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•Ibrutinib–R-mini-CHOP was a deliverable combination in patients with DLBCL aged ≥75 years.•Ibrutinib–R-mini-CHOP improves PFS compared with historical rates reported for R-mini-CHOP, but this study did not demonstrate a superior OS.

In patients with severe congenital neutropenia (SCN), sepsis mortality is reduced by treatment with granulocyte colony-stimulating factor (G-CSF), but myelodsyplastic syndrome and acute myeloid leukemia (MDS/AML) have been reported. We studied 374 patients with SCN and 29 patients with Shwachman-Diamond syndrome (SDS) on long-term G-CSF enrolled in the Severe Chronic Neutropenia International Registry. In SCN, sepsis mortality was stable at 0.9% per year. The hazard of MDS/AML increased significantly over time, from 2.9% per year after 6 years to 8.0% per year after 12 years on G-CSF. After 10 years, the cumulative incidence was 8% for sepsis mortality and 21% for MDS/AML. A subgroup of SCN patients (29%) received more than the median dose of G-CSF (≥ 8 μg/kg/d), but achieved less than the median absolute neutrophil count (ANC) response (ANC < 2.188 × 109/L [2188/μL] at 6-18 months). In these less-responsive patients, the cumulative incidence of adverse events was highest: after 10 years, 40% developed MDS/AML and 14% died of sepsis, compared with 11% and 4%, respectively, of more responsive patients whose ANC was above the median on doses of G-CSF below the median. Risk of MDS/AML may be similar in SDS and SCN. In less-responsive SCN patients, early hematopoietic stem cell transplantation may be a rational option.

Congenital neutropenia and cyclic neutropenia are disorders of neutrophil production predisposing patients to recurrent bacterial infections. Recently the locus for autosomal dominant cyclic neutropenia was mapped to chromosome 19p13.3, and this disease is now attributable to mutations of the gene encoding neutrophil elastase (the ELA2 gene). The authors hypothesized that congenital neutropenia is also due to mutations of neutrophil elastase. Patients with congenital neutropenia, cyclic neutropenia, or Shwachman-Diamond syndrome were referred to the Severe Chronic Neutropenia International Registry. Referring physicians provided hematologic and clinical data. Mutational analysis was performed by sequencing polymerase chain reaction (PCR)-amplified genomic DNA for each of the 5 exons of the neutrophil ELA2 gene and 20 bases of the flanking regions. RNA from bone marrow mononuclear cells was used to determine if the affected patients expressed both the normal and the abnormal transcript. Twenty-two of 25 patients with congenital neutropenia had 18 different heterozygous mutations. Four of 4 patients with cyclic neutropenia and 0 of 3 patients with Shwachman-Diamond syndrome had mutations. For 5 patients with congenital neutropenia having mutations predicted to alter RNA splicing or transcript structure, reverse transcriptase-PCR showed expression of both normal and abnormal transcripts. In cyclic neutropenia, the mutations appeared to cluster near the active site of the molecule, whereas the opposite face was predominantly affected by the mutations found in congenital neutropenia. This study indicates that mutations of the gene encoding neutrophil elastase are probably the most common cause for severe congenital neutropenia as well as the cause for sporadic and autosomal dominant cyclic neutropenia.

Granulocyte colony-stimulating factor (G-CSF) has had a major impact on management of “severe chronic neutropenia,” a collective term referring to congenital, idiopathic, or cyclic neutropenia. Almost all patients respond to G-CSF with increased neutrophils, reduced infections, and improved survival. Some responders with congenital neutropenia have developed myelodysplastic syndrome and acute myeloblastic leukemia (MDS/AML), which raises the question of the role of G-CSF in pathogenesis. The Severe Chronic Neutropenia International Registry (SCNIR), Seattle, WA, has data on 696 neutropenic patients, including 352 patients with congenital neutropenia, treated with G-CSF from 1987 to present. Treatment and patient demographic data were analyzed. The 352 congenital patients were observed for a mean of 6 years (range, 0.1-11 years) while being treated. Of these patients, 31 developed MDS/AML, for a crude rate of malignant transformation of nearly 9%. None of the 344 patients with idiopathic or cyclic neutropenia developed MDS/AML. Transformation was associated with acquired marrow cytogenetic clonal changes: 18 patients developed a partial or complete loss of chromosome 7, and 9 patients manifested abnormalities of chromosome 21 (usually trisomy 21). For each yearly treatment interval, the annual rate of MDS/AML development was less than 2%. No significant relationships between age at onset of MDS/AML and patient gender, G-CSF dose, or treatment duration were found (P > .15). In addition to the 31 patients who developed MDS/AML, the SCNIR also has data on 9 additional neutropenic patients whose bone marrow studies show cytogenetic clonal changes but the patients are without transformation to MDS/AML. Although our data does not support a cause-and-effect relationship between development of MDS/AML and G-CSF therapy or other patient demographics, we cannot exclude a direct contribution of G-CSF in the pathogenesis of MDS/AML. This issue is unclear because MDS/AML was not seen in cyclic or idiopathic neutropenia. Improved survival of congenital neutropenia patients receiving G-CSF therapy may allow time for the expression of the leukemic predisposition that characterizes the natural history of these disorders. However, other factors related to G-CSF may also be operative in the setting of congenital neutropenia.

Tissue-resident memory T (TRM) cells provide long-lasting immune protection. One of the key events controlling TRM cell development is the local retention of TRM cell precursors coupled to downregulation of molecules necessary for tissue exit. Sphingosine-1-phosphate receptor 5 (S1PR5) is a migratory receptor with an uncharted function in T cells. Here, we show that S1PR5 plays a critical role in T cell infiltration and emigration from peripheral organs, as well as being specifically downregulated in TRM cells. Consequentially, TRM cell development was selectively impaired upon ectopic expression of S1pr5, whereas loss of S1pr5 enhanced skin TRM cell formation by promoting peripheral T cell sequestration. Importantly, we found that T-bet and ZEB2 were required for S1pr5 induction and that local TGF-β signaling was necessary to promote coordinated Tbx21, Zeb2, and S1pr5 downregulation. Moreover, S1PR5-mediated control of tissue residency was conserved across innate and adaptive immune compartments. Together, these results identify the T-bet–ZEB2–S1PR5 axis as a previously unappreciated mechanism modulating the generation of tissue-resident lymphocytes.

Background:Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis leading to cytopenias, including anemia and thrombocytopenia.

ABSTRACTA xenograft model of the human disease Langerhans cell histiocytosis (LCH) was investigated with severe combined immunodeficiency (SCID) mice. Transplantation of human LCH biopsy material into SCID mice resulted in the generation of mouse tumors resembling lymphomas. A thymoma cell line (ThyE1M6) was generated from one of these mice and found to display significant levels of Mg2+-dependent reverse transcriptase activity. Electron microscopy revealed particles with type D retroviral morphology budding from ThyE1M6 cells at a high frequency, whereas control cultures were negative. Reverse transcription-PCR of virion RNA with degenerate primers for conserved regions of various mouse, human, and primate retroviruses amplified novel sequences related to primate type D retroviruses, murine intracisternal A particles, Jaagsiekte sheep retrovirus, and murine long interspersed nuclear elements but not other retroviral classes. We demonstrate that these sequences represent a novel group of endogenous retroviruses expressed at low levels in mice but expressed at high levels in the ThyE1M6 cell line. Furthermore, we propose that the activation of endogenous retroviral elements may be associated with a high incidence of thymomas in SCID mice.

In this report, the biological properties of human recombinant interleukin-3 (rhIL-3) were studied. We investigated the range of unfractionated, purified and single cell human progenitors responsive to IL-3; compared the colony types observed with those obtained in the presence of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) or granulocyte-CSF (G-CSF). The results show that IL-3 directly stimulates the formation of colonies derived from eosinophil and, to a lesser degree, granulocyte and macrophage progenitors. In combination with erythropoietin, it supports the development of erythroid and mixed-erythroid colonies. Furthermore, the data show that IL-3 is a more potent stimulus for both erythroid and eosinophil progenitors than GM-CSF. Interleukin-3 stimulates the formation of both compact and dispersed colonies derived from eosinophil progenitors, whereas GM-CSF stimulates the formation of only the compact type. We conclude that some of the proliferative effects of IL-3 observed on unfractionated and semipurified bone marrow populations are indirect and most likely involve accessory cell interactions.

A sensitive and reliable sandwich enzyme-linked immunosorbent assay (ELISA) has been developed for recombinant human granulocyte-macrophage colony-stimulating factor (hGM-CSF). The assay is quantitative between 100 pg/mL and 2.5 ng/mL for bacterially synthesized hGM-CSF in human serum and is more sensitive and specific than the semisolid agar bioassay. As part of a phase I study, the pharmacokinetics of intravenous (IV) bolus injection and subcutaneous (SC) administration of hGM-CSF were studied. Following a single IV dose, an initial high blood level of hGM-CSF occurred, followed by β repid decrease occurring in two apparent phases with a half-life (t½)αof less than five minutes and a t½β of 150 minutes. After an SC injection, detectable serum levels occurred within 15 to 30 minutes, and serum levels were sustained for a variable time depending on the dose. At the highest SC dose (10 µg/kg), a serum level of >1 ng/mL (65 pmol/L) was maintained for >12 hours after a single injection. This corresponds to the concentration of hGM-CSF supporting near-maximum proliferation in vitro.

Ewing's sarcoma (ES) and other primitive peripheral neuroectodermal tumors (pPNETs) can present a significant diagnostic problem, as they may morphologically resemble other small round cell tumors (SRCTs) of childhood. However, ES/pPNET is known to carry a characteristic t(11;22)(q24;q12), the detection of which may aid diagnosis. The recent identification of the EWS and FLI-1 genes flanking the. translocation break point has enabled reverse transcriptase-polymerase chain reaction (RT-PCR) to be used to detect the. putative chimeric transcription factor mRNA produced by the fusion gene. We have assessed the RT-PCR method of detection by examining 40 cases of ES for the presence of EWS/FLI-1 transcripts. Twenty-six (76%) of the 34 cases with intact mRNA yielded fusion transcripts. Four different transcript sizes were delected and two tumors contained two transcripts of different size. No transcripts were detected in a control group of non-ES/pPNET SRCTs. Eight cases with intact mRNA were transcript negative. The MIC2 cell surface antigen, which is reported to be present in over 95% of ES/pPNETs, was present in 32 of 33 tumors (97%), including all 24 EWS/FLI-1 transcript-positive cases examined. Hence MIC2 is a useful screen for ES, with RT-PCR detection of t(11;22) being the optimal method for confirming the diagnosis.

Hematopoietic progenitor cell levels were monitored in the peripheral blood and bone marrow of 30 cancer patients receiving recombinant human granulocyte-colony stimulating-factor (rG-CSF) in a phase I/II clinical trial. The absolute number of circulating progenitor cells of granulocyte-macrophage, erythroid, and megakaryocyte lineages showed a dose-related increase up to 100-fold after four days of treatment with rG-CSF and often remained elevated two days after the cessation of therapy. The relative frequency of different types of progenitor cells in peripheral blood remained unchanged. The frequency of progenitor cells in the marrow was variable after rG-CSF treatment but in most patients was slightly decreased. The responsiveness of bone marrow progenitor cells to stimulation in vitro by rG-CSF and granulocyte-macrophage colony-stimulating factor did not change significantly during rG-CSF treatment. In patients nine days after treatment with melphalan and then rG-CSF, progenitor cell levels were very low with doses of rG-CSF at or below 10 µg/kg/d, but equaled or exceeded pretreatment values when 30 or 60 µg/kg/d of rG-CSF was given,

Normal human bone marrow mononuclear cells were fractionated by differential adherence, immunomagnetic separation, and fluorescence-activated cell sorting (FACS). The resultant fractionated cells were cultured in semisolid medium to monitor the presence of BFU-E, Mix-CFC, and nonerythroid CFC. Two populations of cells were recoverd on the basis of binding by the monoclonal antibody (MoAb) RFB-1. One of these populations contained BFU-E that were stimulated only by erythropoietin (Epo), whereas the second population contained BFU-E responsive to Epo, Epo and recombinant human granulocyte-macrophage colony- stimulating factor (rHGM-CSF), or Epo and human pla-cental-conditioned medium (HPCM). Prior enrichment of clonogenic cells by removal of adherent and Leu-M3+V\\\\\\\\ Leu-4+ve, Leu-7+ve ,B1 +ve WEMG1 +ve, and Glycophorin A+ve cells, followed by FACS fractionation on the basis of RFB-1 binding, consistently resulted in recoveries of BFU-E, Mix-CFC, and nonerythroid CFC of greater than 100% (up to 800%). These procedures also resulted in enrichment of up to 200-fold and frequencies of 1:6 for BFU-E, 1:5 for CFC, and 1:130 for Mix-CFC.

No relevant conflicts of interest to declare.

Hertzberg: Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gill:AbbVie: Honoraria; Roche: Research Funding; Sanofi Aventis: Research Funding; Roche: Honoraria. Ho:Celgene: Other: Travel. Cull:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Amgen: Other: Travel. Grigg:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lewis:Amgen: Other: Travel; Roche: Honoraria, Other: Travel. Renwick:Amgen: Other: Travel; Bayer: Speakers Bureau. Seymour:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Phebra: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

We recently reported on the risk for death from sepsis and myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) in patients with severe congenital neutropenia (SCN) on long-term granulocyte-colony stimulating factor (G-CSF) enrolled in the Severe Chronic Neutropenia International Registry (SCNIR). (Rosenberg et al, Blood2006; 107:4628-35, and Brit J Haematol2008; 140:210-3) We found that after ten years a subgroup of SCN patients receiving more than 8 mcg/kg/day of G-CSF who achieved a median absolute neutrophil count (ANC) response of less than 2.188 × 109/L had an estimated risk of dying from sepsis of 14% and a risk of developing MDS/AML of 40%. In order to understand the risk factors for death from sepsis, we reviewed the clinical diagnosis, hematological data, G-CSF treatment, and clinical course of 9 fatalities due to infections, excluding cases with evidence of MDS or AML or occurring after hematopoietic transplantation. The 5 male and 4 female patients’ ages ranges from 1 month to 18.7 years at the time of initiation of G-CSF. All were treated with G-CSF because of severe neutropenia (ANC less that 0.5 × 109/L) and a history of recurrent fevers and infections. The pre G-CSF median ANC for the 9 patients was 0.027 × 109/L and frequent events pre-G-CSF included fevers, severe mouth ulcers, otitis, sinusitis, pneumonia, cellulitis and abscess formation, but bacteremias were infrequent. When started on G-CSF, five patients were clearly poor responders, despite steady upward titration in the G-CSF dose to 22, 45, 65, 68 and 151 mcg/kg/day, respectively. In each of these patients, the ANCs on G-CSF treatment were frequently reported as less than 0.1 × 109/L and the responses were inconsistent and quite variable. The other 4 patients also had inconsistent responses at lower G-CSF doses and the patients’ compliance with treatment was uncertain. Two are known to have had a protracted “off treatment” periods, and the septic death of one patient occurred when off therapy. Deaths were attributed to sepsis (6 cases), pneumonia (2 cases), and meningitis (1 case). These clinical data suggest that death from sepsis in SCN is usually associated with a poor response to G-CSF as reflected by the requirement for dose escalation substantially above the threshold of 8 mcg/kg/day of G-CSF associated with an increased risk of MDS/AML. Inconsistent treatment and discontinuation of treatment also lead to neutropenia and the risk of sepsis. Although impaired microbicidal function may be a contributor to infections in these patients (Donini, et al. Blood109:4716, 2007), the predominant problem is a poor ANC response; the biological basis for poor responses of some SCN patients to G-CSF is still unknown. Based on these data, we recommend careful consideration of a match related or unrelated donor hematopoietic stem cell transplant for all patients not achieving a consistent ANC >1.0 × 109 with G-CSF therapy.

Cyclic neutropenia is a rare hematological disorder characterized by recurrent severe neutropenia, mouth ulcers, fever and infections beginning soon after birth. The diagnosis depends primarily on observing regular periods of severe neutropenia (neutrophils <500/μL, usually <200/μL) lasting for 2–4 days at approximately 21-day intervals, documented by serial blood counts (a minimum of 2–3 complete blood counts per week for at least six weeks). Severe congenital neutropenia is a similar, but usually more severe disease. Mutations of the ELA2gene are regarded as the cause of most cases of both cyclic neutropenia and severe congenital neutropenia. However, only patients with severe congenital neutropenia, not cyclic neutropenia, are thought to be at risk of evolution to MDS/AML. Since its founding in 1994, the Severe Chronic Neutropenia International Registry (SCNIR) has utilized data from previous studies and enrolled patients with cyclic neutropenia based on the clinical information from their treating physicians. We reviewed 190 cases of cyclic neutropenia (including 30 families) enrolled for 0.5 to 19.9 years, (median 11 years) with a total of 2,035 patient years of observation. 173 of 190 patients were treated with G-CSF (median dose 2.82 mcg/kg/day). We identified three patients who were reported to have developed MDS/AML. Further analysis by three experts from the SCNIR revealed that all three patients lacked sufficient serial blood count data to show well-defined neutrophil cycles prior to G-CSF. Two of the three patients lacked a clinical history of mouth ulcers and fevers consistent with the diagnosis, and the bone marrow evaluation was not consistent with cyclic neutropenia in all three cases. One of two patients tested did not have an ELA2mutation. Thus, using standard criteria for the diagnosis of cyclic neutropenia, none of the three patients fully satisfied the criteria for this diagnosis. In addition, previous family studies, reviews of the published literature, and personal experience of the authors have revealed only one case of leukemia. This case of CML emerged in a 35 year-old patient, who was never treated with G-CSF, 31 years after the diagnosis of cyclic neutropenia. Based upon the review of these cases, we believe it is extremely important to make the diagnosis of cyclic neutropenia by careful analysis of serial blood counts. When the diagnosis is made confidently, it is also important to assure patients that with or without G-CSF treatment, the possibility of evolution to leukemia is unlikely.

Severe congenital neutropenia (SCN) is a heterogeneous disorder of myelopoiesis characterized by an absolute neutrophil count (ANC) persistently below 0.50 x 109/L (500/[um]L), with maturation arrest of neutrophil precursors of the bone marrow at the promyelocyte/myelocyte stage. G-CSF treated and untreated SCN patients are at risk of developing MDS/AML. Clinicians caring for these patients must vigilantly observe for evidence of evolution to malignancy and continually consider hematopoietic transplantation as an alternative therapy. We have previously reported that SCN patients requiring higher daily doses of G-CSF treatment (> 8 mcg/kg/day) are at an increased risk of MDS/AML, and that this risk is not predicted by pre-treatment bone marrow examinations or the pre-treatment ANC. We have reviewed clinical data for 46 patients over a 15-year period who were referred to the Severe Chronic Neutropenia International Registry (SCNIR) and developed MDS/AML. Four patients referred with a history of SCN had increased blasts on the bone marrow evaluation prior to G-CSF treatment or enrollment in the SCNIR. Blood counts were not available for two patients. For the other 40 patients, all treated with G-CSF for a median of 79 months (range 0.8 to 182 months), comparison of blood counts for the periods 12–24 months and 0–3 months before the diagnosis of MDS/AML showed:

BACKGROUND: G-CSF therapy has reduced sepsis mortality in patients with severe congenital neutropenia (SCN), revealing a syndromic predisposition to myelodysplastic syndrome and acute myeloid leukemia (MDS/AML). The MDS/AML risk appears to be higher in SCN patients who are less-responsive to therapy; however, the genetic determinants of susceptibility remain to be elucidated. METHODS: We studied 82 North American and Australian patients with SCN on long-term G-CSF enrolled in the Severe Chronic Neutropenia International Registry. These patients had prospective follow-up, sufficient banked DNA for genotyping, and validated clinical data. RESULTS: Fifty-two patients (63%) were positive for germline mutations in neutrophil elastase (ELA2); the remaining 30 patients (37%) had no detectable mutations. Prior to G-CSF therapy, blood cell counts were significantly different between ELA2 positive and negative patients. Compared with ELA2 positive patients, ELA2 negative patients had significantly higher median absolute neutrophil count (ANC) values (158 versus 53 cells/uL, P=0.02), significantly lower monocyte and eosinophil counts (P<0.001), and significantly lower platelet counts (P=0.002). ELA2 negative patients were maintained on significantly lower doses of G-CSF (5.2 versus 9.9 ug/kg/day, P=0.02), consistent with higher baseline ANC values. However, ELA2 negative patients were significantly less responsive to G-CSF therapy. Compared with ELA2 positive patients, on therapy, ELA2 negative patients had significantly smaller median increases in ANC values (1200 versus 2700 cells/uL, P=0.02); the difference remained significant after controlling for individual G-CSF dose (P=0.04). ELA2 negative patients had 5 MDS/AML events in 132 person-years, versus 8 MDS/AML events in 373 person-years among ELA2 positive patients. Using the Cox proportional hazards model, the hazard of MDS/AML was 3.1-fold higher in ELA2 negative patients compared with ELA2 positive patients. This association was of borderline statistical significance (P=0.08). No patient in either group died of sepsis. We found 34 distinct mutations in 52 ELA2 positive patients. The mutation sites were not clustered in the 8 ELA2 positive patients who developed MDS/AML. We found no associations of phenotype or outcome with specific ELA2 mutations; however, the numbers were limited. CONCLUSIONS: SCN patients without mutations in ELA2 constitute a clinically distinct subgroup. ELA2 negative patients are significantly less responsive to G-CSF therapy than ELA2 positive patients, and they may be at substantially higher risk of leukemia. Additional studies are needed to confirm the latter association and identify the causative gene or genes.

Severe congenital neutropenia (CN) is a general term for a group of disorders characterized by extremely low blood neutrophil counts (ANC < 0.5 x 109 ), early stage maturation arrest of myelopoiesis, and recurrent bacterial infections. More than 90% of CN patients respond to daily G-CSF treatment with a sustained neutrophil increase associated with a significant reduction of infections and improved quality of life. However, prolonged survival unmasks an increased risk of leukemic transformation in some, but not all, subcategories of CN patients. The Severe Chronic Neutropenia International Registry (SCNIR) has collected longitudinal data on on more than 400 patients with various causes of CN. This unique resource allows classification of different subtypes of CN and estimation of the relative frequency of these conditions. Our new classification scheme is as follows: By inheritance - autosomal dominant severe congenital neutropenia (ADCN), autosomal recessive (ARCN, Kostmann syndrome), sporadic CN. By genetic aberrations - ELA2 related CN, SBDS related CN-(Shwachman-Diamond syndrome), G 4.5 on Xq28related neutropenia (Barth syndrome), CXCR4 related neutropenia (myelokathexis and WHIM syndrome). By clinical phenotype - associated symptoms (e. g. metabolic disorders, such as Shwachman-Diamond syndrome, glycogen storage disease 1b, Barth syndrome), G-CSF responsive or non-responsive CN, with or without G-CSF receptor mutations, with or without osteoporosis, or dysplastic features (e. g. organ abnormalities). By ethnic origin - e.g. CN in consanguineous Kurdish families, recessive neutropenia in Swedish family (Kostmann syndrome). Recent research and the work of the SCNIR now permit a much improved classification of CN. The identification of subtypes of CN, their distinctive risks of malignant transformation, and their responses to treatment has contributed substantially to our general understanding of the problem of neutropenia. This knowledge also now allows clinicians to give patients and families much improved prognostic information and better guidelines for therapy.

Background: In patients with severe congenital neutropenia (SCN), mortality from sepsis is reduced by treatment with granulocyte colony-stimulating factor (G-CSF), but myelodsyplastic syndrome and acute myeloid leukemia (MDS/AML) have been reported in treated and untreated patients. Methods: We studied 374 patients with SCN and 29 patients with Shwachman-Diamond Syndrome (SDS) on long-term G-CSF enrolled in the Severe Chronic Neutropenia International Registry. Results: In SCN, mortality from sepsis was stable at 0.9%/year. The hazard of MDS/AML increased significantly over time, from 2.9%/year after 6 years to 8.0%/year after 12 years on G-CSF. After 10 years, the cumulative incidence was 8% for mortality from sepsis and 21% for MDS/AML. The hazard of MDS/AML increased with the dose of G-CSF. Twenty-nine percent of SCN patients received more than the median dose of G-CSF (≥8 μg/kg/day), but achieved less than the median absolute neutrophil count (ANC) response (ANC <2188 cells/μL at 6–18 months). In these less responsive patients, the cumulative incidence of adverse events was highest: after 10 years, 40% developed MDS/AML and 14% died of sepsis, compared to 11% and 4%, respectively, of more responsive patients whose ANC was above the median on doses of G-CSF below the median. An intermediate group achieved an ANC above the median on doses of G-CSF above the median; among them, the 10 year cumulative incidence was 15% for MDS/AML and 3% for mortality from sepsis. In secondary analyses, we found that pre-treatment blood cell counts could not predict the subsequent clinical outcome. Furthermore, on therapy, patients who were less responsive vis-à-vis their neutrophil counts had similar increases in eosinophils, basophils, monocytes, and lymphocytes, and similar decreases in platelets, as other patients maintained on ≥8 μg/kg/day. Consistent with the SCN results, in SDS patients, the limited available data do not suggest that G-CSF therapy is a risk factor for MDS/AML in SDS. Conclusions: The risk of MDS/AML was similarly low in all patients who achieved an ANC above the median on any dose of G-CSF. It appears that G-CSF has reduced mortality from sepsis, and revealed the underlying leukemic predisposition of SCN.

2004 marks the 10th anniversary of the Severe Chronic Neutropenia International Registry (SCNIR), a registry organized to improve understanding and treatment of the hematological disorders causing severe chronic neutropenia. The SCNIR enrolls patients with blood neutrophil counts intermittently or continuously less than 0.5x109/L whose neutropenia is not attributed to cancer, cancer chemotherapy, or systemic autoimmune diseases. Longitudinal data has now been collected on 1163 patients with a range of follow-up of 0.01 to 15.66 years. By diagnostic category the patients include severe congenital neutropenia (422), cyclic neutropenia (205), idiopathic neutropenia (349), autoimmune neutropenia (68), glycogen storage disease (42), Barth syndrome (10), myelokathexis (8), Shwachman-Diamond syndrome (37), immune deficiency syndromes (7), and others (15). Overall, 1053 (90.5%) of these patients have been treated longitudinally with G-CSF (dose range 0.02 to 300 mcg/kg/day, median 3.33 mcg/kg/day) or received G-CSF transiently. Among other treatments, 76 patients were treated with allogeneic bone marrow or stem cell transplants (SCT). The reasons for SCT were myelodysplasia (MDS) or acute myeloid leukemia (AML) (43), chromosomal aberrations or G-CSF receptor mutation (9), partial or non-response to G-CSF (21), or other reasons (3). G-CSF has dramatically changed the natural history of these disorders reducing the occurrence of infection, hospitalization, and antibiotics, and improving patients’ quality of life. A small percentage of patients, 14% (163/1163), show evidence of osteoporosis/osteopenia; the predisposing factors for this complication remain unclear. MDS and AML has occurred in 63 patients: severe congenital neutropenia (13.7%, 58/422), Shwachman-Diamond syndrome (8.1%, 3/37) and 2 others with the clinical diagnoses of cyclic neutropenia (1) and idiopathic neutropenia (1). The SCNIR has also provided a rich resource for studies on the genetic and molecular basis for these disorders. These include the finding of mutations in the gene for neutrophil elastase (ELA2) in causing cyclic and congenital neutropenia, the role of mutations in the gene for the G-CSF receptor in the evolution of severe congenital neutropenia to AML and the importance of apoptosis as the cellular mechanism for several diseases causing severe chronic neutropenia. The SCNIR illustrates the value of a patient registry to improve our understanding of rare hematological diseases.