Conditions: Leukemia
Keywords: Leukemia Hemophagocytic lymphohistiocytosis HLH Alemtuzumab CAMPATH-1H Campath Etoposide VePesid Dexamethasone Decadron Methotrexate Phone call
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 18
Healthy volunteers: no

Brief summary:
The goal of this clinical research study is to compare the effect of adding either alemtuzumab or tocilizumab to the drug combination of etoposide and dexamethasone in controlling HLH. The safety of the drug combinations will also be studied.

This is an investigational study. Alemtuzumab, etoposide, tocilizumab, and dexamethasone are not FDA approved for the treatment of HLH. Etoposide is FDA approved and commercially available for the treatment of testicular cancer and lung cancer. Alemtuzumab is FDA approved and commercially available for the treatment of chronic lymphocytic leukemia. Dexamethasone is a steroid used to reduce inflammation. Tocilizumab is FDA approved and commercially available for the treatment of arthritis. The combination of alemtuzumab, etoposide, tocilizumab, and dexamethasone to treat HLH is investigational. The study doctor can explain how the drugs are designed to work.

Up to 40 participants will be enrolled in this study. All will take part at MD Anderson.

Detailed description:
Study Treatment:

If you are found to be eligible to take part in this study, your doctor will assign you to either Group 1 or Group 2.

You will receive the study treatment in 2 parts. The first part of the study will last about 8 weeks (Weeks 1-8) and will be called the "induction phase". The second part of the study will start after the induction phase and will last about 16 weeks (Weeks 9-16). This part will be called the "maintenance phase". However, the parts of the study may be longer or shorter depending on if/how the disease responds to the treatment, how the biomarkers react to treatment, and what the doctor thinks is in your best interest.

* If you are in Group 1, you will receive alemtuzumab by vein over 2 hours or through an injection under the skin every day on Days 1-4 of the induction phase and about 1 time every 4 weeks during the maintenance phase.
* If you are in Group 2, you will receive tocilizumab by vein over 60 minutes on Day 1 or Day 2 of the Induction phase. Tocilizumab will not be given in the Maintenance Phase.

Participants in both Groups 1 and 2 will receive etoposide by vein about 1 time each week during the induction phase. You will not receive it in the maintenance phase unless the disease stops responding to the study drugs. At that point, you may begin to receive etoposide again. The study doctor will tell you more about this.

The length of time it takes to infuse the study drugs will be different from patient to patient and will depend on rate of injection. Your doctor will discuss this with you.

Participants in both Groups 1 and 2 will receive dexamethasone by vein on Days 1-7 of the induction phase. After this, you will take pills of dexamethasone every day during the induction phase. In the maintenance phase, you will take these pills 3 times each week with at least a day between each dose (for example, Monday, Wednesday, and Friday).

Your dose of the study drugs may be raised, lowered, and/or delayed if the doctor thinks it is in your best interest.

If the disease involves the central nervous system during the Induction phase, you may receive methotrexate. Methotrexate is given 1 time a week for 5 weeks.

Study Visits:

You will have physical exams on the following days:

* Day 1,
* Every week for the first 4 weeks,
* Every 2 weeks during the next 4 weeks,
* Every 4 weeks during the next 16 weeks, and
* Every 8 weeks after that.

Blood (about 3 tablespoons) will be drawn for routine tests on the following days. During the first 4 weeks, these tests must be performed at MD Anderson. After that, these can be performed at a local clinic:

* Day 1,
* Two (2) times each week for the first 4 weeks,
* Every week for the next 4 weeks,
* Every 2 weeks for the next 16 weeks, and
* Every 4 weeks after that.

You will have a bone marrow aspiration/biopsy 4 weeks after starting the study treatment and then every 4-12 weeks after that.

At any time that the doctor thinks it is needed, you may have additional blood draws or bone marrow aspirations/biopsies to check the status of the disease. If you receive treatment for longer than 24 weeks, the timing of these procedures may be changed if the study doctor thinks it is in your best interest.

Length of Study:

You may continue taking the study drug for as long as the doctor thinks it is in your best interest. You will no longer be able to take the study drug if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

Your participation on the study will be over after the follow-up visits.

End-of-Study Visit:

If you are taken off or if you leave the study before you have received treatment for 24 weeks, the following tests and procedures will be performed within 30 days (+/- 7 days) of the last dose of the study drug:

* Blood (about 2-3 tablespoons) will be drawn for routine tests.
* If the doctor thinks it is needed, you will have a bone marrow aspirate to check the status of the disease.

If you cannot make it to MD Anderson for this visit, these procedures may be done with a local doctor and the records can be forwarded to the study doctor.

Follow-Up:

If you respond to the study drugs, you will be followed every 3-6 months for up to 5 years after completion of treatment. You will be called and asked about how you are doing. Each call will last about 5-10 minutes.

Arms:
arm 1: Induction Phase: Participants receive Alemtuzumab daily on Days 1 - 4 with weekly Etoposide, and Dexamethasone by vein on Days 1-7 during the 8-weeks. Participants with central nervous system involvement receive intrathecal methotrexate 12 mg once a week for 5 weeks.

Dexamethasone by vein on Days 1-7 of the induction phase.

Maintenance Phase: Starts Post Induction Phase for16 weeks. Participants receive Alemtuzumab once every 4 weeks and Dexamethasone three times per week. Participants who have evidence of budding relapse may revert back to receiving Etoposide.

If participant responds to study drugs, they will receive a phone call by study staff every 3 - 6 months for up to 5 years after completion of treatment. Each call will last about 5-10 minutes. arm 2: Induction Phase: Participants receive Tocilizumab by vein over 60 minutes on Day 1 or Day 2. Participants receive Alemtuzumab daily on Days 1 - 4 with weekly Etoposide and Dexamethasone by vein on Days 1-7 during the 8-weeks. Participants with central nervous system involvement receive intrathecal methotrexate 12 mg once a week for 5 weeks.

Maintenance Phase: Starts Post Induction Phase and will last 16 weeks. Tocilizumab not given in the Maintenance Phase. Dexamethasone three times per week.

If participant responds to study drugs, they will receive a phone call by study staff every 3 - 6 months for up to 5 years after completion of treatment. Each call will last about 5-10 minutes

Interventions: intervention 1: Alemtuzumab intervention 2: Etoposide intervention 3: Dexamethasone intervention 4: Methotrexate intervention 5: Phone Call intervention 6: Tocilizumab
Intervention descriptions: intervention 1: Group 1 and 2 Induction Phase: Alemtuzumab total dose of 1.0 mg/kg subcutaneously or by vein over 4 days (days 1-4) during the 8 week induction phase. Day 1 0.1 mg/kg, Day 2 0.3 mg/kg, Day 3 0.3 mg/kg, Day 4 0.3 mg/kg.

Group 1 Maintenance Phase: 0.2 mg/kg once every 4 weeks for 6 weeks. intervention 2: Induction Phase: 150 mg/m2 given by vein once a week for 8 weeks.

Maintenance Phase: Participants who have evidence of refractory disease or budding relapse during the maintenance phase may revert back to receiving Etoposide. intervention 3: Induction Phase: 10 mg/m2 for 1 week followed by Dexamethasone 5 mg/m2 for 2 weeks followed by Dexamethasone 2.5 mg/m2 for 2 weeks followed by Dexamethasone 1.25 mg/m2 for 2 weeks.

Maintenance Phase: 1.25 mg/m2 by mouth three times a week for 16 weeks. intervention 4: Participants with central nervous system involvement receive intrathecal methotrexate 12 mg once a week for 5 weeks during the Induction Phase. intervention 5: If participant responds to study drugs, they will receive a phone call by study staff every 3 - 6 months for up to 5 years after completion of treatment. Each call will last about 5-10 minutes. intervention 6: Induction Phase: Tocilizumab at 4 to 8 mg/kg by vein. Day 1 0.1 mg/kg,Day 2 0.3 mg/kg, Day 3 0.3 mg/kg, Day 4 0.3 mg/kg.

Protocol document:
Prot_SAP_000.pdf: 
 
 
HLH therapy in adults 
 
 
2014‐0989 
 
 
01/26/2018 
 
1
 
 
 
 
 
 
Alemtuzumab or Tocilizumab in Combination with 
Etoposide and Dexamethasone for the Treatment 
of Adult Patients with Hemophagocytic 
Lymphohistiocytosis 
 
 
 
PI: Naval Daver 
 
 
MDACC IRB # 2014-0989 
University of Texas  
 
MD Anderson Cancer Center  
 
Leukemia Department, Unit 428  
 
 
 
 


 
 
HLH therapy in adults 
 
 
2014‐0989 
 
 
01/26/2018 
 
2
 
1.0 
OBJECTIVES 
 
1.1 
Primary Objectives 
1.        To determine the overall response rate (ORR) of alemtuzumab or 
tocilizumab in combination with etoposide and dexamethasone in 
patients with HLH. 
 
1.2 
Secondary Objectives:  
1.        To determine the safety of alemtuzumab or tocilizumab in 
combination with etoposide and dexamethasone in patients with 
HLH. 
2.        To determine the median time to response, duration of response, 
disease-free survival (DFS), and overall survival (OS) of 
alemtuzumab or tocilizumab in combination with etoposide and 
dexamethasone in patients with HLH. 
3.        To determine the rates of partial and complete response at 8 
week.  
4.        To determine the incidence of serious infection and other adverse 
events by week 8 and prior to initiation of hematopoetic stem cell 
transplant (HSCT) preparative regimen (or week 24, if HSCT 
preparative regimen not yet begun).  
5.        To determine the overall survival to the initiation of HSCT 
preparative regimen or week 24, if HSCT preparative regimen not 
begun. 
6.        To determine the incidence and median time to reactivation prior to 
initiation of HSCT preparative regimen (or week 24, if HSCT 
preparative regimen not yet begun).         
7.        To determine overall survival to day +100 after HSCT, for patients 
who have undergone HSCT within 6 months of study entry.   
8.        To determine the induction mortality (mortality within first 4 weeks 
and 8 weeks of initiation of therapy) for patients with HLH treated 
with this combination. 
 
 
2.0      BACKGROUND 
 
2.1 
Hemophagocytic lymphohistiocytosis: 
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of severe 
immune activation and deregulation resulting in extreme and often life 
threatening inflammation[1, 2]. HLH occurs as either a primary (familial - 
FHL) or secondary (sporadic - sHLH) disorder[3, 4]. Both conditions 
manifest pathological immune activation and may be difficult to 
differentiate from each other.  
 
Primary HLH is an autosomal recessive disease with an incidence of 
1/50,000 live-born children. Patients often have a clear familial inheritance 


 
 
HLH therapy in adults 
 
 
2014‐0989 
 
 
01/26/2018 
 
3
or genetic mutation. Median survival is less than 2 months if untreated[5]. 
Disease symptoms usually appear during infancy or early childhood. 
Immunological triggers such as vaccinations and viral infections may 
trigger bouts of disease in these patients. However, in many circumstance 
no clear cut immune trigger is identifiable[6].  
 
Secondary HLH includes adults and older children who lack family history 
or known genetic cause for HLH. Secondary HLH often occurs as a result 
of pathological immune activation in response to a trigger. Frequently 
noted triggers include malignancy (especially hematological malignancies 
including acute leukemia’s, MDS and myelofibrosis), infections (especially 
EBV) and rheumatological disorders. The list of triggers associated with 
secondary HLH is extensive[7, 8]. Secondary HLH that develops in the 
setting of malignancy is also known as malignancy-associated 
hemophagocytic syndrome (MAHS). MAHS may manifest as the 
presenting feature of a yet undiagnosed malignancy or may manifest 
during the treatment of a known malignancy.  
 
Categorizing patients into primary or secondary HLH is often difficult and 
may be of limited value. Treatment should be initiated expediently if the 
diagnosis of HLH is suspected. 
 
2.2      Immune activation and HLH: 
           Patients with HLH have deregulation of the immune system including 
predisposing immunodeficiency, immune activation and immunopathology 
(Table 1) [1, 9]. Immune-activation and immune mediated pathology likely 
play a central role in the evolution of HLH. This included acute clinical 
signs and symptoms of immune activation including hepatomegaly, 
jaundice, adenopathy, rash, seizures, and focal neurologic deficits as well 
as laboratory measures such as strikingly high serum levels of numerous 
cytokines including interferon gamma (IFNγ), tumor necrosis factor α 
(TNF-α), interleukin 6 (IL-6), IL-10, and macrophage–colony-stimulating 
factor (M-CSF)[10-12]. Furthermore, biopsies of lymphoid tissues or 
histological examination of liver tissue from HLH patients reveal highly 
activated macrophages and lymphocytes, supporting striking activation of 
the immune system.  
 
            Table 1: Mechanisms of immune deregulation in HLH 


 
 
HLH therapy in adults 
 
 
2014‐0989 
 
 
01/26/2018 
 
4
              
               Adapted from Jordan M et al, Blood 2011[1] 
       
2.3      Proposed immunological model of pathophysiology of HLH:  
           Jordan et al used perforin-deficient mice models to better define the 
immonobiology of HLH. Perforin deficient mice on exposure to lymphocytic 
choriomeningitic virus manifested most of the clinical features of HLH 
along with elevation of multiple serum cytokines and histological evidence 
of hemophagocytosis. They identified that CD8+ cells and IFN-gamma 
were essential to the development of HLH pathophysiology in response to 
LCMV infection (Figure 1). 
 
            Figure 1: Proposed model of pathophysiology of HLH:  
            
         
 
 
            (A) During a normal immune response, presentation of antigen promotes 
CD8+ T-cell responses. In return, CD8+ T cells secrete IFNγ, which 
activates antigen-presenting cells and further promotes antigen 
presentation. This positive feedback loop is restrained by perforin-
dependent mechanisms. It remains unclear whether this occurs via 
specific destruction of professional antigen-presenting cells, general 
destruction of virally infected cells, or additional mechanisms.  


 
 
HLH therapy in adults 
 
 
2014‐0989 
 
 
01/26/2018 
 
5
           (B) In LCMV-infected pfp–/– mice, the failure of perforin-dependent 
mechanisms allows for spiralling immune activation and excessive 
secretion of IFNγ. This leads to the development of an HLH-like 
syndrome. 
  
           Adapted from Jordan M et al, Blood 2004[9] 
 
2.4       Diagnostic criteria for HLH: 
            The initial HLH guidelines in 1991, included 5 features: (1) fever, (2) 
splenomegaly, (3) cytopenis affecting at least two or three lineages in the 
peripheral blood, (4) hypertriglyceridemia and/or hypofibrinogenemia, and 
(5) hemophagocytosis in bone marrow, spleen or lymph nodes[13]. The 
2004 guidelines (Table 2) included 3 additional criteria: (6) low or absent 
NK-cell activity, (7) hyperferritinemia and (8) high levels of s-IL2r. Five of 
eight criteria must be fulfilled to make a diagnosis of HLH[2]. However, 
patients with a molecular diagnosis of HLH do not need to fulfill the 
diagnostic criteria.  These diagnostic criteria have been developed for 
pediatric HLH and have not been validated for adult HLH. These will serve 
as a background for evaluating HLH in adults but are not to be used as 
diagnostic criteria for adult HLH. 


 
 
HLH therapy in adults 
 
 
2014‐0989 
 
 
01/26/2018 
 
6
 
Table 2: Diagnostic criteria of HLH (Guidelines 2004) 


 
 
HLH therapy in adults 
 
 
2014‐0989 
 
 
01/26/2018 
 
7
2.5 
Therapy of HLH: 
 
                        The goal of initial therapy is to suppress the overactive 
immune system thus preventing immune-mediated organ 
damage. Induction therapy is often followed by allogeneic 
stem cell transplant if a suitable donor is available. If no 
suitable donor is identified, patients are followed closely for 
signs of relapse. The HLH-94 protocol proposed in 1997 
included an 8-week regimen with etoposide, dexamethasone 
and intrathecal methotrexate (Figure 2) [14]. This systematic 
therapeutic approach significantly improved the outcomes 
and survival of patients with HLH.  
 
                        The HLH-2004 protocol was opened in 2004. This protocol 
has completed accrual and is closed to new patient entry. 
The results of HLH-2004 are awaited. The major 
modifications from HLH-94 were to move cyclosporine dosing 
to the beginning of induction and add hydrocortisone to 
intrathecal therapy. Until the results of the HLH-2004 study 
are published, the current standard practice outside of a 
clinical protocol has been to treat patients who are not 
enrolled in a clinical study with a strategy based on HLH-94.  
 
Figure 2: Induction therapy for HLH. Based on the HLH-94 study, this 
approach should be considered standard of care for all 
patients not enrolled in clinical trials, based on published 
evidence of efficacy. Etoposide is dosed as 150 mg/m2 per 
dose. 
 
 
 
 
        


 
 
HLH therapy in adults 
 
 
2014‐0989 
 
 
01/26/2018 
 
8
 
                  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Induction therapy for HLH. Based on the HLH-94 study, this approach 
should be considered standard of care for all patients not enrolled in clinical 
trials, based on published evidence of efficacy. Etoposide is dosed as 150 
mg/m2 per dose. Alternatively, for patients weighing < 10 kg, consideration 
may be given to dosing etoposide as 5 mg/kg per dose. Dexamethasone (Dex.) 
is dosed as indicated and may be given orally or intravenously, although the 
latter is preferred at therapy initiation. Intrathecal methotrexate and 
hydrocortisone (IT MTX/HC) should be given to patients with evidence of 
CNS involvement, as early as LP may be safely performed (which may vary 
from the diagram) and dosed as follows: age < 1 year, 6/8 mg (MTX/HC); 1-2 
years, 8/10 mg; 2-3 years, 10/12 mg; > 3 years, 12/15 mg. Weekly intrathecal 
therapy is generally continued until at least 1 week after resolution of CNS 
involvement (both clinical and CSF indices). 
 
The current standard of care consists of a decrescendo course of etoposide and 
dexamethasone, with or without intrathecal therapy (Figure 2). Ideally, critically 
ill patients should be treated at facilities familiar with care of cancer and bone 
marrow transplant patients. It is important to initiate therapy promptly, even in 
the face of unresolved infections, cytopenias, or organ dysfunction. Because 
etoposide is cleared by both renal and hepatic routes, we recommend dose 
reductions of 25% for creatinine clearance of 10-50 mL/minute, 50% for 
creatinine clearance of < 10 mL/minute, and 75% in case creatinine clearance is 
< 10 mL/minute and direct bilirubin is > 3 mg/dL. We do not dose reduce 
etoposide for isolated hyperbilirubinemia or neutropenia. HLA typing is sent at 
the start of induction therapy to avoid downstream delays in HSCT. 
 


 
 
HLH therapy in adults 
 
 
2014‐0989 
 
 
01/26/2018 
 
9
Figure 3 Treatment strategy for HLH. An algorithm for HLH treatment 
strategies in various clinical contexts (Jordan M B et al, Blood 
2011) 
 
 
 
 
 
3.0 RATIONALE FOR THIS STUDY: 
The outcomes with the HLH-94 regimen remain less than ideal with only 
approximately half of patients experiencing complete resolution of disease. 
Furthermore, early mortality remains a significant problem. We have identified 
numerous cases of HLH in leukemia patients including frontline and salvage 
setting. Most frequently the patients have underlying myeloid disorders including 
myelodysplastic syndrome, acute myeloid leukemia or myelofibrosis. The 
mortality among the patients manifesting HLH-features has been high. There is 
no standard of care for HLH in adult patients. Thus, definitive measures to 
diagnose and treat HLH in our patient population are warranted.  
 
Our collaborators (Dr Kenneth McClain and Dr Carl Allen) at Texas Childrens 
Hospital have developed the HIT-HLH, combining anti-thymocyte globulin with 
dexamethasone (20mg/m2/day) for the first week followed by weekly etoposide x 
8 weeks with dexamethasone 10 mg/m2/day. They have discontinued 
cyclosporine as it was associated with increased incidence of neurotoxicity 
without significant therapeutic benefit in prior pediatric HLH studies. The current 
HIT-HLH regimen is similar to the HLH-94, except that patients will receive 2 
fewer doses of etoposide. The data remain confidential as this is an ongoing 


 
 
HLH therapy in adults 
 
 
2014‐0989 
 
 
01/26/2018 
 
10
study, however the interim results do not appear to be compelling (personal 
communication; Kenneth McClain and Carl Allen, Texas Childrens Hospital). 
 
Alemtuzumab is an effective salvage agent for refractory HLH, leading to 
improvement and survival to HSCT in many patients[15]. Alemtuzumab up-front 
in combination with dexamethasone (20mg/m2/day) and etoposide may afford 
the best combination to target HLH. Our collaborators at TCH believe this may 
provide the most effective regimen for HLH and are currently treating newly 
diagnosed pediatric HLH patients with a combination of alemtuzumab, etoposide, 
and dexamethasone. A pediatric protocol incorporating alemtuzumab, etoposide, 
and dexamethasone for the therapy of pediatric HLH is being developed. We 
propose a combination regimen of alemtuzumab with etoposide and 
dexamethasone for adult patients with HLH. 
 
Tocilizumab is and anti-IL6 monoclonal antibody and has shown significant 
activity in cytokine release syndrome, a condition closely related to HLH with 
similar cytokine elevation profile. We have used tocilizumab in refractory cases of 
Adult M-HLH with successful and rapid improvement in levels of ferritin, LDH, 
coagulopathy, organomegaly, and fevers. Tocilizumab is also more tolerable with 
less risk of T-lymphodepletion associated secondary infections such as CMV and 
HSV. Based on our experience with tocilizumab in patients with CART 
associated CRS and in refractory HLH we propose the option to use tocilizumab 
in combination with etoposide and dexamethasone as an alternative to 
alemtuzumab with etoposide and dexamethasone in adults with HLH. The 
tocilizumab may be an especially attractive option in patients who are critically ill 
or already myelosuppressed from recent chemotherapy as it may have a lower 
risk of inducing further myelosuppression and secondary life-threatening 
infections. 
 
For further details on etoposide and alemtuzumab please see the etoposide drug 
insert (Appendix D), alemtuzumab drug insert (Appendix E). 
 
4.0 STUDY DESIGN 
 
 This will be a phase II, single-arm open-label study. All patients will 
be registered through CORe. Up to 40 patients will be enrolled in 
the study. 
 
 The study will consist of two phases: 
(1) Induction phase: Patients will receive treatment on one of two 
arms at the discretion of the treating physician and the PI: 
Arm 1: Alemtuzumab with etoposide and dexamethasone 
during the induction phase . 
 
OR  
Arm 2: Tocilizumab with etoposide and dexamethasone during 
the induction phase.  


 
 
HLH therapy in adults 
 
 
2014‐0989 
 
 
01/26/2018 
 
11
(2) Maintenance phase: The maintenance phase may last up to 16 
weeks and will start after the induction phase. Patients who 
have evidence of budding relapse during the maintenance 
phase may revert back to receiving etoposide. 
 
 Intrathecal methotrexate 12 mg and hydrocortisone 15 mg (IT 
MTX/HC) should be given to patients with evidence of CNS 
involvement, as early as LP may be safely performed. Weekly 
intrathecal therapy is generally continued for at least 5 consecutive 
weeks or until at least 1 week after resolution of CNS involvement 
(both clinical and CSF indices).  
 
 Arm 1: Patients will initially receive alemtuzumab as an SQ or IV 
infusion. SQ administration will be preferred. It is suggested that 
alemtuzumab be administered daily for 4 days (recommended on 
Days 1-4) during the induction phase. The induction phase may 
last up to 8 weeks.  During the maintenance phase it is suggested 
that patients receive alemtuzumab approximately once every 4 
weeks for the up to 16 weeks. Patients may receive alemtuzumab 
more or less frequently during the induction and maintenance 
phase at the discretion of the treating physician only after 
discussion with the PI. Continuation of therapy after 24 weeks of 
therapy may be considered on a case-by-case basis. For further 
details please refer to the Treatment Plan (section 5.0). 
 
Arm 2: Patients will receive tocilizumab on Day 1 or 2 if they are 
thought to be better candidates for the Arm 2 based on review of 
the clinical parameters by the treating physician and the PI. The 
tocilizumab will be administered IV. The tocilizumab dosing may be 
repeated as needed during the initial 4 weeks of therapy to gain 
adequate disease control  
 
 
4.0 PATIENT SELECTION: 
Patient must meet all inclusion and exclusion criteria prior to being enrolled on 
study. Results of all baseline evaluations, which assure that all inclusion and 
exclusion criteria have been satisfied, must be reviewed by the Principal 
Investigator or his/her designee prior to enrollment of that patient. In addition, the 
patient, or if the patient is incapacitated at time of consent, the surrogate 
decision-maker, must be thoroughly informed about all aspects of the study, 
including the study visit schedule and required evaluations and all regulatory 
requirements for informed consent. Written consent will be obtained from the 
patient, or if incapacitated, will be obtained from the surrogate decision-maker, as 
per MDACC Institutional Policy.   
 
The following criteria apply to all patients enrolled onto the study unless 
otherwise specified. 


 
 
HLH therapy in adults 
 
 
2014‐0989 
 
 
01/26/2018 
 
12
 
Inclusion Criteria 
 
 Sign an IRB-approved informed consent document. 
 
 Patients must be >/= 18 years of age. 
 
 A documentation of diagnosis of hemophagocytic lymphocytosis, either 
newly diagnosed or relapsed/refractory by the treating physician and the 
PI in the patients chart. 
 
It must be noted that no diagnostic criteria have been established for 
diagnosis of HLH in adult patients as this was a hitherto poorly identified 
and considered to be a very rare disease in adults. We have seen an 
increasing number of cases of HLH at our institution over the last 2 years 
partly due to referrals and partly due to better understanding of the 
disease through discussions with our collaborators Dr Kenneth McClain 
and Dr Carl Allen at TCH (experts in pediatric HLH). Adult HLH seems to 
occur more frequently post malignancy and has a more fulminant course 
than pediatric HLH. The diagnostic criteria that have been traditionally 
used for children (HLH 1991 and HLH 2004) may not adequately diagnose 
HLH in adults. This is the first adult HLH protocol in the country. In the 
absence of standard diagnostic guidelines if the patient's symptoms are 
highly suspicious for HLH and after an adequate work-up to rule out 
alternate potential alternate etiologies is performed we will treat the patient 
for HLH as missing the diagnosis is associated with high mortality. These 
patients will be discussed with the PI (Dr Daver) prior to enrollment in all 
such cases. 
 
 Organ function as defined below (unless due to the HLH process): 
Serum creatinine </= 3.0 mg/dL 
Total bilirubin </= 5.0 mg/dL 
 
If organ dysfunction is thought to be related to the HLH process this must 
be clearly documented in the chart and the patients may be enrolled on 
study irrespective of creatinine and bilirubin levels. 
 
 Women of childbearing potential must practice contraception. Females of 
childbearing potential:  Recommendation is for 2 effective contraceptive 
methods during the study. Adequate forms of contraception are double 
barrier methods (condoms with spermicidal jelly or foam and diaphragm 
with spermicidal jelly or foam), oral, depo provera, or injectable 
contraceptives, intrauterine devices, and tubal ligation.  Male patients with 
female partners who are of childbearing potential:  Recommendation is for 
male and partner to use at least 2 effective contraceptive methods, as 
described above, prior to study entry and for at least 3 months after the 
last dose of study drug. 


 
 
HLH therapy in adults 
 
 
2014‐0989 
 
 
01/26/2018 
 
13
 
 Negative urine pregnancy test and/or serum pregnancy test within 7 days 
of initiation of therapy. 
 
 Male patients with female partners who are of childbearing potential:  
Recommendation is for male and partner to use at least 2 effective 
contraceptive methods, as described above, prior to study entry and for at 
least 3 months after the last dose of study drug. 
 
 
Exclusion Criteria 
 
 Pregnant or breast feeding women 
 
 Any serious/and or unstable pre-existing medical disorder (aside from 
malignancy exception above), psychiatric disorder, or other conditions that 
could interfere with subject’s safety, obtaining informed consent or 
compliance to the study procedures.  
 
 Patients unwilling or unable to comply with the protocol. 
 
 
5.0 
TREATMENT PLAN 
 
5.1 
General 
All patients will be registered through CORe. 
 
5.2 Schedule 
 
 The current standard of care consists of a decrescendo course of 
etoposide and dexamethasone, with or without intrathecal therapy 
(HLH-2004). Unfortunately, the outcomes in adult patients remain 
dismal suggesting the need for improved regimens. In the more 
recent HIT-HLH protocol (appendix F) our pediatric collaborators 
used 5 days of ATG (or alemtuzumab in patients unable to tolerate 
ATG) with weekly etoposide and continuous dexamethasone. 
However, the outcomes with this combination have not been 
significantly better than the HLH-2004 (personal correspondence, 
Kenneth McClain and Carl Allen).  
 
Alemtuzumab as a single-agent has shown efficacy in relapsed 
HLH. Alemtuzumab has been well tolerated in pediatric patients 
with relapsed HLH with no unexpected toxicities[15]. A pediatric 
protocol combining alemtuzumab, etoposide, dexamethasone for 
the frontline treatment of HLH is currently being developed. 
 Tocilizumab has shown to be very effective in postCART cell CRS. 
We have also used tocilizumab in adult highly refractory HLH 


 
 
HLH therapy in adults 
 
 
2014‐0989 
 
 
01/26/2018 
 
14
cases with success. Tocilizumab is less immunosuppressive than 
alemtuzumab and may be a good alternative especially in patients 
who are already immunosuppressed from recent Myeloablative 
therapies. 
 
We will evaluate the addition of a biologic agent (either 
alemtuzumab or tocilizumab) to etoposide and dexamethasone for 
the treatment of adults with HLH in this phase II study.  
 
5.2.1 Patients will be treated according to the following schedule: 
 
Induction (Week 1-8)  
 
 If patient receives etoposide, dexamethasone, alemtuzumab, 
tocilizumab, or intrathecal metroxate as standard of care prior to 
signing of consent, these medications will not need to be repeated 
upon signing of informed consent, as determined by the Principal 
Investigator. 
 
 Patients will receive etoposide and dexamethasone at a fixed dose 
during the induction phase. This includes fixed dose of etoposide 
150 mg/m2 once a week for up to 8 weeks, dexamethasone 20 
mg/m2 daily for 1 week followed by dexamethasone 10 mg/m2 for 
1 week followed by dexamethasone 5 mg/m2 for 2 weeks followed 
by dexamethasone 2.5 mg/m2 for 2 weeks followed by 
dexamethasone 1.25 mg/m2 for 2 weeks. The induction phase will 
last up to 8 weeks. The dexamethasone will be divided BID, given 
intravenously (IV) for at least 1 week before switching to oral 
formulation. Patients may receive etoposide and dexamethasone 
more or less frequently during the induction phase at the discretion 
of the treating physician after discussion with the PI.  Dosages of 
etoposide and dexamethasone may also be adjusted at the 
discretion of the treating physician and after discussion with the PI.  
The etoposide and dexamethasone backbone will remain the same 
whether the patients are treated on Arm 1 (alemtuzumab 
combination) or arm 2 (tocilizumab combination). 
 
 It is important to initiate therapy promptly, even in the face of 
unresolved infections, cytopenias, or organ dysfunction. Because 
etoposide is cleared by both renal and hepatic routes, we 
recommend dose reductions of 25% for creatinine clearance of 10-
50 mL/minute, 50% for creatinine clearance of < 10 mL/minute, and 
75% in case creatinine clearance is < 10 mL/minute and direct 
bilirubin is > 3 mg/dL. We do not recommend dose reduction of 
etoposide for isolated hyperbilirubinemia or neutropenia. HLA 
typing should be sent at the start of induction therapy to avoid 


 
 
HLH therapy in adults 
 
 
2014‐0989 
 
 
01/26/2018 
 
15
downstream delays in HSCT. Other dose modifications and dose-
reductions will be according to institutional standards. 
 
  Intrathecal methotrexate 12 mg and hydrocortisone 15 mg (IT 
MTX/HC) should be given to patients with evidence of CNS 
involvement (evidence of CNS involvement includes any of the 
following: elevated CSF protein or white count, seizures, focal or 
global neurologic deficit, MRI abnormalities consistent with CNS 
involvement by HLH) as early as lumbar puncture (LP) may be 
safely performed. Weekly intrathecal therapy is generally continued 
for a minimum of at least 5 consecutive doses. For patients with 
persistent CNS disease after 5 consecutive doses, additional 
weekly doses of IT therapy may be given at the discretion of the 
treating physician until at least 1 week after resolution of CNS 
involvement (both clinical and CSF indices). Lumbar puncture and 
IT therapy may be delayed if the treating physician deems that 
performing this procedure is excessively risky due to coagulopathy 
or thrombocytopenia. 
 
  Arm 1: Alemtuzumab Arm: Alemtuzumab dosing will be similar to 
CLL with patients receiving an escalating dose of alemtuzumab 
titrated based on their tolerance of the alemtuzumab infusion. The 
maximum dose of alemtuzumab in this study (alemtuzumab 30 
mg/day) is the same maximum dose used in the CLL Phase 3 
studies [16]. This dosing of alemtuzumab has been well tolerated in 
pediatric population with no unexpected toxicities. A similar dosing 
schema of alemtuzumab, etoposide, and dexamethasone is used 
in a pediatric protocol that is being developed to treat HLH in 
children by our collaborators Dr Kenneth McClain and Carl Allen. 
 
 Arm 2: Tocilizumab arm: The tocilizumab dosing will be similar to 
cytokine release syndrome. The recommended starting dose of 
tocilizumab is 4 to 8 mg/kg IV infusion. The tocilizumab may be 
given before or after or concomitantly with the etoposide. The start 
of tocilizumab administration may be delayed beyond day 1 if this 
is in the best interest of the patient and the reason for delay should 
be documented in the patient chart. Tocilizumab may be 
administered on the same days as etoposide or on other days 
during the induction. The tocilizumab dosing may be repeated as 
needed based on disease features and laboratory parameter 
changes. There is no required interval between tocilizumab doses 
although it is recommended to wait at least 24 hours before re-
dosing. There is no maximum number or dose of tocilizumab that 
cannot be exceeded, although it is recommended that if the 
patients HLH is not responding after 4 consecutive tocilizumab 
infusions in combination with the etoposide and dexamthasone 
then alternate therapy for the HL be considered 


 
 
HLH therapy in adults 
 
 
2014‐0989 
 
 
01/26/2018 
 
16
 
 Patients will receive alemtuzumab as a SQ injection or IV infusion 
(IV infusion will be over approximately 2 hours). Patients may begin 
with SQ injection and switch to IV infusion or vice-versa. The goal 
is to administer a total alemtuzumab dose of 1.0 mg/kg over 4 days 
(days 1-4). The first injection/infusion will include alemtuzumab 0.1 
mg/kg to be administered on day 1 of the induction. The start of 
alemtuzumab administration may be delayed beyond day 1 if this is 
in the best interest of the patient and the reason for delay should 
be documented in the patient chart. Alemtuzumab may be 
administered on the same days as etoposide or on other days 
during the induction. If administered on the same day, 
alemtuzumab should be administered approximately 1-2 hours 
after the etoposide infusion.  
 
A suggested alemtuzumab-dosing schema is as follows:  
Day 1 0.1 mg/kg  
Day 2 0.3 mg/kg 
Day 3 0.3 mg/kg 
Day 4 0.3 mg/kg 
 
Patients may receive alemtuzumab more or less frequently, at a 
lower dose or on a different dosing schedule during the induction 
phase at the discretion of the treating physician after discussion 
with the PI. 
 
 All chemotherapeutic and biologic agents will be dosed, prepared, 
and administered according to MDACC institutional guidelines. BSA 
will be recalculated prior to each subsequent course. 
 
 Alemtuzumab will be administered per local institutional guidelines, 
with dexamethasone (above) serving as the corticosteroid 
premedication, along with acetaminophen, and antihistamines, as 
deemed appropriate. If a patient is unable to tolerate alemtuzumab 
due to severe injection/infusion reactions, then site investigators 
must discuss alternative treatment (such as tocilizumab or ATG) 
with the principal investigator. 
 
 Tocilizumab will be administered as per institutional guidelines, with 
premeds as deemed appropriate. If a patient is unable to tolerate 
tocilizumab due to severe injection/infusion reactions or concern for 
worsening CNS toxicity from the tocilizumab, then site investigators 
must discuss alternative treatment (such as alemtuzumab or ATG) 
with the principal investigator. 
 
Maintenance (Week 9-24 or commencing upon completion of Induction 
Phase) 


 
 
HLH therapy in adults 
 
 
2014‐0989 
 
 
01/26/2018 
 
17
 
 Arm 1: The induction will be followed by a maintenance phase of for 
up to an additional 16 weeks. During the maintenance phase 
alemtuzumab will be administered at a dose of 0.2 mg/kg once 
every 4 weeks along with dexamethasone 1.25 mg/m2 three times a 
week by mouth. Patients who have evidence of refractory disease or 
budding relapse during the maintenance phase may revert back to 
receiving etoposide. Patients may receive alemtuzumab and/or 
dexamethasone more or less frequently, and dosages may also be 
adjusted, during the maintenance phase at the discretion of the 
treating physician after discussion with the PI. The maintenance 
duration may be reduced at the discretion of the treating physician in 
discussion with the PI and the reason for early discontinuation 
should be clearly documented. Continuation of therapy after 24 
weeks of therapy may be considered on a case-by-case basis. 
Other agents such as ruxolitinib (or other drugs with proven benefit 
in pediatric or adult HLH) may be added during the maintenance 
phase of the protocol. 
 
 Arm 2: Patients treated with tocilizumab in combination with 
etoposide and dexamethasone will not be required to receive 
maintenance with tocilizumab. These patients may be considered for 
alternate maintenance approaches such as maintenance with 
ruxolitinib or other anti-HLH medications.  
 
 In general, every attempt should be made to diagnose and treat 
infections, which may be underlying or triggering HLH (regardless of 
whether one considers the patients to have ‘primary’ or ‘secondary’ 
HLH). If the patient is stable, consideration should be given to 
treating the infection before initiating therapy for HLH. Furthermore, 
if the patient is stable, initial treatment for HLH with corticosteroids 
alone may be considered. In such circumstances, the experience 
and judgment of the treating physician and discussion with the 
principal investigator is critical for making such assessments. 
 
5.3 Dose Adjustments 
 
Drug doses may be modified for drug-related > grade 2 
nonhematologic toxicities. Dose interruptions/reductions of 
alemtuzumab and etoposide can also be made in other clinical 
situations where this step is considered to be in the best interest for 
the patient and after discussion with the principal investigator and 
clear documentation of the rationale for dose 
interruption/recommendation.  
 
The following table is a suggestion for dose modifications of 
etoposide in subsequent treatment courses: 


 
 
HLH therapy in adults 
 
 
2014‐0989 
 
 
01/26/2018 
 
18
 
Table 3: Suggested dose modifications for non-hematologic toxicity 
Dose level 
Etoposide (mg/m2) 
0 
150 mg/m2 
-1 
100 mg/m2 
-2 
50 mg/m2 
-3 
50 mg/m2 
 
Investigators should, whenever possible, determine which 
medication is causing the toxicity. Doses of each individual drug can 
be modified if toxicity is considered due a particular drug. The 
dexamethasone dose may be interrupted or reduced at the 
discretion of the treating physician.  
 
Dose modifications of etoposide, alemtuzumab, and tocilizumab for 
organ dysfunction will generally be according to institutional 
standards. These must be discussed with the study PI and 
documented in the medical records.  
 
Modifications of dose schedules other than the above will be allowed 
within the following guidelines: 
 
 Further dose reductions can be made to keep clinically significant 
toxicities grade < 2.  
 
 Dose adjustments by more than 1 dose level (e.g. decrease in 
dose from dose level 0 to dose level -2 in table 3) at a time can be 
considered when judged in the best interest of the patient (e.g. 
sepsis, hemorrhage) when toxicity has resolved. The reason for 
this reduction will be discussed with the PI or Co-PI and 
documented in the medical record. 
 
 A patient who has had a dose reduction because of any of the 
reasons mentioned above may have their dose escalated 
provided the patient has resolution (partial or complete) of the 
toxicity requiring dose adjustments as defined above for at least 2 
weeks. Escalation will be made by 1 dose-level increment only, 
and not more frequent than every 2 weeks.  
 
 Treatment interruptions and dose modifications other than the 
ones mentioned above can be considered after discussion with 
the PI and proper documentation of the rationale. Dose 
adjustment/delay of only one of the agents is permissible if the 
toxicity is most likely judged to be related to one of the agents by 
the investigator.  
 
5.4    Duration of Therapy 


 
 
HLH therapy in adults 
 
 
2014‐0989 
 
 
01/26/2018 
 
19
In the absence of treatment delays due to adverse events, 
treatment may continue until one of the following criteria applies: 
 
1. Clinically significant progressive disease, or 
 
2. Intercurrent illness that prevents further administration of treatment, 
or 
 
3. Patient request, or 
 
4. General or specific changes in the patient's condition render the 
patient unacceptable for further treatment in the judgment of the 
investigator, or 
 
5. Unacceptable toxicity that in the opinion of the investigator makes it 
unsafe to continue therapy. 
 
5.4.1        It is planned that up to a total of 24 weeks of therapy will be 
administered for patients deriving benefit from this regimen 
(Induction up to 8 weeks and maintenance up to 16 weeks). 
Continuation of therapy for patients completing 24 weeks of 
therapy may be considered on a case-by-case basis after 
discussion with the principal investigator. 
  
5.4.2         A minimum of 2 weeks of therapy will be required for a 
patient to be considered as having received an adequate 
trial to evaluate efficacy. All patients receiving at least one 
dose of any of the two drugs will be considered evaluable 
for toxicity. 
 
5.5    Supportive Care: 
         Supportive care measures including blood products, infection 
prophylaxis and growth factors will be administered according to 
institutional and Leukemia Department guidelines. As a number of 
patients with HLH have an underlying malignancy the concomitant 
use of chemotherapy (including but not limited to cytotoxic 
chemotherapy, biologic therapy, immunotherapy, molecularly 
targeted therapy, etc.) and the concurrent use of radiotherapy for 
the underlying tumor is allowed on the protocol. Furthermore, the 
addition of therapy with ruxolitinib as a maintenance or the 
addition of other maintenance therapies with a proven benefit in 
patients with adult or pediatric HLH will be permitted as long as 
the data is collected on the patient chart. 
 
         Infections secondary to myelosuppression are common in patients 
with HLH, and may be related to underlying disease, 
chemotherapy, or both. Therefore, the use of prophylactic 


 
 
HLH therapy in adults 
 
 
2014‐0989 
 
 
01/26/2018 
 
20
antibiotics, antifungal agents, and antiviral agents including anti-
PCP 
(trimethoprim-sulfamethoxazole 
or 
pentamidine) 
is 
recommended 
according 
to 
institutional 
standards. 
Viral 
surveillance/ prophylaxis includes weekly blood PCR’s for EBV, 
CMV, and other viruses the patient is known or suspected to 
harbor. Prompt treatment of EBV viremia with rituximab 
(375mg/m2, IV) weekly to help prevent EBV associated 
lymphoproliferative disorder is strongly suggested. CMV viremia 
should be treated with gancyclovir or foscarnet and cytogam, as 
appropriate. It is suggested that patients with serologic evidence 
or a history of varicella, CMV, or HSV should receive prophylaxis 
with acyclovir.  
 
         Immunoglobulin (IVIG) is suggested to be given to maintain serum 
IgG levels >1000 mg/dl or in the high end of the normal range. 
IVIG may need to be given relatively frequently in patients with 
HLH due to apparent consumption. IgG levels may need to be 
checked weekly or biweekly in such patients.  
 
         Concurrent therapy for CNS prophylaxis or continuation of therapy 
for controlled CNS disease is permitted. 
 
 
6.0 PRETREATMENT AND POSTTREATMENT EVALUATION 
Every effort will be made to adhere to the schedule of events and all 
protocol requirements. Variations in schedule of events and other 
protocol requirements that do not affect the rights and safety of the 
patient will not be considered as deviations.  Such variations may 
include 
laboratory 
assessments 
completed 
outside 
of 
schedule, occasional 
missed 
required 
research 
samples 
such 
correlative assays. 
 
6.1 Pretreatment evaluations 
 A complete history and physical, documentation of all measurable 
disease, concomitant medications and performance status. 
 
 CBC, platelet count, differential (differential can be omitted if WBC 
is ≤0.5 x109/L) within 3 days of initiation of therapy. 
 
 Ferritin, soluble IL2R-alpha (sCD25), , NK function, , IgG/IgA/IgM, 
LDH, 
lymphocyte 
subsets, 
lymphocyte 
mitogens, 
perforin/granzyme protein levels, plasma cytokines (specifically 
IL-6, IL-10, , TNF-alpha), mobilization, uric acid, , , fibrinogen, D-
dimer, PT, PTT, creatinine, total bilirubin, direct and indirect 
bilirubin, albumin, serum sodium level, GGT, ALT or AST, should 
be collected within 3 days of initiation of therapy. These studies 
are not mandatory but may facilitate the diagnosis of HLH and 


 
 
HLH therapy in adults 
 
 
2014‐0989 
 
 
01/26/2018 
 
21
should be ordered at the discretion of the treating physician.  
 
 It is recommended that CSF studies (including but not limited to 
glucose, 
protein, 
LDH, 
cell 
count 
and 
differential, 
viral/bacterial/fungal cultures, EBV PCR, CMV PCR, HSV PCR, 
flow-cytometry) and MRI brain be performed within 7 days of 
initiation of therapy. MRI alone may be performed initially in 
coagulopathic patients. Lumbar puncture and IT therapy may be 
delayed if the treating physician deems that performing this 
procedure is excessively risky due to coagulopathy or 
thrombocytopenia. These studies are not mandatory but may 
facilitate diagnosis of HLH and should be ordered at the discretion 
of the treating physician. 
 
 It is recommended that viral PCRs including EBV, CMV, HHV6, 
adenovirus and other relevant viruses; IgG and IgM for CMV and 
EBV; IgG for VZV and HSV; if Leishmania is a potential concern, 
then serum IgG and IgM titers and marrow PCR should be 
obtained blood and bone marrow cultures; bartonella, brucella, 
leishmania titers and PCR be collected within 7 days of initiation 
of therapy. It is required that Infectious disease be consulted at 
diagnosis to facilitate work-up. These studies are not mandatory 
but may facilitate diagnosis of HLH and should be ordered at the 
discretion of the treating physician. 
 
 It is recommended that HLA typing be collected and Stem Cell 
transplant be consulted at the time of HLH diagnosis to avoid 
delays in identifying donors for HSCT. These studies are not 
mandatory but may facilitate diagnosis of HLH and should be 
ordered at the discretion of the treating physician.  
 
 It is recommended that a CT abdomen or abdominal ultrasound 
be performed within 7 days of initiation of therapy. These studies 
are not mandatory but may facilitate diagnosis by documenting 
splenomegaly and/or hepatomegaly and should be ordered at the 
discretion of the treating physician. 
 
 It is recommended that an EKG and ECHO/MUGA scan be 
obtained within 7 days of initiation of therapy to establish baseline 
organ function and screen for coronary artery vasculopathy. 
These studies are not mandatory but may facilitate diagnosis and 
should be ordered at the discretion of the treating physician. 
 
 Pregnancy test (urine or plasma) in females of childbearing 
potential should be performed within 7 days of initiation of 
therapy. 
 


 
 
HLH therapy in adults 
 
 
2014‐0989 
 
 
01/26/2018 
 
22
 Bone marrow aspirate during the last 28 days preceding study 
initiation. Cytogenetics will be obtained prior to therapy (results 
from prior analysis can be used for this purpose). For patients 
who already have an evidence of hemophagocytosis on tissue 
biopsy from another site, the bone marrow may be omitted after 
discussion and approval with the principal investigator. 
 
 
6.2 Evaluations during study 
 
 Physical exam at least once weekly for the first 4 weeks, at least 
once every 2 weeks for the next 4 weeks, at least once every 4 
weeks for the next 16 weeks, and at least once every 8 weeks 
thereafter.  
 
 CBC, platelet count, differential, ferritin, d-dimer, PT, PTT, LDH, 
fibrinogen, serum sodium, AST, ALT, total bilirubin, creatinine, 
uric acid at least twice weekly for the first 4 weeks, at least once 
every 2 weeks for the next 4 weeks, at least once every 4 weeks 
for the next 16 weeks, at least once every 8 weeks thereafter 
(differential can be omitted if WBC is ≤0.5 x109/L). 
 
 
 It is recommended that soluble IL2R-alpha, , IgG/IgA/IgM, 
lymphocyte subsets be obtained twice a week for the first 4 
weeks, once every 2 weeks for the next 8 weeks, once every 4 
weeks for the next 12 weeks. The IL2R-alpha evaluations may be 
omitted once these values are within normal range. These studies 
are not mandatory but may facilitate assessment of response and 
should be ordered at the discretion of the treating physician. 
 
 Bone marrow aspiration in 4 weeks (+/- 7 days), then every 4-12 
weeks. Bone marrow tests can be ordered more or less frequently 
if mandated by development of peripheral blood counts. No 
repeat bone marrow is necessary if nonresponse or progressive 
disease can be unequivocally diagnosed from peripheral blood 
tests or, in patients with a WBC < 0.3 if the bone marrow test is 
considered noncontributory by the investigator at any time point. 
 
 For patients that remain on study with no significant toxicity for 
more than 24 weeks, subsequent evaluations during study may 
be modified after discussion with the principal investigator. These 
include a decrease in frequency of bone marrow aspirations to 
every 6-12 months (or as clinically indicated), physical 
examination to every 12-16 weeks, and other laboratory tests to 
once every 8-16 weeks. 
 


 
 
HLH therapy in adults 
 
 
2014‐0989 
 
 
01/26/2018 
 
23
 Patients with an objective response at completion of active study 
treatment will be followed for survival at MD Anderson Cancer 
Center (MDACC) every 3 to 6 months for up to 5 years after 
completion of active treatment. If the patient is unable to return to 
MDACC the follow-up visits may be conducted via telephone. 
 
 The first 4 weeks treatment must be performed at MDACC 
(inpatient or outpatient). During the first 4 weeks of treatment all 
the laboratory evaluations will be done at MDACC. Subsequently, 
the patient may have the laboratory work done at a local clinic 
and the results reported to the research nurse for the study. The 
laboratory work done at the local clinic will be forwarded to the 
patient’s attending physician at MDACC or PI of the study, who 
will sign off on the labs to verify that the results have been 
reviewed. 
 
       Outside Physician Participation During Treatment 
 
1. MDACC Physician communication with the outside physician is 
required prior to the patient returning to the local physician.  
This will be documented in the patient record. 
 
2. A letter to the local physician outlining the patient's participation 
in a clinical trial will request local physician agreement to 
supervise the patient's care (Appendix G). 
 
3. Protocol required evaluations outside MDACC will be 
documented by telephone, fax or e-mail. Fax and/or e-mail will be 
dated and signed by the MDACC physician, indicating that they 
have reviewed it. Changes in drug dose and/or schedule must be 
discussed with and approved by the MDACC physician 
investigator, or their representative prior to initiation, and will be 
documented in the patient record. 
 
4. A copy of the informed consent, protocol abstract, treatment 
schema and evaluation during treatment will be provided to the 
local physician. 
 
5. Documentation to be provided by the local physician will 
include progress notes, reports of protocol required laboratory 
and diagnostic studies and documentation of any hospitalizations. 
 
6. The home physician will be requested to report to the MDACC 
physician investigator all life threatening events within 24 hours of 
documented occurrence. 


 
 
HLH therapy in adults 
 
 
2014‐0989 
 
 
01/26/2018 
 
24
7. All follow-up visits will be performed at MDACC. Patients will 
return to MDACC for physical examination as specified on the 
protocol evaluations.  
 
 End of Treatment Visit to be completed 30 days (+/-7 days) after 
the last dose of study drug, when possible. Blood (about 2-3 
teaspoons) will be drawn for CBC, platelet count, differential, 
creatinine, total bilirubin, ALT.  No other procedures or labs will be 
needed. 
 
 Patients with an objective response at completion of active study 
treatment will be followed for survival at MD Anderson Cancer 
Center (MDACC) every 3 to 6 months for up to 5 years after 
completion of active treatment and while still on study. If the 
patient is unable to return to MDACC the follow-up visits may be 
conducted via telephone. 
 
Treatment may be discontinued for a variety of reasons, including patient 
withdrawal, investigator decision, and reasons specified by the protocol. Reasons 
for discontinuation of treatments are described below. 
 
7.0 DISCONTINUATION OF TREATMENT: 
 
7.1 Discontinuation Criteria for Individual Patients 
 
7.1.1 Patient Withdrawal 
Patients may voluntarily withdraw consent to participate in the clinical 
study at any time and without giving any reason. Their withdrawal will 
not jeopardize their relationship with their healthcare providers or affect 
their future care. Patients may also choose to withdraw from study 
treatment, but agree to remain in the study for follow-up procedures.  
 
7.1.2 Investigator Discontinuation of Patient 
The investigator may exercise medical judgment to discontinue study 
treatment if clinically significant changes in clinical status or laboratory 
values are noted. 
 
7.1.3 Criteria for Protocol-Defined Required Discontinuation of 
Treatment 
The protocol requires discontinuation of study treatment for the 
following reasons: 
1.  Patient requests discontinuation. 
2.  Unacceptable toxicity that in the opinion of the investigator makes it 
unsafe to     continue therapy.  
3. Clinically significant progressive disease.  
4. Investigator discretion. 
5.  Patient death. 


 
 
HLH therapy in adults 
 
 
2014‐0989 
 
 
01/26/2018 
 
25
 
7.2 Follow-Up at Treatment Discontinuation or Early Withdrawal 
Patients who discontinue treatment for any reason before 24 weeks 
should complete end-of-treatment procedures within 30 days (+/- 7 days) 
of the last dose of the study drug, when possible. End of treatment 
procedures will include a physical examination, CBC with differential and 
platelets, IgG/IgA/IgM, lymphocyte subsets and a limited chemistry profile 
(total bilirubin, serum creatinine, SGPT or SGOT). A bone marrow 
aspiration may be recommended only if non-response or progressive 
disease cannot be unequivocally diagnosed from peripheral blood. 
Although treatment will be discontinued at that time, all patients who do 
not withdraw consent for follow-up, die, or become lost to follow-up, will 
remain on study for follow-up evaluations as follows: subject will be 
followed for toxicity for at least 30 days after the last protocol treatment. 
The 30-day follow-up visit will be scheduled as a clinic visits for clinical 
evaluation and physical examinations, when possible. If the patient cannot 
make it to the MDACC clinic for this visit, the required follow up treatment 
procedures may be done with a local physician and the records forwarded 
to MDACC. The research nurse will contact the patient by telephone and 
get a verbal assessment of the patient’s condition. The phone 
conversation will then be documented in the patient’s charts.  
 
7.3 Study Stopping Rules 
The principal investigator has the right to terminate this clinical study at 
any time. The principal investigator and MDACC IRB office will be involved 
in any decisions regarding terminating the study, temporarily suspending 
enrollment, or stopping ongoing treatment with study treatment. 
Reasons for terminating the clinical study include, but are not limited to, 
the following: 
 
The incidence or severity of an adverse reaction related to 
treatment in this study or other studies indicates a potential health 
hazard to patients 
 
Study site personnel are noncompliant with study procedures 
 
Pattern of noncompliance is observed 
 
7.4 Protocol Violations and Deviations 
Protocol violations are defined as significant departures from protocol-
required processes or procedures that affect patient safety or benefit 
potential, or confound assessments of safety or clinical activity. A protocol 
deviation is a departure from the protocol that does not meet the above 
criteria. Protocol violations or deviations may be grouped into the following 
classes: 
 
Enrollment criteria 
 
Study activities (missed evaluations or visits) except for those 
allowed per protocol 


 
 
HLH therapy in adults 
 
 
2014‐0989 
 
 
01/26/2018 
 
26
 
Noncompliance with dose or schedule, including dose calculation, 
administration, interruption, reduction, or delay; or discontinuation 
criteria 
 
Investigational product handling, including storage and 
accountability 
 
Informed consent and ethical issues 
 
8 
ADVERSE EVENT REPORTING 
     Please see appendix H for “Leukemia-specific Adverse Event Recording 
and Reporting Guidelines” 
 
9.0 ALEMTUZUMAB ADMINISTRATON GUIDELINES 
 
The following guidelines should be considered during the administration of 
alemtuzumab: 
 
 
Premedicate with diphenhydramine (50 mg) and acetaminophen (500 
mg to 1000 mg) 30 minutes prior to first infusion and each dose 
escalation. Institute appropriate medical management (e.g., steroids, 
epinephrine, meperidine) for infusion reactions as needed. 
 
 
Administer trimethoprim/sulfamethoxazole DS twice daily (BID) 3 times 
per week (or equivalent) as Pneumocystis jiroveci pneumonia (PCP) 
prophylaxis. 
 
 
Administer famciclovir 250 mg BID or equivalent as herpetic prophylaxis. 
 
 
Continue PCP and herpes viral prophylaxis for a minimum of 2 months 
after completion of alemtuzumab or until the CD4+ count is ≥200 cells/µL, 
whichever occurs later. 
 
• 
Administer as an IV infusion over approximately 2 hours 
 
• 
Do not administer as IV push or bolus 
 
• 
Gradually escalate to the maximum recommended single dose of 30 mg. 
Escalation is required at initiation of dosing or if dosing is held ≥7 days 
during treatment. 
 
• 
In clinical trials, the frequency of infusion reactions with alemtuzumab 
was highest in the first week of treatment. The following serious, including 
fatal, infusion reactions have been identified in post-marketing reports: 
syncope, pulmonary infiltrates, acute respiratory distress syndrome 
(ARDS), respiratory arrest, cardiac arrhythmias, myocardial infarction, 
acute 
cardiac 
insufficiency, 
cardiac 
arrest, 
angioedema, 
and 
anaphylactoid shock. Carefully monitor patients during infusions and 
withhold alemtuzumab for Grade 3 or 4 infusion reactions. 


 
 
HLH therapy in adults 
 
 
2014‐0989 
 
 
01/26/2018 
 
27
 
• 
Prolonged myelosuppression have been reported in patients receiving 
alemtuzumab. Alemtuzumab treatment results in severe and prolonged 
lymphopenia with a concomitant increased incidence of opportunistic 
infections. Assess CD4+ counts after treatment until recovery to ≥ 200 
cells/µL. Consider obtaining complete blood counts (CBC) at weekly 
intervals during alemtuzumab therapy and more frequently if worsening 
anemia, neutropenia, or thrombocytopenia occurs. Consider withholding 
alemtuzumab 
for 
severe 
or 
life-threatening 
cytopenias 
(except 
lymphopenia). Consider discontinuing alemtuzumab for autoimmune 
cytopenias 
or 
recurrent/persistent 
severe 
cytopenias 
(except 
lymphopenia). 
 
• 
Administer only irradiated blood products to avoid transfusion associated 
Graft versus Host Disease (TAGVHD), unless emergent circumstances 
dictate immediate transfusion. 
 
• 
Routinely monitor patients for CMV infection during alemtuzumab 
treatment and for at least 2 months following completion of treatment. 
Consider withholding alemtuzumab for serious infections and during 
antiviral treatment for CMV infection or confirmed CMV viremia. Initiate 
therapeutic ganciclovir (or equivalent) for CMV infection or confirmed CMV 
viremia [17]. 
 
• 
It is recommended to not administer live viral vaccines to patients who 
have recently received alemtuzumab 
 
10.0 RESPONSE EVALUATION 
 
There are no standardized response criteria for HLH. Marsh et al 
proposed 
a 
response 
evaluation 
schema 
for 
patients 
with 
relapsed/refractory HLH treated with alemtuzumab. We will use this 
response schema for evaluation of response to alemtuzumab in 
combination with etoposide and dexamethasone. As outlined in section 
6.2 (Evaluations during treatment) patients quantifiable symptoms and 
laboratory markers of HLH will be evaluated and recorded. Information to 
be recorded includes (but is not limited to) levels of soluble IL2R-alpha, 
ferritin, LDH, fibrinogen, and triglyceride; hemoglobin, neutrophil counts, 
platelet counts, AST, ALT, level of consciousness (documented in clinical 
exams in patients with CNS HLH), and presence of hemophagocytosis in 
pathology specimens. 
 
Complete response (CR) is defined as normalization to within 
institutional normal limits of diagnostic clinical and laboratory abnormalities 
associated with HLH, including but not limited to: fever, cytopenias, 
splenomegaly, hepatomegaly or lymphadenopathy, decreased fibrinogen, 
increased triglyceride, increased VLDL, increased sCD25, (optionally), 


 
 
HLH therapy in adults 
 
 
2014‐0989 
 
 
01/26/2018 
 
28
elevated 
bilirubin, 
elevated 
liver 
enzymes, 
hyponatremia, 
hypoalbuminemia, 
elevated 
CNS 
proteins 
or 
mononuclear 
cells/lymphocytes and CNS symptoms. In the case of ferritin, 
normalization OR a 3 fold improvement in the pre-study level will be 
evidence of complete response, provided the post therapy level is also 
below 10000 ng/ml. It is also recognized that hemoglobin and platelet 
counts may be artificially increased with transfusion or may remain low in 
patients with underlying malignancy/recent myelotoxic chemotherapy and 
may not be immediately assessable.  
 
Partial response (PR) is defined as sustained normalization of 3 or more 
of the diagnostic clinical and laboratory abnormalities noted above  (or, 
with ferritin, improvement as described above) and no apparent 
progression of other aspects of disease pathology.  
 
Parameter improvements (PI) is defined as at least a 25% improvement 
in two or more quantifiable symptoms and/or laboratory markers from 
those mentioned above within 8 weeks (+/- 7 days) of initiation of therapy 
with the following caveats: soluble IL-2 receptor response was defined as 
a greater than 1.5-fold decrease. For patients with initial platelet count 
<50,000 a response was defined as an increase in platelets of at least 
100% AND a platelet count >50K in the absence of a transfusion within 7 
days. For patients with initial platelet count >50,000 a response was 
defined as an increase in platelets of at least 100%. Responses based on 
hemoglobin were not used to determine response as these are often 
confounded by transfusions. For patients with an initial ANC of less than 
500, a response was defined as an increase of ANC by at least 100% to 
greater than 500 cells/µl. For patients with an ANC 500–2,000 cells/µl, an 
increase by at least 100% to more than 5,000 cells/µl was considered a 
response. For patients with transaminitis with an ALT greater than 400, an 
ALT response was defined as a decrease of ALT of at least 50%. For 
patients with hemophagocytosis noted on a biopsy specimen within 28 
days of therapy initiation, a response was defined as resolution of 
hemophagocytosis following alemtuzumab. For patients with refractory 
CNS HLH and altered level of consciousness, a response was defined as 
a normal level of consciousness following therapy. For patients who died 
or started preparative regimens for HSCT prior to completing 8 weeks on 
therapy, the last known values were used for evaluation of response. 
 
Reactivation is defined as worsening of two or more HLH-defining 
clinical/laboratory parameters with the following specifications. Numerical 
laboratory values must become abnormal and worsen by >30%, on two 
sequential assessments abnormal and worse by >30% on 2 assessments 
performed on different days). Worsening in clinical criteria (fever, 
splenomegaly, etc.) may also be considered, provided that consistent 
observations of worsening are made over at least three days. Additionally, 
recurrent CNS symptoms felt to be due to HLH may count as a criteria for 


 
 
HLH therapy in adults 
 
 
2014‐0989 
 
 
01/26/2018 
 
29
reactivation. Patients (who previously responded) may also be considered 
to have reactivated if they die prior to a second sequential assessment of 
rising disease markers, and the proximal cause of death was deemed by 
the treating physician to be active HLH (on clinical or pathological 
grounds). Assessment of NK function will not be considered for 
determination of relapse because disease activity and NK function do not 
correlate in most patients and may be inversely correlated in some 
patients 
 
Diagnostic criteria not utilized in assessment of response included 
fibrinogen, as this was not checked consistently in patients; fever, 
because information was often lacking or difficult to interpret; and liver and 
spleen size, as examinations and imaging results were not consistently 
documented. Cerebrospinal fluid (CSF) testing results were not analyzed 
in patients with CNS HLH because sampling was inconsistent. 
 
11.0 STATISTICAL CONSIDERATIONS  
 
This will be a single arm, single center, open label study of alemtuzumab 
or tocilizumab in combination with etoposide and dexamethasone in 
patients with HLH.  
 
11.1 Sample Size 
 
Up to a total of 40 patients will be recruited for this Phase II study to 
receive either alemtuzumab in combination with 
etoposide+dexamethasone or tocilizumab in combination with 
etoposide+dexamethasone. Patients will be allocated to receive the 
tocilizumab or the alemtuzumab arm based on the clinical presentation of 
the HLH, comorbid conditions, underlying organ function, and PI/treating 
physician decision. The patients may not be equally allotted to Arm 1 and 
2. The goal of the study is not to compare between Arms 1 and 2 but to 
evaluate whether the addition of a biologic agent (alemtuzumab or 
tocilizumab) improves the response rate and outcomes in adult patients 
with HLH as compared to etoposide+steroid alone. 
 
The primary objective of the phase II is to determine the efficacy of 
alemtuzumab/tocilizumab in combination with etoposide and 
dexamethasone in patients with HLH. The efficacy of the combination will 
be measured by the overall response rate (ORR), defined as CR and/or 
PR and/or PI within 8 weeks (+/- 7 days) of treatment initiation among 
patients with HLH. ORR and toxicity will be monitored simultaneously 
using the Bayesian approach of Thall, Simon, Estey (1995, 1996) and the 
extension by Thall and Sung (1998).  
 
11.2 
Statistical Design 


 
 
HLH therapy in adults 
 
 
2014‐0989 
 
 
01/26/2018 
 
30
There is no standard therapy or historical data regarding response rates in 
adult patients with HLH. The target ORR with the experimental treatment in 
HLH is 20%. This regimen of the combination treatment will be considered 
worthy of further investigation if it elicits an increase in ORR to 30% with 
acceptable toxicity.  A >30% drug-related grade 3/4 toxicity rate is 
considered unacceptable.  Thus, interim monitoring rules, assuming the prior 
distributions below, were constructed that meet the following two conditions, 
1) Stop if Prob{ p(ORR,E )<p(ORR,H)  + 0.10 | data> 0.975, or 
2) Stop if Prob{ p(TOX,E)>0.30| data}>0.975,  
where P(ORR, E) and P(TOX, E) are the true ORR and toxicity rates for the 
combination treatment, and p(ORR, H) is the true ORR rate of the standard 
treatment. The first rule provides for stopping the study if the data suggest 
that it is unlikely (i.e., probability < 2.5%) that ORR rate of the combination 
treatment is greater than the ORR rate of standard treatment by 10.0%. The 
second condition will stop the study early if excessive therapy-related grade 
3/4 toxicity (>30%) is highly probable (i.e., probability >97.5%) for the 
combination treatment.  Monitoring for toxicity and futility will not begin until 5 
patients have been evaluated, and cohort size for future evaluations is 5. 
The monitoring rule for the toxicity rate, based on these assumptions and 
monitoring conditions above is found in Table 5. For example, accrual will 
cease if 4 or more patients experience toxicities among the first 5 patients. 
 
Table 5. Stop accrual if the number of drug-related clinically significant non-
hematological grade 3/4 toxicities (CTC version 4.3, appendix C) is greater than 
or equal to indicated (i.e., # patients with toxicities) among the number of patients 
evaluated 
# patients 
evaluated  
5 
10 
15 
20 
25 
30 
35 
40 
# patients with 
toxicities 
4-5 
7-
10 
9-
15 
11-
20 
13-
25 
15-
30 
17-
35 
Always stop 
with  
this many 
patients 
Monitoring the ORR rate, based on the above assumptions and monitoring 
conditions is found in Table 6.  For example, accrual will cease if less than 1 
patients experience an overall response within 8 weeks (+/-7 days) of 
initiation of therapy in the first 20 patients treated. 
 
Table 6. Stop accrual if the number with overall response is less than or equal to 
indicated (i.e., # patients with overall response) among the number of patients 
evaluated 
# patients evaluated  
5 
10-
15 
20-
25 
30 
35 
40 
# patients with overall 
response 
Never stop 
with  
0 
0-1 
0-2 0-3 
Always stop  
with 


 
 
HLH therapy in adults 
 
 
2014‐0989 
 
 
01/26/2018 
 
31
this many 
patients 
this many 
patients 
Multc Lean Desktop (version 2.1.0) was used to generate the toxicity and 
futility stopping boundaries and the OC table (Table 7). In order to utilize the 
software for the design, a constant rate of 10% and beta (0.2, 1.8) priors and 
delta of 10% were assumed for the standard treatment response distribution 
and experimental treatment response prior distribution, respectively. In 
addition, a 30% toxicity constant rate and beta (0.6, 1.4) priors were 
assumed for the standard treatment toxicity constant rate and experimental 
treatment toxicity prior distribution, respectively. 
 
The probability of stopping the study early if the true ORR of the combination 
treatment was 20% and the true toxicity rate was 30% was 21.7%.  
Probabilities of stopping early for high true toxicity rates (i.e., 50%) were 
76.6% when the true ORR was 20% and 73.0% when true ORR rate was 
30%. 
 
Table 7.  Operating characteristics for simultaneous monitoring response and 
toxicity rates for patients treated with combination treatment 
True Toxicity Rate 
True ORR 
Prob(stop the trial early) 
0.10 
0.10 
0.6446 
 
0.15 
0.3460 
 
0.20 
0.1635 
 
0.25 
0.0741 
 
0.30 
0.0335 
0.20 
0.10 
0.6473 
 
0.15 
0.3510 
 
0.20 
0.1698 
 
0.25 
0.0811 
 
0.30 
0.0408 
0.30 
0.10 
0.6672 
 
0.15 
0.3875 
 
0.20 
0.2166 
 
0.25 
0.1329 
 
0.30 
0.0948 
0.40 
0.10 
0.7542 
 
0.15 
0.5476 


 
 
HLH therapy in adults 
 
 
2014‐0989 
 
 
01/26/2018 
 
32
Table 7.  Operating characteristics for simultaneous monitoring response and 
toxicity rates for patients treated with combination treatment 
True Toxicity Rate 
True ORR 
Prob(stop the trial early) 
 
0.20 
0.4213 
 
0.25 
0.3595 
 
0.30 
0.3314 
0.50 
0.10 
0.9008 
 
0.15 
0.8174 
 
0.20 
0.7664 
 
0.25 
0.7414 
 
0.30 
0.7301 
 
Statistical Analysis Plan 
All patients who received any dose of the study agent will be included in the 
analysis for efficacy and safety. Demographic/clinical characteristics 
(including duration of response) and safety data of the patients will be 
summarized using descriptive statistics such as mean, standard deviation, 
median and range. For the primary efficacy analysis, we will estimate the 
ORR for the combination treatment, along with the 95% credible interval. 
Patients who drop out of the study before completing the cycles within 8 
weeks +/- 7 days will be treated as “failures” for the primary analysis if they 
do not have a response evaluation. The association between ORR and 
patient’s clinical characteristics will be examined by Wilcoxon’s rank sum test 
or Fisher’s exact test, as appropriate. Toxicity type, severity and attribution 
will be summarized for each patient using frequency tables.  
The distribution of time-to-event endpoints (DFS and OS) including overall 
survival and progression free survival will be estimated using the method of 
Kaplan and Meier. Comparisons of time-to-event endpoints by important 
subgroups will be made using the log-rank tests. Paired t-tests will be used 
to determine the immunological and molecular changes in the peripheral 
blood and bone marrow from baseline to the time of response, and to the 
time of disease progression.  
Statistical analysis of biomarker data: Descriptive statistics including plots, 
mean, median and standard deviations will be used to summarize data. For 
continuous outcomes, t-test and ANOVA will be used to compare outcome 
measures across patient characteristics. Dunnett’s and Tukey’s test that 
properly adjust for multiplicity in multiple tests will be implemented. Pair-wise 
comparisons will be performed using pre- and post-therapy samples from 
each patient. The chi-square test or Fisher’s exact test will be used to test 
the association between two categorical variables such as disease state and 


 
 
HLH therapy in adults 
 
 
2014‐0989 
 
 
01/26/2018 
 
33
performance status. Both univariate and multivariate logistic regressions will 
be performed to model prognostic factors. 
 
12.0 PROTOCOL ADMINISTRATION 
This study will be monitored by the MD Anderson Leukemia 
Department and a protocol-specific monitoring plan will be followed. 
 
Protocol amendments 
 
Changes to the protocol will be made only when protocol 
amendments have been signed by the principal investigator and 
approved by the sponsor and the IRB of the study center. 
 
Archival of data 
 
All patient data (including source data) generated in connection 
with this study will be kept in the archives of the MDACC for at least 
15 years after the study has been completed. All data will be 
available for inspection by company representatives of the Medical 
Department 
 
13.0    REFERENCES 
 
1. 
Jordan MB, Allen CE, Weitzman S, et al. How I treat hemophagocytic 
lymphohistiocytosis. Blood 2011;118:4041-4052. 
2. 
Henter JI, Horne A, Arico M, et al. HLH-2004: Diagnostic and therapeutic 
guidelines for hemophagocytic lymphohistiocytosis. Pediatric blood & cancer 
2007;48:124-131. 
3. 
Henter JI, Arico M, Elinder G, et al. Familial hemophagocytic 
lymphohistiocytosis. Primary hemophagocytic lymphohistiocytosis. 
Hematology/oncology clinics of North America 1998;12:417-433. 
4. 
Janka G, Imashuku S, Elinder G, et al. Infection- and malignancy-associated 
hemophagocytic syndromes. Secondary hemophagocytic lymphohistiocytosis. 
Hematology/oncology clinics of North America 1998;12:435-444. 
5. 
Janka GE. Familial hemophagocytic lymphohistiocytosis. European journal of 
pediatrics 1983;140:221-230. 
6. 
Henter JI, Ehrnst A, Andersson J, et al. Familial hemophagocytic 
lymphohistiocytosis and viral infections. Acta paediatrica 1993;82:369-372. 
7. 
Fisman DN. Hemophagocytic syndromes and infection. Emerging infectious 
diseases 2000;6:601-608. 
8. 
Henter JI, Arico M, Egeler RM, et al. HLH-94: a treatment protocol for 
hemophagocytic lymphohistiocytosis. HLH study Group of the Histiocyte Society. 
Medical and pediatric oncology 1997;28:342-347. 
9. 
Jordan MB, Hildeman D, Kappler J, et al. An animal model of hemophagocytic 
lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the 
disorder. Blood 2004;104:735-743. 


 
 
HLH therapy in adults 
 
 
2014‐0989 
 
 
01/26/2018 
 
34
10. 
Ohga S, Matsuzaki A, Nishizaki M, et al. Inflammatory cytokines in virus-
associated hemophagocytic syndrome. Interferon-gamma as a sensitive indicator of 
disease activity. The American journal of pediatric hematology/oncology 1993;15:291-
298. 
11. 
Akashi K, Hayashi S, Gondo H, et al. Involvement of interferon-gamma and 
macrophage colony-stimulating factor in pathogenesis of haemophagocytic 
lymphohistiocytosis in adults. British journal of haematology 1994;87:243-250. 
12. 
Fujiwara F, Hibi S, Imashuku S. Hypercytokinemia in hemophagocytic syndrome. 
The American journal of pediatric hematology/oncology 1993;15:92-98. 
13. 
Henter JI, Elinder G, Ost A. Diagnostic guidelines for hemophagocytic 
lymphohistiocytosis. The FHL Study Group of the Histiocyte Society. Seminars in 
oncology 1991;18:29-33. 
14. 
Henter JI, Samuelsson-Horne A, Arico M, et al. Treatment of hemophagocytic 
lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow 
transplantation. Blood 2002;100:2367-2373. 
15. 
Marsh RA, Allen CE, McClain KL, et al. Salvage therapy of refractory 
hemophagocytic lymphohistiocytosis with alemtuzumab. Pediatric blood & cancer 
2013;60:101-109. 
16. 
Hillmen P, Skotnicki AB, Robak T, et al. Alemtuzumab compared with 
chlorambucil as first-line therapy for chronic lymphocytic leukemia. Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology 2007;25:5616-
5623. 
17. 
O'Brien SM, Keating MJ, Mocarski ES. Updated guidelines on the management 
of cytomegalovirus reactivation in patients with chronic lymphocytic leukemia treated 
with alemtuzumab. Clinical lymphoma & myeloma 2006;7:125-130.