The Incidence of Leukemia and Mortality from Sepsis in Patients with Severe Congenital Neutropenia Receiving Long-Term G-CSF Therapy.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 669-669 ◽  
Author(s):  
Philip S. Rosenberg ◽  
Blanche P. Alter ◽  
Audrey A. Bolyard ◽  
Mary A. Bonilla ◽  
Laurence A. Boxer ◽  
...  
Keyword(s):  
Cumulative Incidence ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
Intermediate Group ◽  
Cell Counts ◽  
Secondary Analyses ◽  
Shwachman Diamond Syndrome ◽  
Pre Treatment ◽  
Stimulating Factor

Abstract 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.

Stable Long-Term Risk of Leukemia in Patients with Severe Congenital Neutropenia Maintained On G-CSF Therapy.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3206-3206 ◽  
Author(s):  
Philip S. Rosenberg ◽  
Cornelia Zeidler ◽  
Audrey Anna Bolyard ◽  
Blanche P. Alter ◽  
Mary Ann Bonilla ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cumulative Incidence ◽  
Bone Marrow Failure ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
Hazard Curve ◽  
Number Of Patients ◽  
Increasing Trend

Abstract Abstract 3206 Poster Board III-143 BACKGROUND G-CSF therapy reduces sepsis mortality in patients with severe congenital neutropenia (SCN), but effective therapy has revealed a high syndromic predisposition to myelodysplastic syndrome and acute myeloid leukemia (MDS/AML), particularly in patients who require higher doses of G-CSF. Although the long-term risk of MDS/AML after 10 or more years on therapy remains uncertain, prior data on the limited number of patients with long-term follow-up suggested the hazard rate might be as high as 8%/year after 12 years on G-CSF. METHODS We updated prospective follow-up of 374 well-characterized patients with SCN on long-term G-CSF enrolled in the Severe Chronic Neutropenia International Registry (Blood. 2006 Jun 15; 107(12):4628-35). We ascertained event-free time, deaths from sepsis, and MDS/AML events that accrued since our previous report. Follow-up was censored for patients who received a bone marrow transplant. RESULTS The update yielded 3590 person-years of follow-up versus 2043 in the prior report; among patients treated for 10 or more years, there were 849 person-years versus just 67 previously. In all, there were 61 MDS/AML events and 29 deaths from sepsis, versus prior totals of 44 and 19, respectively. After including up-to-date follow-up, the estimated annual hazard of death from sepsis remained qualitatively stable, at 0.81%/year (95% Confidence Interval, CI: 0.56 – 1.16%/year). Similarly, during the first five years after the start of G-CSF therapy, the updated estimate of the hazard curve for MDS/AML showed the same increasing trend as the previous estimate. However, in contrast to the prior estimate that showed a subsequent increasing trend over time (with a large margin of error), the updated hazard curve attained a plateau: after 10 years on G-CSF, the estimated hazard of MDS/AML was 2.3%/year (95% CI: 1.7 – 2.9%/year). Although this aspect of the natural history appears less dire than first suggested, after 15 years on G-CSF, the cumulative incidence was 10% (95% CI: 6 – 14%) for death from sepsis and 22% (95% CI: 17 – 28%) for MDS/AML. Furthermore, for the subset of patients who failed to achieve at 6 months an absolute neutrophil count at or above the median value for the cohort (2188 cells/μL) despite doses of G-CSF at or above the median (8 μg/kg/day), the cumulative incidence after 15 years on G-CSF was 18% (95% CI: 7 – 28%) for death from sepsis and 34% (95% CI: 21 – 47%) for MDS/AML. With additional follow-up, the association of G-CSF dose at 6 months with the relative hazard of MDS/AML became more strongly statistically significant (P = 0.003 versus P = 0.024; the hazard of MDS/AML increased by 1.24-fold (95% CI: 1.08-1.43-fold) per doubling of the dose of G-CSF). CONCLUSIONS For SCN patients maintained on G-CSF therapy, the hazard of MDS/AML over the long-term falls significantly below the range suggested by preliminary data. The updated hazard estimate of 2.3%/year after 10 years on G-CSF (which includes both MDS and AML events) is similar to that for other inherited bone marrow failure syndromes with a high intrinsic risk of AML, notably Fanconi anemia and dyskeratosis congenita. Nonetheless, the cumulative incidence of both MDS/AML and sepsis death rises to very high levels, and the data continue to support the hypothesis that SCN patients with higher G-CSF requirements are also at higher risk of leukemia. Disclosures Boxer: Amgen Inc.: Equity Ownership. Dale:Amgen Inc.: Consultancy, Honoraria, Research Funding, Speaker.

scholarly journals Blood mononuclear cells from patients with severe congenital neutropenia are capable of producing granulocyte colony-stimulating factor

Blood ◽  
1991 ◽  
Vol 77 (6) ◽  
pp. 1234-1237 ◽  
Author(s):  
T Pietsch ◽  
C Buhrer ◽  
K Mempel ◽  
T Menzel ◽  
U Steffens ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Leukemia Cell Line ◽  
Severe Neutropenia ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
Blood Mononuclear Cells ◽  
Stimulating Factor

Abstract Severe congenital neutropenia (SCN) is a disorder of myelopoiesis characterized by severe neutropenia or absence of blood neutrophils secondary to a maturational arrest at the level of promyelocytes. We examined peripheral blood mononuclear cells (PBMC) of SCN patients who demonstrated normalization of their blood neutrophil counts in a phase II clinical study with recombinant human granulocyte colony-stimulating factor (rhG-CSF). When stimulated in vitro with bacterial lipopolysaccharides (LPS), PBMC of those SCN patients produced G-CSF activity, as judged by proliferation induction of the murine leukemia cell line, NFS-60. Western and Northern blot analysis showed G-CSF protein and G-CSF-mRNA indistinguishable in size from those of normal controls. We conclude that PBMC of the SCN patients tested are capable of synthesizing and secreting biologically active G-CSF in vitro.

G-CSFSR Mutations Present in Patients with Severe Congenital Neutropenia Cooperate with PML-RARα To Induce Acute Myeloid Leukemia in Mice.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2193-2193
Author(s):  
Jill R. Woloszynek ◽  
Ghada M. Kunter ◽  
Tim Ley ◽  
Dan C. Link ◽  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Transgenic Mice ◽  
Cumulative Incidence ◽  
Myeloid Leukemia ◽  
Direct Evidence ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
Acute Myeloid

Abstract Severe congenital neutropenia (SCN) is an inherited disorder of granulopoiesis that is associated with a markedly increased risk of developing acute myeloid leukemia (AML) or myelodysplasia (MDS). Somatic mutations of CSF3R, encoding the G-CSF receptor (G-CSFR), are strongly associated with the development of AML/MDS in SCN. These mutations invariably produce a truncated G-CSFR that, though remaining ligand-dependent, transmits a hyperproliferative signal. Transgenic mice carrying a targeted (knock-in) mutation of Csf3r (termed d715) reproducing a mutation found in a patient with SCN have an exaggerated neutrophil response to G-CSF treatment but do not develop AML/MDS. Moreover, we recently showed expression of the d715 G-CSFR confers a strong clonal advantage at the hematopoietic stem cell level that is dependent upon exogenous G-CSF. Collectively, these data suggest that CSF3R truncation mutations are an initiation or early progression factor for leukemic transformation. However, there is, as yet, scant direct evidence supporting this hypothesis. Previous studies have established that activating mutations of receptor tyrosine kinases, such as internal tandem duplications of FLT3, are able to cooperate with PML-RARα to induce AML. Since the CSF3R mutations in SCN also are “activating”, we asked whether the d715 G-CSFR could cooperate with PML-RARα to induce AML in mice. PML-RARα transgenic mice were intercrossed with d715 G-CSFR mice (all inbred > 10 generations onto a C57BL/6 background) to generate the cohorts listed in Table 1. A separate cohort for each genotype was treated chronically with pegylated G-CSF (1 mg/kg every 4–5 days for 6 months) to simulate the high level of serum G-CSF present in patients with SCN. Complete blood counts were performed at 3 months intervals and documented a similar increase in neutrophil counts in all mice treated with G-CSF. The cumulative incidence of AML and median follow-up for each cohort is shown in Table 1. None of the mice without the PML-RARα transgene, regardless of G-CSF treatment, developed AML, confirming that the d715 G-CSFR is not sufficient to induce AML. In mice carrying the PML-RARα transgene but not treated with G-CSF, a nonsignificant trend to increased AML was observed in mice expressing the d715 G-CSFR (P=0.12). However, in mice carrying the PML-RARα transgene and treated with G-CSF, the presence of the d715 G-CSFR significantly increased the penetrance (P=0.009) and reduced the latency of AML. In all cases, the leukemia was characterized by leukocytosis, splenomegaly, and a high percentage of blasts in the bone marrow and spleen that co-express Gr1 and c-Kit. These data provide the first direct evidence that the CSF3R mutations present in patients with SCN are leukemogenic and provide further support for the proposition that patients who acquire CSF3R mutations be considered for early stem cell transplantation. The cumulative incidence of AML and median follow-up for each cohort PML-RAR CSF3R G-CSF Rx N Median follow-up Cumulative AML% No WT No 20 454 0.0% No d715 No 45 250 0.0% No WT Yes 20 488 0.0% No d715 Yes 47 311 0.0% Yes WT No 57 286 6.4% Yes d715 No 67 267 11.9% Yes WT Yes 54 322 20.4% Yes d715 Yes 50 311 44.0%

Spontaneous remission of granulocyte colony-stimulating factor–associated leukemia in a child with severe congenital neutropenia

Blood ◽  
2000 ◽  
Vol 96 (10) ◽  
pp. 3647-3649 ◽  
Author(s):  
Sima Jeha ◽  
Ka Wah Chan ◽  
Andrew G. Aprikyan ◽  
W. Keith Hoots ◽  
Steven Culbert ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Allogeneic Bone Marrow Transplantation ◽  
Spontaneous Remission ◽  
Myelogenous Leukemia ◽  
Allogeneic Bone ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
Stimulating Factor

Leukemia is observed with increased frequency in patients with severe congenital neutropenia (SCN). In the past decade, recombinant human granulocyte colony-stimulating factor (rh G-CSF) has prolonged the survival of patients with SCN increasingly reported to have leukemias. In this communication acute myelogenous leukemia (AML) associated with a mutation of the G-CSF receptor (G-CSF-R) developed in a patient with SCN maintained on long-term G-CSF therapy. The blast count in the blood and bone marrow fell to undetectable levels twice on withholding G-CSF and without chemotherapy administration, but the mutant G-CSF-R was detectable during this period. The patient subsequently underwent successful allogeneic bone marrow transplantation. After transplantation, the patient's neutrophil elastase (ELA-2) mutation and G-CSF-R mutation became undetectable by polymerase chain reaction. This report provides novel insights on leukemia developing in congenital neutropenia.

scholarly journals Understanding Neutropenia: The 20 Year Experience of the Severe Chronic Neutropenia International Registry (SCNIR)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2730-2730
Author(s):  
David C. Dale ◽  
Audrey Anna Bolyard ◽  
Cornelia Zeidler ◽  
Tracy M. Marrero ◽  
Laurence A. Boxer ◽  
...  
Keyword(s):  
Stem Cell ◽  
Genetic Testing ◽  
Rare Diseases ◽  
Severe Neutropenia ◽  
Congenital Neutropenia ◽  
International Registry ◽  
Shwachman Diamond Syndrome ◽  
Chronic Neutropenia

Abstract Background: In 1994 Severe Chronic Neutropenia International Registry (SCNIR) opened for enrollment of patients with at least 3 absolute neutrophil counts (ANC) less than 0.5 x 109/L during a three month period. At that time severe chronic neutropenia (SCN) was categorized as cyclic, congenital, autoimmune or idiopathic based largely on clinical criteria. A randomized trial had established effectiveness of treatment with granulocyte colony-stimulating factor (G-CSF), but long-term consequences of such treatment were unknown. Hypothesis: We began the SCNIR based on the hypothesis that underlying pathophysiology, natural history of patients with chronic neutropenia and benefits and risk of G-CSF therapy could only be accurately established through an international registry with long term follow-up of patients with these rare hematological disorders. Methods: SCNIR enrollment requires informed consent, ANC<0.5 x 109/L at least 3 times over a 3 month period, neutropenia not due to known systemic autoimmune disease (e.g., lupus, rheumatoid arthritis), cancer or cancer chemotherapy. There is a centralized enrollment process directed through offices in the US (Seattle) and Germany (Hannover). Continued enrollment requires annual follow-up information, i.e., clinical status, treatments and blood counts, and bone marrow reports for some categories of patients. Data on pregnancies, stem cell transplantation (SCT), non-hematological features and complications are also collected on standardized forms for subsets of patients. Comprehensive immunological assessments and genetic testing are encouraged but not required for enrollment. For some patient groups, e.g., Shwachman-Diamond syndrome (SDS) and Barth syndrome, the SCNIR now enrolls patients without severe neutropenia to gain perspectives on long-term outcomes for these disorders. Since 1994 the SCNIR has enrolled more than 2000 patients; 174 died, 193 resolved neutropenia, 543 withdrew or were lost to follow-up and almost all others continue in this long term observation study. The median follow-up for enrolled patients is now almost 10 years. The most common patient categories are idiopathic, cyclic (CyN) and congenital neutropenia (CN); 68% of CyN and 65% of CN patients having sequencing studies have mutations in ELANE. Some specific mutations are associated with high frequency (>90%) of severe outcomes (e.g. MDS/AML, failure to respond to G-CSF, death from infections, need for stem cell transplant) often many years after SCNIR enrollment and beginning G-CSF therapy. GSD1 patients improve with G-CSF treatment, but experience splenomegaly and continued problems with infections or complications. The SCNIR through a SDS sub-registry is redefining Shwachman-Diamond syndrome; only about one-half of enrollees have “classic” presentation and a substantial number with “classic presentation” lack mutations in SBDS. The SCNIR is participating in an NIH trial of a CXCR4 antagonist for treatment of WHIM syndrome, as an example of molecularly targeted treatment for this rare disease. The SCNIR is also the key resource for discovery of genetic causes for congenital neutropenia, e.g., G6PC3, HAX1, and TCIRG1 and others, recognition of differences in frequency of autosomal dominant and recessive SCN in populations of Europe and North America and identifying congenital neutropenia cases of unknown cause. Genetic testing has also broadened the clinical spectrum of these disorders. Conclusions: Through the efforts of patients, families, physicians, nurses and investigators, and with support from the NIH, industry, and private philanthropy, chronic neutropenia is now far better understood at the genetic, molecular and cellular level than 20 years ago. Treatment responses to G-CSF are well characterized; novel therapies are emerging; and the prognosis for patients with SCN appears to be improving. The knowledge gained through the SCNIR and availability of G-CSF has redefined clinicians’ approach to chronic neutropenia. The SCNIR is a model of international research collaboration to understand rare diseases in hematology and other areas of medicine. Broad enrollment criteria, physician, patient and family participation, a dedicated staff, and continuing cooperation underlie success of the SCNIR and this model to understanding rare diseases. Disclosures Dale: Amgen: Consultancy, Honoraria, Research Funding. Boxer:Amgen: Equity Ownership. Morrow:Amgen: Employment.

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