Hemophagocytic syndrome in acute myeloid leukemia patients undergoing intensive chemotherapy by Karen Delavigne, Emilie Bérard, Sarah Bertoli, Jill Corre, Eliane Duchayne, Cécile Demur, Véronique Mansat-De Mas, Cécile Borel, Muriel Picard, Muriel Alvarez, Audrey Sarry, Françoise Huguet, and Christian Récher Haematologica 2013 [Epub ahead of print] Citation: Delavigne K, Bérard E, Bertoli S, Corre J, Duchayne E, Demur C, Mansat-De Mas V, Borel C, Picard M, Alvarez M, Sarry A, Huguet F, and Récher C. Hemophagocytic syndrome in acute myeloid leukemia patients undergoing intensive chemotherapy. Haematologica. 2013; 98:xxx doi:10.3324/haematol.2013.097394 Publisher's Disclaimer. E-publishing ahead of print is increasingly important for the rapid dissemination of science. Haematologica is, therefore, E-publishing PDF files of an early version of manuscripts that have completed a regular peer review and have been accepted for publication. E-publishing of this PDF file has been approved by the authors. After having E-published Ahead of Print, manuscripts will then undergo technical and English editing, typesetting, proof correction and be presented for the authors' final approval; the final version of the manuscript will then appear in print on a regular issue of the journal. All legal disclaimers that apply to the journal also pertain to this production process. Copyright 2013 Ferrata Storti Foundation. Published Ahead of Print on October 18, 2013, as doi:10.3324/haematol.2013.097394.
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Hemophagocytic syndrome in acute myeloid leukemia patients undergoing intensive chemotherapy
by Karen Delavigne, Emilie Bérard, Sarah Bertoli, Jill Corre, Eliane Duchayne, Cécile Demur,Véronique Mansat-De Mas, Cécile Borel, Muriel Picard, Muriel Alvarez, Audrey Sarry, Françoise Huguet, and Christian Récher
Haematologica 2013 [Epub ahead of print]
Citation: Delavigne K, Bérard E, Bertoli S, Corre J, Duchayne E, Demur C, Mansat-De Mas V, Borel C, Picard M, Alvarez M, Sarry A, Huguet F, and Récher C. Hemophagocytic syndrome in acute myeloid leukemia patients undergoing intensive chemotherapy. Haematologica. 2013; 98:xxxdoi:10.3324/haematol.2013.097394
Publisher's Disclaimer.E-publishing ahead of print is increasingly important for the rapid dissemination of science.Haematologica is, therefore, E-publishing PDF files of an early version of manuscripts thathave completed a regular peer review and have been accepted for publication. E-publishingof this PDF file has been approved by the authors. After having E-published Ahead of Print,manuscripts will then undergo technical and English editing, typesetting, proof correction andbe presented for the authors' final approval; the final version of the manuscript will thenappear in print on a regular issue of the journal. All legal disclaimers that apply to thejournal also pertain to this production process.
Copyright 2013 Ferrata Storti Foundation.Published Ahead of Print on October 18, 2013, as doi:10.3324/haematol.2013.097394.
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Hemophagocytic syndrome in acute myeloid leukemia patients undergoing
intensive chemotherapy
Running title: Hyperinflammation in AML
Karen Delavigne,1,6 Emilie Bérard,2,3 Sarah Bertoli,1 Jill Corre,4 Eliane Duchayne,4
and analyzed data, and wrote the paper. All the authors checked the final version of the
manuscript.
Disclosure of Conflicts of Interest: the authors declare no competing financial interests.
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References
1. Janka GE. Hemophagocytic syndromes. Blood Rev. 2007;21(5):245-53. 2. Arico M, Janka G, Fischer A, Henter JI, Blanche S, Elinder G, et al. Hemophagocytic lymphohistiocytosis. Report of 122 children from the International Registry. FHL Study Group of the Histiocyte Society. Leukemia. 1996;10(2):197-203. 3. Henter JI, Elinder G, Ost A. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. The FHL Study Group of the Histiocyte Society. Semin Oncol. 1991;18(1):29-33. 4. Henter JI, Horne A, Arico M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124-31. 5. Castillo L, Carcillo J. Secondary hemophagocytic lymphohistiocytosis and severe sepsis/ systemic inflammatory response syndrome/multiorgan dysfunction syndrome/macrophage activation syndrome share common intermediate phenotypes on a spectrum of inflammation. Pediatr Crit Care Med. 2009;10(3):387-92. 6. Risma K, Jordan MB. Hemophagocytic lymphohistiocytosis: updates and evolving concepts. Curr Opin Pediatr. 2012;24(1):9-15. 7. Strauss R, Neureiter D, Westenburger B, Wehler M, Kirchner T, Hahn EG. Multifactorial risk analysis of bone marrow histiocytic hyperplasia with hemophagocytosis in critically ill medical patients--a postmortem clinicopathologic analysis. Crit Care Med. 2004;32(6):1316-21. 8. Zhang K, Jordan MB, Marsh RA, Johnson JA, Kissell D, Meller J, et al. Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH. Blood. 2011;118(22):5794-8. 9. Falini B, Pileri S, De Solas I, Martelli MF, Mason DY, Delsol G, et al. Peripheral T-cell lymphoma associated with hemophagocytic syndrome. Blood. 1990;75(2):434-44. 10. Ferreri AJ, Dognini GP, Campo E, Willemze R, Seymour JF, Bairey O, et al. Variations in clinical presentation, frequency of hemophagocytosis and clinical behavior of intravascular lymphoma diagnosed in different geographical regions. Haematologica. 2007;92(4):486-92. 11. Han AR, Lee HR, Park BB, Hwang IG, Park S, Lee SC, et al. Lymphoma-associated hemophagocytic syndrome: clinical features and treatment outcome. Ann Hematol. 2007;86(7):493-8. 12. Bertozzi AI, Suc A, Rubie H, Duchayne E, Demur C, Robert A. [Hemophagocytic syndrome associated with neutropenia after chemotherapy]. Arch Pediatr. 2002;9(2):125-9. 13. Bertoli S, Berard E, Huguet F, Huynh A, Tavitian S, Vergez F, et al. Time from diagnosis to intensive chemotherapy initiation does not adversely impact the outcome of patients with acute myeloid leukemia. Blood. 2013;121(14):2618-26. 14. LaRochelle O, Bertoli S, Vergez F, Sarry JE, Mansat-De Mas V, Dobbelstein S, et al. Do AML patients with DNMT3A exon 23 mutations benefit from idarubicin as compared to daunorubicin? A single center experience. Oncotarget. 2011;2(11):850-61. 15. Wang S, Degar BA, Zieske A, Shafi NQ, Rose MG. Hemophagocytosis exacerbated by G-CSF/GM-CSF treatment in a patient with myelodysplasia. Am J Hematol. 2004;77(4):391-6. 16. Roth B, Grande PO, Nilsson-Ehle P, Eliasson I. Possible role of short-term parenteral nutrition with fat emulsions for development of haemophagocytosis with multiple organ failure in a patient with traumatic brain injury. Intensive Care Med. 1993;19(2):111-4. 17. Usmani GN, Woda BA, Newburger PE. Advances in understanding the pathogenesis of HLH. Br J Haematol. 2013;161(5):609-22. 18. Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL. How I treat hemophagocytic lymphohistiocytosis. Blood. 2011;118(15):4041-52. 19. Chen RL, Lin KH, Lin DT, Su IJ, Huang LM, Lee PI, et al. Immunomodulation treatment for childhood virus-associated haemophagocytic lymphohistiocytosis. Br J Haematol. 1995;89(2):282-90. 20. Teachey DT, Rheingold SR, Maude SL, Zugmaier G, Barrett DM, Seif AE, et al. Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy. Blood. 2013;121(26):5154-7. 21. Barclay AN, Brown MH. The SIRP family of receptors and immune regulation. Nat Rev Immunol. 2006;6(6):457-64.
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22. Majeti R, Chao MP, Alizadeh AA, Pang WW, Jaiswal S, Gibbs KD, Jr., et al. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell. 2009;138(2):286-99. 23. Jaiswal S, Jamieson CH, Pang WW, Park CY, Chao MP, Majeti R, et al. CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell. 2009;138(2):271-85.
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Table 1: Characteristics of patients at diagnosis of AML
Creatinine (>1.5 x ULN)-n (%) 5 (15.6) 1 (4.5) .3826
Albumin (g/L) N Median (IQR)
29
27 (25- 30)
22
33 (29-37)
.0005
AST (UI/L)-Median (IQR) 31.5 (18- 103.5) 26 (19-38) .1835 ALT (UI/L)-Median (IQR) 31 (15.5-107.5) 29 (16-37) .2241 AST or ALT (>5 x ULN)-n (%) 7 (21.9) 0 (0) .0335
Alkaline phosphatase (UI/L) Median (IQR) >2 x ULN-n (%)
427 (251.5-635.5)
10 (31.3)
214 (175-276)
1 (4.5)
.0005 .0189
γGT (UI/L) Median (IQR) >5 x ULN-n (%)
213 (136-333.5)
19 (59.4)
59.5(34-119)
3 (13.6)
.0001 .0008
Bilirubin (µmol/L) N Median (IQR) >ULN-n (%)
30
13.5 (10-49) 13(40.6)
21
10 (8-11) 3 (13.6)
.0066 .0328
C-reactive protein (mg/L) N Median (IQR)
30
115.5 (57- 178)
19
16 (5- 92)
.0005
21
HLH: Hemophagocytic lymphohistiocytosis; HemoPh+: bone marrow hemophagocytosis.
WBC: White Blood Cells, ULN: Upper Limit of Normal, PTT: Prothrombin time; AST:
aspartate transaminases; ALT: alanine transaminases; γGT: gamma-glutamyltranspeptidase; N
is only mentioned when there is unknown data. Bio-clinical data were collected at time of HLH or
hemophagocytosis onset for HLH+ and HLH-/HemoPh+ groups.
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Table 3: Ferritin levels in HLH+ and HLH-/HemoPh+ patients
HLH+
N=32
HLH-/HemoPh+
N=22 p-value
Ferritin (µg/L)
At HLH/HemoPh+ diagnosis
N
Median (IQR)
31
5093 (2826-11307)
18
1866.5 (660-2789)
0.0004
Maximal value during
evolution*
N
Median (IQR)
32
6953.5 (4425.5-15305.5)
18
3373 (1808-5149)
0.0071
> 500, n (%) 32 (100) 17 (94.4) 0.3600
> 3000, n (%) 26 (81.3) 11 (61.1) 0.1797
> 8000, n (%) 15 (46.9) 2 (11.1) 0.0104
> 10000, n (%) 13 (40.6) 2 (11.1) 0.0287
HLH: Hemophagocytic lymphohistiocytosis; HemoPh+: bone marrow hemophagocytosis. * Evolution represents the time between HLH diagnosis and response to anti-HLH treatment or death.
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Table 4: Infections at HLH+ or HemoPh+ diagnosis.
HLH+ N=32
HLH-/HemoPh+ N=22
Bacterial Infection Site Septicemia Pneumonia Soft tissus Other Bacteria Enterobacteria Cocci gram + Stenotrophomonas maltophlia Other
£ In patients with CR or CRi or complete response with two cycles of induction.
*According to Bonferroni correction p-value=0.033 for HLH-/HemoPh- vs HLH-/HemoPh+, p-value<0.001 for HLH-/HemoPh- vs HLH+ and p-value<0.001 for HLH-/HemoPh+ vs HLH+.
**According to Bonferroni correction p-value=0.396 for HLH-/HemoPh- vs HLH-/HemoPh+, p-value=0.003 for HLH-/HemoPh- vs HLH+ and p-value=0.003 for HLH-/HemoPh+ vs HLH+.
***According to Bonferroni correction p-value=1.000 for HLH-/HemoPh- vs HLH-/HemoPh+, p-value<0.001 for HLH-/HemoPh- vs HLH+ and p-value=0.042 for HLH-/HemoPh+ vs HLH+.
****According to Bonferroni correction p-value=1.000 for HLH-/HemoPh- vs HLH/HemoPh+, p-value=0.018 for HLH-/HemoPh- vs HLH+ and p-value=0.429 for HLH-/HemoPh+ vs HLH+.
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Table 7: Proposed criteria for HLH diagnosis in AML patients
AML patient undergoing intensive chemotherapy
and
Fever
Hepatosplenomegaly
Ferritin > 5000 µg/L
Prolonged neutropenia and/or thrombopenia (outside the expected range for chemotherapy-
induced myelosuppression, e.g, day 35)
Liver abnormalities
These criteria should lead to perform a bone marrow aspiration to reveal hemophagocytosis.
These proposed criteria should be improved by classical criteria for HLH such as genetic
defect of in genes of the cytotoxic pathway (PRF1, UNC13D, STXBP2, RAB27A, STX11,
SH2D1A, or XIAP), natural killer cell activity and soluble CD25.
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Figure Legends
Figure 1: Distribution of anti-HLH treatments according to underlying infections
CS: corticosteroids (either prednisolone 1 mg/kg/d or dexamethasone 10 mg twice a day three
days then taper); IVIg: intravenous immunoglobulins (0.4 g/kg/d for 5 days or 1 g/kg/d for 2
days). Of note, 4 patients had concomitant viral and bacterial infection (1 was treated with
IVIg, 2 with CS + IVIg and 1 with CS + etoposide), 3 had viral and fungal infection treated
with IVIgand 3 other bacterial and fungal infection treated with IVIg.
Figure 2: Overall survival of HLH + and HLH- patients
HLH: Hemophagocytic lymphohistiocytosis; HemoPh+: bone marrow hemophagocytosis.
Supplementary data
Methods
Endpoints
The primary endpoint of the study was overall survival. For each participant, the length of
follow-up corresponds to the period between the date of diagnosis and July 1, 2012 or the date
of death if the patient died during the study period. The response to treatment was evaluated
after full hematological recovery (e.g, when neutrophils and platelet counts were > 1 G/L and
> 100 G/L to document complete responses), or at day 35 in cases of prolonged aplasia, and
defined according to the international consensus criteria as complete response (CR) or
complete response with incomplete blood count recovery (CRi).15 Early death was defined as
death from any cause occurring between the start of chemotherapy and the response
assessment. Resistant disease, death in aplasia and relapses were defined according to Cheson
criteria.15 The duration of neutropenia was defined as the number of days between d1 of
chemotherapy and the first day with neutrophils higher than 0.5 G/L or death for those who
died with less than 0.5 G/L.
Statistical analysis
Statistical analysis was performed on STATA statistical software, release 11.2 (STATA
Corporation, College station, TX, USA). We described patients’ characteristics using number
and frequency for qualitative data and number, median and Inter-Quartile Range (IQR) for
quantitative data. Qualitative variables were compared between groups (HLH+, HLH-
/HemoPh+ and HLH-/HemoPh- patients) using the χ2-test (or Fisher’s exact test in the case of
small expected numbers). Student’s t-test was used to compare the distribution of quantitative
data (or Mann-Whitney’s test when distribution departed from normality or when
homoscedasticity was rejected). Differences in survival functions were tested using the Log-
Rank test. The independent impact of HLH on overall survival was assessed using a Cox
model adjusted for age, secondary AML, white blood cell count, cytogenetics, performance
status and consolidation treatment by autologous or allogeneic stem cell transplantation
(SCT). HLH+ patients first become at risk of HLH+ mortality at the date of HLH+ diagnosis
and patients treated with autologous or allogeneic SCT first become at risk of SCT mortality
at the date of SCT. Since the linearity hypothesis was not fully respected for WBC, this
continuous co-factor was transformed into ordered data: ≤ 50 G/L and > 50 G/L. The
proportional-hazard assumption was tested for each covariate by the “log-log” plot method
curves ((-ln{-ln(survival)}), for each category of nominal covariate, versus ln(analysis time)).
None of the assumptions could be rejected. Interactions between HLH and the independent
covariates were tested in the survival model (none were significant). All reported p-values
were two-sided and the significance threshold was < 0.05.
Supplementary figure.
Light microscopic representative images of May–Grünwald–Giemsa (MGG) stained bone marrow smear showing macrophagescontaining hematopoietic cells in their cytoplasm (x100). A, B, C. Erythroblast. D. Platelets.