Single-agent MOR208 salvage and maintenance therapy in a patient with refractory/relapsing diffuse large B-cell lymphoma: a case report

Our 33-year-old male Caucasian patient presented with a 3-month history of general symptoms (weakness, excessive sweating, and episodes of low-grade fever) and was admitted to our pulmonology ward with dyspnea due to pneumonia and severe anemia (hemoglobin of 8.5 g/dl). A physical examination revealed enlargement of his right suprasternal lymph node, later excised for histopathology (Fig. 1). This confirmed a diagnosis of CD20-positive T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL), an uncommon morphological variant of DLBCL [8]. The neoplastic cells were CD19-positive, partially positive for CD30, and negative for CD15. At diagnosis, routine computed tomography (CT)-based staging confirmed Ann Arbor stage IVB disease, with generalized lymphadenopathy and hepatosplenomegaly (enlarged lymph nodes of the neck [subclavicular on right side], mediastinum [subcarinal, para-aortic, right pulmonary hilum, left pulmonary hilum], right axilla, and abdomen [celiac, para-aortic, para-iliac, spleen]). He also had sclerotic lesions of the ninth, tenth and twelfth thoracic vertebrae. A lumbar puncture with cerebrospinal fluid analysis excluded central nervous system (CNS) lymphoma involvement; in addition, an increased concentration of total protein showed no sign of oligoclonal bands. Our patient was deemed to have an age-adjusted International Prognostic Index (IPI) score [9] of 3 (stage IV, two extra-nodal sites, low lactate dehydrogenase, poor performance status, age <60 years).

Standard R-CHOP immunochemotherapy was administered to our patient as a first-line regimen (Table 1). As in all high-risk cases, liposomal cytarabine (DepoCyte 50 mg) was administered via the intrathecal route during the first four cycles for prophylaxis of CNS relapse. A good clinical response was confirmed by CT imaging after the third cycle (partial response; PR), followed by a complete response (CR) after eight cycles (treatment schema, Fig. 2) that was confirmed by positron emission tomography-computed tomography (PET-CT). During this first-line therapy, our patient twice developed neutropenic fever, which necessitated prolonged hospital admission, despite granulocyte-colony stimulating factor (G-CSF) primary prophylaxis.

Early relapse was confirmed 5 months after completion of first-line therapy. PET-CT imaging revealed multiple sites of high standard uptake values (SUVs), including the mediastinum blood pool structure (MBPS) and various sites in his head and neck region (parotid glands, palatine tonsils, submandibular lymph nodes), thorax (supraclavicular lymph nodes on the left, paratracheal chain), and abdomen (para-aortic lymph nodes, stomach, spleen, and liver [Deauville 5]). Elevated SUVs were also detected in his skeletal system, although there was no infection, nor G-CSF used, at that time. Radiological examination also revealed a right-side pleural effusion; in the absence of hypoalbuminemia or heart failure, this was also most likely related to the lymphoma.

As second-line salvage chemotherapy, our patient received three cycles of rituximab, etoposide, methylprednisolone, cisplatin, and cytarabine (R-ESHAP; Table 1). A PET-CT assessment demonstrated a PR to this second-line chemotherapy. A fourth cycle of salvage chemotherapy was then administered: dexamethasone, carmustine, etoposide, cytarabine, and melphalan (DexaBEAM), followed by ibritumomab tiuxetan, carmustine, etoposide, cytarabine, and melphalan (Z-BEAM)-conditioned ASCT (Table 1). This led to a CR, as confirmed by PET-CT. Our patient’s quality of life during second-line treatment and ASCT was poor, due to prolonged hospital admissions and his great concerns relating to potential severe complications of each of the salvage regimens.

At a 3-month follow-up visit after ASCT, our patient presented in good clinical condition and demonstrated weight gain. He had good hematopoietic reconstitution and elevated liver function tests, despite negative tests for hepatitis B and C. Although there were no clinical symptoms of disease or infection, a PET-CT assessment demonstrated increased metabolic activity consistent with early relapse, with high SUVs in the Waldeyer ring (palatine tonsils, pharyngeal tonsil, submandibular lymph nodes), the cervical lymph nodes on his left side, the axillary lymph nodes bilaterally, and his stomach, spleen (with splenomegaly), MBPS, and liver (Deauville 5).

At this point, our patient was enrolled in the MOR208 clinical study. During the first 12 weeks of treatment, MOR208 was administered intravenously at 12 mg/kg, once a week. Peripheral blood lymphocyte immunophenotyping by flow cytometry revealed prompt clearance of B-lymphocytes from his peripheral blood; in particular, a decrease in CD3−, CD56−, CD16−, and CD45+ B-lymphocytes and a compensatory increase in CD45+ and CD3+ T-lymphocytes was observed (Fig. 3). Three months after starting third-line MOR208 therapy, PET-CT assessments demonstrated a PR, with only a small number of metabolically active lymph nodes (palatine, cervical on his left side, axillary on his left side, axillary on his right side, lower part of his esophagus, MBPS, liver). Following the scheduled 12 weeks of treatment, MOR208 was continued as maintenance therapy, with administration every second week. PET-CT confirmed a CR 9 months later (Fig. 4).

MOR208 was very well-tolerated, with few adverse events. Our patient developed four upper respiratory tract infections, comprising three instances of pharyngitis that required symptomatic treatment and one incident of bronchitis, which necessitated antibiotic therapy (amoxicillin with clavulanic acid). Our patient did not have any hematological adverse events. During treatment with MOR208, our patient’s quality of life and performance status remained high (World Health Organization grade 0, Karnofsky score 100 %). No hospitalizations were required; all procedures were performed in a day clinic. Our patient engaged in full-time work and physical activities. He continues to be well, with an ongoing duration of response of 24 months.

The original CHOP chemotherapy regimen was introduced by the National Cancer Institute in the mid-seventies. The value of this regimen in the treatment of advanced stage NHL was proven 20 years later in a randomized comparison with so-called second-generation and third-generation regimens [10]. The first and, so far, only indisputable improvement to this regimen has been the incorporation of the anti-CD20 monoclonal antibody rituximab [11]. In particular, the addition of rituximab to CHOP was shown to significantly increase the CR rate, and significantly prolong event-free and overall survival in the first-line treatment of elderly patients with DLBCL. The addition of rituximab to re-induction chemotherapy was also shown to significantly prolong failure-free and progression-free survival in patients with relapsing aggressive CD20+ NHL that had not previously been treated with rituximab [12]. In the pre-rituximab era, high-dose therapy with ASCT allowed the rescue of nearly half of the patients responding to salvage therapy [13]. In the post-rituximab era, the CORAL study in patients with CD20+ relapsed/refractory DLBCL who were randomized to rituximab plus one of two salvage chemotherapy regimens showed that in patients with early relapse (<12 months), prior rituximab treatment was associated with poor prognosis [4]. Patients in this study with the molecular activated B-cell (ABC)-like subtype of DLBCL had a particularly poor outcome, irrespective of the assigned salvage therapy [14].

If NHLs are either initially resistant or subsequently develop resistance to rituximab, targeted agents directed against proteins other than CD20 may improve patient outcome. The B-lymphocyte lineage-specific surface antigen CD19 may represent one such alternative anticancer target. Early-stage studies of a number of CD19-targeted agents have provided encouraging data in patients with CLL and DLBCL [15]. In particular, the CD19 antibody MOR208 provided initial evidence for clinical activity in a phase I dose-escalation study in patients with relapsed or refractory CLL/SLL [7], as well as in the phase IIa NHL study in which our patient is enrolled [16]. In the CLL phase I trial, eight (30 %) of 27 enrolled patients had a PR, and a further 16 had stable disease on the basis of CT criteria, physical examination, and laboratory studies (International Workshop on Chronic Lymphocytic Leukemia criteria [17]). In particular, of the 16 patients treated at the recommended phase II dose of 12 mg/kg weekly, six (38 %) had a PR. The most frequent treatment emergent adverse events (TEAEs) of any grade were infusion-related reactions, which occurred in 11 (67 %) of 27 patients (all grade 1–2), despite premedication. The most common grade 3/4 TEAE was neutropenia (six patients, 22 %). Five patients (19 %) had grade 3/4 treatment-related TEAEs. One drug-limiting toxicity, grade 4 neutropenia lasting ≥7 days, was observed at the maximum administered dose of 12 mg/kg. The objective response rate in the NHL phase IIa trial was 23 % (21 of 92 patients); responses were seen in nine (26 %) of 35 patients with DLBCL, nine (26 %) of 34 patients with follicular lymphoma, and in three (27 %) of 11 patients with other indolent NHLs. Nine (10 %) patients experienced infusion-related reactions that were all grade 1–2 (except for one case of dyspnea, grade 4). Non-hematological and hematological TEAEs of grade 3 or above were seen in 24 (26 %) and 14 (15 %) of 92 patients, respectively. However, our patient did not experience severe hematological or non-hematological TEAEs during treatment with MOR208.

In our patient, we observed an early relapse after first-line R-CHOP chemotherapy, consistent with a dynamic and aggressive lymphoma with a likely poor prognosis. Although our patient underwent salvage chemotherapy followed by ASCT supported by the Z-BEAM conditioning regimen, the disease again proved resistant to treatment, and our patient experienced an early relapse. Considering these rapid relapses at both prior treatment steps, it was deemed to be very unlikely that palliative radiotherapy would have effectively cured the disease and prevented distant metastases. Given the exhaustion of all other available treatment options at our institution, third-line treatment with MOR208 was considered as a possible salvage therapy. Our patient was deemed to be eligible for a phase IIa, open-label, multicenter study of single-agent MOR208 in patients with relapsed or refractory DLBCL. The MOR208 regimen was based on the 12 mg/kg weekly dose recommended in the phase I study [7]. This treatment changed the lymphoma dynamics, possibly preventing its spread to distant sites, and provided extended progression-free survival for our patient (5 months after the R-CHOP chemotherapy and 6 months after BEAM ASCT versus over 20 months during the treatment with MOR208; Fig. 2). His quality of life was excellent and greatly improved compared with previous therapies. He participated in normal daily activities and the treatment was conducted primarily in an outpatient setting.

The CD19 monoclonal antibody MOR208 was an effective third-line treatment in this patient with DLBCL, despite a history of early relapse following a standard first-line regimen and a second-line treatment regimen that included ASCT. These results support the development of randomized studies of MOR208 therapy in patients with relapsed or refractory DLBCL.

Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.