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Table 1.  

Characteristic HM (n = 113) HM-HLH (n = 112) P
Age at diagnosis, median (25%, 75%), y 66 (60, 75.5) 62 (53, 69) .0002
Female/male, N (%) 47 (42)/66 (58) 48 (43)/64 (57) .89
T/NK-cell lymphoma, N (%) 32 (28) 26 (23) .45
  PTCL 11 (10) 8 (7)
  Anaplastic large cell lymphoma 4 (4) 4 (4)
  CTCL 3 (3) 2 (2)
  AITL 5 (4) 2 (2)
  GDHSTCL 2 (2) 1 (1)
  Nasal/other NK/T-cell lymphoma 7 (6) 9 (8)
B-cell lymphoma, N (%) 47 (42) 44 (39) .89
  DLBCL 26 (23) 24 (21)
  IVLBCL 5 (4) 7 (6)
  Follicular lymphoma 6 (5) 3 (3)
  T-cell/histiocyte-rich large B-cell lymphoma 1 (1) 3 (3)
  Other types of B-cell lymphoma 9 (8) 7 (6)
Hodgkin lymphoma, N (%) 9 (8) 9 (8)
AML, N (%) 7 (6) 11 (10) .34
MDS, N (%) 8 (7) 10 (9) .64
MPN, N (%) 6 (5) 6 (5) 1
CLL, N (%) 4 (3) 6 (5) .54
Eastern Japan 62 (55) 19 (17)
Western Israel 23 (20) 45 (40)
United States 28 (25) 48 (43)

Table 1. General characteristics of the entire study cohort

P values were calculated with Fisher's exact test.
AITL, angioimmunoblastic T-cell lymphoma; AML, acute myeloid leukemia; CLL, chronic lymphocytic leukemia; CTCL, cutaneous T-cell lymphoma; DLBCL, diffuse large B-cell lymphoma; GDHSTCL, gamma delta hepatosplenic T-cell lymphoma; IVLBCL, intravascular large B-cell lymphoma; MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasms; PTCL, peripheral T-cell lymphoma.

CME / ABIM MOC

An Improved Index for Diagnosis and Mortality Prediction in Malignancy-Associated Hemophagocytic Lymphohistiocytosis

  • Authors: Adi Zoref-Lorenz, MD; Jun Murakami, MD, PhD; Liron Hofstetter, MD; Swaminathan P. Iyer, MD; Ahmed S. Alotaibi, MD; Shehab Fareed Mohamed, MD; Peter G. Miller, MD, PhD; Elad Guber, MD; Shiri Weinstein, MD, PhD; Joanne Yacobovich, MD, MPH; Sarah Nikiforow, MD, PhD; Benjamin L. Ebert, MD, PhD; Adam Lane, PhD; Oren Pasvolsky, MD; Pia Raanani, MD; Arnon Nagler, MD, MSc; Nancy Berliner, MD; Naval G. Daver, MD; Martin Ellis, MD; Michael B. Jordan, MD
  • CME / ABIM MOC Released: 2/17/2022
  • Valid for credit through: 2/17/2023
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  • Credits Available

    Physicians - maximum of 1.00 AMA PRA Category 1 Credit(s)™

    ABIM Diplomates - maximum of 1.00 ABIM MOC points

    You Are Eligible For

    • Letter of Completion
    • ABIM MOC points

Target Audience and Goal Statement

This activity is intended for hematologists, oncologists, internists, geneticists, and other clinicians caring for patients with hemophagocytic lymphohistiocytosis (HLH), a life-threatening inflammatory syndrome that may complicate hematologic malignancies (HMs).

The goal of this activity is to describe the most useful diagnostic and prognostic parameters and optimized laboratory cutoff values, alone and combined in the ‘optimized HLH inflammatory’ (OHI) index, and diagnostic performance of the OHI index, according to an international cohort of 225 adult patients with various HMs both with and without HLH and for whom HLH-2004 criteria were available.

Upon completion of this activity, participants will:

  1. Compare clinical, diagnostic, and prognostic parameters and optimized laboratory cutoff values between patients with hematologic malignancies (HMs) and hemophagocytic lymphohistiocytosis (HLH) with HMs, according to an international cohort study
  2. Describe component features and diagnostic performance of the ‘optimized HLH inflammatory’ (OHI) index, according to an international cohort study
  3. Determine clinical implications of diagnostic performance of the OHI index, according to an international cohort study


Disclosures

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All relevant financial relationships for anyone with the ability to control the content of this educational activity are listed below and have been mitigated according to Medscape policies. Others involved in the planning of this activity have no relevant financial relationships.


Faculty

  • Adi Zoref-Lorenz, MD

    Hematology Institute
    Meir Medical Center
    Kfar Saba, Israel
    Division of Immunobiology
    Cincinnati Children’s Medical Center
    Cincinnati, Ohio
    Sackler School of Medicine
    Tel Aviv University
    Tel Aviv, Israel

  • Jun Murakami, MD, PhD

    Clinical Laboratory
    Transfusion Medicine and Cell Therapy
    University of Toyama
    Toyama, Japan

  • Liron Hofstetter, MD

    Sackler School of Medicine
    Tel Aviv University
    Tel Aviv, Israel
    Institute of Hematology
    Davidoff Cancer Center
    Rabin Medical Center
    Petah Tikva, Israel

  • Swaminathan P. Iyer, MD

    Department of Lymphoma
    The University of Texas MD Anderson Cancer Center
    Houston, Texas

  • Ahmed S. Alotaibi, MD

    Department of Leukemia
    The University of Texas MD Anderson Cancer Center
    Houston, Texas
    Oncology Center
    King Faisal Specialist Hospital and Research Center
    Riyadh, Saudi Arabia

  • Shehab Fareed Mohamed, MD

    Department of Leukemia
    The University of Texas MD Anderson Cancer Center
    Houston, Texas

  • Peter G. Miller, MD, PhD

    Department of Medical Oncology
    Dana-Farber Cancer Institute
    Division of Hematology
    Department of Medicine
    Brigham and Women’s Hospital
    Harvard Medical School
    Boston, Massachusetts
    Broad Institute of MIT and Harvard
    Cambridge, Massachusetts

  • Elad Guber, MD

    Sackler School of Medicine
    Tel Aviv University
    Tel Aviv, Israel
    Pulmonary Institute
    Meir Medical Center
    Kfar Saba, Israel

  • Shiri Weinstein, MD, PhD

    Sackler School of Medicine
    Tel Aviv University
    Tel Aviv, Israel
    Internal Medicine “D”
    Sheba Medical Center
    Ramat Gan, Israel

  • Joanne Yacobovich, MD, MPH

    Sackler School of Medicine
    Tel Aviv University
    Tel Aviv, Israel
    Schneider Children’s Medical Center of Israel
    Petah Tikva, Israel

  • Sarah Nikiforow, MD, PhD

    Department of Medical Oncology
    Dana-Farber Cancer Institute
    Boston, Massachusetts

  • Benjamin L. Ebert, MD, PhD

    Department of Medical Oncology
    Dana-Farber Cancer Institute
    Boston, Massachusetts
    Broad Institute of MIT and Harvard
    Cambridge, Massachusetts
    Howard Hughes Medical Institute
    Bethesda, Maryland

  • Adam Lane, PhD

    Department of Pediatrics
    The University of Cincinnati and Cancer and Blood Diseases Institute
    Cincinnati Children’s Hospital Medical Center
    Cincinnati, Ohio

  • Oren Pasvolsky, MD

    Sackler School of Medicine
    Tel Aviv University
    Tel Aviv, Israel
    Institute of Hematology
    Davidoff Cancer Center
    Rabin Medical Center
    Petah Tikva, Israel

  • Pia Raanani, MD

    Sackler School of Medicine
    Tel Aviv University
    Tel Aviv, Israel
    Institute of Hematology
    Davidoff Cancer Center
    Rabin Medical Center
    Petah Tikva, Israel

  • Arnon Nagler, MD, MSc

    Sackler School of Medicine
    Tel Aviv University
    Tel Aviv, Israel
    Hematology Institute
    Sheba Medical Center
    Ramat Gan, Israel

  • Nancy Berliner, MD

    Division of Hematology
    Department of Medicine
    Brigham and Women’s Hospital
    Harvard Medical School
    Boston, Massachusetts

  • Naval G. Daver, MD

    Department of Leukemia
    The University of Texas MD Anderson Cancer Center
    Houston, Texas

  • Martin Ellis, MD

    Hematology Institute
    Meir Medical Center
    Kfar Saba, Israel
    Sackler School of Medicine
    Tel Aviv University
    Tel Aviv, Israel

  • Michael B. Jordan, MD

    Division of Immunobiology
    Cincinnati Children’s Medical Center
    Division of Bone Marrow Transplantation and Immune Deficiency
    Cincinnati Children’s Hospital Medical Center
    University of Cincinnati College of Medicine
    Cincinnati, Ohio

CME Author

  • Laurie Barclay, MD

    Freelance writer and reviewer
    Medscape, LLC

    Disclosures

    Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.

Editor

  • Andrew Roberts, MBBS, PhD

    Deputy Editor, Blood

    Disclosures

    Disclosure: Andrew Roberts, MBBS, PhD, has disclosed the following relevant financial relationships:
    Received grants for clinical research from: His organization, The Walter and Eliza Hall Institute, received grants for clinical research from AbbVie Inc.; Janssen Pharmaceuticals, Inc.
    Other: His organization, The Walter and Eliza Hall Institute, received royalties related to venetoclax and will control any distribution based on their institutional policies about scientific contribution to commercial income.

CME Reviewer

  • Leigh A. Schmidt, MSN, RN, CMSRN, CNE, CHCP

    Associate Director, Accreditation and Compliance
    Medscape, LLC

    Disclosures

    Disclosure: Leigh A. Schmidt, MSN, RN, CMSRN, CNE, CHCP, has disclosed no relevant financial relationships.


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  • Medscape, LLC designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™ . Physicians should claim only the credit commensurate with the extent of their participation in the activity.

    Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 1.0 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit.

     

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From Blood
CME / ABIM MOC

An Improved Index for Diagnosis and Mortality Prediction in Malignancy-Associated Hemophagocytic Lymphohistiocytosis

Authors: Adi Zoref-Lorenz, MD; Jun Murakami, MD, PhD; Liron Hofstetter, MD; Swaminathan P. Iyer, MD; Ahmed S. Alotaibi, MD; Shehab Fareed Mohamed, MD; Peter G. Miller, MD, PhD; Elad Guber, MD; Shiri Weinstein, MD, PhD; Joanne Yacobovich, MD, MPH; Sarah Nikiforow, MD, PhD; Benjamin L. Ebert, MD, PhD; Adam Lane, PhD; Oren Pasvolsky, MD; Pia Raanani, MD; Arnon Nagler, MD, MSc; Nancy Berliner, MD; Naval G. Daver, MD; Martin Ellis, MD; Michael B. Jordan, MDFaculty and Disclosures

CME / ABIM MOC Released: 2/17/2022

Valid for credit through: 2/17/2023

processing....

Abstract and Introduction

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory syndrome that may complicate hematologic malignancies (HMs). The appropriateness of current criteria for diagnosing HLH in the context of HMs is unknown because they were developed for children with familial HLH (HLH-2004) or derived from adult patient cohorts in which HMs were underrepresented (HScore). Moreover, many features of these criteria may directly reflect the underlying HM rather than an abnormal inflammatory state. To improve and potentially simplify HLH diagnosis in patients with HMs, we studied an international cohort of 225 adult patients with various HMs both with and without HLH and for whom HLH-2004 criteria were available. Classification and regression tree and receiver-operating curve analyses were used to identify the most useful diagnostic and prognostic parameters and to optimize laboratory cutoff values. Combined elevation of soluble CD25 (>3900 U/mL) and ferritin (>1000 ng/mL) best identified HLH-2004–defining features (sensitivity, 84%; specificity, 81%). Moreover, this combination, which we term the optimized HLH inflammatory (OHI) index, was highly predictive of mortality (hazard ratio, 4.3; 95% confidence interval, 3.0–6.2) across diverse HMs. Furthermore, the OHI index identified a large group of patients with high mortality risk who were not defined as having HLH according to HLH-2004/HScore. Finally, the OHI index shows diagnostic and prognostic value when used for routine surveillance of patients with newly diagnosed HMs as well as those with clinically suspected HLH. Thus, we conclude that the OHI index identifies patients with HM and an inflammatory state associated with a high mortality risk and warrants further prospective validation.

Introduction

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome with genetic and acquired etiologies. Familial HLH (FHL) is a genetic disorder caused by granule-mediated lymphocyte cytotoxic function defects occurring mainly in young children.[1] By contrast, most adults with HLH lack FHL genetic variants[2] and ~50% have an underlying cancer, of which hematologic malignancies (HMs) are the most common.[3,4] The diagnosis and treatment of HLH occurring in the context of HMs (HM-HLH) are largely based on extrapolations from clinical experience with FHL, along with expert opinion.[3,5–8]

Overall, HLH affects ~1% of adults with an HM,[9] although the incidence may reach 2.8% in cases with B-cell and T-cell lymphomas.[10] T-cell lymphomas are more commonly associated with the development of HLH (35% of HM-HLH cases) than B-cell lymphoma (32% of HM-HLH cases),[4,5] and myeloid malignancies may also be complicated by HM-HLH.[11–14] HM-HLH has the worst prognosis of all HLH subgroups, with 5-year overall survival ranging from 10% to 30%.[15,16]

HLH is commonly defined by using the enrollment criteria from the HLH-2004 study, which were developed to diagnose pediatric FHL. HLH is diagnosed when a causative genetic mutation is identified or suspected based on family history or when a patient fulfills ≥5 of the HLH-2004 diagnostic criteria.[17] The appropriateness of these criteria for the diagnosis of HM-HLH has not been determined. Furthermore, diagnostic cutoff levels for laboratory markers of HLH have not been optimized or validated in HM-HLH.[18] In addition, although a number of these features are driven by inappropriate immune activation in FHL,[19] their presence in HM may represent nonimmunologic effects of the malignant clone itself, such as infiltration of the marrow or spleen or soluble CD25 (sCD25) production by neoplastic cells. This has led to the suggestion that the syndrome of HM-HLH may be a "mimic" of the syndrome seen in patients with FHL and that patients may not benefit or may even be harmed by the use of HLH-directed therapy.[20] As a result, there is no consensus regarding whether patients fulfilling HLH-2004 diagnostic criteria should be treated with tumordirected therapy, HLH-directed therapy, or both.[7]

Another scoring system, the HScore, was developed to determine the diagnosis of HLH in adults.[21] Although valuable in some contexts, the HScore is imperfect as it was derived from a cohort of patients who were retrospectively defined as having HLH and because sCD25 results were not included in the score due to a lack of data. Moreover, HMs were significantly under-represented in the non-HLH group, limiting the use of the HScore in diagnosing HM-HLH.[21] Tamamyan et al[18] proposed a tool with extended diagnostic criteria for malignancy-associated HLH, adding selected variables to the HLH-2004 that were described in association with adult HLH. This tool was intended to supplement the HLH-2004 criteria to facilitate diagnosis of the syndrome in its early phase and thus reduce early mortality.

We conducted the current study to optimize and simplify HM-HLH diagnosis based on HLH-2004–defining features and used disease outcomes as an external validation measure.