Episode 074: Management of Advanced Stage Diffuse Large B-Cell Lymphoma (DLBCL)

medicine
Written By TheFellowOnCall HemeOncPodcast

In this week’s episode, we delve into the management of advanced stage DLBCL. 

If you have not done so, we highly recommend you listen to our hemepath series before proceeding with this episode.

Furthermore, if you have not listened to the introduction to DLBCL episode (Episode 072) or our early stage DLBCL episode (Episode 073), we highly recommend doing so, as we will be building on these basics this week.

Recap of diagnostic workup for a patient with suspected lymphoma: 

  • Physical exam focusing on evaluation of lymphadenopathy in the neck, supraclavicular, axillary, and inguinal nodes will be key. 

  • Remember to consult surgery early for consideration of excisional lymph node biopsy or alternatively get the procedural radiology team involved early for an ultrasound guided core biopsy. Don’t wait for a PET scan to do this. 

  • Baseline LDH and TLS labs (BMP, phosphate, uric acid) 

  • Obtain baseline transthoracic echo and hepatitis B-panel given implications on treatment options 

  • PET/CT for staging purposes if this is feasible in a timely manner. 

Recap of risk stratification in newly diagnosed DLBCL: 

  • Important to distinguish between early stage and advanced stage with PET/CT

  • Advanced stage is defined by:

    • Involvement of nodes above and below the diaphragm (stage III) or

    • Extensive or multiple sites of extranodal involvement that can’t be encompassed in one radiation field (stage IV)

    • Of note, the spleen is considered a nodal organ but the bone marrow is considered an extranodal site upstaging to stage IV

  • If FDG-avid marrow, this is going to upstage the patient and a bone marrow biopsy will not change management

  • Using the workup described here, we calculate the patient’s IPI score with the mnemonic APLES: Age, Performance Status, LDH, Extranodal disease, Staging

    • The IPI is very important for prognostication and can influence our treatment decisions like the use of CNS prophylaxis which we will discuss in this episode.

Recap of high risk features on pathology report:

  • Using IHC and FISH testing, we can also further risk stratify patients.

  • Germinal-center B subtype (GCB) vs. non-GCB:

    • Can be determined using Hans algorithm discussed in Episode 072

    • Recall that non-GCB has a worse prognosis than GCB.

    • Also remember that patients with CD10+ and Ki67 was 100%, we should always assume Burkitt until proven otherwise

  • Using IHC, we can determine if someone is a “double expressor,” meaning they are IHC positive for MYC and BCL-2. This is prognostic, but does not change management.

  • Using FISH, we determine if someone is truly high risk:

    • High grade B cell lymphoma is characterized by rearrangement in MYC and BCL-2 or BCL-6. It’s called double hit if you have MYC and one other or triple hit if you have all three. We simplified by calling these high grade B cell lymphoma which have the worst prognosis and have a different treatment strategy. 

    • If you ever forget, remember that the 8 ball is the most important ball in pool and MYC is the most important gene rearrangement located on chromosome 8!

    • BCL-6 is on chromosome 3 because it affects 3 proteins

    • BCL-2 is on chromosome 18 with characteristic t(14;18)

 

Treatment approach to patients with high grade B-cell lymphoma:

  • Some historical perspective:

    • In the 1970’s and 1980’s, combination chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) was the standard of care.

    • We discussed the use of radiotherapy last week for early stage disease but in general patients were given 8 cycles of therapy historically. 

    • In the 1980’s and 1990’s, there were several attempts to beat CHOP with more intensive regimens. The thought process was that more was better.

      • Famously, in the 1980’s the NCI developed an intensive regimen called Pro-MACE-CytaBOM and had very impressive results in their single center experience

    • In 1993, CHOP was compared to more intensive approaches including Pro-MACE-CytaBOM in a phase III RCT run by the SWOG cooperative group

      • No difference in PFS or OS

      • Way more toxicity

  • CHOP remained the standard of care with the conclusion that we need to have smarter drugs not more drugs 

  • Finally after 30 years as the standard of care, R-CHOP x 8 cycles was compared to CHOP x 8 cycles in a phase III RCT published in NEJM 2002

    • Trial run by the GELA cooperative group in Europe

    • Included patients who were 60 and older

    • Found that R-CHOP was superior to CHOP for CR, PFS, and OS

  • There was a similar trial run by the US cooperative groups looking at R-CHOP vs. CHOP for older patients published in JCO 2005

    • You will see this called an Intergroup Trial because multiple cooperative groups were involved 

    • One key difference from the European trial was that many patients got 6 cycles of R-CHOP instead of 8 cycles

  • This also looked at the use of maintenance rituximab q6month x 2 years after chemotherapy at a second randomization

    • R-CHOP was superior to CHOP

    • There was no difference between 6 vs. 8 cycles of therapy

    • There was no benefit found for maintenance rituximab if using R-CHOP as a front line treatment

    • This trial solidified R-CHOP x 6 cycles as the standard of care in the US without the need for maintenance rituximab

What is the difference between lymphoma trials incorporating R-CHOP14 versus R-CHOP21 regimens?

  • After CHOP was finally beaten by R-CHOP, researchers thought that potentially dose dense R-CHOP given every 14 days with G-CSF support might be better than standard R-CHOP which is given every 21 days.

  • There were two phase 3 randomized trials that compared R-CHOP14 to R-CHOP21:

    • One trial from the GELA group and one trial from a UK group

    • Both trials showed no difference in PFS or OS

  • This is why we always use R-CHOP21 as our standard regimen

 

What is the approach to a patient with advanced stage disease (without high risk FISH abnormalities)?

  • For patients with IPI of 0-1, R-CHOP x 6 cycles is the way to go and this can include our bulky stage II patients who can’t get the less intensive strategies we discussed last week.

  • For patients with IPI of 2 or higher, we use Pola-R-CHP (below)

 

What is polatuzumab-vedotin? How do we incorporate this into treatment of patients with advanced stage DLBCL?

  • Polatuzumab-vedotin which is an antibody-drug conjugate to CD79b, which is universal component of the B cell receptor found in mature B cell lymphomas

  • The payload is vedotin which is a potent microtubule agent so think neuropathy as a big side effect as well as neutropenia

    • Important to note that G-CSF is required for polatuzumab based regimens

  • It was originally used in the relapsed refractory setting with rituxmab and with bendamustine + rituximab with ORR in the 50-60% range

  • There was then a Phase 1B-2 trial with a regimen of Pola-R-CHP for newly diagnosed DLBCL that had promising results. The polatuzumab replaces vincristine in R-CHOP to prevent severe neuropathy

  • This led to the phase III POLARIX trial which was published in NEJM 2022

    • Included over 800 patients with all stages of DLBCL and IPI of 2 or higher

    • Randomized to Pola-R-CHP x 6 cycles vs. R-CHOP x 6 cycles followed by 2 cycles of maintenance rituximab in both groups

    • Both arms received G-CSF support which you only need to do in R-CHOP for older patients or patients with prior chemotherapy 

    • Improved 2 year PFS at 77% vs. 70%

    • No difference in OS due to good salvage options now with CAR-T

    • First trial to show an improvement against R-CHOP in 20 years and became the standard of care in both the United States and Europe

    • Note that we don’t do those extra 2 cycles of rituximab and this was included due to the preference by some European countries  

What is the role of CNS prophylaxis in patients with DLBCL?

  • We know that for patients who have relapsed disease in the CNS after primary treatment with R-CHOP, the overall prognosis is very poor. CNS relapse risk was variable depending on many different prognostic factors but could be up to 20-30% in some patients. 

  • The idea behind CNS prophylaxis is to provide therapy that could eradicate any microscopic disease present in the CNS at diagnosis and during front line treatment for DLBCL

  • Patients who should get CNS prophylaxis:

    • Patients with CNS-IPI score 4-6 (link to CNS-IPI calculator)

      • A group of researchers from Germany and Canada who ran some of the early trials with rituximab used data from those trials to create a risk score called the CNS-IPI

        • This score is the same as the IPI score except with the addition of kidney and/or adrenal involvement as an additional factor (Essentially APLES + kidney/adrenal involvement

      • If the score was 4-6, then the patient was deemed high risk meaning at >10% risk of CNS relapse and CNS prophylaxis is recommended

    • Patients with high grade B-cell lymphoma testicular lymphoma (considered a sanctuary site), breast lymphoma, and primary cutaneous leg type lymphoma the latter of which we will discuss in a rare lymphomas episode in the future

    • Patients with epidural location of the lymphoma (high risk of contiguous spread) 

  • CNS prophylaxis is either intrathecal (IT) methotrexate (MTX) x 4 cycles during front line therapy or high-dose MTX x 2 cycles after completion of planned front line chemotherapy 

    • Notably the data for the efficacy of CNS prophylaxis is minimal and really retrospective in nature

  • Best data comparing IT MTX vs. HD MTX was presented at EHA 2023

    • Randomized trial comparing IT MTXx4 to HD MTX x 2 in those with high IPI (3 or more) or high risk extranodal site that we mentioned above

    • Did not require a high CNS IPI

    • No difference in CNS relapse rates between the two strategies (~5% in each arm)

    • Patients with high CNS IPI had CNS relapse ~10% in the study

What is the utility of an interim PET/CT? Is there a preference of PET/CT vs. CT?

  • Recall that we use Lugano response criteria on a 5 point scale (AKA Deauville score) was really designed to help us determine CR at the end of treatment. It was also used as a way for an interim check to change our management. 

  • For advanced stage patients, the 5-point scale at interim PET doesn’t really matter too much unless there are new sites of disease and the patient is primary refractory prior to completing induction therapy which is very rare

  • For this reason, it is reasonable to obtain an interim CT as opposed to PET/CT to evaluate for reduction in tumor volume and assess for obvious new sites of disease

  • We often default to PET/CT because it’s nice to know that these areas of tumor are becoming less active but again this rarely, if ever, would change management

    • It’s also common to get it after 3 cycles as this is what would change our management for patients with early stage disease when deciding whether to do R-CHOP x 4 vs. R-CHOP x 3 followed by IFRT. If not in a CR, we would proceed with radiation as opposed to additional cycle of R-CHOP for example. 

  • In the POLARIX trial, the interim imaging was done after the 4th cycle of therapy

 

What about the use of PET/CT at the end of treatment?

  • PET/CT at the end of treatment is used to determine if patient had a complete response to treatment.

  • CR is defined by a score of 3 or less.

  • Patients with a score of 4 or 5 should either get short interval imaging or repeat biopsy to rule out refractory disease. 

 

What if the patient has advanced stage DLBCL with high risk FISH features (“double hit” or “triple hit”)?

  • Treatment of choice in this situation would be dose-adjusted R-EPOCH (DA-R-EPOCH)

    • Added etoposide to R-CHOP; but instead of R-CHOP, medications in R-EPOCH agents are given continuously 

    • Dose-adjusted means that we titrate the dose of the agents based on their degree of myelosuppression; you’re uptitrating the dose to the patient’s degree of myelosuppresion (HemOnc.org link above has the dose-adjustment protocol!) 

  • In the CALGB 50303 study, we attempted to determine is this regimen better than R-CHOP for all patients? 

    • Only 5% of the population included in the study had high grade B-cell lymphoma, so it is hard to draw any conclusions in this regard. 

    • However, for all-comers, the study did find that there was no benefit to using DA-R-EPOCH over R-CHOP, including for patients who were double expressor. 

  • The use of DA-R-EPOCH for high grade B-cell lymphoma comes from retrospective studies and a Phase II study 

    • In single rearrangement of MYC or double hit, PFS of 80% if they got DA-R-EPOCH

Is there data to support autologous stem cell transplants in CR1 for patients with high grade (double hit) B-cell lymphoma?

Do we use PET/CT to guide radiation treatment? 

  • If PET negative for bulky disease or extranodal disease

  • If Deauville 4-5 to one site of disease, radiotherapy to the PET-avid area

  • It does not provide great systemic therapy, but provides good local control

References

The crew behind the magic:

  • Show outline: Vivek Patel

  • Production and hosts: Ronak Mistry, Vivek Patel, Dan Hausrath

  • Editing: Resonate Recordings

  • Shownotes: Ronak Mistry

  • Social media management: Ronak Mistry

We are proud to partner with HemOnc.org!

Want to learn more about the trials that lead to the regimens discussed today? What about dosing schedules? See links in the show notes for a link to HemOnc.org

TheFellowOnCall HemeOncPodcast
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Episode 073: Management of Early Stage Diffuse Large B-Cell Lymphoma (DLBCL)