Application of immunotherapy in relapsed/refractory B-cell acute lymphoblastic leukemia / 中国药房

Immunotherapy， as an emerging treatment method， has been proven to improve the prognosis of patients with relapsed/refractory B-cell acute lymphoblastic leukemia （B-ALL） and has good application prospects. Immunotherapy， including chimeric antigen receptor T cell immunotherapy （CAR-T） and monoclonal antibodies， has shown great potential for application， and has been approved for marketing. This article summarizes the application of the above two therapies in the treatment of relapsed/ refractory B-ALL， and concludes that CAR-T is a kind of personalized immunotherapy， and the selection of ideal targets is an important part of its action. Currently， the ideal targets in clinical studies include CD19， CD22 and CD19/CD22. Monoclonal antibodies， including blinatumomab and inotuzumab ozogamicin， have shown superior therapeutic efficacy for relapsed/refractory B- ALL. Immunotherapy has shown superior therapeutic effects compared to conventional chemotherapy， expanding the selection of treatment options for relapsed/refractory B-ALL.

Efficacy of CLAE Chemotherapy Regimen Followed by Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Relapsed/Refractory Acute Leukemia / 中国实验血液学杂志

OBJECTIVE@#To observe the efficacy and safety of CLAE intensive chemotherapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with relapsed/refractory acute leukemia (R/R AL).@*METHODS@#CLAE regimen [cladribine 5 mg/(m2·d), d 1-5; cytarabine 1.5 g/(m2·d), d 1-5; etoposide 100 mg/(m2·d), d 3-5] followed by allo-HSCT was used to treat 3 R/R AL patients. The patients received CLAE chemotherapy in relapsed or refractory status and underwent bone marrow puncture to judge myelodysplastic state. After an interval of 3 to 5 days, followed by preconditioning regimen for allo-HSCT [fludarabine 30 mg/(m2·d), d -7 to d -3; busulfan 0.8 mg/kg q6h, d -6 to d -3 or d -5 to d -2. If the bone marrow hyperplasia was not active and the blasts were less than 10%, busulfan should be used for 3 days. If the bone marrow hyperplasia was active and the blasts were more than 10%, busulfan should be used for 4 days]. Cyclosporin A, mycophenolate mofetil and short-term methotrexate were used for graft-versus-host disease (GVHD) prevention. After transplantation, the status of minimal residual disease (MRD) and bone marrow chimerism were regularly monitored in all 3 patients, and demethylation drugs or dasatinib were used to prevent recurrence 3 months after transplantation.@*RESULTS@#2 patients with t(11;19) translocation and relapse/refractory acute myeloid leukemia recurred within 6 months after induction of remission, and received intensive chemotherapy with CLAE regimen followed by haploidentical allo-HSCT and unrelated donor allo-HSCT, respectively. The two patients both relapsed 6 months after transplantation, then achieved complete remission by donor lymphocyte infusion, interferon, interleukin-2 and other methods, and disease-free survival was 2 years after transplantation. The other patient was chronic myelogenous leukemia who developed acute lymphoblastic leukemia during oral administration of tyrosine kinase inhibitor, accompanied by T315I and E255K mutations in ABL1 kinase region and additional chromosomal abnormalities. After morphological remission by induction chemotherapy, central nervous system leukemia was complicated. Intensive chemotherapy with CLAE regimen followed by sibling allo-HSCT was performed in the positive state of MRD. The patient relapsed 3 months after transplantation, and achieved remission after chimeric antigen receptor T-cell (CAR-T) therapy, however, he died 5 months after transplantation because of severe cytokine release syndrome (CRS) and GVHD.@*CONCLUSION@#CLAE regimen followed by allo-HSCT may be an effective salvage treatment option for R/R AL patients to prolong the overall survival.

Advances in the Treatment of Glucocorticoid Resistance and Relapsed Immune Thrombocytopenia --Review / 中国实验血液学杂志

Immune thrombocytopenia (ITP) is an immune-mediated acquired hemorrhagic autoimmune disease. At present, the first-line therapeutic drugs for ITP include glucocorticoids and intravenous immunoglobulins. However, about 1/3 of the patients had no response to the first-line treatment, or relapsed after dose reduction or withdrawal of glucocorticoids. In recent years, with the gradual deepening of the understanding on the pathogenesis of ITP, the drugs targeting different pathogenesis continually emerge, including immunomodulators, demethylating agents, spleen tyrosine kinase (SYK) inhibitors and neonatal Fc receptor (FcRn) antagonist. However, most of these drugs are in clinical trials. This review summarized briefly the recent advances in the treatment of glucocorticoids resistance and relapsed ITP, so as to provide reference for the clinical treatments.

Efficacy and Safety of Decitabine Combined with Modified EIAG Regimen in the Treatment of Patients with Relapsed/Refractory Acute Myeloid Leukemia and High-risk Myelodysplastic Syndrome / 中国实验血液学杂志

OBJECTIVE@#To investigate the efficacy, prognosis and safety of decitabine combined with modified EIAG regimen in the treatment of patients with relapsed/refractory acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS).@*METHODS@#The clinical data of 44 patients with relapsed/refractory AML and high-risk MDS admitted to our hospital from January 2017 to December 2020 were analyzed retrospectively. The patients were equally divided into D-EIAG group (decitabine combined with EIAG regimen) and D-CAG group (decitabine combined with CAG regimen) according to clinical treatment regimen. The complete response (CR), CR with incomplete hematologic recover (CRi), morphologic leukemia-free state (MLFS), partial response (PR), overall response rate (ORR), modified composite complete response (mCRc), overall survival (OS) time, 1-year OS rate, myelosuppression and adverse reactions between the two groups were compared.@*RESULTS@#In D-EIAG group, 16 patients (72.7%) achieved mCRc (CR+CRi+MLFS), 3 patients (13.6%) achieved PR, and ORR (mCRc+PR) was 86.4%. In D-CAG group, 9 patients (40.9%) achieved mCRc, 6 patients (27.3%) achieved PR, and ORR was 68.2%. Difference was observed in mCRc rate between the two groups (P=0.035), but not in ORR (P>0.05). The median OS time of D-EIAG group and D-CAG group was 20 (2-38) months and 16 (3-32) months, and 1-year OS rate was 72.7% and 59.1%, respectively. There was no significant difference in 1-year OS rate between the two groups (P>0.05). After induction chemotherapy, the median time for absolute neutrophil count recovery to 0.5×109/L in D-EIAG group and D-CAG group was 14 (10-27) d and 12 (10-26) d, for platelet count recovery to 20×109/L was 15 (11-28) d and 14 (11-24)d, the median red blood cell suspension transfusion volume was 8 (6-12) U and 6 (6-12) U, and the median apheresis platelet transfusion volume was 4 (2-8) U and 3 (2-6) U, respectively. There were no statistically significant differences in comparison of the above indicators between the two groups (P>0.05). The hematological adverse reactions of patients were mainly myelosuppression. Grade III-IV hematological adverse events occurred in both groups (100%), with no increase in the incidence of non-hematological toxicities such as gastrointestinal reactions or liver function damage.@*CONCLUSION@#Decitabine combined with EIAG regimen in the treatment of relapsed/refractory AML and high-risk MDS can improve remission rate, provide an opportunity for subsequent therapies, and have no increase in adverse reactions compared with D-CAG regimen.

Clinical Observation of Venetoclax Combined with Demethylating Agents on the Treatment of Relapsed/Refractory Acute Myeloid Leukemia / 中国实验血液学杂志

OBJECTIVE@#To investigate the efficacy and safety of venetoclax (VEN) combined with demethylating agents (HMA) in the treatment of relapsed/refractory acute myeloid leukemia (R/R AML).@*METHODS@#The clinical data of 26 adult R/R AML patients who received the combination of VEN with azacitidine (AZA) or decitabine (DAC) in Huai'an Second People's Hospital from February 2019 to November 2021 were retrospectively analyzed. The treatment response, adverse events as well as survival were observed, and the factors of influencing the efficacy and survival were explored.@*RESULTS@#The overall response rate (ORR) of 26 patients was 57.7% (15 cases), including 13 cases of complete response (CR) and CR with incomplete count recovery (CRi) and 2 cases of partial response (PR). Among the 13 patients who got CR/CRi, 7 cases achieved CRm (minimal residual disease negative CR) and 6 cases did not, with statistically significant differences in overall survival (OS) and event-free survival (EFS) between the two groups (P=0.044, 0.036). The median OS of all the patients was 6.6 (0.5-15.6) months, and median EFS was 3.4 (0.5-9.9) months. There were 13 patients in the relapse group and refractory group, respectively, with response rate of 84.6% and 30.8% (P=0.015). The survival analysis showed that the relapse group had a better OS than the refractory group (P=0.026), but there was no significant difference in EFS (P=0.069). Sixteen patients who treated for 1-2 cycles and 10 patients who treated for more than 3 cycles achieved response rates of 37.5% and 90.0%, respectively (P=0.014), and patients treated for more cycles had superior OS and EFS (both P<0.01). Adverse effects were mainly bone marrow suppression, complicated by various degrees of infection, bleeding, and gastrointestinal discomfort was common, but these could be all tolerated by patients.@*CONCLUSION@#VEN combined with HMA is an effective salvage therapy for patients with R/R AML and is well tolerated by patients. Achieving minimal residual disease negativity is able to improve long-term survival of patients.

Treatment response of a two-dose regimen of dose-adjusted inotuzumab ozogamicin in relapsed/refractory B-cell acute lymphoblastic leukemia / 中华血液学杂志

Objective: To observe the treatment response of a two-dose regimen of inotuzumab ozogamicin (inotuzumab), a monoclonal antibody targeting CD22, for patients with heavily treated relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), including those failed or relapsed after chimeric antigen receptor (CAR) -T-cell therapy. Methods: Pediatric and adult patients who received two doses of inotuzumab and who were evaluated after inotuzumab treatment were included. Antibody infusions were performed between March 2020 and September 2022. All patients expressed CD22 antigen as detected by flow cytometry (>80% leukemic cells displaying CD22) before treatment. For adults, the maximum dosage per administration was 1 mg (with a total of two administrations). For children, the maximum dosage per administration was 0.85 mg/m(2) (no more than 1 mg/dose; total of two administrations). The total dosage administered to each patient was less than the standard dosage of 1.8 mg/m(2). Results: Twenty-one patients with R/R B-ALL were included, including five children (<18 years old) and sixteen adults. Seventeen patients presented with 5.0% -99.0% leukemic blasts in the bone marrow/peripheral blood or with extramedullary disease, and four patients were minimal residual disease (MRD) -positive. Fourteen patients underwent both CD19 and CD22 CAR-T-cell therapy, four underwent CD19 CAR-T-cell therapy, and three underwent blinatumomab therapy. Eleven patients underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). After inotuzumab treatment, 14 of 21 patients (66.7% ) achieved a complete response (CR, one was MRD-positive CR), and all four MRD-positive patients turned MRD-negative. Four of six patients who failed recent CD22 CAR-T-cell therapy achieved a CR after subsequent inotuzumab treatment. Seven patients (33.3% ) demonstrated no response. Grade 1-3 hepatotoxicity occurred in five patients (23.8% ), one child with no response experienced hepatic veno-occlusive disease (HVOD) during salvage transplantation and recovered completely. Conclusion: For patients with heavily treated R/R B-ALL, including those who had undergone allo-HSCT and CD19/CD22 CAR-T-cell therapy, the two-dose regimen of inotuzumab resulted in a CR rate of 66.7%, and the frequency of hepatotoxicity and HVOD was low.

Clinical analysis of long-term survival and influencing factors of chimeric antigen receptor T-cell therapy in relapsed/refractory acute B-cell lymphoblastic leukemia / 中华血液学杂志

Objective: To analyze the survival and influencing factors of chimeric antigen receptor (CAR) T-cell therapy in relapsed/refractory acute B-cell lymphoblastic leukemia (R/R B-ALL) . Methods: Clinical information of patients who received CAR-T-cell therapy and achieved complete remission of R/R B-ALL between May 2015 and June 2018 at the Shaanxi Provincial People's Hospital was obtained. Kaplan-Meier analysis was used to evaluate the overall survival (OS) and leukemia-free survival (LFS) times of patients, and Cox regression analysis was performed to analyze the prognostic factors that affect patient survival after CAR-T therapy. Results: Among the 38 patients with R/R B-ALL, 21 were men, with a median age of 25 (6-59) years and a median OS time of 18 (95% CI 3-33) months. Multivariate Cox regression analysis showed that positive MLL-AF4 fusion gene expression was an independent risk factor for OS and LFS (OS: HR=4.888, 95% CI 1.375-17.374, P=0.014; LFS: HR=6.683, 95% CI 1.815-24.608, P=0.004). Maintenance therapy was a protective factor for OS and LFS (OS: HR=0.153, 95% CI 0.054-0.432, P<0.001; LFS: HR=0.138, 95% CI 0.050-0.382, P<0.001). In patients with MRD negative conversion, LFS benefit (HR=0.209, 95% CI 0.055-0.797, P=0.022) and OS difference was statistically insignificant (P=0.111). Moreover, patients with high tumor burden were risk factors for OS and LFS at the level of 0.1 (OS: HR=2.662, 95% CI 0.987-7.184, P=0.053; LFS: HR=2.452, 95% CI 0.949-6.339, P=0.064) . Conclusion: High tumor burden and high-risk genetics may affect the long-term survival rate of patients with R/R B-ALL receiving CAR-T, and lenalidomide-based maintenance therapy may improve their prognosis.

Safety and short-term effectiveness of blinatumomab in the treatment of childhood relapsed/refractory acute lymphoblastic leukemia / 中国当代儿科杂志

OBJECTIVES@#To study the safety and short-term effectiveness of blinatumomab in the treatment of childhood relapsed/refractory acute lymphoblastic leukemia (R/R-ALL).@*METHODS@#Six children with R/R-ALL who received blinatumomab treatment from August 2021 to August 2022 were included as subjects, and a retrospective analysis was performed for their clinical data.@*RESULTS@#Among the six children, there were three boys and three girls, with a median age of 10.5 (5.0-13.0) years at the time of inclusion. Of all six children, one had refractory ALL and did not achieve remission after several times of chemotherapy, and 5 relapsed for the first time, with a median time of 30 (9-60) months from diagnosis to relapse. Minimal residual disease (MRD) before treatment was 15.50% (0.08%-78.30%). Three children achieved complete remission after treatment, among whom two had negative conversion of MRD. Five children had cytokine release syndrome (CRS), among whom 3 had grade 1 CRS and 2 had grade 2 CRS. Four children were bridged to allogeneic hematopoietic stem cell transplantation, with a median interval of 50 (40-70) days from blinatumomab treatment to transplantation. The six children were followed up for a median time of 170 days, and the results showed an overall survival rate of 41.7% (95%CI: 5.6%-76.7%) and a median survival time of 126 (95%CI: 53-199) days.@*CONCLUSIONS@#Blinatumomab has good short-term safety and effectiveness in the treatment of childhood R/R-ALL, and its long-term effectiveness needs to be confirmed by studies with a larger sample size.

The clinical observation of relapsed or refractory acute myeloid leukemia in patients with high CD117 expression but no FLT3-ITD mutation treated with sorafenib alone / 天津医药

@#Objective To make a primary investigation of outcomes in relapsed or refractory (R/R) acute myeloid leukemia (AML) patients who were FLT3-ITD mutation negative and treated with sorafinib alone. Methods The clinical responses and survival of R/R AML patients who underwent sorafenib treatment only were retrospectively analyzed. The side effects and response results were assessed according to common terminology criteria for adverse events (CTCAE) v 4.0 from US National Institutes of Health and NCCN guideline. Results Four out of seven patients achieved complete remission by sorafenib treatment alone. The median time required for remission was 36 days in the four patients. Among them, only 1 patient stopped the maintenance treatment because of side effect of serious skin lesion. Three patients showed no response to sorafenib, including 2 accepted stem cell transplantation and 1 retrieved to salvage chemotherapy. All of them achieved complete remission later. One patient developed grade 1 adverse event of liver. Another one developed grade 3 skin lesion. All patients experienced neutropenia of more than 7 days without unendurable infections and early deaths. The median follow-up time for the whole cohort was more than 22 months. Three patients passed away for relapse of AML and their disease-free survival time with sorafenib ranged from 2 to 20 months. All four patients accepted stem cell transplantation were still surviving no matter whether or not they were responsive to sorafinib before. The median survival time for these seven patients was 650 days. Conclusion The R/R AML patients with negative FLT3-ITD mutation and high expression of CD117 treated with sorafenib alone have good remission and long term survival.

Efficacy and prognostic analysis of ICE regimen for 84 patients with relapsed/refractory diffuse large B-cell lymphoma / 上海交通大学学报（医学版）

Objective · To evaluate the efficacy and prognostic factors of ifosfamide-cisplatin-etoposide (ICE) chemotherapy as salvage regimen for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL).Methods · A retrospective analysis was performed on 84 relapsed/refractory DLBCL patients who were treated with ICE salvage regimen at Ruijin Hospital (Shanghai Jiao Tong University School of Medicine,China) from July 2004 to June 2016.Overall survival (OS) was analyzed by Kaplan-Meier method and multivariate Cox proportional hazards models.Results· Of the 84 patients who were treated with ICE regimen,37 (44.0％) patients had responses,including 26 (31.0％) achieving complete remission.The median number of cycles per patient was 3 (range 1-6 cycles).The 1-year and 2-year OS rates were 49.5％ and 30.0％,respectively.The median OS time was 12.2 months.On univariate analysis,patients with early progression/recurrence (P=0.041) and a high-intermediate/high risk according to the international prognostic index (IPI) (P=0.024) and NCCN-IPI (P=0.002) had poorer outcomes.While improved outcome was found in patients in complete remission after chemotherapy (P=0.000).The multivariate analysis revealed that the intermediate-high/high risk according to NCCN-IPI was an independent risk factor,and remission after chemotherapy was an independent prognostic factor for prolonging survival.Conclusion· The ICE regimen can be used as an effective salvage therapy for patients with relapsed/refractory DLBCL.

Review on special emphasis of bortezomib on relapsed/refractory myeloma.

Refractory or relapsed Multiple Myeloma (MM) is a plasma cell neoplasia characterized by paraproteins in the urine or serum and a bone marrow plasmacytosis of over 10%. Multiple/refractory myeloma is a neoplasm of plasma cells and exact cause of multiple myeloma is remain unidentified, it is characterized by accumulation of malignant plasma cells in the bone marrow, leading to bone marrow failure, anemia, skeletal destruction, renal failure, increased susceptibility to infection and hypercalcemia. The survival time for the patients with refractory or multiple myeloma can be prolonged with treatment of newer and more target specific approach. The proteasome inhibitors are an important class of anti-myeloma drugs that have efficacy to disrupt the proteolytic structure of tumor cells and enhancing their susceptibility to apoptosis. Bortezomib has a significant clinical efficacy against refractory multiple myeloma. Bortezomib is the most commonly used and clinically tested proteasome inhibitor and which is effective in prolonging the overall survival in several trials. Bortezomib combinations with other drugs such as dexamethasone and cyclophosphamide are the choice of treatment for standard risk patients following the mSMART guidelines. The success with lower dosage of bortezomib in elderly patient’s proven efficacious subcutaneous usage and its useful proteasome inhibitor to enhance patient’s compliance and reduces toxicity and costs of therapy. This review discusses on special emphasis of bortezomib on relapsed/refractory multiple myeloma as front-line treatment.

Bendamustine for Relapsed and Refractory Hodgkin Lymphomas: Four Cases and a Review of the Literature.

Aims: The management of relapsed/refractory Hodgkin lymphoma is challenging and new choices are needed. Brentuximab vedotin and bendamustine are two effective drugs in these cases. The aim of this study is to present the response to bendamustine after brentuximab failure. Study Design: Retrospective study evaluating the response to bendamustine in four cases with relapsed or refractory Hodgkin lymphoma. Place and Duration of Study: Cukurova University Faculty of Medicine Department of Oncology, between 2012 and 2014. Methodology: Clinical and metabolic responses to bendamustine in four cases with relapsed refractory Hodgkin lymphoma were evaluated. Informed consent was obtained from the patients. Bendamustine was used in four cases with very refractory Hodgkin lymphoma after Brentuximab failure. The dosage was 120 mg/M2 for two consecutive days in 4 weeks, without growth factor support. Results: Four cases with relapsed or refractory Hodgkin lymphoma were treated with bendamustine after brentuximab vedotin failure. Complete metabolic response was documented in two cases,one case did not respond and only short duration of response was determined in one case. Conclusion: Bendamustine is an effective and cost-effective choice in cases with relapsed/refractory Hodgkin lymphoma after brentuximab vedotin failure. However response is of short duration and definitive treatment must be performed as soon as possible.

Effects of arsenic trioxide combined with thalidomide for the treatment of relapsed/refractory multiple myeloma / 白血病·淋巴瘤

Objective To evaluate the efficacy and side effects of arsenic trioxide (ATO) combined with thalidomide in the treatment of relapsed/refractory multiple myeloma (MM). Methods 35 patients with relapsed/refractory MM were treated with ATO (10 mg/d) and Vit C (2 g/d) for 14 days,28 days per cycle.Meanwhile they were orally administered thalidomide 50 mg/d,and then one week later orally thalidomide was added to 100-150 mg/d. After 3 cycles of treatment, response and the side effects were evaluated. Patients responsed to the regimen were continued the treatment of thalidomide and were followed up to estimate the PFS. Responses were assessed according to the criteria of the EBMT.Adverse events were graded according to the criteria of the WHO.Results The overall response Was 71.43 ％ (25/35),CR 5.71％ (2/35),PR 34.29 ％ (12/35),MR 31.43 ％ (11/35).After a median follow-up of 11 months,the median PFS was 9 months.The major adverse reactions were digestive tract reaction,leukocytopenia,liver function damage,peripheral neuropathy.They were mild,and could be tolerated.Conclusions The combination of ATO and thalidomide is a feasible and active regimen in treatment of relapsed/refractory MM with better compliance in general.