The patient received induction therapy with VDCP (vindesine, daunorubicin, cyclophosphamide, and dexamethasone) on September 1, 2016. Then, he was administered with six courses of alternative therapy with Hyper-CVAD-A (cyclophosphamide, vindesine, doxorubicin, and dexamethasone), MAVP (methotrexate, cytarabine, vindesine, and dexamethasone), and central nervous system prophylaxis. One month after the last round of therapy, B-ultrasound showed that the inguinal lymph nodes were enlarged; the largest was 2.3 × 0.6 cm.

Therefore, the patient was enrolled in our clinical trials of ASCT bridging CD19 CART as consolidation therapies (NCT02672501). Peripheral blood lymphocyte separation and collection after a bone marrow aspiration biopsy showed complete remission, followed by CE regimen chemotherapy (cyclophosphamide 2g day1-2 and etoposide 330mg day1-2). When the patient’s blood routine level dropped to the lowest level, G-CSF (granulocyte-colony stimulating factor) 400ug were injected for 4 consecutive days. Peripheral blood mononuclear cells were collected using apheresis. The conditioning therapy for the patient undergoing ASCT was CEAC (semustine, etoposide, cytarabine, and cyclophosphamide), which included semustine (250 mg/m2) on day -6, cytarabine (500 mg/m2) every 12 h, and etoposide (300 mg/m2) and cyclophosphamide (1.0 g/m2) from days -5 to -2. The patient developed fever (37.8°C) and nasal congestion on day-4, and recovered after cefoperazone-sulbactam treatment. Autologous hematopoietic stem cells were infused on day 0 with a mononuclear cell dose of 4.2 × 108/kg and a CD34+ cell dose of 2.69 × 106/kg. On day +5, he developed fever (38.2°C) due to agranulocytosis, which returned to normal after 2 days of cefoperazone-sulbactam treatment. Additionally, 6 × 106/kg CART cells were infused 7 d after ASCT. The CART products included 32.8% CD45+CD62L+ naive CART cells, 44.7% CD45RA-CD62L+ central memory CART cells, and 15.9% CD45RA-CD62L- effector memory CART cells. Grade 1 cytokine release syndrome was reached according to the Penn grading scale, because the patient developed a high fever with a body temperature of 39°C 2 h after infusion. Vancomycin was added to prevent infection and body temperature returned to normal 2 days later without using steroids and tocilizumab. No manifestations of neurotoxicity and other adverse effects in this patient. The time of neutrophil and platelet engraftment was 10 days and 11 days after ASCT, respectively. The patient achieved CR and has been in remission for four years.

This case study shows that combination of autologous stem cell transplantation and chimeric antigen receptor T-cells for Burkitt lymphoma is safe and feasible, what are your thoughts?

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On February 9, she received induction chemotherapy with VIP regimen (vincristine, idarubicin, and dexamethasone) and successfully achieved CR.Next, consolidation chemotherapy including VILP (VIP+ asparaginase) and hyper-CVAD regimen was performed. The patient refused allo-HSCT at the time of the first CR.In November 2016, bone marrow examination showed 41% lymphoblastic cells, indicating leukemia relapse.After re-induction therapy with VILP regimen, the patient attained her second CR. She subsequently underwent an umbilical cord blood transplantation (UCBT) in May 2017. Allografts were from a 4/6 HLA-matched unrelated umbilical cord blood according to low-resolution. The doses of total nucleated cells and CD34+ cells infused were 3.9×107/kg and 3.0×105/kg, respectively. The conditioning regimen included intravenous busulfan at 3.2 mg/kg/d for 4 days, cyclophosphamide at 60 mg/kg daily for 2 days, and fludarabine at 30 mg/m2 daily for 4 days. Cyclosporine and mycophenolate mofetil were used for GVHD prophylaxis. Neutrophil and platelet engraftment was observed on day 22 and day 37 after umbilical cord blood infusion, respectively. The patient maintained CR for 19 months with complete donor chimerism and without graft-versus-host disease.However, in January 2019, 21% of lymphoblasts were detected in the bone marrow by morphological analysis and flow cytometry. The patient relapsed again after UCBT. Intriguingly, chimerism testing using short tandem repeats still showed complete donor chimerism at this time point. This was termed “donor cell-derived leukemia”(DCL). Chemotherapy with VIP regimen failed to induce remission (32% lymphoblasts in bone marrow). The patient had no opportunity for second transplantation due to lack of available donors. CAR-T cell therapy was recommended for the patient. She was enrolled in our clinical trial of anti-CD19 CAR-T cell therapy. The patient received lymphodepletion pretreatment with FC regimen (fludarabine 30 mg/m2 daily for 3 days, cyclophosphamide 300 mg/m2 daily for 3 days) from March 13, 2019 to March 15, 2019. After the lymphodepletion pretreatment, anti-CD19 CAR-T cells were infused at a total dose of 2.0×106/kg for 3 consecutive days (0.2×106/kg at day 0, 0.6×106/kg at day 1, 1.2×106/kg at day 2). Body temperature, cytokine levels, and c-reactive protein (CRP) were monitored. The patient developed a fever with a maximum body temperature of 38°C on day 6. The temperature rose to 39°C and the blood pressure dropped to 83/58 mmHg on day 7. The patient was diagnosed with grade 2 cytokine release syndrome (CRS). Non-steroidal anti-inflammatory drugs (NSAIDs) and tocilizumab (8 mg/kg) were used for CRS. Afterward, the temperature dropped gradually and returned to normal after a week. The highest serum level of interleukin 6 (IL-6) was 363 pg/mL on day 7. The copy number of anti-CD19 CAR in peripheral blood reached its peak on day 10, which was 1.08×105 copies/μg.DNA. On April 4, 2019 (day 17), the bone marrow smear found no lymphoblast, and FCM revealed MRD negative (MRD<0.01% by 8-color flow cytometry). On day 118 after CAR-T cells infusion, the copy number of CAR was not detected. The patient remained in MRD-negative status for 5 months. On August 20, 2019, flow cytometry examination showed MRD levels of 0.05% for 2 consecutive bone marrow samples within a 1-month interval. The immunophenotype of MRD was CD34+CD10+CD19+CD22+ CD58dim CD20-CD123-. Given the increased MRD levels, the patient was given 3 million IU of interferon-α-2b, three times a week. She achieved MRD negative again after 42 days of interferon-alpha treatment. Interferon-α-2b was used for 2 years. Notably, analysis of immune cell subsets from peripheral blood showed a significant increase in the proportion of CD16+ CD56+ NK cells. To date, the patient has maintained CR for 41 months after CAR-T cells followed by interferon-α therapy. No adverse reactions were observed during interferon-α treatment. The patient is still under follow-up now.

The present case suggested that anti-CD19 CAR-T cell followed by interferon-α treatment was effective in donor cell-derived B-ALL, Can sequential interferon-α therapy helps maintain durable remission in all leukemia patients who relapse after allo-HSCT?

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The patient was enrolled in the chemo-immunotherapy GIMEMA LAL2317 protocol, which exploits a risk-oriented strategy based on disease characteristics and MRD evaluation at fixed time-points, intercalating a maximum of two cycles of blinatumomab into a pediatric-like chemotherapy backbone (clinicaltrial.gov NCT03367299).

Our patient, classified as very high risk, underwent three cycles of chemotherapy, obtaining a complete morphologic remission (CR) after induction. Central nervous system (CNS) prophylaxis was carried out as per protocol. MRD assessment by RQ-PCR Ig gene rearrangement remained strongly positive (>10-2) after all three chemotherapy cycles. After a single cycle of blinatumomab which induced the molecular remission (<10-5), the patient underwent an allogeneic hematopoietic stem cell transplant (HSCT) from an HLA-identical sister. Conditioning consisted of treosulfan, fludarabine and TBI 4 Gy, and the graft versus host disease (GvHD) prophylaxis included post-transplantation cyclophosphamide and sirolimus. A post-transplant aspirate documented a CR with full donor chimerism, FISH and a molecular MRD negativity. Sirolimus was discontinued six months later. The patient never developed GvHD.

In January 2021, 18 months after the HSCT, a BM evaluation detected a relapse (5% blasts). The patient had also a palpable mass in her right breast, whose histology was compatible with an ALL localization. No CNS disease was detected.

The patient was deemed fit for anti-CD19 CAR-T cell therapy with tisagenlecleucel. After lymphapheresis in early February, we started a bridging treatment with ponatinib 45 mg daily for 30 days on compassionate use and 1 mg/kg prednisone for 14 days. No cardiac, hepatic or hematologic toxicity was reported. In mid-February, we repeated a BM aspirate that confirmed a morphologic relapse (12% blasts). A third aspirate after a month of ponatinib showed a stable disease (8% blasts) and on physical examination a reduction of the palpable breast nodule was documented. We withdrew bridging drugs and started lymphodepletion with fludarabine-cyclophosphamide, followed by a CAR-T cell infusion on March 2021. The patient developed a grade 4 neutropenia and received three doses of tocilizumab for grade 1 cytokine release syndrome (CRS). No neurotoxicity occurred. Three months later the patient was in CR with a full donor chimerism and a MRD negativity. A breast ultrasound revealed a regression of her nodule. In June 2021, maintenance with ponatinib at a lower dose (15 mg/day) was initiated. In November 2022, 20 months after the CAR-T cell infusion the patient is in good clinical conditions and in persistent molecular CR. She still receives ponatinib maintenance with excellent tolerance, except for a 10-day discontinuation due to a transient G4 neutropenia. At late time-points (day 180 and 270), the patient still had circulating anti-CD19 CAR-T cells (4.0 and 4.3/mcl, respectively). At the last available follow-up (365 days, April 2022), circulating CAR-T cells were no longer.

In your clinical practice, have your ever used a bridging therapy with CAR-T cells?

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