Remission of HIV-related naïve and high-risk Burkitt’s lymphoma treated by autologous stem cell transplantation plus cART

Patient

A 27-year-old male was admitted to our unit upon presentation of a painless mass in the right groin in April 2015. Biopsies of the lesion revealed lymphoma, and antibodies against HIV were positive. He refused to accept any treatment for the concomitant HIV infection. In the following 3 months, the mass became larger and ulcers formed on the skin. In addition, the right thigh also became involved. He suffered from recurrent fever, with a body temperature fluctuating from 38 to 40.5 °C, and his body weight decreased by approximately 12 kg within 3 months.

In August 2015, a biopsy of the mass aspirate showed BL, and the immunohistochemical results were positive for CD20 and EBV-encoded RNA (EBER)1/2. In addition, a bone marrow biopsy showed the total chromosomes to be normal, whereas the percentage of unidentified cells was 1.8%.

Using positron emission tomography–computed tomography (PET–CT), we found increased abnormal metabolism of fludeoxyglucose (FDG) in the right groin; the region had dimensions (in cm) of 12.0 × 16.5 × 27.0, and the boundaries were not clear. The right thigh, anterior to the bilateral mandible, neck, axillary, retroperitoneal vessel, right iliac fossa, pelvic wall, and right inguinal lymph nodes shown increased metabolism of FDG. A blood count showed abnormal levels of lactate dehydrogenase (LDH; 1579 U/L) as well as a white blood cell (WBC) count of 4.42 × 10⁹/L, a neutrophil count of 2.92 × 10⁹/L, a hemoglobin level of 122 g/L, and platelet count of 330 × 10⁹/L. The patient was diagnosed as having stage IV BL.

The HIV RNA load was 51,386 copies/mL, and the CD4+ T cell count was 107 cells/μL at the time of BL diagnosis. In addition, the patient was co-infected with EBV, and the EBV DNA load was 4.09 × 10⁴ copies/mL. No other serious opportunistic infections were present, and the CD4+ T cell count was < 200 cells/μL; therefore, he was started on cART immediately with lamivudine (300 mg daily), tenofovir (300 mg daily), and efavirenz (600 mg daily) on the 25th of August 2015. These medications were not changed, and drug resistance did not occur.

The patient was started on a standard dose of rituximab, piraubicin, vincristine, etoposide, cyclophosphamide, and prednisone acetate (R-EPOCH) chemotherapy on the 31st of August 2015 (day 0). The patient developed a fever on the 6th of September because of a Staphylococcus aureus infection in his ulcer, based on a drug-sensitivity test. The patient is allergic to penicillin; therefore, he received lincomycin (400 mg, q.d.s.). Local debridement was performed every day, and his temperature returned to normal 7 days after treatment. Lincomycin was stopped on day 16 because of a continuous negative result in blood culture. He was diagnosed with agranulemia (neutrophil count = 0.01 × 10⁹/L) on day 13, and granulocyte-colony stimulating factor (G-CSF; 150 μg, q.d.s) was given until the neutrophil count reached 0.5 × 10⁹/L. Meanwhile, he suffered a pulmonary infection and meropenem (0.5 g, b.d.s.) was added until the symptoms were controlled completely (achieved on day 30). A bone marrow biopsy showed that proliferation of the bone marrow was active, and abnormal cells were not detected.

The second cycle of chemotherapy comprised rituximab, methotrexate, and cytosine arabinoside (Ara-C). It was started on the 21st of September (day 22) and stopped on the 23rd of September (day 24). No serious complications occurred, and the EBV DNA load was reduced to 5 × 10³ copies/mL on day 30.

From the 9th of October (day 40) to the 23rd of October (day 54), he received a third cycle of chemotherapy with rituximab, cyclophosphamide, vinorelbine, pirarubicin, and dexamethasone (R + HyperCVAD). The EBV DNA load was undetectable after the third cycle of chemotherapy.

From the 30th of October (day 61) to the 1st of November (day 63), a fourth cycle of chemotherapy (rituximab plus methotrexate/Ara-C (R-MA)) was undertaken. In addition, six intrathecal injections of methotrexate, Ara-C, and dexamethasone were used during the second and fourth cycles of chemotherapy. After the fourth cycle of chemotherapy, the HIV RNA load was < 40 copies/mL, the CD4+ T cell count was 193 cells/μL, and the LDH level was 91 U/L. PET–CT showed that the tumor volume in the right groin and the maximum standardized uptake value (SUVmax) were reduced significantly, which suggested that tumor activity had been inhibited (Fig. 1a).

During the second and fourth cycles of chemotherapy, when the neutrophil count was < 0.5 × 10⁹/L, G-CSF (150 μg, q.d.s.) was administered until the neutrophil count reached 0.5 × 10⁹/L. Symptoms of myelosuppression were treated by infusion of packed red blood cells (RBCs) and concentrated platelets, and oral mucositis was treated by gargling with chlorhexidine. The details of the chemotherapy regimens are summarized in Fig. 2.

Apheresis and processing of peripheral blood stem cells (PBSCs)

Before stem cell mobilization, the R-EPOCH regimen was used between the 20th of November (day 113) and the 25th of November (day 118) 2015 (Fig. 2). On the 27th of November, the WBC count was 0.5 × 10⁹/L, and G-CSF (5 μg/kg per day) was used for PBSC mobilization for the next 5 days. When the WBC count reached 4 × 10⁹/L on the 2nd of December (day 125), PBSC apheresis was undertaken using a continuous blood-cell separator (COBE® Spectra; Terumo BCT, Lakewood, CO, USA). Then, CD34-positive cells were analyzed using a FACScan™ flow cytometer (Becton Dickinson, Franklin Lakes, NJ, USA). A total of 1.03 × 10⁶/kg CD34-positive cells were obtained after undertaking apheresis twice on two consecutive days. PBSC products were combined with a cytoprotectant containing a final concentration of 10% dimethylsulfoxide (Research Industries, Salt Lake City, UT, USA) and freezing at − 150 °C for transfusion.

Conditioning regimen and PBSC transfusion

The conditioning regimen consisted of carmustine, etoposide, Ara-C, and melphalan, which began on the 11th of January (day 164) and stopped on the 16th of January 2016 (day 169). During PBSC transfusion, only myelosuppression occurred, and serious infections were not observed. Neutropenia was treated by G-CSF (1.5 μg/kg per day), and symptoms of anemia and thrombocytopenia were treated by infusion of packed RBCs and concentrated platelets. Mobilized PBSCs were infused 2 days after completion of melphalan treatment on the 18th of January (day 171) and the 19th of January (day 172).

Remission status

After the fourth cycle of chemotherapy, PET–CT scans of the bilateral mandible and neck, chest, abdomen, spine, and big vessels in the para-retroperitoneal, pelvic bones, and bilateral upper femur showed that multiple FDG metabolic abnormalities had disappeared. A follow-up study using bone marrow biopsies showed no morphological evidence of lymphoma, and laboratory studies did not show abnormal blood parameters. The patient remains in complete remission from his lymphoma 30 months after transplantation. In addition, after the third cycle of chemotherapy, EBV DNA was undetectable, and the EBV infection has never recurred in the follow-up study.

Engraftment

The patient reached a total neutrophil count of 0.5 × 10⁹/L at 14 days and a platelet count > 25 × 10⁹/L without further infusion of platelets at 25 days after ASCT. A bone marrow biopsy showed active proliferation of nucleated cells, as well as recovery of normal hematopoiesis of the bone marrow at 30 days after ASCT.

HIV viral load and CD4+ T cell count

The patient has remained in complete remission from BL for 30 months after ASCT. The HIV RNA load was < 40 copies/mL after the fourth cycle of chemotherapy, and the CD4+ T cell count was 323 cells/μL in August 2018, as shown in Fig. 1b.