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

medicine
Written By TheFellowOnCall HemeOncPodcast

This week, we pick up on our discussion about management of DLBCL, focusing on the primary refractory setting. A big part of this discussion is the role of CAR-T therapy. If you have not done so already, we highly recommend you check out episode 075 for the fundamentals of CAR-T before proceeding with this episode!

How do we approach patients with relapsed and/or refractory DLBCL?

  • For these patients, the first thing we need to assess is their “fitness” 

    • Patient should be fit enough to care for themselves and have adequate organ function 

    • Age should not preclude patients from curative CAR-T therapy and should be referred for evaluation

  • After patient fitness, we need to determine the time of relapse from initial chemotherapy as this will inform our treatment algorithm. There are two buckets:

    • WIthin 12 months = “Primary refractory”

    • After 12 months = “relapse” 

How do we approach patients with primary refractory disease? 

  • The short answer is refer them for CAR-T evaluation as soon as possible and start some therapy to temporize. 

    • Historically, we used platinum based salvage chemotherapy but there are more options in the current era (below)

  • Historical context: 

    • The thought in the late 1980’s was to identify patients with relapsed DLBCL who had chemotherapy sensitive disease that would then respond to higher doses of chemotherapy followed by autologous stem cell rescue with the goal of curative intent

      • We knew that relapsed DLBCL was sensitive to platinum based chemotherapy 

    • The first pivotal trial was published in 1995 called PARMA

      • Enrolled ~200 patients with relapsed DLBCL 

      • Patients got 2 cycles of salvage platinum based chemotherapy with a regimen called DHAP (Dexamethasone [D], high dose cytarabine [HA], and cisplatin [P])

      • If patients had a PR or better, they were randomized to more DHAP chemotherapy + XRT or ablative high dose chemotherapy with XRT followed by autologous stem cell rescue

      • Roughly 50% of the patients had a PR or better and underwent randomization

        • Of these patients, the 5 year OS was improved by ~20% absolute percentage points from 30 to 50% favoring autologous transplant

      • Platinum salvage followed by high dose chemotherapy and autologous transplant became the standard of care for patients with chemo sensitive disease after 2 cycles of platinum based salvage 

    • There was then a follow up study in the rituximab era called CORAL (Collaborative Trial in Relapsed Aggressive Lymphoma)

      • Unlike PARMA, this also included patients with primary refractory disease

      • Randomized patients to platinum based salvage chemotherapy with R-DHAP vs. R-ICE 

      • Roughly 400 patients included and all got 3 cycles of R-DHAP or R-ICE followed by repeat imaging and proceeded to BEAM conditioning with autologous stem cell rescue if they achieved a PR or better

      • ORR rate was ~60% in both arms with CR rate ~20-30%

        • Those with primary refractory or relapse within 12 months of induction therapy had worse ORR at ~40% and fewer CR

      • R-ICE and R-DHAP were both appropriate salvage options

      • 4 year OS ~50%

  • The prior standard of care for patients with relapsed/refractory DLBCL was to treat patients with platinum based chemotherapy regimens, and for who were chemosensitive, based on these data was to proceed with BEAM conditioning followed by autologous stem cell rescue. 

    • At best, 60% of patients responded and moved on to auto. 

What other regimens were trialed? 

  • Historically you will see other regimens including ESHAP, DHAX, and MINE but none of those had the level of evidence as R-ICE and R-DHAP and we know that R-ICE is less toxic due to less renal toxicity 

  • Bottom line is that it is a recipe including some combination of the following:

    • Platinum agent

    • Antimetabolite

    • Topoisomerase inhibitor

    • Alkylator 

  • The other regimens other than R-ICE that are important to know are R-GDP and R-GemOx

    • There was a phase III RCT that randomized patients to R-GDP vs. R-DHAP and found that R-GDP was non inferior with less toxicity and improved QOL as it is given outpatient

      • ORR in that study were ~43% in both arms which is lower than the 60% in the CORAL trial and likely more representative of what we see in clinic

    • R-GemOx does not have phase III randomized data and has mainly been used as salvage in those who were not candidates for autologous transplant

      • ORR in those studies range from ~40-60% (majority of patients had relapse >12 months after induction therapy so more favorable patient population)

      • This is a reasonable option for some patients who may be more frail but would not use over R-GDP or R-ICE based on lack of phase III evidence

  • The best options for fit patients who may be transplant candidates is R-ICE or R-GDP. 

How did we know about the poor prognosis for those who had primary refractory or early relapse compared to other patients?

  • Important patient level pooled analysis from randomized trials and academic databases called SCHOLAR-1

  • Looked at all patients who were primary refractory, relapsed < 12 months from induction, or refractory to salvage therapy if relapsed > 12 months

  • ORR ~26% with CR ~10% 

  • 2 year OS ~20%

As we alluded to above, given the poor prognosis of primary refractory DLBCL, CAR-T therapy with either Axi-cel or Liso-cel is our current standard of care. How did we get here? 

  • Refer back to Episode 075 for a refresher on the fundamentals of CAR-T therapy

  • There are three important CD-19 CAR-T products to know

    • Axicabtagene Ciloleucel (Yescarta) → CD28 costimulatory domain 

      • Approved in the primary refractory and early relapse setting with an OS benefit

      • More CRS and ICANS

    • Tisagenlecleucel (Kymriah) → 41BB costimulatory domain

      • Less CRS and ICANS but not approved in the primary refractory setting and only approved for those with later relapses

      • May be better for some older, frial patients

    • Lisocabtagene Maraleucel (Breyanzi) → 41BB costimulatory domain

      • Less CRS and ICANS than axi-cel and now also approved for the primary refractory and early relapse setting

      • OS data is not yet mature

  • There were single arm studies run for each of these products that led to approval in the relapsed setting after attempt at autologous transplant

    • ZUMA-1 was a phase II study for axi-cel which included only primary refractory or relapse within 12 months

    • JULIET was a phase II study for tisa-cel which did not have the restriction to just the highest risk patients

    • TRANSCEND for liso-cel which was the same as JULIET and actually a phase I study

    • Bottom line 

      • All had impressive response rates 70-80% with CR ~50% for axi-cel and liso-cel 

      • Tisa-cel had slightly lower response rates at ~50% with CR ~40%

      • ZUMA-1 has shown the curative potential of CAR-T with long term follow up published in 2023 showing a 40% durable survival rate which is impressive considering the SCHOLAR-1 data of only 20% in this population

  • There were then three phase III trials comparing each CAR-T product to standard of care platinum salvage chemotherapy followed by high dose chemotherapy with BEAM conditioning and autologous stem cell rescue

    • ZUMA-7 for axi-cel has now demonstrated on OS benefit

      • CRS 92% with 11% grade 3 or higher

      • ICANS 60% with 20% grade 3 or higher

  • BELINDA for tisa-cel did not beat standard of care autologous transplant

  • TRANSFORM for liso-cel has a PFS benefit but OS data still maturing

    • CRS 50% with only 1% grade 3 or higher

    • ICANS 11% with only 4% grade 3 or higher

Why was there no benefit shown with Tisa-cel? Was it a difference in study design? 

  • Let’s start with the similarities

    • Enrolled the highest risk patients with primary refractory or early relapse

    • All patients underwent leukapheresis prior to randomization 

    • It was expected that patients would proceed to CAR-T in the standard of care arm if they progressed given the approvals from the single arm studies 

  • The key difference:

    • Patients in the ZUMA-7 trial only got steroid monotherapy if needed after leukapheresis prior to CAR-T 

    • Patients in TRANSFORM and BELINDA could receive platinum based chemotherapy as a temporizing measure prior to CAR-T as the product was being manufactured 

    • Therapy given after leukapheresis is defined as bridging therapy

  • The next logical question then is how long did it take to get the CAR-T because we know lymphoma moves quickly

    • ZUMA-7 had a median of ~14 days

    • BELINDA had a median of ~50 days

    • TRANSFORM had a median of ~30 days

  • The fact that there was no benefit in BELINDA could very well be related to slower manufacturing times with patients have progression in the interim and we do not have a good sense on the ideal bridging therapy or how it might affect outcomes

After referral and approval of CAR-T, we often need to do something for our patients while we await their treatment, which can take a while. Other than platinum salvage options, what else can we do? 

  • There is no correct answer in this space but in addition to those salvage options, we could consider Pola-R or radiation therapy

    • Steroid monotherapy may not be ideal because we don’t want patients to be on steroids for several weeks given side effects of long term steroid use and potential issues with collection of good lymphocytes for CAR-T manufacturing

    • Polatuzumab-vedotin (ADC to CD79B) can be combined with rituximab with promising response rates in phase 2 trials

  • The main reason why you could consider a non-platinum based option is that we think we don’t necessarily need a good response prior to CAR-T and even stable disease with temporizing would be sufficient

Once a patient is approved for CAR-T, then what happens next? 

  • Patients ideally get fludarabine + cyclophosphamide daily for 3 days starting 5 days prior to CAR-T infusion. We call that Day -5, -4, and -3

    • There was a fludarabine shortage and patients got bendamustine for lymphodepletion which is also an option

  • They then get two days off

  • On Day 0, the CAR-T product is infused in the patient

  • Depending on the center, this is either done as inpatient or outpatient with close monitoring

  • What to look out for: 

    • CRS is most common in the first two weeks

    • Neurotoxicity as well though this is most common ~2-3 weeks after CAR-T infusion

    • Refer to episode 075 for a refresher on these! 

After they get through the first several weeks, how do we monitor these patients?

  • Monthly lab checks in the first few months 

    • In addition to CBC, CMP, also check IgG levels

      • A complication of CAR-T conditioning and treatment is B-cell aplasia

      • If IgG levels are <400, give IVIg to prevent infections 

  • Day +30 after CAR-T: PET/CT + lab work 

    • They don’t need to have a complete response on PET by Day 30 because the CAR-T cells will continue to work 

    • In addition to CBC, CMP, also check IgG levels

      • A complication of CAR-T conditioning and treatment is B-cell aplasia

      • If IgG levels are <400, give IVIg to prevent infections 

  • Day +90-100 after CAR-T: Next check PET/CT 

  • At 6 month mark: optional PET/CT (consider in patients who you are worried about) 

  • At 1 year mark: final PET/CT 

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 077: Management of relapsed diffuse large B-cell lymphoma (DLBCL) - part 1
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Episode 075: Intro to CAR-T, Bispecifics (BiTE), and Autologous Transplant