SALT LAKE CITY–Diffuse large b-cell lymphoma accounts for approximately one-third of all cases of non-Hodgkin lymphoma, which is classified by the VA as a presumptive disease for veterans exposed to Agent Orange while serving in Vietnam.

Two studies presented at the recent American Society of Hematology annual meeting highlighted the importance of personalizing treatment for those veterans.

DLBCL is an aggressive tumor with a median survival of less than one year without treatment. The current standard of care combines rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) in the first line. This immunochemotherapy regimen cures more than 60% of patients, according to the National Cancer Institute.

Researchers at the VA Audie Murphy Hospital and the University of Texas Health Science Center, both in San Antonio, sought to better understand the factors affecting treatment outcomes in veterans with DLBCL. They undertook a retrospective analysis of patients with DLBCL treated at their hospital compared to patients with and without insurance who were treated in a community setting in the same ZIP code between 2007 and 2017. All patients received R-CHOP.1

They found that VA patients proceeded from definitive diagnosis to treatment slightly faster than their counterparts treated in the community, 20 days compared to 22 days for those with insurance and 21.5 days for those without insurance.

Despite prompt treatment, veterans failed initial therapy with R-CHOP at twice the rate of the other two groups. Among veterans, the failure rate was 40% compared to 18% for insured patients and 20% for uninsured patients in the neighboring hospitals.

The investigators suggested that an “older patient population, advanced stage and multiple co-morbidities are the possible contributing factors for difference in treatment outcomes for DLBCL in the VA community.”

The demographics supported that conclusion. Veterans were significantly older and about 50% more likely to have an advanced stage of the disease at diagnosis. The average age at diagnosis among veterans was 64.5 years, while the average age of the two community-treated groups was about seven years younger. Nearly 4 out of 5 veterans had Stage 3 or 4 DLBCL at diagnosis compared to 53% of the insured and 43% of the uninsured patients treated in the community.

The high failure rate of the powerful first-line combination in veterans is a cause for concern. A metaanalysis of 28 studies found that the prognosis for patients with DLBCL who fail first-line immunochemotherapy “is poor, with median survival of less than one year and less than half of patients who relapse still alive at one year post relapse.” Further, the analysis determined that patients over age 65 had a median overall survival less than half that of younger patients.2  

Determining the best treatment for older patients, such as those typically seen in the VA, requires a careful balance that takes into account age, comorbidities, stage and the possibility of a cure. While R-CHOP toxicity rarely kills younger patients, it might account for up to 5% of deaths in treated patients older than age 70.3

On the other hand, a recent large study determined that “among patients aged 75 to 79 years, overall survival seemed higher in patients receiving standard treatment [with R-CHOP], regardless of comorbidity, while the overall survival benefit associated with standard treatment diminished in patients older than 80 years with high comorbidity scores.”4

When R-CHOP Fails

The standard treatment for DLBCL patients with relapsed or refractory disease is chemotherapy or chemoimmunotherapy followed by high-dose therapy and an autologous stem cell transplant. “Unfortunately, a significant proportion of older patients are unable to tolerate such treatment,” noted researchers at the Salt Lake City VAMC and others in a presentation at ASH.5

To understand the treatments used and the outcomes in older veterans who have failed first-line therapy, the Salt Lake City team analyzed records of 230 veterans with DLBCL treated between 2001 and 2015. R-CHOP was the first-line therapy for 94%; 6% received R-CHOP plus etoposide.

More than two-thirds (68%) of the patients had Stage 3 or 4 disease and lactate dehydrogenase levels above the upper limit of normal (67%) at diagnosis. All the veterans were older than age 65 when they began second-line treatment; 97% were male, and 74% were non-Hispanic white.

The investigators divided the veterans into two groups. Group 1 included 109 patients who received a second-line therapy typically associated with intention to proceed to high-dose chemotherapy and then autologous stem cell transplant. The second group (121) received other regimens.

The team’s goal was “to identify which older patients with relapsed/refractory DLBCL may benefit from more-aggressive treatments consisting of traditional high dose chemotherapy followed by autologous transplant vs. those patients who may benefit more from less-aggressive treatments that focus on disease control while minimizing treatment toxicities and treatment impact on quality of life,” said co-author Kelli Rasmussen, MS, a senior research analyst at the Salt Lake City VAMC.  

The total study population had a median of 10.6 months between the start of first-line therapy and initiation of a second line, and 66% started the second line within one year of beginning first-line treatment.

In Group 1, the most common second-line treatment was ifosfamide, carboplatin, etoposide with or without rituximab, which 62% received, followed by etoposide, methylprednisolone, cytarabine, cisplatin with or without rituximab, used for 20% of patients. Fourteen of these patients (13%) proceeded to stem cell transplant at the VA.

The researchers found greater variation in treatment for patients in Group 2, with 23% receiving bendamustine with or without rituximab; 17% receiving gemcitabine and oxaliplatin with or without rituximab; and 22% receiving R-CHOP or CHOP with or without etoposide. Two of these patients went on to receive a stem cell transplant.

The median survival of all the patients in the study was eight months with 56% or 130 patients surviving greater than one year, Rasmussen told U.S. Medicine. “Of these 130 DLBCL patients, preliminary results suggest eight patients proceeded to receive a stem cell transplant.”

While high-dose chemotherapy followed by stem cell transplant is the recommended treatment for patients who fail first-line therapy, that aggressive course of treatment accounted for only 6% of the patients who survived for more than one year.

“Our findings suggest that in a significant proportion of patients, a high-dose chemotherapy treatment regimen may not be appropriate, and other less-toxic treatment regimens should be considered,” Rasmussen said.

This study is “the first step in ongoing research we hope will provide patients and physicians with a better understanding of the effectiveness, toxicities and outcomes of therapies used in older patients with relapsed/refractory DLBCL,” Rasmussen added. “These results further highlight the importance of personalized medicine and how treatment decisions should be tailored to take into consideration each patient’s individual clinical context and personal preferences.”

1. Jones JT, Espinoza-Gutarra MR, Kakarla S, Martinez MJ, Gregorio D, Surapaneni P, Mader M, Nooruddin Z. Veterans treated with R-CHOP for diffuse large b-cell lymphoma compared to neighboring hospital: An interesting discovery for treatment outcomes. ASH 2018. Abstract 3604. December 2, 2018.

2. McMillan A, Martìn A, Haioun C, Chiappella A, Di Rocco A, Rueda A, Palaska C, Davies AJ. Post Relapse Survival Rates in Diffuse Large B-Cell Lymphoma. Blood. 2016;128(22):4204. Coiffier B, Sarkozy C. Diffuse large B-cell lymphoma: R-CHOP failure—what to do? ASH Education Book. December 2, 2016; 1:366-378.

3. Coiffier B, Sarkozy C. Diffuse large B-cell lymphoma: R-CHOP failure—what to do? ASH Education Book. December 2, 2016; 1:366-378.

4. Lawrence, Leah. Can Elderly Patients With DLBCL Tolerate Standard Treatment? CancerNetwork. July 10, 2018.

5. Halwani AS, Rasmussen KM, Pail V, Li C, Young C, Burningham Z, et al. Treatment practices and outcomes in older adults with relapsed/refractory diffuse large b-cell lymphoma treated in the Veterans Health Administration. ASH 2018. Abstract 4205. December 3, 2018.