Fresh or frozen grafts for allogeneic stem cell transplantation: conceptual considerations and a survey on the practice during the COVID-19 pandemic from the EBMT Infectious Diseases Working Party (IDWP) and Cellular Therapy & Immunobiology Working Party (CTIWP).

The COVID-19 pandemic has had a significant impact on medical practices, including the delivery of allogeneic hematopoietic cell transplantation (HCT). In response, transplant centers have made changes to their procedures, including an increased use of cryopreservation for allogeneic haematopoietic progenitor cell (HPC) grafts. The use of cryopreserved grafts for allogeneic HCT has been reviewed and analysed in terms of potential benefits and drawbacks based on existing data on impact on cell subsets, hematological recovery, and clinical outcomes of approximately 2000 patients from different studies. A survey of European Society for Blood and Marrow Transplantation centers was also conducted to assess changes in practice during the pandemic and any unnecessary burdens on HPC donors. Before the pandemic, only 7.4% of transplant centers were routinely cryopreserving HPC products, but this percentage increased to 90% during the pandemic. The results of this review and survey suggest that cryopreservation of HPC grafts is a viable option for allogeneic HCT in certain situations, but further research is needed to determine long-term effects and ethical discussions are required to balance the needs of donors and patients when using frozen allografts.

Harmonizing Definitions for Diagnostic Criteria and Prognostic Assessment of Transplantation-Associated Thrombotic Microangiopathy: A Report on Behalf of the European Society for Blood and Marrow Transplantation, American Society for Transplantation and Cellular Therapy, Asia-Pacific Blood and Marrow Transplantation Group, and Center for International Blood and Marrow Transplant Research.

Transplantation-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized complication of hematopoietic cell transplantation (HCT) associated with significant morbidity and mortality. However, TA-TMA is a clinical diagnosis, and multiple criteria have been proposed without universal application. Although some patients have a self-resolving disease, others progress to multiorgan failure and/or death. Poor prognostic features also are not uniformly accepted. The lack of harmonization of diagnostic and prognostic markers has precluded multi-institutional studies to better understand incidence and outcomes. Even current interventional trials use different criteria, making it challenging to interpret the data. To address this urgent need, the American Society for Transplantation and Cellular Therapy, Center for International Bone Marrow Transplant Research, Asia-Pacific Blood and Marrow Transplantation, and European Society for Blood and Marrow Transplantation nominated representatives for an expert panel tasked with reaching consensus on diagnostic and prognostic criteria. The panel reviewed literature, generated consensus statements regarding diagnostic and prognostic features of TA-TMA using the Delphi method, and identified future directions of investigation. Consensus was reached on 4 key concepts: (1) TA-TMA can be diagnosed using clinical and laboratory criteria or tissue biopsy of kidney or gastrointestinal tissue; however, biopsy is not required; (2) consensus diagnostic criteria are proposed using the modified Jodele criteria with additional definitions of anemia and thrombocytopenia. TA-TMA is diagnosed when ≥4 of the following 7 features occur twice within 14 days: anemia, defined as failure to achieve transfusion independence despite neutrophil engraftment; hemoglobin decline by ≥1 g/dL or new-onset transfusion dependence; thrombocytopenia, defined as failure to achieve platelet engraftment, higher-than-expected transfusion needs, refractory to platelet transfusions, or ≥50% reduction in baseline platelet count after full platelet engraftment; lactate dehydrogenase (LDH) exceeding the upper limit of normal (ULN); schistocytes; hypertension; soluble C5b-9 (sC5b-9) exceeding the ULN; and proteinuria (≥1 mg/mg random urine protein-to-creatinine ratio [rUPCR]); (3) patients with any of the following features are at increased risk of nonrelapse mortality and should be stratified as high-risk TA-TMA: elevated sC5b-9, LDH ≥2 times the ULN, rUPCR ≥1 mg/mg, multiorgan dysfunction, concurrent grade II-IV acute graft-versus-host disease (GVHD), or infection (bacterial or viral); and (4) all allogeneic and pediatric autologous HCT recipients with neuroblastoma should be screened weekly for TA-TMA during the first 100 days post-HCT. Patients diagnosed with TA-TMA should be risk-stratified, and those with high-risk disease should be offered participation in a clinical trial for TA-TMA-directed therapy if available. We propose that these criteria and risk stratification features be used in data registries, prospective studies, and clinical practice across international settings. This harmonization will facilitate the investigation of TA-TMA across populations diverse in race, ethnicity, age, disease indications, and transplantation characteristics. As these criteria are widely used, we expect continued refinement as necessary. Efforts to identify more specific diagnostic and prognostic biomarkers are a top priority of the field. Finally, an investigation of the impact of TA-TMA-directed treatment, particularly in the setting of concurrent highly morbid complications, such as steroid-refractory GVHD and infection, is critically needed.

A real-life overview of a hematopoietic cell transplant program throughout a four-year period, including prospective registry, exclusion causes and final donor selection.

Traceability of patients who are candidates for Hematopoietic cell transplant (HCT) is crucial to ensure HCT program quality. Continuous knowledge of both a detailed registry from a HCT program and final exclusion causes can contribute to promoting a real-life vision and optimizing patient and donor selection. We analyzed epidemiological data reported in a 4 year-monocentric prospective registry, which included all patients presented as candidates for autologous (Auto) and/or allogeneic (Allo) HCT. A total of 543 patients were considered for HCT: 252 (42.4%) for Allo and 291 (57.6%) for Auto. A total of 98 (38.9%) patients were excluded from AlloHCT due to basal disease progression more commonly (18.2%). Seventy-six (30.2%) patients had an HLA identical sibling, whereas 147 (58.3%) patients had only Haplo. UD research was performed in 106 (42%) cases, significantly more often in myeloid than lymphoid malignancies (57% vs 28.7%, p < 0.001) but 61.3% were finally canceled, due to donor or disease causes in 72.4%. With respect to Auto candidates, a total of 60 (20.6%) patients were finally excluded; progression was the most common cause (12%). Currently, Haplo is the most frequent donor type. The high cancellation rate of UD research should be revised to optimize further donor algorithms.

Advantages of non-cryopreserved autologous hematopoietic stem cell transplantation against a cryopreserved strategy.

Autologous stem cell transplantation (auto-HSCT) is an effective treatment strategy for hematological malignancies. The standard mode of handling hematopoietic progenitors for the autologous procedure (CRYO) consists on its collection and freezing with dimethyl sulfoxide (DMSO) and its subsequent thawing and re-infusion. This process is toxic and expensive. Non-cryopreserved (non-CRYO) is a less expensive mode of auto-HSCT. We designed a comparative study between both strategies performed in two different centers to analyze the short-term complications. In total 111 auto-HSCT were performed from January/2015 to October/2016 (42 non-CRYO and 74 CRYO). There were 74 males and 69 (62%) patients had the underlying diagnosis of multiple myeloma. No differences were seen on the characteristics of the apheresis products and their viability. Engraftment was significantly faster in the non-CRYO group (p = 0.001). Febrile neutropenia and severe mucositis were lower in the non-CRYO group (40% vs 92% p = 0.0001 and 11% vs 64%, p = 0.001, respectively). In addition, length of hospitalization was 5 days shorter in the non-CRYO group (p = 0.0001). Overall responses and transplantation outcomes were similar. Our data demonstrate a clear advantage of the non-CRYO over CRYO auto-HSCT with faster engraftment, lower incidence of febrile neutropenia and shorter hospital stay after the transplantation procedure. These data are especially relevant for centers with high transplant activity or with limited resources.

Haplo-Cord transplantation compared to haploidentical transplantation with post-transplant cyclophosphamide in patients with AML.

For patients with AML, the best alternative donor remains to be defined. We analyze outcomes of patients who underwent myeloablative umbilical cord blood or haploidentical hemopoietic stem cell transplantation (HSCT) in Spain. Fifty-one patients underwent single umbilical cord blood transplantation supported by a third party donor (Haplo-Cord) between 1999 and 2012, and 36 patients received an haploidentical HSCT with post-transplant cyclophosphamide (PTCY-haplo) between 2012 and 2014 in GETH centers. The Haplo-Cord cohort included a higher proportion of patients with high disease risk index and use of TBI in the conditioning regimen, and hematopoietic cell transplantation-age Comorbidity Age Index was higher in PTCY-haplo patients. Cumulative incidence of neutrophil engraftment was 97% in the Haplo-Cord and 100% in the PTCY-haplo group, achieved in a median of 12 and 17 days, respectively (P=0.01). Grade II-IV acute GvHD rate was significantly higher in the PTCY-haplo group (9.8% vs 29%, P=0.02) as well as chronic GvHD rates (20% vs 38%, P=0.03). With a median follow-up of 61 months for the Haplo-Cord group and 26 months for the PTCY-haplo cohort, overall survival at 2 years was 55% and 59% (P=0.66), event-free survival was 45% vs 56% (P=0.46), relapse rate was 27% vs 21% (P=0.79), and non-relapse mortality was 17% vs 23% (P=0.54), respectively. In this multicenter experience, Haplo-Cord and PTCY-haplo HSCT offer valid alternatives for patients with AML. Neutrophil engraftment was faster in the Haplo-Cord cohort, with similar survival rates, with higher GvHD rates after haploidentical HSCT.

Severe infections after single umbilical cord blood transplantation in adults with or without the co-infusion of CD34+ cells from a third-party donor: results of a multicenter study from the Grupo Español de Trasplante Hematopoyético (GETH).

BACKGROUND: Umbilical cord blood transplantation (CBT) is an established alternative source of stem cells in the setting of unrelated transplantation. When compared with other sources, single-unit CBT (sCBT) is associated with a delayed hematologic recovery, which may lead to a higher infection-related mortality (IRM). Co-infusion with the sCBT of CD34+ peripheral blood stem cells from a third-party donor (TPD) (sCBT + TPDCD34+) has been shown to markedly accelerate leukocyte recovery, potentially reducing the IRM. However, to our knowledge, no comparative studies have focused on severe infections and IRM with these 2 sCBT strategies. METHODS: A total of 148 consecutive sCBT (2000-2010, median follow-up 4.5 years) were included in a multicenter retrospective study to analyze the incidence and risk factors of IRM and severe viral and invasive fungal infections (IFIs). Neutrophil engraftment occurred in 90% of sCBT (n = 77) and 94% sCBT + TPDCD34+ (n = 71) recipients at a median of 23 and 12 days post transplantation, respectively (P < 0.01). RESULTS: The 4-year IRM was 24% and 20%, respectively (P = 0.7), with no differences at day +30 (5% and 4%, respectively) and day +100 (10% and 8%, respectively). In multivariate analysis early status of the underlying malignancy, cytomegalovirus (CMV)-seronegative recipient and high CD34+ cell content in the cord blood unit before cryostorage (≥1.4 × 10(5) /kg) were protective of IRM. Among the causes of IRM, bacterial infections and IFIs were more common in sCBT (15% vs. 4%), while CMV disease and parasitic infections were more common in the sCBT + TPDCD34+ cohort (5% vs. 16%). CONCLUSION: These data show that sCBT supported with TPDCD34(+) cells results in much shorter periods of post-transplant leukopenia, but the short- and long-term rates of IRM were comparable to those of sCBT, presumably because immune recovery is equally delayed in both graft types.

Plerixafor in patients with lymphoma and multiple myeloma: effectiveness in cases with very low circulating CD34+ cell levels and preemptive intervention vs remobilization.

This retrospective study presents data from 105 consecutive multiple myeloma and lymphoma patients who had PB CD34+ cell counts <10/µL on day 4 of steady-state G-CSF mobilization for autologous hematopoietic cell transplantation. Our results confirm the capacity of plerixafor to improve mobilization outcomes in this clinical setting. In addition, they show that the effectiveness of plerixafor, compared with G-CSF only, translates to patients with very low (<3.5/µL) circulating CD34+ cell counts: overnight CD34+ cell count expansion (5.3- vs 1.7-fold), overall CD34+ cell yield (2.29 vs 0.15 × 10(6) CD34+ cells per kg) and patients yielding ⩾2 × 10(6) CD34+ cells per kg (63% vs 3%). Furthermore, our data also show that preemptive plerixafor is significantly more effective and more efficient than in remobilization: CD34+ cell yield in the first apheresis (3.28 vs 2.0 × 10(6) CD34+ cells per kg) and overall (3.73 vs 2.44 × 10(6) CD34+ cells per kg), patients yielding ⩾2 × 10(6) CD34+ cells per kg in the first apheresis (85% vs 44%) and overall (92% vs 64%), all this requiring less days and doses of plerixafor treatment (1.08 vs 1.48). These data would advocate using plerixafor as an early preemptive intervention based on day 4 circulating CD34+ counts, including very high-risk patients with very low circulating levels.

Fungal and viral infections after allogeneic hematopoietic transplantation from unrelated donors in adults: improving outcomes over time.

Umbilical cord blood (CB) is increasingly used as an alternative source of stem cells in adult unrelated transplantation. Although registry studies report similar overall outcomes in comparison with BM/PB, comparative studies focusing on severe infections and infection-RM (IRM) with a long follow-up are scarce. A total of 434 consecutive unrelated transplants (1997-2009) were retrospectively analyzed to compare overall outcomes, incidence and risk factors of severe viral and invasive fungal infections in CB (n=65) vs BM/PB recipients (n=369). The 5-year OS was 38 vs 43%, respectively (P=0.2). CB transplantation (CBT) was associated with a higher risk of invasive aspergillosis (100-days-cumulative incidence 16 vs 6%, P=0.04) and CMV infection without differences in RM. No statistically significant differences were found regarding NRM (NRM of 38% in CB vs 37% in BM/PB at 1 year) nor IRM (30% in CB vs 27% in BM/PB at 1 year). In the overall population, NRM and IRM improved in more recent years. In adults who receive a single CBT, the risk of severe infections is increased when compared with unrelated BM/PB recipients, but mortality from infections is similar, leading to similar NRM and survival.

Etiology, clinical features and outcomes of pre-engraftment and post-engraftment bloodstream infection in hematopoietic SCT recipients.

We conducted an observational study to assess the etiology, clinical features and outcomes of bloodstream infection (BSI) in 172 hematopoietic SCT (HCST) recipients. One hundred episodes of BSI in the pre-engraftment period (early onset) were compared with 89 episodes in the post-engraftment phase (late onset). More patients with late-onset BSI received an allogeneic HSCT, had GVHD and had received corticosteroids, whereas patients with early-onset BSI were more likely to have neutropenia, severe mucositis and a central venous catheter (CVC) in place. CVC was the most frequent site of infection, followed by an endogenous source. Pneumonia and gastrointestinal infection were particularly frequent in late-onset BSI, whereas mucositis was more frequent in the early-onset group. Gram-positive organisms predominated over Gram negatives. Streptococcus pneumoniae was more frequent in patients with late-onset BSI. Patients with late-onset BSI presented worse outcomes regarding septic shock, intensive care unit admission and early and overall case-fatality rates. Early-onset BSI was mainly related to the presence of neutropenia, mucositis and CVC, whereas late-onset BSI mainly affected severely immunosuppressed allogeneic HSCT recipients with GVHD and corticosteroids. Late-onset BSI caused high case-fatality rates. BSI due to S. pneumoniae was especially frequent late after transplantation. The development of better vaccination strategies is needed.

Bacteraemia due to multidrug-resistant Gram-negative bacilli in cancer patients: risk factors, antibiotic therapy and outcomes.

OBJECTIVES: To assess the risk factors, antibiotic therapy and outcomes of multidrug-resistant Gram-negative bacilli (MDRGNB) bacteraemia in hospitalized patients with cancer. METHODS: Episodes of MDRGNB bacteraemia were compared with a susceptible control group in a 4 year prospective study. RESULTS: Of 747 bacteraemias, 372 (49.7%) were caused by a Gram-negative bacilli (GNB). Fifty-one of these (13.7%) were caused by a multidrug-resistant (MDR) strain. Previous antibiotics [odds ratio (OR) 3.57; 95% confidence interval (CI) 1.63-7.80] and urinary catheter (OR 2.41; 95% CI 1.01-5.74) were identified as independent risk factors for MDRGNB acquisition. The most frequent mechanism of resistance was extended-spectrum ß-lactamase (ESBL) production (45%), mainly by Escherichia coli, followed by Amp-C cephalosporinase hyperproduction (24%). Patients with MDRGNB bacteraemia more frequently received inadequate initial antibiotic therapy (69% versus 9%; P < 0.001) and time to adequate therapy was longer in this group (41% versus 4%; P < 0.001). Patients in the resistant group more frequently required intensive care unit (ICU) admission (14% versus 5%; P = 0.023), had greater need for mechanical ventilation (14% versus 3%; P = 0.005) and had a higher overall case-fatality rate (41% versus 21%; P = 0.003). Risk factors for mortality were solid tumour (OR 5.04; 95% CI 2.49-10.19), current corticosteroid use (OR 4.38; 95% CI 2.39-8.05), ICU admission (OR 11.40; 95% CI 3.19-40.74) and MDRGNB bacteraemia (OR 3.52; 95% CI 1.36-9.09). CONCLUSIONS: MDRGNB bacteraemia was common among cancer patients, especially in those exposed to antibiotics and urinary catheter. The most frequent mechanism of resistance was ESBL production. Patients with MDRGNB more frequently received inadequate empirical antibiotic therapy and presented poorer outcomes with a higher overall case-fatality rate (within 30 days).

Clinical efficacy and safety of primary antifungal prophylaxis with posaconazole vs itraconazole in allogeneic blood and marrow transplantation.

Posaconazole has been recently approved for primary antifungal prophylaxis in patients with prolonged neutropenia after AML induction chemotherapy and patients with GVHD. We now present the first experience of the efficacy and safety of posaconazole during the early phase of post-allogeneic BMT (n=33; from June 2007), in comparison with itraconazole primary prophylaxis (n=16; up to May 2007). More patients receiving posaconazole were T-cell depleted (P=0.003). Groups were otherwise comparable in terms of age, sex, disease, neutrophil engraftment, incidence of GVHD, use of unrelated donors and type of conditioning. Safety data as well as the incidence of fever (84%) and persistent fever (27%) during the 100-day treatment period were comparable for both antifungal agents. Patients receiving posaconazole had a lower cumulative incidence of proven or probable invasive fungal disease, as defined by the European Organization for Research and Treatment of Cancer criteria (0 vs 12%; P=0.04), which associated with a higher probability of fungal-free survival (91 vs 56%; P=0.003) and an improved probability of OS (91 vs 63%; P=0.011) compared with patients receiving itraconazole. Our single-centre experience suggests that antifungal prophylaxis with posaconazole may lead to a better outcome than itraconazole for patients in the early high-risk neutropenic period after allogeneic BMT.

[Immune reconstitution and regulation following autologous hematopoietic transplantation using palifermin]. / Reconstitución de la inmunidad e inmunorregulación tras el trasplante autólogo de sangre periférica.

In the last decade there has been increasing awareness of the importance of thymus gland function in the reconstitution of host immunity following hematopoietic transplantation. A functional thymus contributes to foster T compartment reconstitution, with an increased diversity of T receptor rearrangement, and a more physiological distribution of the functional subpopulations. Palifermin, a keratinocyte growth factor (KGF) approved for reducing the incidence and severity of oral mucositis, has been proposed as a possible strategy for improving thymus function and immune reconstitution after hematopoietic transplantation. In vitro and animal models show palifermin to protect the thymus from chemo-/radiotherapy induced damage, increasing thymic production, accelerating immune reconstitution, improving response to vaccines, and reducing the incidence of graft-versus-host disease in animal models. To date, no studies have analyzed this possible application in humans. This study reports preliminary data on immune reconstitution in 50 autologous transplant recipients (30 treated with palifermin and 20 controls). The results suggest that palifermin at the doses and involving the regimens indicated for the prevention of oral mucositis has no effect upon thymus gland function in adult patients, and induces no changes in T immune recovery (either CD4 or CD8) or in the percentage of functional T subpopulations or T helper lymphocytes.

[Histopathological findings and biomarker analysis in cutaneous graft-versus-host disease ]. / Histología y biomarcadores en la enfermedad del injerto contra el huésped cutánea.

Graft-versus-host disease (GVHD) remains the greatest source of morbidity-mortality in allogenic transplant patients. Although in most cases the more easily obtainable clinical and laboratory test parameters suffice to confirm the diagnosis and establish the stage of the disease biopsies of the affected organ are sometimes needed. At present there is great Interest in the study of factors allowing a prognosis of the course and type of response to treatment in patients with CVHD. In this sense, It would be necessary to objectively Identify and validate biomarkers capable of predicting biological or pathological processes in patients with cVHD. To this effect we have performed serial analyses of skin tissue using peripheral blood and tissue biomarkers in a prospective observational study conducted in three transplant centers. The still preliminary results Indicate that certain histopathological findings classically attributed to CVHD ore also seen in patients not clinically affected by the disease--this probably being related to other physiopathological phenomena occurring during transplantation. The study of these findings, combined with biomarker analysis, will allow improved understanding of the underlying etiopathogenesis, as well as the definition of new diagnostic, prognostic and response-evaluating criteria.