B‐Cell lymphoproliferative disorder not associated with Epstein‐Barr Virus in a child with relapsed acute lymphoblastic leukemia

Lymphoproliferative disorder (LPD) is described in only a few children receiving chemotherapy for cancer. In all of them, an association between LPD and EBV (Epstein‐Barr Virus) was found. We report on a patient who developed LPD not associated with EBV while receiving chemotherapy for relapsed acute lymphoblastic leukemia (ALL). Despite discontinuation of chemotherapy, administration of intravenous immunoglobulins and surgery the patient died. Growing experience with this disorder may allow better treatment options in the future and will show whether LPD not associated with EBV requires different therapeutic strategies. Med Pediatr Oncol 2003;40:13–17, © 2003 Wiley‐Liss, Inc.     

MIEP方案治疗复发或难治非霍奇金淋巴瘤疗效报告

目的　观察MIEP化疗方案治疗复发或难治非霍奇金淋巴瘤 (NHL)临床疗效和毒副作用。方法　 3 5例复发或难治NHL患者给予米托蒽醌 (MIT) 10mg/m2 静滴 ,d1;异环磷酰胺 (IFO) 1 2g/m2 静滴 ,d1～ 4,美司那 (Mesna) 40 0mg用IFO后 0、4、8h静推 ;依托泊甙 (VP 16) 65mg/m2 静滴 ,d1～ 4;强的松 (PRED) 10 0mg口服 ,d1～ 5。 2 1～ 2 8天为一周期 ,至少 3个周期。结果　MIEP方案化疗的疗效CR 2 8 6% ,PR 3 7 1% ,总有效率 65 7%。中位生存期为 19个月。毒副作用主要为骨髓抑制 ,白细胞减少发生率为 10 0 % ,其中Ⅲ度、Ⅳ度发生率为 71 4%。结论　MIEP方案治疗复发或难治非霍奇金淋巴瘤有效率高 ,毒性反应可耐受。     

DICE作为二线方案治疗难治或复发性非霍奇金淋巴瘤

目的:观察DICE作为二线方案治疗难治或复发性非霍奇金淋巴瘤(NHL)有效性及不良反应耐受性。方法:采用DICE方案治疗28例复发或难治性非霍奇金淋巴瘤。其中,复发组16例,难治组12例并探讨足三里穴位封闭或粒细胞集落刺激因子(G-CSF)预防化疗对造血系统的抑制作用。结果:28例中,完全缓解CR7例(25.0%),部分缓解PR8例(28.6%),有效率53.6%。复发组的有效率明显高于难治组(10/16比4/12;P<0.01)。乳酸脱氢酶(LDH)升高12例中CR2例,LDH正常组16例CR5例,有显著性差异(P<0.01)。DICE方案的不良反应主要表现为恶心呕吐、脱发和可逆性骨髓抑制,患者均能耐受,无1例出现治疗相关性死亡。结论:DICE方案对复发性NHL有效,但对难治性NHL相对无效,提示复发性和难治性NHL可能有不同的生物学行为,对两者应该选择不同的治疗措施,LDH可以作为NHL化疗是否敏感的指标之一。     

A prospective,multicenter phase II study of continuous infusion of FLAG for patients older than 60 yr with resistant acute myeloid leukemia: a comparison with intensive younger patients’ trial

Relapsed or refractory acute myeloid leukemia (R/R AML) in elderly (≥60 yr old) patients were eligible. Induction chemotherapy consisted fludarabine and cytarabine (ARAC) as a 24‐hr CI without idarubicin (C‐FLAG), which was compared with the results of C‐FLAG with idarubicin (CI‐FLAG2) in younger patients’ trial. A total of 33 and 68 patients were enrolled in C‐FLAG and CI‐FLAG2, respectively. CR, CRp, and CRi were achieved in 10 (30.3%), 3 (9.1%), and 2 (6.1%), respectively. When comparing outcomes between C‐FLAG and CI‐FLAG2, there were no difference in terms of CR rate (P = 0.572) and objective response rate (ORR; P = 0.899). Favorable predictors on ORR in C‐FLAG were PB WBC ≤ 20K/uL at salvage (P = 0.024) and early evaluation peripheral BLAST = 0% (P = 0.013) on multivariate analysis. The overall survival of patients who achieve CR/CRp/CRi showed significantly prolonged survival compared with patients who did not in C‐FLAG (P < 0.001) and was a favorable predictor of longer survival by multivariate analysis (P = 0.009). Median overall survival was 3.19 (95% CI, 2.05–4.33) months and similar with that of CI‐FLAG2 (P = 0.841). Attenuated salvage regimen C‐FLGA in elderly patients was as effective as more intensive younger patients’ regimen CI‐FLAG2 in terms of response and survival although elderly patients had more unfavorable clinical characteristics.     

Hematopoietic Stem Cell Transplantation From Haploidentical Donors in Aplasia After Cladribine/Cytarabine Chemotherapy for Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

IntroductionSurvival rate of patients with chemorefractory acute myeloid leukemia (AML) or myelodysplastic syndrome with excess blasts (MDS-EB) is poor. Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative therapy in these patients.Patients and MethodsWe report a retrospective analysis of outcomes of therapy of 24 patients with AML or MDS-EB refractory to high-dose salvage chemotherapy or who had failed previous HCT, who received T-cell–replete HLA haploidentical HCT in aplasia after cladribine/cytarabine-based chemotherapy followed by reduced intensity or myeloablative conditioning. All patients had active disease before commencement of the treatment.ResultsOf the patients, 91.7% achieved complete remission (CR), whereas 2 patients (8.2%) died in aplasia. One-year relapse rate was 49.3%. Cumulative incidence of nonrelapse mortality (NRM) was 25.6%. In a subgroup of patients with HCT–comorbidity index score ≤ 3, NRM was 15.4%. Two-year overall survival and relapse-free survival were 30.6% and 22.6%, respectively. Incidence of grade 3 and 4 acute graft versus host disease was 21.3% and 8.3, respectively.ConclusionWe found that sequential therapy with HCT in aplasia after cladribine/cytarabine chemotherapy is feasible, results in high CR rates, and has acceptable toxicity profile; however, posttransplant relapse is common in patients treated with active disease.     

Innovation in Chemistry,Manufacturing, and Controls—A Regulatory Perspective From Industry

This review describes the landscape of novel modalities such as cell and gene therapies, viruses, other novel biologics, oligomers, and emerging technologies, including modern analytics. We summarize the regulatory history and recent landmark developments in some major markets and examine specific chemistry, manufacturing, and controls (CMC) challenges, including suggestions for exploration of potential science-based approaches in support of regulatory strategy development from an industry perspective. In addition, we evaluate the economic factors contributing to patient access to innovation and discuss the impact of regulation. There is a desperate need for a consistent form of regulation where global approaches to regulatory strategies can be harmonized, and specific CMC challenges can be dealt with using the appropriate science and risk-based tools. Although these tools are well described in current guidance documents, the specifics of applicability to complex novel modalities can still result in differing regulatory advice and outcomes. The future goals for efficiently regulating innovative modalities and technologies could be aided by more regulatory harmonization, regulatory education, and industry cooperation through consortia, enabling industry to supply key information to regulators in a transparent yet well-defined manner, and utilizing mutually understood risk-benefit analyses to produce drugs with appropriate safety, efficacy, and quality characteristics.     

Long event-free survival after anti-BCMA CAR-T cell treatment for relapsed and refractory multiple myeloma patients: Two case reports

Introduction:Chimeric antigen receptor T (CAR-T) cells targeting B-cell maturation antigen (BCMA) have been used in the treatment of relapsed and refractory multiple myeloma (RRMM). The response rate and the depth of responses induced by anti-BCMA CAR-T cells are impressive. However, despite this, remissions are not sustained, and the majority of patients eventually relapse.Patient concerns:Two patients with multiple myeloma (MM) were selected to enroll in a phase I study involving anti-BCMA CAR-T cells (ChiCTR-OPC-16009113) because they did not have the good effect after traditional treatment. One is a 48-year-old male patient who received a diagnosis of IgG lambda MM in June 2015, he has received 4 cycles of cyclophosphamide, bortezomib, and dexamethasone (CyBorD) and obtained a complete response (CR). Approximately 11 months later, the disease progressed. Subsequent treatment included regimens incorporating liposomal doxorubicin, bortezomib, and dexamethasone (3 cycles); the response was poor, and the disease kept progressing. Another 65-year-old female patient received a diagnosis of IgG lambda MM in September 2016, she has received induction therapy with 1 cycle of bortezomib and dexamethasone (VD) and 4 cycles of lenalidomide and dexamethasone, the response was poor.Diagnosis:Both patients were diagnosed with RRMM according to the International Myeloma Working Group criteria.Interventions:Both patients received infusions of anti-BCMA CAR-T cells following an induction chemotherapy regimen of cyclophosphamide and fludarabine.Outcomes:Both of them achieved a stringent CR at the 30th day with minimal residual disease-negative bone marrow by flow cytometry and serum monoclonal protein was undetectable at 4 and 10 months after cell transfusion. The CR has persisted in the 2 patients for >36 months.Conclusions:Our findings demonstrate the anti-BCMA CAR-T cell treatment is a feasible therapeutic option for patients with RRMM. Fewer early lines of treatment may be beneficial to maintain the efficacy of CAR-T cells.Trial registration:ChiCTR-OPC-16009113.     

Successful usage of tacrolimus (FK506) in resistant/relapsed rheumatic diseases

Aim: This study reports the first successful usage of tacrolimus in various resistant or relapsed rheumatic diseases in Asian patients Methods: This is an open prospective study of the efficacy of tacrolimus for patients with various relapsed/resistant rheumatic diseases who were intolerant of or failed conventional therapy. Patients were enrolled in the study from the period November 2001 to September 2002. Results: A total of 20 patients were included in the study. Their disease conditions were as follows: SLE with relapsed lupus nephritis (six patients); SLE with antiphospholipid syndrome (APS) (two patients); rheumatoid arthritis (five patients); psoriatic arthritis (three patients); scleroderma (two patients); anti–Jo?1 syndrome (two patients). Improvement in their conditions were noted in all but one patient who was intolerant to tacrolimus. Conclusions: Tacrolimus (FK506) is a new armamentarium that can be added to the choice of immunosuppressive agents for rheumatologists, especially for those patients with severe or resistant diseases.