Outcome of an Elderly Female With Diffuse Large B-cell Lymphoma With Central Nervous System and Orbital Involvement Treated With Modified Methotrexate and R-CHOP Therapy: A Case Report

Abstract

The National Comprehensive Cancer Network (NCCN) recommends a regimen of rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHOP) with methotrexate (MTX) given at ≥3 g/m² for stage IV diffuse large B-cell lymphoma with parenchymal involvement. Tumor lysis syndrome (TLS) may occur after initiation of treatment. MTX, though beneficial, may induce toxicity, especially in elderly patients with comorbidities. This paper discusses a case of 74-year-old female with secondary central nervous system lymphoma with multiple comorbidities and high risk for TLS given a modified schedule of R-CHOP and a lower dose of MTX at 2–2.5 g/m² with a good treatment response. This paper aims to contribute additional information on optimal treatment for this disease.

INTRODUCTION

Treatment guidelines for stage IV diffuse large B-cell lymphoma (DLBCL) with brain parenchyma involvement established by the National Comprehensive Cancer Network (NCCN) recommend a regimen of rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHOP) with high-dose methotrexate (MTX) for six cycles [1]. R-CHOP is a chemotherapy regimen that includes intravenous (IV) rituximab 375 mg/m², IV cyclophosphamide 750 mg/m², IV doxorubicin 50 mg/m² with a dose cap of 2 mg, and IV vincristine 1.4 mg/m² on day 1 and prednisone 100 mg on days 1–5 [2]. MTX is recommended at ≥3 g/m² for a total of six cycles alternating with R-CHOP [1].

Though beneficial, MTX may induce toxicity, especially in elderly patients with comorbidities. Toxicity can be avoided through urine alkalinization and administration of leucovorin [3]. MTX therapy at doses greater than 3 g/m² has been shown to penetrate the blood-brain barrier and enter the cerebrospinal fluid at therapeutic levels. Most studies employed doses between 3 and 8 g/m², but the optimal dose for initial treatment has yet to be identified [4]. For the treatment approach to secondary central nervous system lymphoma (SCNSL), there is still a lack of randomized trials to compare regimens, and there are no international consensus guidelines [5]. Tumor lysis syndrome (TLS) is a complication that may result following chemotherapy. It is described as hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia. Symptoms affected include renal, cardiac, neurological, and muscular manifestations. Patients at high risk include those with DLBCL with an elevated baseline lactate dehydrogenase of twice the upper limit of normal and bulky disease [6]. This paper discusses a case of an elderly female with multiple comorbidities and high risk for TLS given a modified schedule of R-CHOP and a lower dose of MTX. We aim to contribute additional information on the optimal treatment for this disease.

CASE REPORT

The patient is a 74-year-old female, previously independent in all activities of daily living. She presented with a 4-week history of progressive unilateral-to-bilateral blurring of vision and left periorbital swelling. This was accompanied by word-finding difficulty, memory lapses, headache, and generalized pain. Her comorbidities include hypertension, diabetes mellitus type 2, dyslipidemia, and post-surgical hypothyroidism. A systemic exam revealed that she had a body mass index of 54 and a swelling on the left periorbital area with generalized edema. Neurologic examination revealed a Montreal Cognitive Assessment–Philippines (MoCA-P) of 3/30—oriented to month, place, and city; acalculia; anomic aphasia; visual acuity of 20/200 in the right eye; and counting fingers at 0.91 m in the left eye.

On workup, cranial non-contrast magnetic resonance imaging showed a mass on the posterolateral left orbit extending to the apex and ovoid lesions in the left temporal and parietal lobes, which are appreciated in Fig. 1. Further studies on positron emission tomography (PET) scan revealed there were soft tissue lesions in bilateral orbits and multiple hypermetabolic nodal and subcutaneous nodular diseases in the neck, chest, and abdomen. Hypermetabolic lesions in the brain, lungs, spleen, pancreas, omentum/mesentery, and axial and lower appendicular osseous structures were seen as well. PET scan findings are showed in Fig. 2. These findings led to an axillary biopsy being done. On pathology studies, the Hans algorithm was used to guide the diagnosis of the type of lymphoma. The results showed positive for CD20, Ki-67, CD79a, CD10, MUM1, BCL2, and C-MYC, as seen in Fig. 3. A diagnosis of diffuse large B-cell lymphoma and of SCNSL was made. Prior to treatment, blood chemistry labs showed leukopenia as low as 3,670 mm³, elevated liver enzymes with aspartate aminotransferase (AST) at 73 U/L and lactate dehydrogenase (LDH) at 1,358 U/L, and elevated uric acid at 8 mg/dL. Prior to initiation of MTX, the patient also had poor urinary alkalinization despite bicarbonate administration. The patient was given TLS prophylaxis with IV hydration, allopurinol 100 mg/tablet three times a day, and sodium bicarbonate 650 mg three times a day. Given the patient’s advanced age and multiple comorbidities, we elected to modify the standard MTX dose to 2 g/m² for the initial cycles. This decision was guided by the need to minimize the risk of chemotherapy-induced toxicity. Subsequent dose escalation to 2.5 g/m² was performed after observing stabilization in liver enzymes and renal function. The R-CHOP regimen was altered as well such that one chemotherapeutic drug was given per day instead of all four drugs given on day one.

Fig. 1. Cranial magnetic resonance imaging.

Fig. 2. PET scan. A: Pretreatment (whole body and cranial axial views). Lesions in the orbits, left parietotemporal areas (arrow). There were multiple hypermetabolic nodal and subcutaneous nodular disease in the neck, chest, and abdomen. B: After 2nd cycle. Residual mildly gypermetabolic left neck node. Resolution of the enlarged thoracic and abdominopelvic lymph nodes. Regression of splenic lesion. No discrete brain or other orbital lesion. C: One month post-treatment. Metabolic resolution of the left cervical, mediastinal, and right hilar lymph nodes. Stable metabolic activity in the left hilar lymph nodes. D: Three months post-treatment. No enlarged neck, thoracic, and abdominopelvic lymph nodes. Bilateral hilar nodes are reactive or inflammatory in nature.

Fig. 3. Results of immunohistochemical staining.

The first two cycles of R-CHOP were given as follows: rituximab 500 mg with prednisone 50 mg twice daily on day 1, doxorubicin 50 mg/m² with prednisone 50 mg twice daily on day 2, cyclophosphamide 750 mg/m² + prednisone 50 mg twice daily on day 3, vincristine 2 mg + prednisone 50 mg twice daily on day 4, and prednisone 50 mg twice daily on day 5. The first two doses of MTX were given on days 7 and 52, and R-CHOP was given on days 34 to 38 and 66 to 70. After the second cycle of the regimen, a repeat PET scan revealed a significant tumor response with minimal residual of the lesions as seen in Fig. 2. A repeat examination after the second cycle revealed a MoCA-P of 20/30 and visual acuity of 20/50 on the right and 20/100 on the left.

The regimen was to be given for six cycles of alternating MTX and R-CHOP. Due to eventual improvement in blood chemistry labs after the third cycle of MTX at 2 g/m², the 4th–6th cycles were given at 2.5 g/m². The third to sixth doses of MTX were given on days 88, 119, 160, and 194. From cycle 3 onwards, rituximab was given at 375 mg/m² on day 1 of chemotherapy, and doxorubicin, cyclophosphamide, and vincristine were given on day 2 with prednisone still on days 1–5. These were given on days 104–108, 133–137, 171–175, and 212–216. The most common side effects in the patient were febrile neutropenia and hospital-acquired pneumonia, which were treated with filgrastim and antibiotics, respectively. These caused a delay for the administration of the next cycle. Uric acid did not increase further, LDH decreased to 191 U/L, and AST decreased to 46 U/L at the end of treatment. During the course, there were three episodes of hyperkalemia at most 5.6 mEq/L and two episodes of low calcium at most 7.7 mg/dL. The patient was able to complete six cycles of the regimen and stayed for a total of 8 months. A succeeding PET scan was done 1 month and 3 months after the last cycle of treatment (Fig. 2). The last scan showed a sustained complete response.

DISCUSSION

R-CHOP is the standard therapy for DLBCL. In cases with CNS involvement, the recommended regimen of NCCN is R-CHOP combined with high-dose MTX [1]. However, elderly patients are unique due to individual characteristics and comorbidities. Elderly cancer patients are more fragile and more sensitive to chemotherapy-related toxicities [7].

The optimal regimen for treating elderly or frail patients with SCNSL is yet to be defined. Evidence is mainly derived from primary CNS lymphoma (PCNSL) studies. A meta-analysis of 20 PCNSL studies including patients >60 years old found that high-dose MTX-based therapy was associated with more favorable outcomes than therapies without high-dose MTX in elderly patients [5]. Another study examined elderly patients given a dose of 1–2.5 g/m² of MTX. Of these patients, the 89-year-old given 1 g/m² had an overall survival of 6.3 months; the 90-year-old started at 2 g/m², raised to 3 g/m², but decreased back to 2.5 g/m² due to pleural effusion, had an overall survival of 5.8 months; and the 86-year-old, who initially started at 2 g and then increased to 3.5 g, had a 17.2-month overall survival and was still alive as the study was published [8]. Another study reported a case of a 64-year-old patient on chronic hemodialysis with PCNSL. The patient was treated with MTX at 100 mg/m², and dialysis was done 24 hours thereafter. The patient had no significant toxicity and was in complete remission after 1 year of treatment [9].

A study done in 2015 on DLBCL with CNS involvement at initial presentation employed R-CHOP and MTX at 1–1.5 g/m² at a dose intensity of 4-week intervals. The study concluded that the dose of MTX or interval of each chemotherapy cycle used in this trial was considered insufficient due to CNS lesions progressing in all relapsed and refractory patients [10].

For this patient, caution was considered due to the risk of TLS. She had no significant nephrotoxicity and cardiotoxicity. Although there were episodes of hypocalcemia and hyperkalemia, these did not cause significant clinical symptoms for the patient and do not fulfill the laboratory criteria of TLS, which include a calcium ≤7 mg/dL and potassium ≥6 [11]. Otherwise, the patient was able to tolerate the medications. Despite the poor urinary alkalinization, the patient was also able to tolerate MTX administration. The patient had myelosuppression presenting as febrile neutropenia and pneumonia during the hospital stay, which could have been aggravated by MTX but was appropriately managed. Due to these complications from the therapy, it is important to have close monitoring for elderly patients.

Although there are studies that have employed a lower dose of MTX in the past, results vary. This patient, even with a lower dose of MTX and an unconventional schedule of R-CHOP compared to standard treatment, still achieved complete remission. There is still room for additional research, especially on the dose that will best fit elderly patients and their risk for worsening of comorbidities. The current dose of 3 g/m² is recommended by guidelines; however, the dose of 2–2.5 g/m² used on our patient still produced a good clinical outcome.

Although this case report demonstrates the feasibility of a modified R-CHOP regimen with reduced-dose MTX in an elderly patient, the limitations of a single case prevent generalization; further studies in larger cohorts are needed to validate these findings and establish standardized dosing protocols. This case report supplies data that could contribute to finding the optimal regimen we can give to patients with SCNSL.

In conclusion, the regimen and optimal treatment dose of elderly patients with DLBCL with CNS involvement are yet to be defined. Dose adjustment of systemic chemotherapy can still offer treatment response. This information can help with the available data on the search for the lowest dose to lessen the risk of adverse events without compromising the effectiveness of treatment.

Availability of Data and Material

Data sharing not applicable to this article as no datasets were generated or analyzed during the study.