Chimeric antigen receptor T-cell therapy as a bridge to haematopoietic stem cell transplantation for refractory/relapsed B-cell acute lymphoblastic leukemia

Although chimeric antigen receptor T cells (CAR-T) targeted at CD19 or CD22 have achieved high complete remission (CR) in refractory/relapsed B-cell acute lymphoblastic leukaemia (B-ALL), it is uncertain if allogeneic haematopoietic stem cell transplantation (allo-HSCT) should be performed after CAR-T therapy to accomplish a sustainable remission. Fifty-two cases with relapsed/refractory B-ALL who underwent allo-HSCT after CR by CD19 or CD22 CAR-T were enrolled. The median time from CAR-T infusion to allo-HSCT was 50 (34–98) days. Myeloablative reduced-intensity conditioning (RIC) with total body irradiation/fludarabine-based or busulfan/fludarabine-based regimens was used. Incidences of grade II–IV acute graft-versus-host disease (aGVHD) and severe aGVHD were 23·1% and 5·8% respectively. Of 48 evaluable cases, 16 developed chronic GVHD (cGVHD) and in three of them the pattern was extensive. With a median follow-up of 334 (41–479) days, one-year overall survival and event-free survival (EFS) were 87·7% and 73·0%. One-year relapse rate and transplant-related mortality (TRM) were 24·7% and 2·2% respectively. With quick bridge to allo-HSCT after CAR-T therapy, high EFS for refractory/relapsed B-ALL has been achieved in this relatively large cohort. Our myeloablative RIC regimens have resulted in low incidences of aGVHD, cGVHD, viral reactivation and very low TRM even majority of transplants from haploidentical donors. Long-term follow-up is warranted.     

Sequential chemotherapy and myeloablative allogeneic hematopoietic stem cell transplantation for refractory acute lymphoblastic leukemia

The prognosis of patients receiving allogeneic hematopoietic stem cell transplantation (HSCT) for refractory acute lymphoblastic leukemia (ALL) is very poor. To improve survival rates, we attempted to intensify the conditioning regimen with daunorubicin, vincristine, prednisolone, medium-dose etoposide, cyclophosphamide, and total body irradiation (DNR/VCR/PSL plus medium-dose VP/CY/TBI). Four patients in relapse or induction failure of B-precursor ALL without other complications underwent allogeneic HSCT. Initially, chemotherapy comprising DNR 60 mg/m(2) for 3 days, VCR 1.4 mg/m(2) for 1 day, and PSL 60 mg/m(2) for 3 days was administered, which was followed by medium-dose VP/CY/TBI; some modifications were made for individual patients. All patients achieved engraftment and complete remission after HSCT. Regimen-related toxicities were tolerable and no patient died within 100 days. Two patients were alive without disease on days 563 and 1,055. The third patient relapsed on day 951, while the fourth died on day 179 without disease. Our results indicate that intensified myeloablative HSCT should be considered for patients with refractory ALL.     

Favorable outcome of allogeneic hematopoietic stem cell transplantation for relapsed or refractory acute promyelocytic leukemia in childhood

The optimal therapy for children with relapsed or refractory acute promyelocytic leukemia (APL) is unclear. We therefore reviewed our institutional outcomes for children undergoing allogeneic hematopoietic stem cell transplantation (HSCT) for advanced APL. Between 1986 and 2003, 12 allogeneic HSCTs (five related donor, seven unrelated donor) were performed for 11 patients (median age, 13 years) with relapsed (n = 8) or refractory (n = 3) APL. All patients engrafted, after a median of 18.5 days. Grade B-D acute graft-versus-host disease (GVHD) developed after five transplants (42%; 90% CI, 18-68%), and the cumulative incidence of chronic GVHD was 45% (90% CI, 19-71%). The cumulative incidence of overt relapse post-HSCT was 10% (90% CI, 0-28%). The overall 5-year survival was 73% (90% confidence interval (CI), 51-95%), with a median post-HSCT follow-up of 64 months. The Lansky/Karnofsky performance scores are 100% in six of eight survivors. In view of the low risk of subsequent relapse and favorable survival suggested by other reports and our own experience, we continue to recommend allogeneic HSCT for children with advanced APL for whom a suitably HLA-matched donor is identified.     

Graft-versus-adult T-cell leukemia/lymphoma effect following allogeneic hematopoietic stem cell transplantation

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has proven effective in adult T-cell leukemia/lymphoma (ATL) patients. To study the graft-versus-ATL (Gv-ATL) effects after allo-HSCT, we analyzed 21 ATL patients who had been treated at our hospital. Of these, 18 had acute-, 2 had lymphoma- and 1 had chronic-type ATL; at allo-HSCT, seven patients were in CR, one was in PR, five had stable disease (SD) and eight had progressive disease (PD). Disease state after allo-HSCT was CR in 14, PR in 3, SD in 1 and PD in 3 patients. Among 15 patients who survived longer than 100 days, ATL relapsed in 10 patients, skin relapsed in 9 patients and 5 had relapsed on the skin alone. After we discontinued immunosuppressant therapy in these 10 patients, 8 manifested GVHD; ATL was ameliorated to CR in 6 patients. Donor lymphocytes were infused into two patients who did not show GVHD; one obtained CR. In five patients with skin relapse alone, four patients achieved CR following the discontinuation of the immunosuppressants. Our results demonstrate that relapse of ATL after allo-HSCT tends to develop on skin, and Gv-ATL effects played a critical role in the outcome of allo-HSCT for ATL.     

Clinical research of high-risk and refractory acute myeloid leukemia with allogeneic hematopoietic stem cell transplantation therapy

目的 探讨异基因造血干细胞移植( allo- HSCT)治疗高危难治急性髓系白血病(AML)的疗效和移植时机.方法 选取allo-HSCT治疗的AML患者47例,其中高危AML 17例,难治AML20例,骨髓增生异常综合征(MDS)转AML10例.第1次完全缓解期(CR1 )23例,第2次完全缓解期(CR2)11例,未缓解进展期(NR)13例.接受同胞供者骨髓和(或)外周血干细胞移植16例,非血缘脐血移植31例.所有患者均采用清髓性预处理方案,环孢素联合霉酚酸酯预防移植物抗宿主病(GVHD).结果 47例患者46例(97.9％)获得植入,中性粒细胞绝对计数≥0.5×109/L和血小板≥20×109/L的中位时间分别为14.5(10 ～ 36)天和26(12-90)天.16例发生急性GVHD(34.8％),Ⅲ度以上4例.在可评估的39例患者中,10例出现慢性GVHD( 25.6％),复发6例(12.8％),移植相关死亡12例(25.5％),32例(68.1％)患者存活.高危难治AML患者CR1、CR2、NR期移植生存率分别为75.5％、72.7％和40.0％.MDS转AML患者CR和NR期移植生存率分别为0％和75.0％.结论 allo-HSCT有助于提高高危难治AML疗效,降低复发率,提高生存率,且最好在首次缓解期进行移植.对于MDS转AML患者可立即行allo-HSCT,无需等待化疗达完全缓解.     

Clinical outcome of allogeneic hematopoietic stem cell transplantation with FLAG sequential busulfan/cyclophosphamide conditioning regimen for refractory/relapsed acute myeloid leukemia

正Objective To investigate the therapeutic effects of allogeneic hematopoietic stem cell transplantation (alloHSCT) with FLAG sequential busulfan/cyclophosphamide (Bu/Cy) conditioning regimen for refractory/relapsed acute myeloid leukemia.Methods From February2012 to June 2017, 21 patients with refractory/relapsed acute myeloid leukemia underwent allo-HSCT with FLAG     

Membranous nephropathy with nephrotic syndrome developed after allogeneic hematopoietic stem cell transplantation for acute lymphoblastic leukemia

A 38-year-old man was diagnosed with acute lymphoblastic leukemia. We performed myeloablative bone marrow transplantation from an unrelated donor during the patient's first complete remission. After engraftment, he developed acute graft-versus-host disease involving the gastrointestinal tract on day 32. Steroids and mycophenolate mofetil were initiated from day 39. His symptoms improved and the dose of immunosuppressants was tapered and then discontinued on day 421. On day 491, he developed nephrotic syndrome (NS). Based on renal biopsy, membranous nephropathy was diagnosed. There were no apparent symptoms or abnormal laboratory data suggestive of chronic graft-versus-host disease (cGVHD). Steroid therapy was initiated from day 518 and proteinuria improved significantly. NS is very rare following allogeneic hematopoietic stem cell transplantation (allo-HSCT). When there is no concomitant cGVHD, as in this case, allo-HSCT-associated NS is difficult to distinguish from idiopathic NS.     

Nelarabine as salvage therapy and bridge to allogeneic stem cell transplant in 118 adult patients with relapsed/refractory T-cell acute lymphoblastic leukemia/lymphoma. A CAMPUS ALL study

The outcome of relapsed or refractory (R/R) T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/T-LBL) in adults is poor, with less than 20% of patients surviving at 5 years. Nelarabine is the only drug specifically approved for R/R T-ALL/T-LBL, but the information to support its use is based on limited available data. The aim of this observational phase four study was to provide recent additional data on the efficacy and safety of nelarabine in adults with R/R T-ALL/T-LBL and to evaluate the feasibility and outcome of allogeneic hematopoietic stem cell transplant (SCT) after salvage with nelarabine therapy. The primary endpoints were overall response rate (ORR) and overall survival (OS). Additional endpoints were safety, SCT rate and post-SCT OS. Between May 2007 and November 2018, 118 patients received nelarabine salvage therapy at 27 Italian hematology sites. The median age was 37 years (range 18-74 years), 73% were male, 77 had a diagnosis of T-ALL and 41 of T-LBL, and 65/118 (55%) had received more than two lines of therapy. The median number of nelarabine cycles was two (range 1-4); 43/118 (36%) patients had complete remission (CR), 16 had partial remission (14%) and 59 (50%) were refractory, with an ORR of 50%. The probability of OS, from the first dose of nelarabine, was 37% at 1 year with a median survival of 8 months. The OS at 1 year was significantly better for the 47 patients (40%) who underwent SCT after nelarabine salvage therapy (58% vs 22%, log-rank P < .001). The probability of OS at 2 and 5 years from SCT was 46% and 38%, respectively. Seventy-five patients (64%) experienced one or more drug-related adverse events (AE). Grade III-IV neurologic toxicities were observed in 9/118 (8%) of cases and thrombocytopenia or/and neutropenia (grade III-IV) were reported in 41% and 43% of cases, respectively. In conclusion, this is one of the largest cohorts of adult patients with R/R T-ALL/T-LBL treated in real life with nelarabine. Taking into account the poor prognosis of this patient population, nelarabine represents an effective option with an ORR of 50% and a CR rate of 36%. In addition, 40% of cases following nelarabine salvage therapy could undergo SCT with an expected OS at 2 and 5 years of 46% and 38%, respectively. The safety profile of nelarabine was acceptable with only 8% of cases showing grade III-IV neurological AE.     

Maintenance therapy after allogeneic hematopoietic cell transplantation for acute myeloid leukemia

With improvements in the safety of allogeneic hematopoietic cell transplantation, disease recurrence following the procedure is now the most frequent reason for treatment failure. Administration of maintenance therapy after transplantation is one way to try and prevent recurrence. This paper provides a brief review of the topic.     

Long-term safety and activity of humanized CD19 chimeric antigen receptor T cells for children and young adults with relapsed/refractory acute lymphoblastic leukemia

<正>Objective To investigate the efficacy and safety of humanized CD19-specific chimeric antigen receptor T cells(hCART19s) in treating children and young adults with relapsed/refractory acute lymphoblastic leukemia(R/R ALL) and to analyze relevant factors affecting its curative effect and prognosis.