Treatment of inborn errors of immunity patients with inflammatory bowel disease phenotype by allogeneic stem cell transplantation.

Patients with inborn errors of immunity (IEI) can suffer from treatment-refractory inflammatory bowel disease (IBD) causing failure to thrive and consequences of long-term multiple immunosuppressive treatments. Allogeneic haematopoietic stem cell transplantation (alloHSCT) can serve as a curative treatment option. In this single-centre retrospective cohort study we report on 11 paediatric and young adult IEI patients with IBD and failure to thrive, who had exhausted symptomatic treatment options and received alloHSCT. The cohort included chronic granulomatous disease (CGD), lipopolysaccharide-responsive and beige-like anchor protein (LRBA) deficiency, STAT3 gain-of-function (GOF), Wiskott-Aldrich syndrome (WAS), dedicator of cytokinesis 8 (DOCK8) deficiency and one patient without genetic diagnosis. All patients achieved stable engraftment and immune reconstitution, and gastrointestinal symptoms were resolved after alloHSCT. The overall survival was 11/11 over a median follow-up of 34.7 months. Graft-versus-host disease (GVHD) was limited to grade I-II acute GVHD (n = 5), one case of grade IV acute GVHD and one case of limited chronic GVHD. Since treatment recommendations are limited, this work provides a centre-specific approach to treatment prior to transplant as well as conditioning in IEI patients with severe IBD.

Donor-type red blood cell transfusion to deplete isoagglutinins prior to allogeneic stem cell transplantation from ABO major incompatible bone marrow donors.

ABO incompatibility affects approximately 40% of allogeneic stem cell transplants in Caucasian patient populations. Because bone marrow (BM), the preferred graft from paediatric sibling donors and for non-malignant diseases, has a red blood cell (RBC) content similar to blood, anti-donor isoagglutinins must either be depleted from the recipient or RBCs removed from the graft. To achieve tolerability of unmanipulated BM grafts, we used controlled infusions of donor ABO-type RBC units to deplete isoagglutinins before the transplant. This retrospective study evaluates the outcomes of 52 ABO major incompatible BM transplants performed at our centre between 2007 and 2019. The use of donor-type RBC transfusions was well tolerated. They effectively reduced isoagglutinins levels, typically achieving target titres after one (60%) or two (29%) transfusions. The approach allowed for successful and uneventful infusions of unmanipulated BM which provided timely engraftment. The transplant outcomes were not inferior to those of a matched-pair control group of patients with ABO-identical donors.

Guidance to Bone Morbidity in Children and Adolescents Undergoing Allogeneic Hematopoietic Stem Cell Transplantation.

Allogeneic hematopoietic stem cell transplantation (HSCT) is widely performed in children and adolescents with hematologic diseases, including very high-risk leukemia. With increasing success and survival rates, the long-term sequelae of HSCT have become important. Here, we provide guidance to the prevention and treatment of the most common bone morbidities-osteoporosis and osteonecrosis-emerging in the context of HSCT in children and adolescents. We give an overview on definitions, symptoms, and diagnostics and propose an algorithm for clinical practice based on discussions within the International Berlin Frankfurt Münster (BFM) Stem Cell Transplantation Committee and the Pediatric Disease Working Party of the European Society for Blood and Marrow Transplantation, our expert knowledge, and a literature review.

Clearance of Hematologic Malignancies by Allogeneic Cytokine-Induced Killer Cell or Donor Lymphocyte Infusions.

Well-established donor lymphocyte infusion (DLI) and novel cytokine-induced killer (CIK) cell therapy for the treatment of relapsing hematologic malignancies after allogeneic hematopoietic stem cell transplantation (HSCT) were compared with respect to feasibility, safety, and efficacy. Altogether, a total of 221 infusions were given to 91 patients (DLI, n = 55; CIK, n = 36). T cell recovery was significantly improved after CIK cell therapy (P < .0001). Although patients with CIK cell treatment showed a significantly worse prognosis at the time of HSCT (risk score, 1.7 versus 2.1; P < .0001), DLI and CIK cell therapy induced complete remission (CR) in 29% and 53% patients, respectively, whereas relapse occurred in 71% and 47%. In both groups, all patients with overt hematologic relapse at the time of immunotherapy (DLI, n = 11; CIK, n = 8) succumbed to their disease, while 36% and 68% patients with DLI or CIK cell therapy applied due to molecular relapse or active disease at the time of transplantation achieved CR. The 6-month overall survival rate in the latter patients was 57% and 77%, respectively, with a median follow-up of 27.9 months (range, .9 to 149.2 months). The 6-month cumulative incidence of relapse was 55% and 22% in patients who received DLI and CIK cell therapy, respectively (P = .012). Acute graft-versus-host disease developed in 35% of the patients who received DLI and in 25% of those who received CIK. No transfusion-related deaths occurred. These data, while underscoring the therapeutic value of conventional DLI, suggest the improved safety and to a certain extent efficacy of CIK cell therapy for patients at high risk for post-transplantation relapse of various hematologic malignancies.

Mobilized peripheral blood stem cell apheresis via Hickman catheter in pediatric patients.

BACKGROUND: Autologous stem cell transplantation remains an integral treatment tool for certain childhood malignancies. In children, a central venous catheter is typically necessary to provide adequate flow rates for preparative apheresis. In this study, the feasibility and efficiency of collecting CD34+ cells via an indwelling Hickman catheter, preimplanted for chemotherapy, instead of placing an additional temporary central venous catheter was evaluated. STUDY DESIGN AND METHODS: Forty-eight pediatric leukaphereses for autologous hematopoietic stem cell transplantation using Spectra Optia MNC, Version 3.0 were reviewed. We compared preimplanted Hickman catheters with a temporary Shaldon catheter, inserted for apheresis. Apheresis was considered successful if a dose of 2 × 106 CD34+ peripheral blood stem cells/kg BW was achieved. RESULTS: In 43 (89.6%) of the 48 patients, a Hickman catheter was used for leukapheresis. Only 5 patients (10.4%) received a temporary Shaldon catheter. In both groups, apheresis was performed without apparent adverse reactions. The dose of collected CD34+ peripheral blood stem cells was 12.7 × 106 (range, 2.3-70.7 × 106 ) cells/kg BW in the Hickman group and 16.2 × 106 (range, 3.8-48.4 × 106 ) cells/kg BW in the Shaldon group, showing no statistically significant difference (p = 0.58). In both groups, the primary endpoint of a minimal CD34+ cell concentration of 2 × 106 cells/kg BW was achieved at a maximum of two leukapheresis sessions. Apheresis efficacy was further confirmed by the collection efficiency of 40.2% in the Hickman group and 27.8% in the Shaldon group (p = 0.32). CONCLUSION: These data indicate the reliable feasibility and efficacy of mobilized apheresis via an indwelling Hickman catheter. In light of this, the routine insertion of a dialysis catheter for the purpose of leukapheresis should be critically reconsidered.

Allogeneic hematopoietic stem cell transplantation from unrelated donors is associated with higher infection rates in children with acute lymphoblastic leukemia-A prospective international multicenter trial on behalf of the BFM-SG and the EBMT-PDWP.

Severe infections (SI) significantly impact on non-relapse mortality after hematopoietic stem cell transplantation (HSCT). We assessed 432 children and adolescents with acute lymphoblastic leukemia (ALL) after total body irradiation based myeloablative HSCT within the multicenter ALL-BFM-SCT 2003 trial for SI grade 3 or higher according to common terminology criteria for adverse events. A total 172 patients experienced at least one SI. Transplantation from matched unrelated donors (MUD) was associated with any type of SI in the pre-engraftment period (hazard ratio [HR]: 2.57; P < .001), and with any SI between day +30 and + 100 (HR: 2.91; P = .011). Bacterial (HR: 2.24; P = .041) and fungal infections (HR: 4.06; P = .057) occurred more often in the pre-engraftment phase and viral infections more often before day +30 (HR: 2.66; P = .007) or between day +30 and + 100 (HR: 3.89; P = .002) after HSCT from MUD as compared to matched sibling donors. Chronic GvHD was an independent risk factor for any type of SI after day +100 (HR: 2.57; P < .002). We conclude that allogeneic HSCT from MUD in children and adolescents with pediatric ALL is associated with higher infection rates, which seems attributable to an intensified GvHD prophylaxis including serotherapy and methotrexate.

Outcome of relapse after allogeneic HSCT in children with ALL enrolled in the ALL-SCT 2003/2007 trial.

Relapse remains the major cause of treatment failure in children with high-risk acute lymphoblastic leukaemia (ALL) undergoing allogeneic haematopoietic stem-cell transplantation (allo-SCT). Prognosis is considered dismal but data on risk factors and outcome are lacking from prospective studies. We analysed 242 children with recurrence of ALL after first allo-SCT enrolled in the Berlin-Frankfurt-Munster (BFM) ALL-SCT-BFM 2003 and ALL-SCT-BFM international 2007 studies. Median time from allo-SCT to relapse was 7·7 months; median follow-up from relapse after allo-SCT until last follow-up was 3·4 years. The 3-year event-free survival (EFS) was 15% and overall survival (OS) was 20%. The main cause of death was disease progression or relapse (86·5%). The majority of children (48%) received salvage therapy without second allo-SCT, 26% of the children underwent a second allo-SCT and 25% received palliative treatment only. In multivariate analyses, age, site of relapse, time to relapse and type of salvage therapy were identified as significant prognostic factors for OS and EFS, whereas factors associated with first SCT were not statistically significant. Combined approaches incorporating novel immunotherapeutic treatment options and second allo-SCT hold promise to improve outcome in children with post allo-SCT relapse.

Pre-Emptive Immunotherapy for Clearance of Molecular Disease in Childhood Acute Lymphoblastic Leukemia after Transplantation.

Monitoring of minimal residual disease (MRD) or chimerism may help guide pre-emptive immunotherapy (IT) with a view to preventing relapse in childhood acute lymphoblastic leukemia (ALL) after transplantation. Patients with ALL who consecutively underwent transplantation in Frankfurt/Main, Germany between January 1, 2005 and July 1, 2014 were included in this retrospective study. Chimerism monitoring was performed in all, and MRD assessment was performed in 58 of 89 patients. IT was guided in 19 of 24 patients with mixed chimerism (MC) and MRD and by MRD only in another 4 patients with complete chimerism (CC). The 3-year probabilities of event-free survival (EFS) were .69 ± .06 for the cohort without IT and .69 ± .10 for IT patients. Incidences of relapse (CIR) and treatment-related mortality (CITRM) were equally distributed between both cohorts (without IT: 3-year CIR, .21 ± .05, 3-year CITRM, .10 ± .04; IT patients: 3-year CIR, .18 ± .09, 3-year CITRM .13 ± .07). Accordingly, 3-year EFS and 3-year CIR were similar in CC and MC patients with IT, whereas MC patients without IT experienced relapse. IT was neither associated with an enhanced immune recovery nor an increased risk for acute graft-versus-host disease. Relapse prevention by IT in patients at risk may lead to the same favorable outcome as found in CC and MRD-negative-patients. This underlines the importance of excellent MRD and chimerism monitoring after transplantation as the basis for IT to improve survival in childhood ALL.

Epidemiology, risk factors, and prognosis of capillary leak syndrome in pediatric recipients of stem cell transplants: a retrospective single-center cohort study.

CLS involves sudden loss of intravascular fluids into the interstitial spaces. CLS was described as a possible complication after SCT. Few studies report the incidence of CLS in pediatric populations. We aimed to assess CLS incidence, its risk factors, and impact on the survival. The clinical charts of patients <18 years of age transplanted at our institution between 2002 and 2012 were reviewed. CLS was defined by weight gain >3% in 24 hours and positive intake balance despite furosemide administration. In total, 234 patients underwent 275 allogeneic SCT procedures in the analyzed time frame. Fifteen patients developed CLS (5.4%). The probability of developing CLS was significantly increased in patients suffering from sepsis (14.3% vs 0.6%, P<.001). Patients with CLS exhibited an increased risk of acute GvHD in the first 30 days after SCT (10.8% vs 1.8%, P=.002). Ten of the patients with CLS required intensive care. CLS strongly impacts OS at day +100 after SCT and is a predictive factor of TRM at the same date (42.9% vs 5%, P<.0001). The biological relation among sepsis, GvHD, and CLS development in terms of cytokine release and endothelial damage warrants further studies.

Monitoring of hematopoietic chimerism after transplantation for pediatric myelodysplastic syndrome: real-time or conventional short tandem repeat PCR in peripheral blood or bone marrow?

Quantitative real-time PCR (qPCR) has been proposed as a highly sensitive method for monitoring hematopoietic chimerism and may serve as a surrogate marker for the detection of minimal residual disease minimal residual disease in myelodysplastic syndrome (MDS), until specific methods of detection become available. Because a systematic comparison of the clinical utility of qPCR with the gold standard short tandem repeat (STR)-PCR has not been reported, we retrospectively measured chimerism by qPCR in 54 children transplanted for MDS in a previous study. Results obtained by STR-PCR in the initial study served as comparison. Because the detection limit of qPCR was sufficiently low to detect an autologous background, we defined the sample as mixed chimera if the proportion of recipient-derived cells exceeded .5%. The true positive rates were 100% versus 80% (qPCR versus STR-PCR, not significant), and mixed chimerism in most cases was detected earlier by qPCR than by STR-PCR (median, 31 days) when chimerism was quantified concurrently in peripheral blood and bone marrow. Both methods revealed a substantial rate of false positives (22.7% versus 13.6%, not significant), indicating the importance of serial testing of chimerism to monitor its progression. Finally, we propose criteria for monitoring chimerism in pediatric MDS with regard to the subtypes, specimens, PCR method, and timing of sampling.

Immunomagnetic selection or irradiation eliminates alloreactive cells but also reduces anti-tumor potential of cytokine-induced killer cells: implications for unmanipulated cytokine-induced killer cell infusion.

BACKGROUND AIMS: Cytokine-induced killer (CIK) cells may offer a novel therapeutic approach for patients with malignancies relapsing after allogeneic stem cell transplantation. Although CIK cells display negligible alloreactivity and cause minimal graft versus-host-disease (GVHD), high CIK cell doses required during relapse may pose a risk for severe GVHD, specifically in the mismatched or haploidentical transplantation setting. Manipulation of CIK cells may reduce risk for GVHD without affecting the anti-tumor potential. METHODS: In this pre-clinical study, we provide a detailed functional comparison of conventional and irradiated, CD56-enriched or T-cell receptor α/ß-depleted CIK cells. RESULTS: In vitro analysis showed retained anti-leukemic and anti-tumor potential after CIK cell manipulation. Even being sequentially infused into immunodeficient mice grafted with malignant cells, cytotoxic effects were fewest after irradiation but were improved by CD56 enrichment and were best with conventional CIK cells. Hence, considering the proliferative capacity of inoculated malignancies and effector cells, a single dose of conventional CIK cells resulted in prolonged disease-free survival and elimination of rhabdomyosarcoma cells, whereas sequential infusions were needed to achieve comparable results in leukemia-bearing mice. However, this mouse model has limitations: highly effective conventional CIK cells demonstrated both limited xenogenic GVHD and low alloreactive potential in vitro. CONCLUSIONS: Our study revealed that conventional CIK cells demonstrate no significant alloreactive potential but provide the strongest anti-tumor efficacy compared with manipulated CIK cells. Conventional CIK cells may therefore be tested in high numbers and short-term intervals in patients with impending relapse even after mismatched transplantation.

Preemptive immunotherapy in childhood acute myeloid leukemia for patients showing evidence of mixed chimerism after allogeneic stem cell transplantation.

Previous studies have shown that children with acute myeloid leukemia (AML) who developed mixed chimerism (MC) were at high risk for relapse after allogeneic stem-cell transplantation (allo-SCT). We investigated the feasibility of intensified preemptive immunotherapy in children receiving allo-SCT for AML. Eighty-four children were registered in our trial from May 2005 to April 2009; of these, 71 fulfilled the inclusion criteria and were treated according to the study protocol. Serial and semiquantitative analyses of posttransplantation chimerism were performed. Defined immunotherapy approaches were considered in MC patients. Continuous complete chimerism (CC) was observed in 51 of 71 patients. MC was detected in 20 patients and was followed by immunotherapy in 13. Six of 13 MC patients returned to CC without toxicity and remained in long-term remission. Overall, the probability of event-free survival (pEFS) was 66% (95% confidence interval [95% CI] = 53%-76%) for all patients and 46% (95% CI = 19%-70%) in MC patients with intervention; however, this number increased to 71% (95% CI = 26%-92%) in 7 of 13 MC patients on immunotherapy who were in remission at the time of transplantation. All MC patients without intervention relapsed. These results suggest that MC is a prognostic factor for impending relapse in childhood AML, and that preemptive immunotherapy may improve the outcome in defined high-risk patients after transplantation.

The cytotoxic potential of interleukin-15-stimulated cytokine-induced killer cells against leukemia cells.

BACKGROUND AIMS: Cytokine-induced killer (CIK) cells may serve as an alternative approach to adoptive donor lymphocyte infusions (DLI) for patients with acute leukemia relapsing after haplo-identical hematopoietic stem cell transplantation (HSCT). We investigated the feasibility of enhancing CIK cell-mediated cytotoxicity by interleukin (IL)-15 against acute myeloid and lymphoblastic leukemia/lymphoma cells. METHODS: CIK cells were activated using IL-2 (CIK(IL-2)) or IL-15 (CIK(IL-15)) and phenotypically analyzed by fluorescence-activated cell sorting (FACS). Cytotoxic potential was measured by europium release assay. RESULTS: CIK(IL-2) cells showed potent cytotoxicity against the T-lymphoma cell line H9, T-cell acute lymphoblastic leukemia (T-ALL) cell line MOLT-4 and subtype M4 acute myeloid leukemia (AML) cell line THP-1, but low cytotoxicity against the precursor B (pB)-cell ALL cell line Tanoue. IL-15 stimulation resulted in a significant enhancement of CIK cell-mediated cytotoxicity against acute lymphoblastic leukemia/lymphoma cell lines as well as against primary acute myeloid and defined lymphoblastic leukemia cells. However, the alloreactive potential of CIK(IL-15) cells remained low. Further analysis of CIK(IL-15) cells demonstrated that the NKG2D receptor is apparently involved in the recognition of target cells whereas killer-cell immunoglobulin-like receptor (KIR)-HLA mismatches contributed to a lesser extent to the CIK(IL-15) cell-mediated cytotoxicity. In this context, CD3 (+) CD8 (+) CD25 (+) CD56(-) CIK(IL-15) cell subpopulations were more effective in the lysis of AML cells, in contrast with CD56 (+) CIK(IL-15) cells, which showed the highest cytotoxic potential against ALL cells. CONCLUSIONS: This study provides the first evidence that CIK(IL-15) cells may offer a therapeutic option for patients with refractory or relapsed leukemia following haplo-identical HSCT.

Prediction model for the incidence and prevalence of type 1 diabetes in childhood and adolescence: evidence for a cohort-dependent increase within the next two decades in Germany.

OBJECTIVE: To provide data on type 1 diabetes (T1D) epidemiology in childhood over a period of 20 years and to predict prevalence and cohort-age-specific incidence rates (IRs) for the next two decades in Germany. METHODS: The Baden-Wuerttemberg Diabetes Incidence Registry (DIARY) includes children and adolescents below 15 years of age with new onset of T1D (period 1987-2006, n = 5108 cases). RESULTS: The mean age- and sex-standardized IR was 15.3/100 000/year (95% CI 14.8-15.7) and the average increase in the IR was 4.4% per year (95% CI 3.9-4.9). Within the next 20 years (2007-2026), the risk for developing diabetes will increase like the square of a linear function with calendar year for all age ranges. There is a strong correlation between the predicted IRs of the cohorts and the observed IRs (n = 300; root mean square error = 0.56; r(2) = 0.71) and a negative correlation between mean age at onset and T1D IR (p = 0.02). On 31 December 2006, the prevalence of T1D was 0.126% (95% CI 0.121-0.132). The predicted prevalence (end of 2026) is estimated to be 0.265% (95% CI 0.25-0.28; predicted cases: n = 2950; 95% CI 2900-3000). CONCLUSIONS: In comparison to observations made in the past, the risk of disease rises even faster than expected: The younger the child, the quicker the increase of the cohort-age-specific IR and the higher the risk for T1D during lifetime.

Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency.

Human cells homozygous for rare loss-of-expression (LOE) TYK2 alleles have impaired, but not abolished, cellular responses to IFN-α/ß (underlying viral diseases in the patients) and to IL-12 and IL-23 (underlying mycobacterial diseases). Cells homozygous for the common P1104A TYK2 allele have selectively impaired responses to IL-23 (underlying isolated mycobacterial disease). We report three new forms of TYK2 deficiency in six patients from five families homozygous for rare TYK2 alleles (R864C, G996R, G634E, or G1010D) or compound heterozygous for P1104A and a rare allele (A928V). All these missense alleles encode detectable proteins. The R864C and G1010D alleles are hypomorphic and loss-of-function (LOF), respectively, across signaling pathways. By contrast, hypomorphic G996R, G634E, and A928V mutations selectively impair responses to IL-23, like P1104A. Impairment of the IL-23-dependent induction of IFN-γ is the only mechanism of mycobacterial disease common to patients with complete TYK2 deficiency with or without TYK2 expression, partial TYK2 deficiency across signaling pathways, or rare or common partial TYK2 deficiency specific for IL-23 signaling.

Clinical relevance of Wilms tumor 1 gene mutations in childhood acute myeloid leukemia.

Wilms tumor 1 (WT1) mutations have recently been identified in approximately 10% of adult acute myeloid leukemia (AML) with normal cytogenetics (CN-AML) and are associated with poor outcome. Using array-based comparative genome hybridization in pediatric CN-AML samples, we detected a WT1 deletion in one sample. The other WT1 allele was mutated. This prompted us to further investigate the role of WT1 aberrations in childhood AML. Mutations were found in 35 of 298 (12%) diagnostic pediatric AML samples. In 19 of 35 (54%) samples, more than one WT1 aberration was found: 15 samples had 2 different mutations, 2 had a homozygous mutation, and 2 had a mutation plus a WT1 deletion. WT1 mutations clustered significantly in the CN-AML subgroup (22%; P < .001) and were associated with FLT3/ITD (43 vs 17%; P < .001). WT1 mutations conferred an independent poor prognostic significance (WT1 mutated vs wild-type patients: 5-year probability of overall survival [pOS] 35% vs 66%, P = .002; probability of event-free survival 22% vs 46%, P < .001; and cumulative incidence of relapse or regression 70% vs 44%, P < .001). Patients with both a WT1 mutation and a FLT3/ITD had a dismal prognosis (5-year pOS 21%). WT1 mutations occur at a significant rate in childhood AML and are a novel independent poor prognostic marker.

ABO incompatibile graft management in pediatric transplantation.

Up to 40% of donor-recipient pairs in SCT have some degree of ABO incompatibility, which may cause severe complications. The aim of this study was to describe available options and survey current practices by means of a questionnaire circulated within the EBMT Pediatric Diseases Working Party investigators. Major ABO incompatibility (donor's RBCs have antigens missing on the recipient's cell surface, towards which the recipient has circulating isohemagglutinins) requires most frequently an intervention in case of bone marrow grafts, as immediate or delayed hemolysis, delayed erythropoiesis and pure red cell aplasia may occur. RBC depletion from the graft (82%), recipient plasma-exchange (14%) were the most common practices, according to the survey. Graft manipulation is rarely needed in mobilized peripheral blood grafts. In case of minor incompatible grafts (donor has isohemagglutinins directed against recipient RBC antigens), isohemagglutinin depletion from the graft by plasma reduction/centrifugation may be considered, but acute tolerability of minor incompatible grafts is rarely an issue. According to the survey, minor ABO incompatibility was either managed by means of plasma removal from the graft, especially when isohemagglutinin titer was above a certain threshold, or led to no intervention at all (41%). Advantages and disadvantages of each method are discussed.

Supportive Care During Pediatric Hematopoietic Stem Cell Transplantation: Prevention of Infections. A Report From Workshops on Supportive Care of the Paediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT).

Specific protocols define eligibility, conditioning, donor selection, graft composition and prophylaxis of graft vs. host disease for children and young adults undergoing hematopoietic stem cell transplant (HSCT). However, international protocols rarely, if ever, detail supportive care, including pharmaceutical infection prophylaxis, physical protection with face masks and cohort isolation or food restrictions. Supportive care suffers from a lack of scientific evidence and implementation of practices in the transplant centers brings extensive restrictions to the child's and family's daily life after HSCT. Therefore, the Board of the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) held a series of dedicated workshops since 2017 with the aim of initiating the production of a set of minimal recommendations. The present paper describes the consensus reached within the field of infection prophylaxis.

NCI First International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation: report from the Committee on Disease-Specific Methods and Strategies for Monitoring Relapse following Allogeneic Stem Cell Transplantation. Part I: Methods, acute leukemias, and myelodysplastic syndromes.

Relapse has become the major cause of treatment failure after allogeneic stem cell transplantation. Outcome of patients with clinical relapse after transplantation generally remains poor, but intervention prior to florid relapse improves outcome for certain hematologic malignancies. To detect early relapse or minimal residual disease, sensitive methods such as molecular genetics, tumor-specific molecular primers, fluorescein in situ hybridization, and multiparameter flow cytometry (MFC) are commonly used after allogeneic stem cell transplantation to monitor patients, but not all of them are included in the commonly employed disease-specific response criteria. The highest sensitivity and specificity can be achieved by molecular monitoring of tumor- or patient-specific markers measured by polymerase chain reaction-based techniques, but not all diseases have such targets for monitoring. Similar high sensitivity can be achieved by determination of donor chimerism, but its specificity regarding detection of relapse is low and differs substantially among diseases. Here, we summarize the current knowledge about the utilization of such sensitive monitoring techniques based on tumor-specific markers and donor cell chimerism and how these methods might augment the standard definitions of posttransplant remission, persistence, progression, relapse, and the prediction of relapse. Critically important is the need for standardization of the different residual disease techniques and to assess the clinical relevance of minimal residual disease and chimerism surveillance in individual diseases, which in turn, must be followed by studies to assess the potential impact of specific interventional strategies.