Hemophagocytic lymphohistiocytosis (HLH) is a rare and rapidly progressing clinical syndrome with unknown incidence in adults that results from severe immune activation. Characteristic findings include fever, hepatosplenomegaly, lymphadenopathy, pancytopenia, rash, and neurological symptoms with elevated triglycerides, ferritin, and hypofibrinogenemia.

HLH is often described as primary hemophagocytic lymphohistiocytosis (inherited), with underlying genetic abnormality, or secondary (acquired) to another underlying condition such as a viral infection, an autoimmune disease, or a malignancy.

To the best of our knowledge, this is the first case report of HLH complicating a nodular lymphocyte—predominant Hodgkin lymphoma (NLPHL) in an adult treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. The NLPHL showed the additional, unusual feature of cyclin D1 expression, which, to our knowledge, also has not been previously reported.The patient died after treatment failure following 3 regimens of therapy.

High clinical suspicion of HLH should prompt immediate immunochemotherapy to reverse the otherwise high likelihood of a fatal outcome.

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome caused by an exaggerated inflammatory response and cytokine defect resulting in organ infiltration by activated cytotoxic T lymphocytes and histiocytes.

 Disproportionate levels of TNF-alpha; interleukins (IL) 4, 6, 8, 10, and 12; and soluble IL-2 receptor (sCD25) have been recorded in patients with HLH in combination with impaired/absent natural killer (NK) cell activity.

 The aforementioned parameters can aid in distinguishing this syndrome from etiologies with similar manifestations. Primary HLH, which generally affects infants and young children, is attributed to defects in perforin function. The incidence of secondary HLH in adults is unknown. Secondary HLH, either as a presenting phenomenon or developing during the course of a primary disease, has a broad range of associations, including infections (eg, Epstein-Barr virus [EBV] and cytomegalovirus [CMV]), rheumatic diseases, and malignancies, such as lymphoma).

Clinical and laboratory findings are characteristic yet nonspecific, which can delay the diagnosis. Findings include prolonged fever, hepatosplenomegaly, lymphadenopathy, pancytopenia, rash, and neurological symptoms, usually with a rapidly progressing course.

 Classic laboratory features include elevated triglycerides, markedly elevated ferritin levels, hypofibrinogenemia, and abnormal liver function tests. Bone marrow examination often reveals characteristic hemophagocytes— histocytes with engulfed hematopoietic elements, including nucleated erythroid precursors, white blood cell precursors, and platelets&mdash;which are best depicted in marrow aspirate smears.

HLH is a challenging diagnosis due to its rarity and it’s nonspecific presentation, and laboratory findings. Prompt recognition and diagnosis is important, given the necessity of early treatment to assure the best possible outcome. The main goal of therapy, especially when HLH is associated with malignancy, is to direct therapy toward the underlying condition while attempting to control the amplified inflammatory reaction.

Our patient is a 26-year-old Caucasian man with past medical history significant for nodular lymphocyte—predominant Hodgkin lympoma (NLPHL) stage IIIBs (lymph node involvement above and below the diaphragm with splenic involvement). Lymph node biopsy findings at diagnosis were typical of NLPHL, including macronodular architecture with a predomi- nance of small lymphocytes, lesser numbers of histocytes, and a minor population of admixed lymphocyte–predominant (LP) cells (Figure). LP cells expressed CD45, CD20, CD79a, BCL6, and epithelial membrane antigen, and lacked expression of CD10, CD15, and CD30. Interestingly, cyclin D1 was also expressed by cells consistent with LP cells (large, pleomorphic cells having highly lobated nuclei). The patient completed 6 cycles of rituximab, doxorubicin, vincristine, and predni- sone (R-CHOP) with resolution of the presenting symptoms following 2 cycles. The patient achieved unconfirmed complete remission at the end of therapy due to a small residual node on the left infraclavicular region.

After 4 months, a positron emission tomography/computed tomography (PET/CT) scan to follow up on the residual findings described above showed persistent local uptake. This was removed by surgery, with pathology showing extensive necrosis. A second PET/CT scan showed no further abnormal findings. One year after completion of therapy, the patient was seen in the office with recurrent symptoms (mainly night sweats) and was found to have pancytopenia upon blood count. A third PET/CT scan showed an enlarged left supraclavicular mass (4.3 × 1.3 cm) with a standardized uptake value of 13. Laboratory investigation showed the following results: white blood cell count, 1.2 × 103/mcL; absolute neutrophils, 0.6 × 103/mcL; hemoglobin, 11 g/dL; mean corpuscular volume, 87 fL; platelet count, 130.000/mcL; ferritin, 1387 ng/mL; alanine transaminase, 122 U/L; aspartate transaminase, 121 U/L; total bilirubin, 2.5 mg/dL; alkaline phosphatase, 303 U/L; albumin, 3.5 g/dL; prothrombin time, 18 seconds; creatinine, 0.8 mg/ dL. Bone marrow biopsy showed normal trilineage hematopoie- sis and increased cellularity (70%) without evidence of lympho- matous involvement. The patient underwent local radiation therapy to the supraclavicular area.

Six weeks later the patient was hospitalized for possible sepsis, because he presented with fever, splenomegaly, and cytopenias. The laboratory investigations showed hypertriglycerdemia and hyperferritenemia, with elevated liver enzymes. A bone marrow biopsy showed scattered histocytes displaying hemophagocytosis of both myeloid and erythroid precursors, and normal to increased cellularity with no evidence of lymphoma. He was treated with oral prednisone 100 mg daily and rituximab 375 mg/m2 intravenous once weekly for 4 weeks with mild improvement in his symptoms. He required intravenous hydration on 2 occasions following drenching sweating.

The patient developed severe jaundice due to progressive hepatic failure, acute kidney injury, and bloody diarrhea after a few weeks, which required readmission. Salvage therapy with alemtuzumab, per standard protocol, and dexamethasone 40 mg intravenous daily for 4 days was initiated with no significant response. The patient was subsequently treated with pentostatin 4 mg/m2 without a response. His condition further deteriorated with the development of disseminated intravascular coagulation. The patient was transferred to hospice and died shortly thereafter.

NLPHL is a rare type of Hodgkin lymphoma (HL), accounting for just 5% of cases. Unique findings include variants of Hod- gkin Reed-Sternberg cells (HRS cells), also known as LP cells. These display an intact B-cell program, expressing pan B-cell markers including CD20 and CD79a; express CD45; and typ- ically lack expression of CD15 and CD30, distinct from HRS cells found in classical HL. Morphologic and immunopheno- typic features in this case were typical of NLPHL with notable cyclin D1 expression by LP cells.

We are unaware of any previous case report of HLH developing in the course of NLPHL. It can be argued that our patient had HLH at initial diagnosis of NLPHL but it was not pursued. The poor prognosis of HLH mandates initiation of therapy as soon as possible, not wait for confirmation investigations when clinically suspected. Updated diagnostic criteria used in the HLH-2004 trial by the Histiocyte Society are described in the 

In our case, diagnosis of HLH was delayed at least 6 weeks following development of bicytopenia, fever, splenomegaly, and a markedly elevated ferritin. Four of 5 criteria required for HLH diagnosis were met. NK activity, soluble CD25, triglycerides, and fibrinogen were not assessed at that time, which might have been useful investigations. The patient was actually fulfilling the proposed diagnostic criteria, as HLH-2004 criteria are not specific and mainly used for clinical trials.

 The proposed criteria are 3 of 4 clinical manifestations (fever, splenomegaly, cytopenias, and hepatitis) in addition to 1 of 4 investigational findings (hemophagocytosis, high ferritin, low fibrinogen, and absent/decreased NK cell function).

In a series of 34 patients with HL—associated hemophagocytic syndrome, most patients with were male, predominantly lymphocyte depleted, and mixed cellularity subtypes of classical HL (85%) with EBV involvement (95%).

 None of these patients had NLPHL (14 patients with unknown type). Treatment of triggering infection improves outcomes. Described culprits include EBV, CMV, HIV, herpes simplex virus, varicella zoster virus, and Leishmania. Our patient was EBV immunoglobulin (Ig) G positive and IgM negative. In adult patients, NK/T-cell degranulation, activity studies, and genetic testing can be used to explore the possibility of late onset of a congenital variety, which was not performed in our case.

Malignancy-associated HLH has a worse prognosis compared with other secondary forms and there are no evidence-based guidelines to direct therapy.

 A common practice is to initiate treatment aimed at the presenting malignancy and to add other measures to control the hyperimmune reaction based on the response to initial therapy.

The Histiocyte Society initiated a prospective international collaborative therapeutic study in 1994 (HLH-94) that aimed to improve survival. Standard treatment for primary HLH (HLH- 94 protocol) includes 8 weeks of initial therapy, consisting of etoposide (150 mg/m2 twice weekly for 2 weeks and then weekly) and dexamethasone (initially 10 mg/m

 for 1 week, and 1 week of tapering). The initial therapy was followed by a continuation therapy and bone marrow transplant for patients with persistent disease or known familial disease.

Patients with unresolved nonfamilial disease stopped therapy. The continuation therapy included dexamethasone and etoposide alternating every second week in combination with daily oral cyclosporin. Intrathecal methotrexate was administered for patients with progressive neurological symptoms or consistent abnormal cerebrospinal fluid findings. The HLH-94 study enrolled 119 patients who were younger than 15 years of age. The study excluded 6 patients who were subsequently found to have specific underlying disorders (4 with hematolymphoid malignancies). This study is the only known study to date to show an improved survival with an estimated 3-year probability of overall survival of 55% (95% CI, 46%-64%). However, given the patient demographics, we speculate that the majority of the patients enrolled had a familial predisposition.

Rituximab showed good response if the trigger was EBV infection.

 So et al also reported a case of HLH and autoimmune hemolytic anemia associated with systemic lupus erythematosus successfully treated with rituximab that was refractory or intolerable to conventional therapy.

 During the second presentation, our patient did not respond to 4 weeks of rituximab and steroid treatment. He was also treated with cyclosporine, dexamethasone, and etoposide without significant improvement.

Alemtuzumab may be appropriate, instead of etoposide, in the case of liver failure, clinical deterioration, or no improvement within 2 to 3 weeks of HLH-94 therapy.

 Cyclophosphamide, doxorubicin, vincristin, prednisone (CHOP) therapy for 8 weeks in 17 adult patients showed a 2-year overall survival of 44%14; however, our patient received R-CHOP as an initial therapy for NLPHL and repeat of the same regimen was not entertained. Unfortunately, most trials in the literature included limited numbers of patients and the various regimens used in those trials were not compared with HLH-94-based therapy, which remains the standard of care. Although hematopoietic stem cell transplantation in familial HLH has been shown to improve outcomes, its role in secondary types has not been defined.

Despite improvements in the diagnosis and treatment of HLH, this entity remains an often-fatal clinical syndrome that requires prompt recognition and intervention. HLH can be associated with NLPHL, and clinician awareness of early manifestations is crucial to avert fatal outcomes. More effective therapies are also required to improve patient outcomes and should be a focus of further studies.

: Delshad Ahmad, Mohamed Akkad, and Anas Al-Janadi are with Michigan State University; Brian Olsen is with William Osler Health System.

: Anas Al-Janadi, MD, Breslin Cancer Center, Michigan State University, 401 W. Greenlawn Ave, Lansing, MI 48910.

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Articles

This is the first case report of hemophagocytic lymphohistiocytosis complicating a nodular lymphocyte–predominant Hodgkin lymphoma in an adult treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone.

Hemophagocytic Lymphohistiocytosis in a Patient With Nodular Lymphocyte–Predominant Hodgkin Lymphoma: A Case Report

activating mutations were described in lung cancer over a decade ago, and in that time, targeted therapy with epidermal growth factor receptor (

) tyrosine kinase inhibitors (TKIs) have become the treatment of choice as first-line therapy. Targeted therapy improves responses and progression-free survival when compared with chemotherapy in these patients with advanced disease. Despite improvements in outcomes, resistance develops and the majority of patients expe- rience tumor progression and are not cured. The intro- duction of third-generation 

TKIs that effectively block activating mutations and the T790M resistance mutation while sparing wild-type 

has led to improved outcomes following the development of resis- tance. The future of 

therapy will explore the use  of these agents and combinations to potentially delay or eliminate resistance to increase efficacy and ultimately survival. This review will focus on current therapies used in the first-line setting for advanced 

mutation positive non—small cell lung cancer (NSCLC) followed by emerging data that may lead to a transition in the choice for initial therapy in these patients.

Lung cancer is the leading cause of cancer related mortality worldwide in both men and women.

 Patients with advanced epidermal growth factor receptor (EGFR) mutated non—small-  cell lung cancer (NSCLC) treated with tyrosine kinase inhibitors (TKIs), such as gefitinib, erlotinib, and afatinib, show improved progression-free survival (PFS) compared with standard chemo- therapy as first-line therapy.

 Unfortunately, patients develop resistance through multiple routes, including acquired 

 In order to combat this resistance, second- and third-generation 

TKIs have been developed.  In order to prevent or delay the development of resistance, multiple strategies have been investigated, such as the  combina- tion of high-dose pulses with low-dose continuous 

TKI therapy or co-targeting bypass signaling pathways as in the com- bined inhibition of both 

 The development of third-generation TKIs has improved patient outcomes; however, therapeutic resistance still occurs. As the options for therapy increase, the available data should be considered in choosing a frontline treatment.

TKIs have been established as frontline therapy for patients with metastatic 

mutant lung. Differentiating between these treatment options requires an evaluation of the studies that have been performed.

The IPASS trial led the field, and was a randomized, phase 3 trial that compared gefitinib to carboplatin and paclitaxel  in 1217 previously untreated never or light ex-smokers  with advanced NSCLC, but did not require 

mutation. The pri- mary endpoint was PFS, and at 12 months, the PFS was 24.9% with gefitinib and 6.7% with carboplatin/paclitaxel. In the sub- group of patients with an 

mutation, PFS was significantly longer among those who received gefitinib.

mutation had improved PFS with chemotherapy, highlighting the importance of molecularly testing for activating 

A randomized, phase 3 trial compared gefitinib versus carboplatin/paclitaxel in previously untreated patients with 

 Analysis of the first 200 patients revealed that PFS was significantly longer in patients in the gefitinib group resulting in early termination. The gefitinib group had a median PFS of 10.8 versus 5.4 months in the chemotherapy group and a higher response rate of 73.7% versus 30.7%.

A third study comparing gefitinib and cisplatin plus docetaxel had similar results.

 This randomized, phase 3 study involved   177 previously untreated patients diagnosed with stage IIIB/IV NSCLC or postoperative recurrence with 

mutations and evaluated PFS as the primary endpoint. The gefitinib group had significantly longer median PFS compared with the cisplatin   plus docetaxel group (9.2 versus 6.3  months).

A randomized, phase 3 trial compared erlotinib with  carbo- platin/gemcitabine in 165 patients with stage IIIB/IV NSCLC and 

mutations.5 The analysis of PFS included 82 patients in the erlotinib group and 72 in the chemotherapy   group. Median PFS was significantly longer in the patients treated with erlotinib than those treated with chemotherapy (13.1 versus 4.6 months).

The EURTAC trial compared erlotinib versus platinum-based chemotherapy for first-line treatment of patients with advanced NSCLC with 

mutations in a randomized, phase 3 trial.

   In that study, 86 patients received erlotinib and 87 received standard chemotherapy. The preplanned interim analysis showed the study met its primary endpoint and enrollment was stopped. The median PFS in the erlotinib group was 9.7 months com-  pared with 5.2 months in the chemotherapy  group.

The LUX-Lung 3 study was a randomized, phase 3 trial  that compared afatinib to pemetrexed/cisplatin in  previously

untreated EGFR-positive stage IIIB/IV NSCLC patients.

 The study enrolled 345 patients who were randomly assigned in a  2:1 ratio and stratified by 

mutation (exon 19 deletion, L858R, or other). The median PFS was 11.1 months for the afatinib group and 6.9 months for the chemotherapy group. Median PFS among patients with exon 19 deletions and L858R deletions was 13.6 months for afatinib and 6.9 months for chemotherapy. The LUX-Lung 6 trial randomized 364 patients with previ- ously untreated 

mutation positive stage IIIB/IV NSCLC to receive either afatinib (242 patients) or gemcitabine-cisplatin (122 patients) a 2:1 ratio and stratified patients by 

muta- tion (exon 19 deletion, L858R, or other).4 Median PFS in the afatinib group was 11.0 months and 5.6 months in the gemcit- abine-cisplatin group.

A pooled analysis of LUX-Lung 33 and LUX-Lung 64 in- cluded 631 of the 709 patients randomized and evaluated overall survival (OS) in patients with exon 19 (n = 355) and exon 21 mutations (n = 276).

 OS was significantly longer in  the del19-positive tumors in the afatinib group than in the chemotherapy group (31.7 versus 20.7 months). There were   no significant differences by treatment group for patients with 

L858R-positive tumors. This study showed that OS was improved for patients with del19 

The LUX-Lung 7 trial was a randomized phase 2B trial that compared first-line treatment with either afatinib or gefitinib  in patients with 

 In the study, 160 patients received afatinib and 159 patients received gefitinib until disease progression. PFS was 11.0 months with afatinib and 10.9 months with gefitinib and median  time

to treatment failure was 13.7 months with afatinib and 11.5 months with gefitinib, and the results were statistically signifi- cant. Furthermore, survival was increased with afatinib at 27.9 versus 24.5 months, but the result was not   significant.

The current frontline options with afatinib, erlotinib, and ge- fitinib offer improved outcomes over standard chemotherapy in 

-mutant NSCLC patients. Toxicities are manageable and most commonly include rash, and skin toxicity, and diarrhea.

 Despite the benefit to patients, progression invariably occurs so we must consider novel strategies that might increase  survival.=

Enhancing outcomes for patients may require combination therapy or new generation inhibitors that can prevent or over- come resistance mechanisms. The strategies with early results include combination erlotinib and bevacizumab, afatinib and cetuximab, and osimertinib as first-line therapy for 

mu- tant NSCLC, and other agents and combinations are under investigation.

A randomized, phase 2 study in 154 patients with stage IIIB/ IV or recurrent non-squamous NSCLC with 

mutations  and no previous therapy for advanced disease compared erlo- tinib alone versus erlotinib plus bevacizumab.

 The median PFS was 16.0 months in the erlotinib plus bevacizumab group   and 9.7 months in the erlotinib alone group. Additional studies are ongoing to confirm these results and assess  toxicities.

Osimertinib, a third-generation EGFR TKI, is approved  as treatment for patients with 

TKI resistance due to emergence of the T790M mutation, and demonstrated  over 50% objective response rate (ORR).

 With the hypothesis that early treatment with osimertinib can prevent the emergence of T790M as a mechanism of resistance and improve PFS, cohorts were studied using osimertinib as first-line therapy. Sixty pa- tients from 2 phase 1 expansion cohorts of the original AURA trial received either 80 mg per day (n = 30) or 160 mg per day   (30 patients) of osimertinib as first-line therapy. The ORR was 77%. Median PFS was 19.3 months for the 160 mg dose, and  has not yet been reached for the 80 mg dose.

  This early data   are promising, and a phase 3 trial (FLAURA) is evaluating the efficacy of osimertinib in treatment-naïve 

mutation posi- tive NSCLC patients  (NCT02296125).

Afatinib plus cetuximab demonstrated clinical activity in 

-mutated lung cancers with acquired resistance compared with gefitinib or erlotinib, both with and without T790M mutations in a phase 1b study.

  This combination is now   being studied as a frontline therapy for 

Central nervous system (CNS) metastases, including leptome- ningeal carcinomatosis, are a challenge in patients with 

mutation positive lung cancer. Progression within the brain  often occurs in the absence of systemic tumor growth due to inadequate drug concentration in the CNS. Pulse dose erlotinib has been shown to be tolerated while increasing penetration   into the brain.

 A phase 1 study evaluated twice weekly pulse dose erlotinib at 1200-mg days 1 and 2 followed by 50 mg   on days 3 to 7 in treatment-naïve NSCLC patients with 

 The study demonstrated similar survival and responses seen in phase 3 trials, but of the 34 patients enrolled, none had progression in an untreated metastasis or developed new CNS metastases while on study. Additional trials evaluat-  ing activity of next-generation 

inhibitors in patients with CNS metastases are planned.

TKIs is effective, but patients develop resis- tance, most commonly due to T790M. Molecular analysis of cir- culating tumor cells or cell-free DNA may provide a strategy for monitoring changes in tumor genotypes and the development of drug resistant mutations during treatment. One study found  that the T790M was detectable in pretreatment tumor biopsies and circulating tumor cells during treatment and that T790M mutations were associated with reduced PFS (7.7 versus 16.5 months), and an increase in the number of cells with T790M mutations correlated with disease  progression.

TKIs in the frontline setting are ongoing and the results are forthcoming. These trials will help clarify the optimal use of TKIs in 

mutation positive NSCLC, and future studies will address the question of proper sequencing of therapy to provide the best outcomes for patients. The timing of third-generation EGFR inhibitors, such  as earlier use of osimertinib will likely lead to new mechanisms  of resistance, the emergence of the C797S 

 Additional studies to understand these mecha- nisms and therapies to overcome resistance will be  needed.

Emily A. Barber is with the University of California, Irvine, and Karen L. Reckamp is with the City of Hope Comprehensive Cancer Center.

Karen Reckamp discloses that she has provided consultant services to Amgen, Ariad, Astellas, Nektar, and received research support (to institution) from Ariad, Bris-   tol Myers Squibb, Boehringer Ingelheim, Clovis, Eisai, Novartis, Pfizer, Xcovery, Adaptimmune, Medimmune,  Stemcentrx.

: Karen L. Reckamp, MD, City of Hope City of Hope Comprehensive Cancer Center, 1500 E. Du- arte Road, Bldg 51, Duarte, CA 91010. phone: (626)   256-4673,

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This review will focus on current therapies used in the first-line setting for advanced EGFR mutation positive non–small cell lung cancer (NSCLC) followed by emerging data that may lead to a transition in the choice for initial therapy in these patients.

June 2017 | Invited Presentations

Hemophagocytic Lymphohistiocytosis in a Patient With Nodular Lymphocyte–Predominant Hodgkin Lymphoma: A Case Report

Best Initial Treatment Strategies for EGFR-Mutant Lung Cancer