Nonrestrictive diet does not increase infections during post-HSCT neutropenia: data from a multicenter randomized trial.

Infections are a major cause of morbidity and mortality during neutropenia after hematopoietic stem cell transplantation (HSCT). The use of a low-microbial protective diet (PD) in the peritransplantation period is a standard of care, although its efficacy has never been tested prospectively. We conducted a multicenter, randomized, noninferiority trial, enrolling all consecutive adult patients undergoing high-dose induction chemotherapy or HSCT with the objective to compare nonrestrictive diet (NRD) vs PD. Overall, 222 patients were enrolled, randomly assigned, and analyzed. One hundred seventy-five subjects (79%) received autologous HSCT (auto-HSCT), 41 (18%) received allogeneic HSCT (allo-HSCT), and 6 (3%) patients received high-dose induction chemotherapy. There was no significant difference in terms of incidence of grade ≥2 infections and death during neutropenia in the 2 arms. In multivariable analysis, only multiple myeloma diagnosis, fluoroquinolone prophylaxis, and the absence of mucositis were associated with a lower incidence of grade ≥2 infections. We did not report any significant variation in terms of hospitalization length, incidence of mucositis and gastrointestinal infections, body weight, and serum albumin variations in the 2 arms. In allo-HSCT recipients, the incidence of acute graft-versus-host disease grade ≥3 was similar. NRD was associated with higher patient-reported satisfaction. In conclusion, NRD is not inferior to a traditional PD during neutropenia after HSCT, and our results demonstrated that implementing a restrictive diet unnecessary burdens patients' quality of life. The clinical trial was registered prospectively in the clinical trial registry of the Istituto Nazionale dei Tumori of Milan as INT54/16.

Low-Risk Myelodysplastic Syndrome Revisited: Morphological, Autoimmune, and Molecular Features as Predictors of Outcome in a Single Center Experience.

Low-risk myelodysplastic syndromes (LR-MDS) are a very heterogeneous disease, with extremely variable clinical features and outcome. Therapeutic strategies are still limited and mainly consist of erythropoiesis-stimulating agents (ESAs) and transfusion support. The contribution of molecular lesions and of autoimmune phenomena to pathogenesis and clinical course, including leukemic evolution, is a field of open investigation. We analyzed data from a cohort of 226 patients with LR-MDS followed at our center in the last 20 years, focusing on morphological, immunological (antiplatelets and anti-erythrocyte autoantibodies, anti-erythroblast antibodies), and molecular features. Hypoplastic bone marrow was found in 7% of the cases correlating with younger age, deeper cytopenia, lower dysplasia, and worse response to ESAs. A marker of autoimmunity was observed in 46% of the tested cases, who were younger, were less frequent dysplastic changes, and responded better to ESAs and steroids. Finally, 68% of the tested cases displayed at least one somatic mutation, most commonly SF3B1, TET2, ASXL1, and SRSF2, associated with older age, presence of neutropenia, and lower response to ESAs. Leukemic evolution (2.2%) was associated with presence of somatic mutations, and survival was favorably related to response to ESAs and transfusion independence. Overall, granular evaluation and re-evaluation are pivotal in LR-MDS patients to optimize clinical management.

Safety of outpatient stem cell mobilization with low- or intermediate-dose cyclophosphamide in newly diagnosed multiple myeloma patients.

OBJECTIVES: Autologous stem cell transplantation is the gold standard for eligible newly diagnosed multiple myeloma patients. Patients are usually hospitalized for administration of mobilization chemotherapy. We aimed to assess safety and efficacy of mobilization therapy with low-dose (2 g/m2 ) and intermediate-dose (3-4 g/m2 ) cyclophosphamide administered as outpatient. METHODS: A total of 176 consecutive newly diagnosed transplant-eligible myeloma patients receiving outpatient mobilization were retrospectively evaluated. Induction therapy was mainly performed with new drugs (91%). RESULTS: Chemotherapy was very well tolerated with 16.6% of patients having all-grade adverse events (AEs) and only 1.2% having severe AEs. The most frequently reported AEs were nausea and vomiting grade 1-2 (6.8%). Only 5.7% of patients required hospitalization for AEs. Stem cell collection was successful in 93.1% of patients, with a median CD34+ harvest of 8.7 × 106 /kg. Target for 2 autologous stem cell transplantation (at least 6 CD34+  × 106 /kg) was reached by 76.3% of patients. Administration of plerixafor on demand was necessary in 12.1% of patients. CONCLUSIONS: Outpatient mobilization with low- and intermediate-dose cyclophosphamide appears an efficient and safe procedure, with minimal and manageable AEs and low rate of hospitalization.

Eltrombopag in Immune Thrombocytopenia, Aplastic Anemia, and Myelodysplastic Syndrome: From Megakaryopoiesis to Immunomodulation.

Eltrombopag is an orally available thrombopoietin receptor agonist indicated for the treatment of immune thrombocytopenia (ITP). Beyond the effect on megakaryopoiesis, the drug also showed a stimulating effect on the hematopoietic stem cell with consistent clinical efficacy in aplastic anemia (AA) and myelodysplastic syndromes (MDS). Eltrombopag is highly effective in ITP and less so in AA and MDS. This observation underlines the importance of residual normal hematopoiesis, which is maximal in ITP, minimal/absent in AA, and dysregulated in MDS. In ITP, the drug at 50-75 mg daily induced up to 85% responses both in clinical trials and real-life studies, with the possibility of tapering and discontinuation. In AA, eltrombopag at 150 mg daily was effective in about 40% of cases relapsed/refractory to standard immunosuppression or ineligible for bone marrow transplant. In MDS, the drug seems less effective, with responses in about a quarter of patients at various schedules. The efficacy of eltrombopag in ITP, AA, and MDS suggests the existence of common immune-pathological mechanisms in these diseases, including autoimmunity against peripheral blood cells and bone marrow precursors, as well as a possible evolution of one condition into the other. Additional mechanisms of action emerging from the clinical use of eltrombopag include modulation of T-regulatory cells, restoration of Fc-γ receptor balance in phagocytes, and an iron-mobilizing effect. In this review, we analyzed the most recent literature on eltrombopag use and efficacy in patients with ITP, AA, and MDS, exploring the basis for different dosing, combined treatments, and discontinuation in each context.

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.

Post-transplantation Cyclophosphamide and Sirolimus after Haploidentical Hematopoietic Stem Cell Transplantation Using a Treosulfan-based Myeloablative Conditioning and Peripheral Blood Stem Cells.

Haploidentical hematopoietic stem cell transplantation (HSCT) performed using bone marrow (BM) grafts and post-transplantation cyclophosphamide (PTCy) has gained much interest for the excellent toxicity profile after both reduced-intensity and myeloablative conditioning. We investigated, in a cohort of 40 high-risk hematological patients, the feasibility of peripheral blood stem cells grafts after a treosulfan-melphalan myeloablative conditioning, followed by a PTCy and sirolimus-based graft-versus-host disease (GVHD) prophylaxis (Sir-PTCy). Donor engraftment occurred in all patients, with full donor chimerism achieved by day 30. Post-HSCT recovery of lymphocyte subsets was broad and fast, with a median time to CD4 > 200/µL of 41 days. Cumulative incidences of grade II to IV and III-IV acute GVHD were 15% and 7.5%, respectively, and were associated with a significant early increase in circulating regulatory T cells at day 15 after HSCT, with values < 5% being predictive of subsequent GVHD occurrence. The 1-year cumulative incidence of chronic GVHD was 20%. Nonrelapse mortality (NRM) at 100 days and 1 year were 12% and 17%, respectively. With a median follow-up for living patients of 15 months, the estimated 1-year overall and disease-free survival (DFS) was 56% and 48%, respectively. Outcomes were more favorable in patients who underwent transplantation in complete remission (1-year DFS 71%) versus patients who underwent transplantation with active disease (DFS, 34%; P = .01). Overall, myeloablative haploidentical HSCT with peripheral blood stem cells (PBSC) and Sir-PTCy is a feasible treatment option: the low rates of GVHD and NRM as well as the favorable immune reconstitution profile pave the way for a prospective comparative trial comparing BM and PBSC in this specific transplantation setting.