First-Line Therapy Options in Diffuse Large B-Cell Lymphoma

EP: 1.Case Presentation: A 76-Year-Old Man with Relapsed Diffuse Large B-Cell Lymphoma

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EP: 2.First-Line Therapy Options in Diffuse Large B-Cell Lymphoma

EP: 3.Options for Second-Line Treatment in Relapsed/Refractory Diffuse Large B-Cell Lymphoma

EP: 4.Novel Therapies in Development for Relapsed/Refractory Diffuse Large B-Cell Lymphoma

EP: 5.Future Directions for Treatment of Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Laurie Sehn, MD: What to do next? This patient was deemed transplant ineligible based on age and comorbidities. At the age of 76 with numerous medical comorbidities, most centers would consider him transplant ineligible, which means he needed to go on to further medical management with standard approaches. He was treated with the combination of polatuzumab and bendamustine with rituximab.

This is a gentleman with intermediate-risk diffuse large B-cell lymphoma [DLBCL]. We knew from the beginning that, although R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] has curative potential for these patients, unfortunately, not all patients can be cured with R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone]. In general, we see that despite R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone], 10% to 15% of patients exhibit primary refractory disease, and about another 20% to 25% of patients will ultimately relapse, despite having an initial response. Where does this patient fit? The definition of primary refractory disease alters somewhat. It’s not quite consistent, but for the most part, primary refractory refers to patients who either don’t respond at all or relapse within the first 6 months. Given that this patient had an initial CR [complete response] but relapsed at the 6-month mark, I would consider him to have primary refractory disease.

How do we determine risk in our patients at the time of their presentation? From a clinical standpoint, we still rely on IPI [International Prognostic Index] scores. There are 5 simple clinical parameters that divide patients into risk groups and likelihood of cure with R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone], but some other parameters also come into play. This patient had a GCB subtype of diffuse large B-cell lymphoma. By cell-of-origin testing, usually done in clinical practice by immunohistochemistry, patients are usually determined to have GCB or non-GCB subtype. Patients with the GCB subtype can actually have a better outcome than the non-GCB subtype.

This patient did have GCB subtype but unfortunately relapsed nonetheless. It’s important to recognize that within the GCB subtype is where we see the majority of patients with double- or triple-hit lymphoma. Those patients need to be identified up front. It’s customary to do FISH [fluorescence in situ hybridization] testing for all patients at the time of diagnosis to identify patients with double- or triple-hit lymphoma, meaning those with a dual or triple rearrangement of MYC, with BCL2 or BCL6. This is the 1 subgroup of patients you want to separate out because many of us treat those patients with more intensive therapy.

This patient did not have double- or triple-hit lymphoma, but at age 76, even if he did, I’m not sure I would have done anything different. In my own setting, for patients with double- or triple-hit lymphoma, we’re preferentially using dose-adjusted R-EPOCH [rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin] rather than R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone]. But that’s not suitable for all patients because it does lead to a step up in toxicity. You have to judge whether a patient would be appropriate for stepping up to dose-adjusted R-EPOCH [rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin] if they have double- or triple-hit lymphoma.

For all other patients, those who don’t have double- or triple-hit lymphoma, R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] still remains the standard of care. We measure cell of origin and recognize that patients with non-GCB cell of origin DLBCL, or ABC subtype, if it’s done by gene expression profiling, have different biology and a poor outcome overall with R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone]. However, there haven’t been any clinical trials that have proven that we can improve the outcome for those patients by the addition of other agents. It remains a research question at this time.

We know that patients with GCB vs non-GCB DLBCL have different biology and different mechanisms of action at work that drive their lymphomas. It would nice to develop unique treatments for these patients based on their biology that might preferentially benefit them, but at this point, we don’t have a clinical trial that has proved benefit of adding any novel agent preferentially to either GCB or non-GCB subtype. Regardless of cell of origin, R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] remains the standard of care.

As I mentioned, it’s important to do FISH testing in these patients to identify the patients with double- or triple-hit lymphoma. We all recognize that it can take some time to get the results back from FISH testing. Many of these patients need to go onto treatment in real time and get on something, sometimes before you can get the FISH testing results back. In my own clinic, I would normally start R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone]. It’s perfectly appropriate to give the patient a cycle of R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] while you wait for the FISH testing to be done. Subsequently, if you find the patients prove to have double- or triple-hit lymphoma, which occurs in about 10% of cases with diffuse large B-cell lymphoma, those patients can be considered for more intensified therapies. But not every patient may be appropriate. The default for patients you think are not candidates for more intensive therapies, such as dose-adjusted R-EPOCH [rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin], would be R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone].

This transcript has been edited for clarity.

Case Overview: A 76-Year-Old Man with R/R DLBCL

Initial presentation

• A 76-year-old man presented with progressive fatigue, enlarged lymph nodes in the neck and groin, pruritus and decreased appetite
• PMH: prediabetes, hypertension, medically controlled; BPH; osteoporosis
• PE: palpable cervical and inguinal lymphadenopathy; splenomegaly
• ECOG PS 2
  
  

Clinical workup

• Labs: Hb 9.9 g/dL; all others WNL
• Hepatitis B, C and HIV negative
• Excisional biopsy of the lymph node confirmed DLBCL
• IHC confirmed GCB subtype
• FISH panel: t(14;18) with a BCL2 rearrangement
• Flow cytometry: CD19-postitive
• Whole body PET/CT scan showed FDG avidity in the cervical and inguinal regions, largest node 3.8 cm; splenomegaly
• Ann Arbor stage III DLBCL
• IPI score intermediate-risk age > 60 years, stage 3
• PET scan shows diffuse lymphadenopathy

Treatment

• Treated with R-CHOP x 6 cycles; some dose reductions
• First post-treatment PET/CT scan was markedly improved; CR
• 6 months later there was active relapse of disease
  • Repeat biopsy confirms R/R DLBCL, GCB subtype
• Patient is ineligible for high-dose chemotherapy followed by ASCT based on age and ECOG PS
• Initiated treatment with polatuzumab + bendamustine and rituximab