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.

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.

Inclusion Criteria:

1. Sign an IRB-approved informed consent document.
2. Patients must be >/= 18 years of age.
3. • 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.
4. Continued from No. 3: 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.
5. Organ function as defined below (unless due to the HLH process): Serum creatinine \