Eltrombopag Added to Immunosuppression in Severe Aplastic Anemia.

BACKGROUND: A single-group, phase 1-2 study indicated that eltrombopag improved the efficacy of standard immunosuppressive therapy that entailed horse antithymocyte globulin (ATG) plus cyclosporine in patients with severe aplastic anemia. METHODS: In this prospective, investigator-led, open-label, multicenter, randomized, phase 3 trial, we compared the efficacy and safety of horse ATG plus cyclosporine with or without eltrombopag as front-line therapy in previously untreated patients with severe aplastic anemia. The primary end point was a hematologic complete response at 3 months. RESULTS: Patients were assigned to receive immunosuppressive therapy (Group A, 101 patients) or immunosuppressive therapy plus eltrombopag (Group B, 96 patients). The percentage of patients who had a complete response at 3 months was 10% in Group A and 22% in Group B (odds ratio, 3.2; 95% confidence interval [CI], 1.3 to 7.8; P = 0.01). At 6 months, the overall response rate (the percentage of patients who had a complete or partial response) was 41% in Group A and 68% in Group B. The median times to the first response were 8.8 months (Group A) and 3.0 months (Group B). The incidence of severe adverse events was similar in the two groups. With a median follow-up of 24 months, a karyotypic abnormality that was classified as myelodysplastic syndrome developed in 1 patient (Group A) and 2 patients (Group B); event-free survival was 34% and 46%, respectively. Somatic mutations were detected in 29% (Group A) and 31% (Group Β) of the patients at baseline; these percentages increased to 66% and 55%, respectively, at 6 months, without affecting the hematologic response and 2-year outcome. CONCLUSIONS: The addition of eltrombopag to standard immunosuppressive therapy improved the rate, rapidity, and strength of hematologic response among previously untreated patients with severe aplastic anemia, without additional toxic effects. (Funded by Novartis and others; RACE ClinicalTrials.gov number, NCT02099747; EudraCT number, 2014-000363-40.).

Multi-parametric MRI in the diagnosis and scoring of gastrointestinal acute graft-versus-host disease.

OBJECTIVES: Acute gastrointestinal graft-versus-host disease (GI-aGVHD) is a severe complication of allogeneic hematopoietic stem cell transplantation (HSCT). Diagnosis relies on clinical, endoscopic, and pathological investigations. Our purpose is to assess the value of magnetic resonance imaging (MRI) in the diagnosis, staging, and prediction of GI-aGVHD-related mortality. METHODS: Twenty-one hematological patients who underwent MRI for clinical suspicion of acute GI-GVHD were retrospectively selected. Three independent radiologists, blinded to the clinical findings, reanalyzed MRI images. The GI tract was evaluated from stomach to rectum by analyzing fifteen MRI signs suggestive of intestinal and peritoneal inflammation. All selected patients underwent colonoscopy with biopsies. Disease severity was determined on the basis of clinical criteria, identifying 4 stages of increasing severity. Disease-related mortality was also assessed. RESULTS: The diagnosis of GI-aGVHD was histologically confirmed with biopsy in 13 patients (61.9%). Using 6 major signs (diagnostic score), MRI showed 84.6% sensitivity and 100% specificity in identifying GI-aGVHD (AUC = 0.962; 95% confidence interval 0.891-1). The proximal, middle, and distal ileum were the segments most frequently affected by the disease (84.6%). Using all 15 signs of inflammation (severity score), MRI showed 100% sensitivity and 90% specificity for 1-month related mortality. No correlation with the clinical score was found. CONCLUSION: MRI has proved to be an effective tool for diagnosing and scoring GI-aGVHD, with a high prognostic value. If larger studies will confirm these results, MRI could partly replace endoscopy, thus becoming the primary diagnostic tool for GI-aGVHD, being more complete, less invasive, and more easily repeatable. KEY POINTS: • We have developed a new promising MRI diagnostic score for GI-aGVHD with a sensitivity of 84.6% and specificity of 100%; results are to be confirmed by larger multicentric studies. • This MRI diagnostic score is based on the six MRI signs most frequently associated with GI-aGVHD: small-bowel inflammatory involvement, bowel wall stratification on T2-w images, wall stratification on post-contrast T1-w images, ascites, and edema of retroperitoneal fat and declivous soft tissues. • A broader MRI severity score based on 15 MRI signs showed no correlation with clinical staging but high prognostic value (100% sensitivity, 90% specificity for 1-month related mortality); these results also need to be confirmed by larger studies.

International guidelines regarding the role of IVIG in the management of Rh- and ABO-mediated haemolytic disease of the newborn.

Haemolytic disease of the newborn (HDN) can be associated with significant morbidity. Prompt treatment with intensive phototherapy (PT) and exchange transfusions (ETs) can dramatically improve outcomes. ET is invasive and associated with risks. Intravenous immunoglobulin (IVIG) may be an alternative therapy to prevent use of ET. An international panel of experts was convened to develop evidence-based recommendations regarding the effectiveness and safety of IVIG to reduce the need for ETs, improve neurocognitive outcomes, reduce bilirubin level, reduce the frequency of red blood cell (RBC) transfusions and severity of anaemia, and/or reduce duration of hospitalization for neonates with Rh or ABO-mediated HDN. We used a systematic approach to search and review the literature and then develop recommendations from published data. These recommendations conclude that IVIG should not be routinely used to treat Rh or ABO antibody-mediated HDN. In situations where hyperbilirubinaemia is severe (and ET is imminent), or when ET is not readily available, the role of IVIG is unclear. High-quality studies are urgently needed to assess the optimal use of IVIG in patients with HDN.

Treosulfan compared with reduced-intensity busulfan improves allogeneic hematopoietic cell transplantation outcomes of older acute myeloid leukemia and myelodysplastic syndrome patients: Final analysis of a prospective randomized trial.

The phase III study was designed to compare event-free survival (EFS) after treosulfan-based conditioning with a widely applied reduced-intensity conditioning (RIC) busulfan regimen in older or comorbid patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic cell transplantation (HCT). A previously reported confirmatory interim analysis of the randomized clinical study including 476 patients demonstrated statistically significant noninferiority for treosulfan with clinically meaningful improvement in EFS. Here, the final study results and pre-specified subgroup analyses of all 570 randomized patients with completed longer-term follow-up are presented. Patients presenting HCT-specific comorbidity index >2 or aged ≥50 years were randomly assigned (1:1) to intravenous (IV) fludarabine with either treosulfan (30 g/m2 IV) or busulfan (6.4 mg/kg IV) after stratification by disease risk group, donor type, and participating institution. The primary endpoint was EFS with disease recurrence, graft failure, or death from any cause as events. EFS of patients (median age 60 years) was superior after treosulfan compared to RIC busulfan: 36-months-EFS rate 59.5% (95% CI, 52.2-66.1) vs. 49.7% (95% CI, 43.3-55.7) with a hazard ratio (HR) of 0.64 (95% CI, 0.49-0.84), p = 0.0006. Likewise, overall survival (OS) with treosulfan was superior compared to busulfan: 36-month-OS rate 66.8% vs. 56.3%; HR 0.64 (95% CI, 0.48-0.87), p = 0.0037. Post hoc analyses revealed that these differences were consistent with the confirmatory interim analysis, and thereby the treosulfan regimen appears particularly suitable for older AML and MDS patients.

Quality of evidence-based guidelines for platelet transfusion and use: A systematic review.

BACKGROUND: Guidelines for platelet (PLT) transfusion are an important source of information for clinicians. Although guidelines intend to increase consistency and quality of care, variation in methodology and recommendations may exist that could impact the value of a guideline. We aimed to determine the quality of existing PLT transfusion guidelines using the Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument and to describe the inconsistencies in recommendations. STUDY DESIGN AND METHODS: A systematic search was undertaken for evidence-based guidelines from January 1, 2013, to January 25, 2019. Citations were reviewed in duplicate for inclusion and descriptive data extracted. Four physicians appraised the guideline using the AGREE II instrument and the scaled score for each item evaluated was calculated. The protocol was registered in PROSPERO. RESULTS: Of 6744 citations, 6740 records were screened. Seven of 28 full-text studies met the inclusion criteria. The median scaled score (and the interquartile range of the scaled score) for the following items were as follows: scope and purpose, 94% (8%); stakeholder involvement, 63% (18%); rigor of development, 83% (14%); clarity of presentation, 94% (6%); applicability, 58% (20%); and editorial independence, 77% (4%). Overall quality ranged from 4 to 7 (7 is the maximum score). Inconsistent recommendations were on prophylactic PLT transfusion in hypoproliferative thrombocytopenia in the presence of risk factors and dose recommendations. CONCLUSION: Inconsistencies between guidelines and variable quality highlight areas for future guideline writers to address. Areas of specific attention include issues of stakeholder involvement and applicability.

Peripherally inserted central catheters in allogeneic hematopoietic stem cell transplant recipients.

BACKGROUND: Central venous catheters (CVC) are essential for the management of patients with hematologic malignancies, facilitating chemotherapy infusion, antibiotics, parenteral nutrition, blood products, and blood samples collection. In this population, peripherally inserted central catheters (PICC) seem to be associated with lower complications, compared with conventional percutaneously inserted devices (CICC). Data on the PICC in allogeneic hematopoietic stem cell recipients (allo-HSCT) are limited. METHODS: We have prospectively evaluated the safety and efficacy of 100 polyurethanes or silicone PICC, inserted into 100 adult allo-HSCT recipients, at the Hematology of Sapienza University of Rome (Italy), between October 2012 and August 2017. RESULTS: The median duration of PICC placement was 117 days. Overall, 68% of patients maintained the device for the entire transplant procedure and PICC were removed after day 100 from allo-HSCT; of these, 44% did not experienced any PICC-related complications. Catheter-related bloodstream infections (CRBSI) occurred in 32% of patients (2.5/1000 PICC days), associated with thrombosis in 8 cases. CRBSI were observed in 42% of patients with polyurethane and 20% with silicone PICC (p = 0.02). Catheter-related thrombosis occurred in 9% of patients, never requiring anticipated PICC removal. Mechanical complications occurred in 15% of cases (1.2/1000 PICC days). On the whole, adverse events were manageable and did not affect transplant outcome. No deaths related to PICC-complications were observed. CONCLUSIONS: PICC are a safe and reliable long-term venous access in allo-HSCT recipients.

Antithrombotic therapy with rivaroxaban in five patients with paroxysmal nocturnal haemoglobinuria and thrombotic events.

Five patients with paroxysmal nocturnal haemoglobinuria and thrombotic complications under oral antithrombotic treatment with vitamin K antagonist were switched to receive the direct oral anticoagulant rivaroxaban an factor Xa inhibitor. In all five patients haematological and biochemical parameters and adverse events were evaluated for a period of twelve months. Therapy with rivaroxaban was well tolerated in all cases and one patient showed a significant reduction of bleeding and transfusion requirement. All patients obtained a significant reduction in days of hospitalization with a consequent improvement in their quality of life after rivaroxaban treatment.

A survey on the implementation of Patient Blood Management programs in Italy.

BACKGROUND: Since 2012, in line with the World Health Organization (WHO) resolution WHA63.12 of 05/21/2010, the Italian National Blood Center has been promoting patient blood management (PBM). In order to verify the level of PBM implementation nationwide, we submitted a survey to all healthcare providers. MATERIAL AND METHODS: In line with what was proposed in the international scientific literature in the field, a series of indicators were used derived from the four main blocks related to PBM strategies: the management of patient anemia; the optimization of hemostasis; blood conservation strategies; patient-centred decision-making. We also added two blocks containing important information on general PBM management and other PBM-related aspects. RESULTS: The survey showed good implementation of anemia screening programs in accordance with the timelines established by national and international guidelines, and the single unit policy is used in line with national guideline recommendations. However, the survey also revealed limited auditing of PBM programs and reduced monitoring and reporting of clinical outcomes and indicators. DISCUSSION: The first national survey on the level of PBM implementation in Italy shows widespread adoption of diagnostic-therapeutic care pathways aimed at the diagnosis and treatment of anemia in the perioperative setting.

Donor specific anti-HLA antibodies in hematopoietic stem cell transplantation. Single Center prospective evaluation and desensitization strategies employed.

BACKGROUND: In the setting of mismatched-hematopoietic stem cells transplantation, the detection of antibodies directed against donor-specific HLA allele(s) or antigen(s) (DSA) represents a barrier for engraftment. It is thus necessary to plan an immunosuppressive strategy, or to select an alternative donor. This prospective study aimed at evaluating the efficacy of our strategy for testing DSAs and the efficacy of the desensitization strategy (DS) employed between November 2017 and November 2020. MATERIALS AND METHODS: The anti-HLA antibody search was performed using the Luminex bead assays (Lifecode ID and LSA I/II-Immucor) and expressed as mean fluorescence intensity (MFI >1,000 positive). If the patient had DSAs and no alternative donors, a DS was employed with rituximab (day -15), 2 single volume plasmaphereses (PP; days -9 and -8), intravenous immunoglobulins (day -7) and infusion of HLA selected platelets, if persistent DSAs were directed against class I HLA. DS was scheduled with or without PP, according to the DSA MFI (>1,000 or <5,000) and FCXM (flow cytometry crossmatch). RESULTS: Twenty-two out of 126 patients (17.46%) showed anti-HLA antibodies, 5 of them DSAs (3.97% of total); 3 patients underwent DS obtaining engraftment. Female gender (p=0.033) and a history of previous pregnancies or miscarriages (p=0.009) showed a statistically significant impact on alloimmunization. Factors associated with a delayed neutrophil engraftment were patient's female gender (p=0.039), stem cell source (p=0.025), and a high HSCT-specific comorbidity index (p=0.028). None of the analyzed variables, including the DSA detection, influenced engraftment. CONCLUSIONS: Our study confirms the importance to test DSAs in mismatched-hematopoietic stem cells transplantation The DS used proved successful in removing DSAs. Prospective multicenter studies are needed to better define and validate consensus strategies on DSA management in HSCT.

Case Report: Severe cutaneous adverse event associated with checkpoint inhibition in the setting of CAR T-cell therapy: beyond CRS.

Anti-CD19 chimeric antigen receptor (CAR) T cell therapy actually represents the standard of care for multiple relapsed or refractory primary mediastinal B-cell lymphoma (r/r PMBCL). Checkpoint inhibitors, such as pembrolizumab, appear to be a safe and effective treatment strategy for patients who are ineligible for or resistant to autologous stem cell transplantation. Although preclinical studies suggested that checkpoint inhibitors may enhance the vitality and anti-tumor activity of CAR T cells, there are no substantial/robust clinical data about the immune-mediated toxicity of their association. We describe a case of a severe cutaneous adverse event arising immediately after Cytokine Release Syndrome (CRS) on day +6 from CAR T cells infusion in a young r/r PMBCL patient who previously received pembrolizumab. These skin lesions were interpreted as an immune mediated adverse event, considering their prompt improvement and fully recovering achieved with the addition of immunoglobulin infusion to systemic steroid therapy. This case of life-threatening cutaneous adverse event calls for further investigations about off-target immune-related adverse events deriving from the combination of CAR T cell therapy and checkpoint inhibition, whose synergic therapeutic effect is promising.

Management of oral leukoplakia in patients with Fanconi anemia.

Fanconi anemia (FA) is a rare genetic disease involving an increased risk of developing acute myeloid leukemia and solid tumors, especially head-and-neck squamous cell carcinomas, for which the oral cavity is the most frequent site of occurrence. The patient presented in this study underwent allogeneic hematopoietic stem cell transplantation (HSCT) and developed nonhomogeneous oral leukoplakia after 7 years, which was promptly removed and diagnosed with high-grade epithelial dysplasia. Many risk conditions for oral squamous cell carcinoma were featured in the present case including FA, allogeneic HSCT, graft-versus-host disease, immunosuppressive therapy, female gender, nonsmoker, tongue location and nonhomogeneous type of leukoplakia. Close follow-up of the entire upper aerodigestive tract mucosa and early removal of all suspected lesions are highly recommended in the management of such patients.

Immuno-hematological monitoring after allogeneic stem cell transplantation: a single-center, prospective study of 104 patients.

BACKGROUND: The impact of ABO incompatibility on the outcome of hematopoietic stem cell transplantation (HSCT) is still debated. We report the results of a prospective, single-center study evaluating the impact of ABO mismatch on the development of immediate and late immuno-hematological complications, and the efficacy of the protocol used at the "Sapienza" University (Rome, Italy) to manage ABO incompatibility in patients undergoing HSCT. MATERIALS AND METHODS: From January 2013 to December 2016, we prospectively analyzed all patients undergoing HSCT. Graft manipulation or desensitization strategies were used according to ABO incompatibility, donor sex and donor transfusion history. Red blood cell and platelet transfusions were given based on immunohematological features. RESULTS: From January 2013 to December 2016, 104 consecutive patients underwent HSCT from a matched related donor (29.81%), matched unrelated donor (53.58%), cord blood (1.9%) or haploidentical donor (14.42%). Forty-nine patients (47%) were ABO-identical and 55 (53%) ABO-incompatible (23 major, 25 minor, 7 bidirectional). Donor engraftment, graft failure or other complications did not differ between ABO compatible or incompatible patients. ABO incompatibility did not show a significant impact on graft-versus-host disease, overall survival or disease-free survival. Factors associated with the need for prolonged red blood cell support were ABO incompatibility (p=0.0395), HLA disparity between donor and recipient (p=0.004) and the onset of hemorrhagic cystitis (p=0.015). In multivariate analysis HLA disparity was the only statistically significant condition (p=0.004). DISCUSSION: ABO incompatibility does not represent a barrier to allogeneic HSCT. It is, however, associated with prolonged transfusion requirements. Close immunohematological monitoring, as a shared standard procedure, allows appropriate transfusion support to be provided and limits post-HSCT immuno-hematological complications.

Autologous stem cell transplantation in favorable-risk acute myeloid leukemia: single-center experience and current challenges.

BACKGROUND: Autologous stem cell transplantation (ASCT) has gained growing consideration as a treatment option for favorable-risk acute myeloid leukemia (FR-AML) in first complete remission (CR1), compared with chemotherapy. MATERIALS AND METHODS: We report the long-term outcomes of 117 consecutive patients with FR-AML fit for intensive chemotherapy diagnosed in our center between 1999 and 2020, who underwent ASCT. RESULTS: Sixty-five of the 117 were eligible for intensive post-remission treatment, and 42 of those 65 received ASCT. Median follow up was 132 months. Overall survival (OS) and disease-free survival (DFS) were 75% and 76%. Higher doses of CD34 + stem cell infusions negatively impacted DFS in multivariate analysis. Core-binding factor (CBF) leukemia was an independent prognostic factor for improved DFS. No differences based on pre-transplant measurable residual disease (MRD) were observed. In CBF leukemia, 10-year DFS is 72% for MRD-positive patients versus 100% for MRD negative patients. CONCLUSIONS: ASCT is effective and safe in FR-AML patients. In CBF leukemia, ASCT provides excellent results regardless of achievement of bone marrow MRD negativity. In NPM1-mutated/FLT3-wild type (mNPM1) AML, early molecular response seems to have more impact on prognosis. Prospective investigation of the role of gemtuzumab ozogamicin in this setting is ongoing.

Allelic HLA Matching and Pair Origin Are Favorable Prognostic Factors for Unrelated Hematopoietic Stem Cell Transplantation in Neoplastic Hematologic Diseases: An Italian Analysis by the Gruppo Italiano Trapianto di Cellule Staminali e Terapie Cellulari, Italian Bone Marrow Donor Registry, and Associazione Italiana di Immunogenetica e Biologia dei Trapianti.

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.