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Role of CNS Prophylaxis in DLBCL

Panelists: Julio Chavez, MD, Moffitt Cancer Center; Nathan H. Fowler, MD, The University of Texas MD Anderson Cancer Center; Andre Goy, MD, MS, John Theurer Cancer Center - Hackensack University Medical Center; Kami Maddocks, MD, The Ohio State University; Peter Martin, MD, Weill Cornell Medicine; Grzegorz S. Nowakowski, MD, Mayo Clinic
Published: Thursday, Feb 13, 2020



Transcript: 

Grzegorz S. Nowakowski, MD: Very interestingly, there was a subset analysis that showed that maybe some patients, particularly our younger patients or males, underdosed with rituximab. Several studies were actually designed to answer this question except for…

Andre Goy, MD, MS: That was explained to be because of faster clearance.

Grzegorz S. Nowakowski, MD: Faster clearance of rituximab. The ones that were randomized were done by Hoblin Group, which randomized patients to standard dose R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] versus increased-dose rituximab, R-CHOP. There was a second randomization to maintenance. Both strategies saw no difference in the outcome. Increasing the dose of rituximab with CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone] did not improve the outcome. Additional rituximab maintenance to saturate all the possible receptors did not really affect the outcome of those patients, which again supports the initial findings of rituximab maintenance in this situation but is probably not very helpful.

Andre Goy, MD, MS: To conclude this frontline therapy, I have 1 more thing before we go into the wrap-up session. I want to talk about CNS [central nervous system] prophylaxis and how we manage CNS disease in patients who really present with large-cell lymphoma with CNS relapse…. But what’s the CNS prophylaxis, and when do you do that? Dr Maddocks?

Kami Maddocks, MD: For CNS prophylaxis, there’s a CNS IPI [International Prognostic Index] score to help us identify patients at high risk of CNS progression or relapse. That is calculated by the IPI plus adrenal or renal involvement. We know that patients with double-hit lymphoma have a higher risk of CNS and double expressor lymphoma. At least retrospectively, they have a much higher risk of CNS relapse or progression.

As far as CNS prophylaxis, there are no good prospective data to suggest what the best way to do that is. But I would say that people usually use either high-dose methotrexate or IT [intrathecal] methotrexate, mostly in the form of 3 cycles of IV [intravenous] methotrexate with the frontline therapy or for intrathecal methotrexate.

Andre Goy, MD, MS: I agree with this. With the rituximab era and the lower-risk CNS, secondary CNS, we see much less. The patients who have high-risk of… these patients are not really prophylaxed well with IT, and I would recommend IV methotrexate.

So do each of you, very quickly, want to tell me when do you do and when you don’t do—or you do more—in R-CHOP in a patient with large-cell lymphoma. Nathan?

Nathan H. Fowler, MD: I still do dose-adjusted R-EPOCH [rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin hydrochloride] and primary mediastinal large-cell lymphomas and patients who have HIV-associated diffuse large B-cell lymphoma and double hits.

Julio Chavez, MD: I’m the same basically, HIV-associated large-cell lymphoma, primary B-cell lymphoma, and double-hit lymphoma, dose-adjusted EPOCH [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin hydrochloride], and the rest of the patients, R-CHOP.

Andre Goy, MD, MS: How do you play with the CNS prophylaxis in double-hit lymphoma?

Julio Chavez, MD: It’s a little challenging because it depends on the patient. If it’s a patient who is young and can tolerate high-dose methotrexate, we pursue high-dose methotrexate. Some of the risk strategies do it on day 15, and actually there are published data that day 15 high-dose methotrexate may actually affect the intensification with EPOCH. What I’ve been doing—this is off trial—is to complete the EPOCH and then do the 3 cycles of high-dose methotrexate at least every 2 weeks. You can finish in 3 weeks, in 4 weeks.

Andre Goy, MD, MS: Peter, when do you want an R-CHOP?

Peter Martin, MD: Same settings. I agree. HIV primary, primary mediastinal, double hit.

Andre Goy, MD, MS: Are you doing double hit?

Peter Martin, MD: In double hit we’re doing R-EPOCH, although as I mentioned, there is a randomized phase II trial adding venetoclax that I hope will be positive. We can certainly do better. Additionally, I will say that the CALGB 50803 [Alliance] trial did show a small trend toward improved outcomes in younger patients with very high IPI scores.

If I have a patient who I think has a very aggressive lymphoma biology through some magic gestalt that I think all of us have intuitively, I have occasionally treated some of those patients with R-EPOCH.

Additionally, I agree with everything that’s been said about adding high-dose methotrexate to patients who I believe have a high risk of CNS relapse. Not included in the CNS IPI are the testicular DLBCLs [diffuse large B-cell lymphomas]. Those patients were not in the clinical trials, but I think clearly, they warrant high-dose methotrexate. Occasionally as well, all those are examples of more intensive therapy.

I think that now that there’s evidence to de-intensify therapy. So patients with stage I/II DLBCL who have a very low IPI score were in the FLYER trial. The FLYER trial that was presented last year at ASH [American Society of Hematology] Annual Meeting & Exposition, those patients did equally well when treated with 4 cycles of R-CHOP plus 2 additional doses of rituximab. Presented here at ASH Dan Persky is a SWOG trial that essentially is a single-arm phase II trial but confirms that patients with lower-risk DLBCLs, who had a good response after 3 cycles, can get 1 more cycle of R-CHOP and probably do not need additional therapy beyond that. I think that’s good news for our young patients, whom we may have been overtreating in the past.

Grzegorz S. Nowakowski, MD: This will be similar to our practice. Thinking about this, we have to remember that modern data show us that double-hit lymphoma are not necessarily as bad as we initially thought. If initially we’re looking at the curves, it almost looked like everybody was dying and dying very quickly. It was almost like a death sentence. This has changed quite a bit. If you do actually prospectively in everybody, even with R-CHOP, the PFS [progression-free survival] is around 40%, and this has been shown now from a number of studies. Having said so, it’s definitely still worse than in the outcomes seen with R-CHOP in non-double-hit lymphoma. So in our practice, we use CODOX-M/IVAC [cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate, alternating with ifosfamide, etoposide, and cytarabine] for younger patients less than 60 years old and then use either dose-adjusted EPOCH or R-CHOP in patients over 60 years old, depending on the performance status and ability to tolerate chemotherapy. Participation in clinical trials is clearly preferred in this setting.

Andre Goy, MD, MS: Absolutely, yeah.

Kami Maddocks, MD: I agree with everything that’s been said already. The few things that I would add are in an older patient we would consider R-mini-CHOP as opposed to R-CHOP if they’re very old or have a lot of comorbidities. Or in somebody who had cardiac dysfunction, substituting the etoposide. I also agree with Grzeg, that for the most part in double-hit patients, I would use dose-adjust R-EPOCH. But if I have a really young person who’s behaving almost like they have Burkitt lymphoma, I’ll use the R-CODOX [rituximab, cyclophosphamide, vincristine, doxorubicin] regimen.

Andre Goy, MD, MS: We use the CODOX-M/IVAC as well in patients with double hit and patients with a double expresser or is very high risk. As Peter said, if the patient that has really bad presentation, we actually use EPOCH in older patients. Otherwise we use modified hyper-CVAD [cyclophosphamide, vincristine, doxorubicin, dexamethasone] if they have a high CNS risk, where we increase the dose of methotrexate to make sure we have CNS prophylaxis. I wanted to cover when you do less in R-CHOP, but I didn’t have to because we covered that.

Transcript Edited for Clarity

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Transcript: 

Grzegorz S. Nowakowski, MD: Very interestingly, there was a subset analysis that showed that maybe some patients, particularly our younger patients or males, underdosed with rituximab. Several studies were actually designed to answer this question except for…

Andre Goy, MD, MS: That was explained to be because of faster clearance.

Grzegorz S. Nowakowski, MD: Faster clearance of rituximab. The ones that were randomized were done by Hoblin Group, which randomized patients to standard dose R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] versus increased-dose rituximab, R-CHOP. There was a second randomization to maintenance. Both strategies saw no difference in the outcome. Increasing the dose of rituximab with CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone] did not improve the outcome. Additional rituximab maintenance to saturate all the possible receptors did not really affect the outcome of those patients, which again supports the initial findings of rituximab maintenance in this situation but is probably not very helpful.

Andre Goy, MD, MS: To conclude this frontline therapy, I have 1 more thing before we go into the wrap-up session. I want to talk about CNS [central nervous system] prophylaxis and how we manage CNS disease in patients who really present with large-cell lymphoma with CNS relapse…. But what’s the CNS prophylaxis, and when do you do that? Dr Maddocks?

Kami Maddocks, MD: For CNS prophylaxis, there’s a CNS IPI [International Prognostic Index] score to help us identify patients at high risk of CNS progression or relapse. That is calculated by the IPI plus adrenal or renal involvement. We know that patients with double-hit lymphoma have a higher risk of CNS and double expressor lymphoma. At least retrospectively, they have a much higher risk of CNS relapse or progression.

As far as CNS prophylaxis, there are no good prospective data to suggest what the best way to do that is. But I would say that people usually use either high-dose methotrexate or IT [intrathecal] methotrexate, mostly in the form of 3 cycles of IV [intravenous] methotrexate with the frontline therapy or for intrathecal methotrexate.

Andre Goy, MD, MS: I agree with this. With the rituximab era and the lower-risk CNS, secondary CNS, we see much less. The patients who have high-risk of… these patients are not really prophylaxed well with IT, and I would recommend IV methotrexate.

So do each of you, very quickly, want to tell me when do you do and when you don’t do—or you do more—in R-CHOP in a patient with large-cell lymphoma. Nathan?

Nathan H. Fowler, MD: I still do dose-adjusted R-EPOCH [rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin hydrochloride] and primary mediastinal large-cell lymphomas and patients who have HIV-associated diffuse large B-cell lymphoma and double hits.

Julio Chavez, MD: I’m the same basically, HIV-associated large-cell lymphoma, primary B-cell lymphoma, and double-hit lymphoma, dose-adjusted EPOCH [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin hydrochloride], and the rest of the patients, R-CHOP.

Andre Goy, MD, MS: How do you play with the CNS prophylaxis in double-hit lymphoma?

Julio Chavez, MD: It’s a little challenging because it depends on the patient. If it’s a patient who is young and can tolerate high-dose methotrexate, we pursue high-dose methotrexate. Some of the risk strategies do it on day 15, and actually there are published data that day 15 high-dose methotrexate may actually affect the intensification with EPOCH. What I’ve been doing—this is off trial—is to complete the EPOCH and then do the 3 cycles of high-dose methotrexate at least every 2 weeks. You can finish in 3 weeks, in 4 weeks.

Andre Goy, MD, MS: Peter, when do you want an R-CHOP?

Peter Martin, MD: Same settings. I agree. HIV primary, primary mediastinal, double hit.

Andre Goy, MD, MS: Are you doing double hit?

Peter Martin, MD: In double hit we’re doing R-EPOCH, although as I mentioned, there is a randomized phase II trial adding venetoclax that I hope will be positive. We can certainly do better. Additionally, I will say that the CALGB 50803 [Alliance] trial did show a small trend toward improved outcomes in younger patients with very high IPI scores.

If I have a patient who I think has a very aggressive lymphoma biology through some magic gestalt that I think all of us have intuitively, I have occasionally treated some of those patients with R-EPOCH.

Additionally, I agree with everything that’s been said about adding high-dose methotrexate to patients who I believe have a high risk of CNS relapse. Not included in the CNS IPI are the testicular DLBCLs [diffuse large B-cell lymphomas]. Those patients were not in the clinical trials, but I think clearly, they warrant high-dose methotrexate. Occasionally as well, all those are examples of more intensive therapy.

I think that now that there’s evidence to de-intensify therapy. So patients with stage I/II DLBCL who have a very low IPI score were in the FLYER trial. The FLYER trial that was presented last year at ASH [American Society of Hematology] Annual Meeting & Exposition, those patients did equally well when treated with 4 cycles of R-CHOP plus 2 additional doses of rituximab. Presented here at ASH Dan Persky is a SWOG trial that essentially is a single-arm phase II trial but confirms that patients with lower-risk DLBCLs, who had a good response after 3 cycles, can get 1 more cycle of R-CHOP and probably do not need additional therapy beyond that. I think that’s good news for our young patients, whom we may have been overtreating in the past.

Grzegorz S. Nowakowski, MD: This will be similar to our practice. Thinking about this, we have to remember that modern data show us that double-hit lymphoma are not necessarily as bad as we initially thought. If initially we’re looking at the curves, it almost looked like everybody was dying and dying very quickly. It was almost like a death sentence. This has changed quite a bit. If you do actually prospectively in everybody, even with R-CHOP, the PFS [progression-free survival] is around 40%, and this has been shown now from a number of studies. Having said so, it’s definitely still worse than in the outcomes seen with R-CHOP in non-double-hit lymphoma. So in our practice, we use CODOX-M/IVAC [cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate, alternating with ifosfamide, etoposide, and cytarabine] for younger patients less than 60 years old and then use either dose-adjusted EPOCH or R-CHOP in patients over 60 years old, depending on the performance status and ability to tolerate chemotherapy. Participation in clinical trials is clearly preferred in this setting.

Andre Goy, MD, MS: Absolutely, yeah.

Kami Maddocks, MD: I agree with everything that’s been said already. The few things that I would add are in an older patient we would consider R-mini-CHOP as opposed to R-CHOP if they’re very old or have a lot of comorbidities. Or in somebody who had cardiac dysfunction, substituting the etoposide. I also agree with Grzeg, that for the most part in double-hit patients, I would use dose-adjust R-EPOCH. But if I have a really young person who’s behaving almost like they have Burkitt lymphoma, I’ll use the R-CODOX [rituximab, cyclophosphamide, vincristine, doxorubicin] regimen.

Andre Goy, MD, MS: We use the CODOX-M/IVAC as well in patients with double hit and patients with a double expresser or is very high risk. As Peter said, if the patient that has really bad presentation, we actually use EPOCH in older patients. Otherwise we use modified hyper-CVAD [cyclophosphamide, vincristine, doxorubicin, dexamethasone] if they have a high CNS risk, where we increase the dose of methotrexate to make sure we have CNS prophylaxis. I wanted to cover when you do less in R-CHOP, but I didn’t have to because we covered that.

Transcript Edited for Clarity
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