 days (range, 15 to 49 days), the 30-day incidence of ANC recovery was 97% (95% confidence interval [CI], 89% to 99%), the median time to achieve an unsupported platelet count >20 × 109/L was 26 days (range, 12 to 67 days), and the 60-day rate of platelet engraftment was 99% (95% CI, 89% to 100%). Cumulative incidence of full donor chimerism by day 100 was 88% (95% CI 79-90). Grade II-IV acute GVHD occurred in 35% of the patients (95% CI, 26% to 45%) at a median of 40 days (range, 23 to 166 days). The incidence of moderate to severe chronic GVHD was 5% (95% CI, 2% to 10%). No differences between the TBI and TMLI cohorts were seen in terms of engraftment, full donor chimerism, and GVHD. No organ toxicity was observed in the first months after transplantation in either cohort. The overall 2-year OS and PFS rates were 63%, and 54%, respectively, and were comparable in the 2 groups (P = .548). The strongest finding was that TBI can be safely replaced by TMLI in terms of engraftment, achievement of full donor chimerism status, GVHD incidence, and extrahematologic toxicities.

Feasibility and Efficacy of CD45RA+ Depleted Donor Lymphocytes Infusion After Haploidentical Transplantation With Post-Transplantation Cyclophosphamide in Patients With Hematological Malignancies.

Allogeneic stem cell transplantation from haploidentical donor using post-transplantation cyclophosphamide has been used to cure hematological diseases. Because of slow immunological reconstitution, there is an increased incidence of viral infection. The aim of our study was to prospectively evaluate the efficacy and the feasibility of a CD45RA+ depleted donor lymphocytes infusion (DLI) in terms of reduction of viral infection early after haploidentical transplantation. This a prospective single-center study. We enrolled 23 patients, of whom 19 were evaluable. Graft-versus-host disease (GVHD) prophylaxis was the same for all patients. The primary endpoint was 100-day cumulative incidence of viral infections. The primary endpoint was met, because the 100-day cumulative incidence of viral infection was 32%. The median time from transplantation to first CD45RA+ depleted DLI was 55 days (range, 46-63). 28% of patients had cytomegalovirus reactivation, no patients reactivated human herpesvirus-6; 1 patient developed BK virus related hemorrhagic cystitis. Most of the patients received the planned 3 infusions. Only 1 patient had development of grade 2 acute GVHD, and 2 patients had moderate chronic GVHD. All evaluable patients were off immunosuppressive therapy at last follow-up. The median follow-up was 12 months (range, 3-23), the 1-year overall survival and progression-free survival were 79% and 75%, respectively; the 100-day and 1-year non-relapse mortality were 5% and 12%, respectively. CD45RA+ depleted DLI are feasible in patients treated with haploidentical transplantation. The toxic profile is good with a low risk for development of both acute and chronic GVHD.

Osteolytic Lesions in Primary Myelofibrosis and Effect of Ruxolitinib Therapy: Report of a Case and Literature Review.

Here, we report the case of a young female affected by primary myelofibrosis (PMF) who developed an osteolytic lesion of the humerus during the follow-up, and the possible efficacy of ruxolitinib in controlling this rare event. After 26 years of follow-up, the patient reported onset of acute pain at the proximal region of the left upper limb. An X-ray revealed an osteolytic bone lesion in the proximal third of the humeral shaft, which was then confirmed by magnetic resonance imaging. A biopsy of the lytic lesion was done, revealing hypercellular bone marrow with hyperplastic granulopoiesis associated with megakaryocytic proliferation and atypia, accompanied by a diffuse and dense increase in reticulin fibrosis with extensive intersections and coarse bundles of thick fibers, consistent with a grade 3 collagen fibrosis. No new therapeutic intervention was initially required; however, 2 years later, the patient reported symptomatic splenomegaly and drenching night sweats, so ruxolitinib therapy was started. By week 8, the patient had near resolution of constitutional symptoms and a reduction of > 50% of the spleen size that normalized by 6 months; in addition, a repeat bone marrow biopsy showed a decrease in reticulin fibrosis grade. Interestingly, after 9 months of ruxolitinib therapy, further magnetic resonance imaging of the left upper limb showed the absence of bone lytic lesions and a substantial normalization of the bone tissue. In conclusion, with the present case report, we confirm ruxolitinib efficacy in reducing bone marrow fibrosis grade and assume its possible role in the resolution of osteolytic lesions in PMF. Obviously, further studies with a greater number of patients are needed to document the exact frequency of these unusual findings and the possible role of ruxolitinib in their treatment.