Episode 077: Management of relapsed diffuse large B-cell lymphoma (DLBCL) - part 1

medicine
Written By TheFellowOnCall HemeOncPodcast

In our last episode, we discussed our approach to primary refractory DLBCL. This week, we start our conversation about relapsed DLBCL! This is an important and complex discussion, so we have split it into two episodes to help you follow along.

If you have not done so already, we recommend you check out episode 076 for a discussion about the primary refractory setting.

This episode is sponsored by HemOnc.org

Reminder about how to think about patients with relapsed disease?

  • Fitness assessment is critical at this juncture

    • Are they fit for chemotherapy followed by autologous transplant vs. CAR-T 

  • Let’s assume that this patient is fit for intensive therapy, then we think of two things: Primary refractory or relapsed within 12 months vs. relapse after 12 months

    • Remember that disease refractory after six cycles of chemotherapy or relapse within 12 months is the highest risk patients and they should always go to CAR-T

  • In patients with relapsed disease AFTER 12 months our current (2023) approach would be a “risk adapted approach” starting with salvage platinum-based chemotherapy followed by EITHER: 

    • High-dose chemotherapy → autologous stem cell rescue if there is a response to treatment OR 

    • Proceed with CAR-T if they did not have a great response to chemotherapy (“chemorefractory disease”)

      • It is important to keep in mind we would not start with CAR-T like we could in the primary refractory or relapse within 12 month patient because these later relapses weren’t included in those pivotal phase III trials

  • Last thing that is important to know: 

    • If the patients are refractory to platinum-based salvage chemotherapy they are considered “relapsed/refractory” and have the same poor prognosis as the primary refractory and relapse within 12 months (SCHOLAR-1); they should proceed to CAR-T at that point

  • For less fit patients, we will discuss treatment options later in the episode

  • Refer back to episode 076 for a discussion on salvage regimens

What are options that we would need to incorporate into our treatment for patients with relapsed disease now with CNS involvement? 

  • Agents with good parenchymal penetration (meaning a mass in the brain):

    • IV high-dose methotrexate (3.5 g/m2) which requires inpatient administration 

      • Note that this dose gets good parenchymal and leptomeningeal penetration (i.e. in the CSF)

    • IV high-dose cytarabine

    • IV thiotepa

    • IV rituximab (not great but has some efficacy)

    • These are the agents in a regimen called MATRix which is a standard of care treatment for primary CNS lymphoma

  • Agents with good leptomeningeal therapeutic benefit: 

    • Note here: we are administering intrathecally to spare the patients the systemic effects of chemotherapy 

    • IT methotrexate

    • IT cytarabine

    • IT methotrexate + IT cytarabine + IT hydrocortisone → called “triple therapy”

  • Bottom line for patients with systemic relapse and CNS relapse: 

    • If you have parenchymal involvement, then use high dose IV methotrexate based chemotherapy as part of your regimen which can be followed by or alternated with R-ICE if you need both brain control and systemic control 

      • There was a phase II study called MARIETTA run in European countries that looked at sequential MATRix followed by R-ICE followed by high dose chemotherapy and autologous stem cell rescue 

    • If you have leptomeningeal relapse only and no parenchymal involvement, then go with triple IT therapy (methotrexate, cytarabine, and hydrocortisone)

      • Twice weekly until CSF cleared (4 minimum) then

      • Weekly x 4

      • Then monthly x 4 (could omit this if going to transplant at that point)

      • All of this is totally arbitrary and extrapolated from data in B-ALL…we don’t know how much IT therapy to give

If a patient’s CSF is cleared of disease and there is CR shown after several rounds of platinum-based chemotherapy, where do we go from here? 

  • This is where the response adapted approach to high dose chemotherapy followed by autologous transplant vs. CAR-T comes into play

    • We don’t actually know the correct answer for this case and only have single arm data or retrospective data with significant limitations

  • There is a theory that if a patient does not have detectable disease, then the CAR-T wouldn’t work as well as the high dose chemotherapy strategy

    • The largest analysis to date has suggested that this may not be the case but only included 33 patients

  • Current approach: 

    • If a patient achieves a CR: Proceed with high-dose chemotherapy followed by autologous stem cell transplant

    • If a patient achieves a PR: Consider part of their disease “chemo refractory” and proceed with CAR-T

      • In this case transplant would still be an acceptable option but most would prefer to proceed with CAR-T

  • If a patient has stable disease or worsening disease: Proceed to CAR-T

Which CAR-T product do we use? 

  • All three CAR-T products are approved for these patients

    • We don’t know which is better in this setting and there are pros and cons to each

    • Axi-cel

      • ZUMA-1 Phase 2 trial led to approval

      • Included patients who were primary refractory, refractory to second line treatment, or relapse after autologous transplant (highest risk patients)

      • Recent OS benefit showed a durable 40% cure rate

      • Pros: longest follow up and demonstrated OS benefit in phase III trial

      • Cons: higher toxicity

    • Tisa-cel

      • JULIET Phase 2 trial led to approval

      • Included refractory and relapsed patients

      • Similar PFS as Axi-cel but not as long of follow up

      • Less CRS and ICANS than Axi-cel → may be better for older patients and potentially outpatient CAR-T administration

      • Pros: less toxicity

      • Cons: no benefit in the phase 3 trial though that included only primary refractory or early relapse patients

    • Liso-cel

      • TRANSCEND Phase 1 Trial

      • Similar efficacy to axi-cel and tisa-cel

      • Less CRS and ICANS than Axi-cel

      • Pros: less toxicity and possibly same efficacy as axi-cel

      • Cons: no OS benefit in phase 3 trial pending longer follow up

What sort of conditioning regimen is recommended for patients with relapsed disease who also have CNS involvement in preparation for an autologous stem cell transplant? 

  • We previously discussed the BEAM (BCNU, etoposide, cytarabine, melphalan) regimen for conditioning

  • We would want to ensure that we also add something with good CNS penetration, such as thiotepa with BCNU

What if a patient with refractory disease undergoes platinum-based salvage and still has refractory disease? We discussed that these patients should go to CAR-T, but what we can give them while they wait for the approval process? 

  • If stable: we can observe

  • If small area of disease that is concerning: can consider radiation

  • If not a small area, can consider using Polatuzumab-rituxan based regimen (below) 

What are treatment options for patients with late relapsed DLBCL who are poor candidates for CAR-T or autologous stem cell transplant? 

  • Historically, R-GemOx was a great option for these patients

Other options that we use in current practice: 

  • The approval is based on a phase 1b/2 trial which included transplant ineligible patients with relapsed or refractory DLBCL and excluded transformed lymphoma from follicular and high-grade DLBCL

  • The phase 1b portion was safety data for 6 patients who got Pola-BR

  • The phase 2 portion included two parts:

    • Randomized 80 patients to BR vs. Pola-BR

    • Extension cohort where an additional 106 patients just got Pola-BR

  • Study design: Patients got 3 cycles → interim scan → another 3 cycles → end of treatment scan

  • Study outcomes (Note: there were many study design flaws, which we discuss below):

  • ORR was only 22.5% in BR which is odd that most patients with a response got in a CR

  • When you look closely at the original publication prior to the extension cohort, there are roughly 50% of patients in the BR arm with missing data on their response so it truly is unclear if the control arm response rates are reliable

    • There were 14 patients who never got imaging and 4 patients who had interim imaging after 3 cycles with progressive disease by the investigator but stable disease by central review

    • This is a huge limitation to interpreting all of these results and it is clear that this would lead to informative censoring for these results

  • Although extension cohort did show high activity for Pola-BR (ORR of 42% and CR of 39%), very odd that all patients who had a response went into a CR

This episode is sponsored by HemOnc.org

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 078: Management of relapsed diffuse large B-cell lymphoma (DLBCL) - Part 2
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Episode 076: Management of primary refractory diffuse large B-cell lymphoma (DLBCL)