Efficacy of Pola-R-CHP and Autologous Stem Cell Transplantation in Untreated Burkitt Lymphoma: A Case Report

Introduction

Burkitt lymphoma (BL), an aggressive B-cell lymphoma that accounts for 1% to 5% of non-Hodgkin lymphoma cases, is typically characterized by monomorphic intermediate-sized mature malignant B cells that express CD10, bcl-6 but not bcl-2, with high Ki-67 positivity (~100%), and c-MYC translocation [1]. The conventional upfront treatment of BL includes highly dose-intensive chemoimmunotherapy regimens plus rituximab adopted from pediatric leukemia, but treatment-related toxicity worsens with increasing age [2,3]. Dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) reduces drug exposure over patients with low-risk diseases and alleviates toxicity associated with high drug concentrations, by prolonging drug exposure with infusional chemotherapy, which makes it preferable for young and elderly patients [4]. For patients with chemosensitive relapsed/refractory BL and other patients with lymphoma, autologous stem cell transplantation (ASCT) is currently the standard care, in which first-line ASCT consolidation remains active in high-risk/high-grade B-cell lymphoma [5]. Polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) is now recommended for intermediate-/high-risk diffuse large B-cell lymphoma (DLBCL), with promising results in the POLARIX trial and manifested promising effectiveness in the real-world setting [6,7]. The extended application of polatuzumab vedotin in other aggressive B-cell lymphoma is currently under exploration [8]. In BL, polatuzumab vedotin plus bendamustine and rituximab (Pola-BR) showed long-term effectiveness in treating 2 patients with refractory disease [9,10]. This report describes the first case of a 56-year-old woman with BL treated with upfront Pola-R-CHP followed by ASCT.

Case Report

An 56-year-old Asian female patient with aggravating abdominal pain and constipation within 1 month received a diagnosis of incomplete intestine obstruction. An abdominal contrast-enhanced computed tomography (CT) scan indicated suspected lymphoma, with multiple retroperitoneal, right iliac, and right pelvic masses. An apparent weight loss due to dysphagia and poor nutrition status resulted in extreme weakness within 1 month. No fever or night sweats were observed. The Eastern Cooperative Oncology Group (ECOG) performance status score was 2. Hemoglobin, creatinine, and electrolyte levels were within the reference range. The lactate dehydrogenase (LDH) was 903 U/L, 3 times higher than the upper limit of normal (range: 109–245 U/L). The Epstein-Barr virus copy number in peripheral blood mononuclear cells was 1×105. Hepatitis B virus (HBV) core antibody was positive. HIV screening was negative. Bone marrow involvement was excluded. Positron emission tomography/computed tomography (PET/CT) revealed multiple enlarged lymph nodes (posterior mediastinal, retroperitoneal, and pelvic area), with elevated standard uptake value (SUVmax 21.0; maximum size of involved lymph node 81.0×53.0 mm) and extensive extra nodal involvement (stomach, bilateral mammary glands, bilateral adrenal glands, uterus, left chest wall, interval of medial and lateral pterygoid, and multiple bones; Figure 1A, 1D). The formal pathological report indicated BL, with a mature B cell phenotype (CD19, CD20, CD79a, CD10, Bcl-6 positive, and Bcl-2, CD5, MUM-1 negative in immunochemistry staining) with high proliferative rate (Ki-67+, 90%) and high c-Myc expression (90%+) (Figure 2A–2G). Fluorescence in situ hybridization analysis showed translocation of c-Myc, with the IgH gene (Figure 2H). The Epstein-Barr virus encoding region was positive via in situ hybridization. Certral nervous system (CNS) involvement was excluded through cerebrospinal fluid examination. The final diagnosis was BL with B symptoms, Ann Arbor Stage IV. The Burkitt Lymphoma International Prognostic Index score was 3. She was stratified to a high-risk group, without CNS involvement.

Standard treatments for patients with BL under 60 years old include intensive chemotherapy, such as hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone plus rituximab (Hyper-CVAD-R), cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate (CODOX-M)/ifosfamide, etoposide and high-dose cytarabine (IVAC), plus rituximab or DA-EPOCH, were not suitable as induction therapy for this patient because of her poor physical condition, low body weight, and malnutrition [3,4,11]. Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) is not adequate therapy due to its insufficient treatment intensity, but a following ASCT consolidation can improve further remission [12]. Pola-R-CHP offers a progression-free survival (PFS) benefit over CHOP in patients with DLBCL and an IPI score of 2–5. Furthermore, signaling through the B-cell antigen receptor (BCR) component Igβ (CD79b) is also required for the tumor growth of BL [13]. Polatuzumab vedotin can be effective in this type of lymphoma. Therefore, Pola-R-CHP (intravenous polatuzumab vedotin 1.8 mg/kg on day 1, rituximab 375 mg/m2 on day 1, cyclophosphamide 750 mg/m2 on day 1, epirubicin 70 mg/m2 on day 1 [the substitution of doxorubicin with epirubicin was on the basis of a phase 3 trial of anthracycline dose optimization in untreated DLBCL or follicular lymphoma grade 3B [14]], and oral prednisone 100 mg from day 1 to day 5; 21 days 1 cycle) was chosen for this patient in frail condition. Once the disease was chemo-sensitive and the patient’s performance status recovered, a sequential high-dose therapy with ASCT would be given after the completion of induction therapy. Supportive hydration and alkalization, to prevent tumor lysis, and parenteral nutrition containing intralipid, glucose, and vital amino acids/vitamins/minerals were given for nutrition support. Entecavir was given as prophylaxis of HBV reactivation. Granulocyte colony-stimulating factor (G-CSF) was given as secondary prophylaxis, as it was not reimbursed by national health care in China for primary prophylaxis. After the first dose of therapy, her abdominal pain and constipation were rapidly relieved. An interim PET/CT scan after cycle 3 showed complete metabolic remission (CMR) with multiple lymph node and extranodal lesions regressed (Figure 1B, 1E with 2 points by the Deauville 5-point scales). The major hematological toxicity was grade 3 neutropenia. After the fourth cycle, the patient developed grade 3 pneumonia. In consideration of potential concomitant interstitial pneumonia, due to immunotherapy, 2 cycles of CHP were given, while polatuzumab vedotin plus rituximab (Pola-R) were suspended. No additional dose adjustment was made. The patient recovered from fever and pneumonia under best supportive care. Sequential 4 times of preventive intrathecal methotrexate (10 mg once) and dexamethasone (5 mg once) injections were given. The patient remained in CMR by PET/CT assessment after 6 cycles of induction therapy (Figure 1C, with 2 points by Deauville 5-point scales). A biopsy via upper gastrointestinal endoscopy confirmed no residue of lymphoma cells in the stomach. Her performance status score recovered to 1, and she underwent ASCT as planned.

With stem cell mobilization (cyclophosphamide 3 g/m2, G-CSF 7.5 g/kg) after the confirmation of CMR by 6 cycles of treatment (4 cycles of Pola-R-CHP and 2 cycles of CHP in consideration of suspected interstitial pneumonia due to Pola-R), mononuclear cells of 8.23×108/kg and peripheral blood CD34+ cells of 2.43×108/kg were collected. After 2 cycles of postponed Pola-R, continuous complete remission (CR) status was confirmed by CT scan. Bendamustine (150 mg/m2, day -7 and day -6), etoposide (150 mg/m2, days -5 to -3), cytarabine (150 mg/m2, days -5 to -3) and melphalan (140 mg/m2, day -2, stem cell infusion on day 0) (BeEAM) was selected as the conditioning regimen. During the transplantation, a grade 4 febrile neutropenia and thrombocytopenia, a grade 3 diarrhea due to opportunistic infection of Candida albicans, and a grade 1 elevation of transaminase were observed. Supportive hematopoietic growth factor, prophylactic intravenous meropenem and vancomycin, oral fluconazole, platelet transfusion, and best supportive care were given. A post-transplant PET/CT confirmed durable CMR status. An intensified follow-up period of every 3 months (including blood tests and contrast-enhanced CT examination) was ongoing, to detect possible early relapse. The last CT scan showed a sustained response for 12.9 months after the initiation of chemoimmunotherapy.

Discussion

We reported a case of a patient with BL who was unfit for standard therapies and was treated with upfront Pola-R-CHP, followed by high-dose therapy and ASCT consolidation. The regimen was effective, with acceptable toxicity, which was relieved by best supportive care.

The standard first-line treatment of adult BL was originally adopted from pediatric leukemia, with the addition of a CD20-targeted regimen. The efficacy of such a highly dose-intensive strategy is promising, although at the cost of hematologic and infectious toxicity. In a cohort of 31 adult patients with BL/acute lymphoblastic leukemia (B-ALL) receiving hyper-CVAD-R, the CR was 86% [3]. Major treatment toxicity included myelosuppression (all patients) and infections (13 febrile neutropenia, 3 sepsis, 2 pneumonia, and 3 others). In a long-term follow-up of hyper-CVAD-R in 54 patients with BL, CR was 96%, while the 5-year relapse-free survival and overall survival (OS) were 59% and 55%, respectively [15]. Patients in arm of CODOX-M/IVAC plus rituximab had a CR rate of 90% [11]. The 3-year PFS and OS were 74% and 77%. Over 90% of patients developed grade 4 neutropenia, while 70% experienced at least 1 episode of febrile neutropenia. A multicenter clinical trial evaluating DA-EPOCH-R confirmed that low-intensity infusional chemotherapy was effective and safe in certain BL patients with relatively lower-risk disease and predominantly an absence of CNS involvement [4]. The 4-year event-free survival and OS rates of all patients were 84.5% and 87%, and those of high-risk patients were 82.1% and 84.9%. The overall population was physically fit, for the median age was 49 years and only 18% of patients had a ECOG performance status ≥2. Grade 3–4 thrombocytopenia (17% cycles), febrile neutropenia (16% cycles), mucositis (19% patients), grade 3–4 sensory neuropathy (5% patients), and grade 2–4 motor neuropathy (6% patients) were the most common adverse events. Four of the 5 treatment-related deaths occurred in patients >50 years old with an ECOG performance status ≥2, each resulting from sepsis or multiorgan failure.

CD79b is expressed in almost all types of B-cell non-Hodgkin lymphoma. A humanized anti-CD79b antibody-drug conjugate, polatuzumab vedotin, in combination of R-CHP, showed a 6.5% higher 2-year PFS rate in previously untreated intermediate-/high-risk DLBCL in the POLARIX trial [6]. On the other hand, there were limited data on using polazutumab in treating patients with BL. For untreated aggressive large B-cell lymphoma other than BL, one phase I study demonstrated an acceptable safety profile of polatuzumab vedotin plus dose-adjusted etoposide, prednisone, cyclophosphamide, doxorubicin, and rituximab (DA-EPCH-R), since the substitution of vincristine with polatuzumab vedotin did not affect the escalation of chemotherapy dosing (NCT04231877) [8]. Having an overall response rate of 100% and CR rate of 76%, this cohort had a 12-month event-free survival and OS rate of 72% and 94%. Five serious adverse events and 3 dose-limiting toxicities were observed in 18 patients. Further, a trial evaluating ASCT followed by polatuzumab vedotin every 4 months for 2 years is in recruitment (NCT04491370), which may provide more evidence of the polatuzumab vedotin maintenance in refractory/relapsed BL in the future.

Polatuzumab vetodin was previously reported in 2 refractory BL patients separately, both of whom had a promising disease-free survival of over 1 year after the Pola-BR protocol [9,10]. In the present, newly diagnosed BL case, the diagnosis was clear, since the pathological test results showed typical morphology of BL, while the abdominal mass aligned with the clinical manifestations of this subtype of lymphoma. The performance status might be even poorer than that of those patients with refractory disease, due to her severe abdominal pain symptom and malnutrition status. Because of her intolerance to standard regimens of BL, Pola-R-CHP was given, with rapid tumor regression and symptom relief. Since her performance status was greatly improved, ASCT was applied as planned. The overall safety of polatuzumab-vetodin-based therapy for BL was acceptable. However, 1 patient with refractory disease had disseminated tuberculosis, due to secondary immunodeficiency due to lymphoma treatment. Our patient recovered well from a grade 3 pneumonia during the induction treatment. Long-term monitoring of immune function and disease status remains important.

The role of first-line ASCT in BL was convincing before the era of highly dose-intensive chemotherapy. CHOP, a standard regimen for aggressive NHL, adopted alone, was not suitable for BL. Reported retrospectively, intravenous and intrathecal methotrexate plus CHOP (MmCHOP) had a poor 5-year PFS rate of only 30.8%, compared with MmCHOP consolidated with high-dose therapy and ASCT (70.6%) [12]. To note, the German Berlin-Frankfurt-Munster (BFM) arm had a promising 5-year PFS of 73.7%. All patients who received either the BFM regimen or MmCHOP with high-dose therapy were continuously disease-free. However, this study enrolled BL and Burkitt-like lymphoma in adolescents and adults and might not represent adult BL patients alone. A pilot study (abstract only available) enrolled 23 patients with BL who underwent highly dose-intensive chemotherapy and ASCT [16]. None of the 8 patients who had ASCT at CR1 (CR after first-line induction therapy) relapsed, indicating a potential benefit of ASCT. However, since all patients enrolled underwent ASCT, it was still unknown whether patients at CR1 could gain extra benefit from transplantation. A larger cohort with stratification and extended follow-up might redetermine the role of ASCT after highly dose-intensive therapies in BL.

In the present case, a patient with BL with high tumor burden and severe malnutrition at baseline was evaluated as being unable to undergo a standard highly dose-intensive chemoimmunotherapy, and received an upfront Pola-R-CHP regimen. After the first few doses of therapy and best supportive care, her performance status was improved, and she was able to receive sequential high-dose therapy and ASCT consolidation as planned. Herein, we report a clinical case in which an initially “unfit” patient with BL benefited from moderate-intense induction therapy and sequential consolidation therapy after recovery to a fit status. Long-term follow-up is required.

Conclusions

This is a case of a patient with BL receiving upfront Pola-R-CHP with ASCT consolidation. A quick and durable response was confirmed. The treatment was well tolerated. A lasting response to Pola-R-CHP followed by ASCT consolidation is possible, although long-term follow-up is required. Our case suggests a clinical strategy of treating unfit patients with BL who can convert into a fit status with Pola-R-CHP and ASCT consolidation afterward. Further research is required to confirm the effectiveness and safety of Pola-R-CHP in untreated patients with BL.