Double hit and Triple hit (DL & TL)

Double-hit lymphoma (DHL) and triple-hit lymphoma (THL) or also known as ‘high grade B-cell lymphoma’ are aggressive (fast-growing) lymphomas with signs and symptoms that may be similar to those of diffuse large B-cell lymphoma.  Other features include both diffuse large B-cell lymphoma and Burkitt lymphoma and are unclassifiable into a specific type of high-grade B-cell lymphoma.

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Double-hit & triple-hit lymphoma fact sheet

Overview of double-hit lymphoma (& triple-hit lymphoma)

Double-hit lymphoma (DHL) and triple-hit lymphoma (THL) or also known as ‘high grade B-cell lymphoma’ are aggressive (fast-growing) lymphomas with signs and symptoms that may be similar to those ofdiffuse large B-cell lymphoma.  Other features include both diffuse large B-cell lymphoma and Burkitt lymphoma and are unclassifiable into a specific type of high-grade B-cell lymphoma. 

Double-hit lymphoma (DHL) occurs in around 5-10% of all people who are diagnosed with diffuse large B-cell lymphoma (DLBCL). Triple-hit lymphoma (THL) accounts for around 2% of all diffuse large B-cell lymphomas. 

Double-hit lymphoma (DHL) is a subtype of B-cell NHL formally called “High Grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6”. It is characterised by rearrangements (parts of genes switch places within chromosomes) in two particular genes.  One rearrangement involves the MYC gene, and the other involves the BCL2 gene or, less commonly, the BCL6 gene.  

Triple-hit lymphoma (THL): is a rarer subtype of B-cell NHL, where rearrangements are present in all three genes (MYC, BCL2 and BCL6) and the condition is called ‘triple-hit lymphoma’. 

These changes are usually detected only if the pathologist is asked to check, using a specialist test called FISH (fluorescence in-situ hybridisations) to confirm a diagnosis of double-hit lymphoma.

The normal role of these important genes in cell regulation includes:

  • MYC gene regulates approximately 15% of human genes and has a role in the progression of the cell cycle, apoptosis (programmed cell death) and cellular result in rapid growth of lymphoma cells
  • BCL2 gene regulates cell death (apoptosis) by either inducing it or inhibiting it. In DHL, the changes in this gene result in an anti-apoptotic effect in lymphoma cells, leading to their prolonged survival.
  • BCL6 gene has a role in regulating activation, survival, DNA damage response and cell cycle arrest. 

They do however act differently in certain ways and more resistant, therefore they have been categorized as their own subtype.  Double-hit lymphoma and triple-hit lymphoma often start in extranodal sites (outside the lymph nodes).  They seem to behave more aggressively than the more common diffuse large B-cell lymphoma (DLBCL) and may need more intensive treatment.

What is double-expressor lymphoma?

Double expresser lymphoma (DEL) is an aggressive (fast-growing) B-cell non-Hodgkin lymphoma (NHL). Double expresser lymphoma (DEL) is different from double-hit lymphoma (DHL) and is a subtype of diffuse large B-cell lymphoma (DLBCL).  Double-expressor lymphoma (DEL) has increased expression of MYC and BCL2 proteins not related to underlying chromosomal rearrangements.

This does not imply that a patient has double-hit lymphoma (DHL) and these double expresser lymphomas (DEL) generally are thought to have a better prognosis, although worse to standard diffuse large B-cell lymphoma.  

There is not a standard treatment for DEL either and often doctors will treat with more intense immunochemotherapy as they do DHL.

Treatment and prognosis

There is a poorer prognosis when treated with standard chemoimmunotherapy, that is used in the treatment of diffuse large B-cell lymphoma, and so can be treated with more intense treatments.  Because double-hit and triple-hit lymphoma are fairly new classifications of lymphoma, ongoing research is helping doctors learn more about the best ways to treat this disease.  

Who is affected by double-hit lymphoma (DHL) & triple-hit lymphoma (THL)?

Double-hit lymphoma (DHL) occurs in around 5-10% of all people who are diagnosed with diffuse large B-cell lymphoma (DLBCL)Triple-hit lymphoma (THL) accounts for around 2% of all diffuse large B-cell lymphomas. DHL/THL often develop in older people, aged over 60 years.  

Double-hit lymphoma (DHL) and triple-hit lymphoma (THL) may occur in people with a history of indolent (slower growing) lymphoma, called follicular lymphoma. This is known as transformed lymphoma (changes to a fast-growing lymphoma over time). 

Symptoms of double-hit (DHL) 

Double-hit lymphoma (DHL) or triple-hit lymphoma (THL) can start anywhere in the body and can have many different symptoms.  They often start in extranodal sites (outside of the lymph nodes). The exact symptoms they cause depend on the type of lymphoma and where it is located in the body. 

About half of all people with double-hit or triple-hit lymphoma have lymphoma in the bone marrow.  Around 10% have symptoms caused by lymphoma in their central nervous system (brain and spinal cord).  Most people have advanced stage disease at diagnosis.

Most symptoms of lymphoma can also be symptoms of many other illnesses. Because the symptoms can be very general, it can be hard to diagnose. Most common symptoms include:

  • Painless lumps in the neck, groin or armpit, that are enlarged lymph nodes. 
  • Fatigue (tiredness or lack of energy)
  • Loss of appetite

B symptoms are what doctors call the following symptoms and can include:

  • Night sweats (drenching sleepwear & bedding)
  • Persistent fevers (especially at night (>38C)
  • Unexplained weight loss
  • Itchy skin

Diagnosis and Staging 

biopsy is always required for diagnosis of lymphoma. A biopsy is a surgical procedure to remove part of or all of an affected lymph node or other tissue to look under the microscope by a pathologist to see what the cells look like.  The biopsy can be done under local or a general anaesthetic depending on what part of the body is being biopsied. The biopsy can be one of three ways:

  • Fine needle aspirate
  • Core needle biopsy
  • Excisional node biopsy

An excisional node biopsy is the best investigative option, as it collects the most adequate amount of tissue to be able to do the necessary testing for a diagnosis.

Waiting for results can be a difficult time.  It may help to talk to family, friends or a specialist nurse. 

For more info see
Tests, Diagnosis and Staging

Staging

There are four stages from stage 1 (lymphoma in one area) through to stage 4 (lymphoma that is widespread). 

  •  Early stage means stage 1 and some stage 2 lymphoma.  This can also be referred to as ‘localised’.  Stage 1 or 2 means that the lymphoma is found in one area or a few areas close together.
  • Advanced stage means the lymphoma is stage 3 and stage 4, and it is widespread.   In most cases, the lymphoma has spread to many parts of the body that are far from each other.  

DHL and THL are often diagnosed at an advanced stage.

What is the ‘grade’ of lymphoma?

Lymphomas are also often grouped as either indolent or aggressive.  Indolent lymphomas are usually slow growing and aggressive lymphomas are fast growing.  The grade is also referred to as the clinical behaviour of the lymphoma.   

Double/triple-hit lymphoma is a high-grade lymphoma.  

It is important to know the stage and grade of the lymphoma

Staging scans and tests

The scans and tests needed for staging and before treatment can start may include:

  • Positron emission tomography (PET) scan 
  • Computed tomography (CT) scan 
  • Bone marrow biopsy 
  • Lumbar puncture & magnetic resonance imaging (MRI) – If lymphoma is suspected in the brain or spinal cord

Patients may also undergo a number of baseline tests prior to any treatment commencing to check organ functions.  These are often repeated during and after the treatment has completed to assess whether the treatment has affected the functioning of organs.  Sometimes the treatment and follow-up care may need to be adjusted to help manage side effects. These may include:

  •  Physical examination
  •  Vital observations (blood pressure, temperature, & pulse rate)
  •  Heart scan
  •  Kidney scan
  •  Breathing tests
  •  Blood tests

It may take some time for all the necessary biopsies and tests to be done (an average of 1-3 weeks), but it is important for the doctors to have a complete picture of the  lymphoma and the general  health of the patient  in order to make the best treatment decisions 

Many of the staging and organ function tests are done again after treatment to check whether the lymphoma treatment has worked and the effect this has had on the body.

It is important to note that lymphoma is what is known as a systemic cancer.  It can spread throughout the lymphatic system and nearby tissue and organs.  Many patients are diagnosed at an advanced stage and the lymphoma can still be successfully treated.  Lymphoma is very unlike advanced stage solid tumour cancers, such as bowel or lung cancer.

For more info see
Staging Scans & Tests

Prognosis of double-hit (DHL)

There is a poorer prognosis when treated with standard chemoimmunotherapy, that is used in the treatment of diffuse large B-cell lymphoma.  Prognosis will also depend on many individual factors that the doctor will discuss with the patient, when deciding on the best treatment. Because double-hit or triple-hit lymphoma is a fairly new classification of lymphoma, ongoing research is helping doctors learn more about the best ways to treat this disease.  

Treatment for double-hit (DHL)

Once all the results from the biopsy and the staging scans have been completed, the doctor will review these to decide the best possible treatment for a patient.   At some cancer centres, the doctor will also meet with a team of specialists to discuss the best treatment and this is called a multidisciplinary team (MDT) meeting.  

Doctors take into consideration many factors about the lymphoma and the patient’s general health to decide when and what treatment is required. This is based on:

  • The stage of lymphoma
  • Symptoms (including the size and location of the lymphoma) 
  • How the lymphoma is affecting the body
  • Age
  • Past medical history & general health
  • Current physical and mental wellbeing
  • Patient preferences

Before treatment is started it is important that adequate information is provided about the treatment that is planned, the possible side effects and what to expect.  Education from the cancer nurses prior to receiving treatment, can be extremely helpful and should include instructions about becoming unwell or needing medical or nursing assistance.

As double-hit or triple-hit lymphoma are highly aggressive (fast-growing) treatment will need to start soon after diagnosis.  The standard first line treatments for DHL and THL may include one of the following:

  • DA-EPOCH-R (dose adjusted etoposide, prednisolone, vincristine, doxorubicin and rituximab)
  • R- Hyper CVAD (rituximab, hyper-fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with high dose methotrexate and cytarabine)
  • R- CODOX-M (rituximab, cyclophosphamide, vincristine, doxorubicin, methotrexate alternating with rituximab, ifosfamide, etoposide and cytarabine)
  • Autologous stem cell transplant (AuSCTmay be offered to patients in first remission to consolidate the response to the initial chemotherapy and aim to increase the chance of making the lymphoma go away for good
  • Radiotherapy for some people generally after chemotherapy, typically with limited stage disease
  • Intrathecal chemotherapy: DHL is thought to more commonly relapse in the central nervous system (CNS) than other lymphomas, so patients may receive a medication to prevent this called CNS prophylaxis, to reduce this risk. This involves chemotherapy such as methotrexate and/or cytarabine administered by a lumbar puncture by a doctor to inject directly into the cerebrospinal fluid surrounding the brain and spinal cord. 
  • Clinical trial participation
For more info see
Treatment of Lymphoma

Common side effects of treatment

There are many different side effects of the treatment and these are dependent on the treatment that has been given.  The treating doctor and/or cancer nurse can explain the specific side effects prior to the treatment.  Some of the more common side effects of treatment may include:

Some of the more common side effects of treatment for DHL/THL (not all) include:

  • Anaemia (low red blood cells that carry oxygen to your body)
  • Thrombocytopenia (low platelets to help bleeding and clotting)
  • Neutropenia (low white blood cells that fight infection)
  • Nausea and vomiting
  • Bowel problems such as constipation and diarrhoea
  • Fatigue (tiredness and lack of energy)
  • Reduced fertility

The medical team, doctor, cancer nurse or pharmacist, should provide information about:

  • What treatment will be given
  • What are the common and possible side effects for the treatment 
  • What side effects do you need to report to the medical team
  • What are the contact numbers, and where to attend in case of emergency 7 days a week and 24 hours per day  

If not, please ask these questions before you leave the cancer treatment after the first treatment has been completed.

For more info see
Side effects of treatment

Fertility preservation

Some treatments for lymphoma can reduce fertility and this is more likely with certain chemotherapy protocols (combinations of drugs) and high-dose chemotherapy used before a stem cell transplant Radiotherapy to the pelvis also increases the likelihood of reduced fertility.  Some antibody therapies may also affect fertility, but this is less clear.  

The doctor should advise on whether fertilitymay be affected or whether fertility preservation should be done before the start of treatment. 

Follow-up care 

Once treatment has completed, post treatment staging scans are done to review how well the treatment has worked.  The scans will show the doctor if there has been a:

  • Complete response (CR or no signs of lymphoma remain) or a
  • Partial response (PR or there is still lymphoma present, but it has reduced in size)

If all goes well regular follow-up appointments will be made for every 3-6 months to monitor the below:  

  • Review the effectiveness of the treatment
  • Monitor any ongoing side effects from the treatment
  • Monitor for any late effects from treatment over time
  • Monitor signs of the lymphoma relapsing

These appointments are also important so that the patient can raise any concerns that they may need to discuss with the medical team. A physical examination and blood tests are also standard tests for these appointments.  Apart from immediately after treatment to review how the treatment has worked, scans are not usually done unless there is a reason for them. For some patient’s appointments may become less frequent over time

Relapsed or refractory double-hit lymphoma (DHL)

Double-hit lymphoma (DHL) usually responds well to immunochemotherapy.  Second-line treatment that can be successful include:

  • Salvage chemotherapy with ICE-R, (ifosfamide, cyclophosphamide and rituximab)
  • Autologous stem cell transplant (AuSCT)
  • Chimeric antigen receptor (CAR) T-cell Therapy (after 2 or more previous lines of treatment)
  • Combination of other chemotherapy
  • Clinical trial participation

If a relapse is suspected another biopsy need to be done often with the same staging tests that were explained above in the staging section. 

For more info see
Relapsed and Refractory Lymphoma

Treatment under Investigation for double-hit (DHL) 

Many new individual and combination medicines are currently being tested in clinical trials in Australia and around the world for both newly diagnosed and relapsed or refractory double-hit lymphoma (DHL) or triple-hit lymphoma (THL) including:

  • Chimeric antigen receptor T-cell therapy (CAR-T cell therapy)
  • Bispecific antibody therapy
  • Small molecule inhibitors of BCL2 such as Venetoclax (with DA-EPOCH-R)
  • Ibrutinib (ImbruvicaTM), bendamustine and rituximab

For the most current information on treatment under investigation see double-hit & triple-hit lymphoma fact sheet PDF

For more info see
Understanding Clinical Trials

What happens after treatment?

 Late Effects  

Sometimes a side effect from treatment may continue or develop months or years after treatment has completed.

Finishing treatment

This can be a challenging time for many people and some of the common concerns can be related to:

  • Physical
  • Mental wellbeing
  • Emotional health
  • Relationships
  • Work, study and social activities
For more info see
Finishing Treatment

Health and wellbeing

A healthy lifestyle, or some positive lifestyle changes after treatment can be a great help after the treatment has been finished.  Making small changes such as eating and increasing fitness can improve health and wellbeing and help the body to recover.  There are many self-care strategies that can help during the recovery phase. 

For more info see
Health & Wellbeing

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