Hong-Li Zhu

Tolerance and efficacy of autologous or donor-derived T cells expressing CD19 chimeric antigen receptors in adult B-ALL with extramedullary leukemia

The engineering of T lymphocytes to express chimeric antigen receptors (CARs) aims to establish T cell-mediated tumor immunity rapidly. In this study, we conducted a pilot clinical trial of autologous or donor- derived T cells genetically modified to express a CAR targeting the B-cell antigen CD19 harboring 4-1BB and the CD3ζ moiety. All enrolled patients had relapsed or chemotherapy-refractory B-cell lineage acute lymphocytic leukemia (B-ALL). Of the nine patients, six had definite extramedullary involvement, and the rate of overall survival at 18 weeks was 56%. One of the two patients who received conditioning chemotherapy achieved a three-month durable complete response with partial regression of extramedullary lesions. Four of seven patients who did not receive conditioning chemotherapy achieved dramatic regression or a mixed response in the haematopoietic system and extramedullary tissues for two to nine months. Grade 2–3 graft-versus-host disease (GVHD) was observed in two patients who received substantial donor-derived anti-CD19 CART (chimeric antigen receptor-modified T) cells 3–4 weeks after cell infusions. These results show for the first time that donor-derived anti-CD19 CART cells can cause GVHD and regression of extramedullary B-ALL. This study is registered at www.clinicaltrials.gov as NCT01864889.

Low-dose decitabine-based chemoimmunotherapy for patients with refractory advanced solid tumors: a phase I/II report.

Aberrant DNA methylation is one of the main drivers of tumor initiation and progression. The reversibility of methylation modulation makes it an attractive target for novel anticancer therapies. Clinical studies have demonstrated that high-dose decitabine, a hypomethylating agent, results in some clinical benefits in patients with refractory advanced tumors; however, they are extremely toxic. Low doses of decitabine minimize toxicity while potentially improving the targeted effects of DNA hypomethylation. Based on these mechanisms, low-dose decitabine combined with chemoimmunotherapy may be a new treatment option for patients with refractory advanced tumors. We proposed the regimen of low-dose decitabine-based chemoimmunotherapy for patients with refractory advanced solid tumors. A favorable adverse event profile was observed in our trial that was highlighted by the finding that most of these adverse events were grades 1-2. Besides, the activity of our cohort was optimistic and the clinical benefit rate was up to 60%, and the median PFS was prolonged compared with PFS to previous treatment. We also identified a significant correlation between the PFS to previous treatment and clinical response. The low-dose DAC decitabine-based chemoimmunotherapy might be a promising protocol for improving the specificity and efficiency of patients with refractory advanced solid tumors. This trial is registered in the ClinicalTrials.gov database (identifier NCT01799083).

Repeated transfusions of autologous cytokine-induced killer cells for treatment of haematological malignancies in elderly patients: a pilot clinical trial

The elderly population is susceptible to haematological malignancies, and these elderly patients are intolerant to cytotoxic drugs. Therefore, the exploration of a safe and reliable strategy exclusive of chemotherapy is critical in improving the prognosis of elderly patients with haematological malignancies. We evaluated the safety and the efficacy of autologous cytokine‐induced killer (CIK) cells combined with recombinant human interleukin 2 (rhIL‐2) in the treatment of haematological malignancies in elderly patients. Peripheral blood mononuclear cells were isolated from 20 elderly patients with haematological malignancies, then augmented by priming with interferon gamma, rhIL‐2 and CD3 monoclonal antibody. The autologous CIK cells (2–3 × 109) were transfused back to patients, followed by a subcutaneous injection of IL‐2 (1 mU/day) for 10 consecutive days. The regimen was repeated every 4 weeks. The host cellular immune function, tumour‐related biological parameters, imaging characteristics, disease condition, quality of life and survival time were assessed. Fourteen patients received 8 cycles of transfusion and 6 received 4 cycles. No adverse effects were observed. The percentages of CD3+, CD3+CD8+ and CD3+CD56+ cells were significantly increased (p < 0.05), and the levels of serum β2 microglobulin and lactate dehydrogenase (LDH) were markedly decreased (p < 0.05) after autologous CIK cell transfusion. Cancer‐related symptoms were profoundly alleviated, as demonstrated by the improved quality of life (p < 0.01). Complete remission was observed in 11 patients, persistent partial remission in 7 patients and stable disease in 2 patients. At the end of follow‐up, the mean survival time was 20 months. Transfusion with autologous CIK cells plus rhIL‐2 treatment is safe and effective for treating haematological malignancies in elderly patients. Copyright

Diagnosis and Treatment of Rituximab-Induced Acute Tumor Lysis Syndrome in Patients With Diffuse Large B-Cell Lymphoma

Acute tumor lysis syndrome (ATLS) is a recognized complication of the treatment of malignant lymphomas and is associated with significant morbidity and mortality. However, there have been few reports of the occurrence of ATLS in patients treated with rituximab. This study reports 2 patients with high-grade diffuse large B-cell non-Hodgkins lymphoma who presented high tumor load, were sensitive to treatment and had multiple risk factors for ATLS. Both patients developed ATLS after treatment with rituximab and, despite aggressive supportive therapy, died of multiple organ failure. These cases illustrate that ATLS can occur after treatment with rituximab and that a high index of suspicion is necessary for the prompt diagnosis of ATLS.

Imatinib-induced decompensated heart failure in an elderly patient with chronic myeloid leukemia: case report and literature review.

Because it is safe and well tolerated, imatinib is a standard first-line therapy for chronic myeloid leukemia (CML). Although there have been sporadic reports of imatinib-induced cardiotoxicity, including left ventricle (LV) dysfunction and heart failure, the evidence for it is contradictory. Here, we reported a case of an 88-year-old male patient with CML developed decompensated heart failure following imatinib therapy. Four days after the initiation of imatinib, the patient developed orthopnea, edema and a pleural effusion accompanied by abdominal distension, nausea and vomiting. The chest X-ray film showed an enlarged cardiac profile. The echocardiogram demonstrated a decreased LV ejection fraction and enlarged left-side cardiac chambers. B-type natriuretic peptide concentrations were markedly increased. The patient recovered soon after the withdrawal of imatinib and introduction of comprehensive therapy for heart failure. Imatinib-induced cardiotoxicity in elderly patients is a potentially serious complication that merits further evaluation.

Individualized liposomal doxorubicin-based treatment in elderly patients with non-Hodgkin's lymphoma.

Background: We retrospectively evaluated the efficacy and safety of individualized liposomal doxorubicin-based treatment in elderly patients with non-Hodgkin’s lymphoma and poor general health. Patients and Methods: 22 patients (median age 83.5 years) were treated with liposomal doxorubicin combined with CHOP-based chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone) or other individualized doxorubicin-based treatments including liposomal doxorubicin combined with rituximab. Efficacy and adverse reactions were measured. Results: Patients received a total of 80 courses of chemotherapy (mean dose 143.6 mg/patient liposomal doxorubicin). The numbers of patients achieving complete remission, uncertain complete remission, partial remission, stable disease, or progressive disease were 10 (45.5%), 4 (18.2%), 4 (18.2%), 1 (4.5%), and 3 (13.6%), respectively. The most frequently reported adverse reaction was bone marrow suppression. No serious infections were reported. 3 (13.6%) patients showed skin changes. None experienced congestive heart failure or acute myocardial infarction. There were no chemotherapyrelated deaths. Overall survival rates at 1, 3, and 5 years were 81.8, 59.1, and 40.9%, and progression-free survival rates were 83.3, 66.7, and 54.5%. Conclusions: Individualized liposomal doxorubicin-based chemotherapy is effective and safe for elderly patients with non-Hodgkin’s lymphoma.

Treatment of multiple solitary plasmacytomas with cytokine-induced killer cells

BACKGROUND AIMS Currently available treatment methods for advanced plasmacytoma include surgery, chemotherapy, radiotherapy, immunomodulatory agents, hematopoietic stem cell transplantation and donor lymphocyte infusion. We report a case of advanced refractory multiple solitary plasmacytomas in a 68-year-old Asian man with multiple bone lesions, in whom autologous cytokine-induced killer (CIK) cells were administered in an effort to eliminate residual tumor lesions. METHODS CIK cells were infused monthly for 21 courses. RESULTS The patient has survived 63 months since the first hospital visit without disease progression for 40 months. CONCLUSIONS This case represents the first report of autologous CIK cell immunotherapy used successfully to suppress multiple solitary plasmacytomas and resolve bone lesions.

Ultra-Low-Dose Decitabine Combined With Autologous Cytokine-Induced Killer Cells for Elderly Patients With Acute Myeloid Leukemia Transformed From Myelodysplastic Syndrome

PURPOSE Elderly acute myelocytic leukemia (AML) patients have limited treatment options because they poorly tolerate standard-dose chemotherapy. The present article describes our experience with ultra-low-dose decitabine combined with infusion of autologous cytokine-induced killer (CIK) cells for 2 elderly patients with myelodysplastic syndrome-transformed AML. METHODS Decitabine (10 mg) was given on days 1 to 5, and CIK cells on day 14 with 2 to 8 × 10(9) cells per infusion. FINDINGS The therapeutic regimen resulted in marked hematologic recovery and was associated with better than expected survival in both cases. IMPLICATIONS Our experience suggests that the combination therapy is safe and effective for elderly patients with myelodysplastic syndrome-transformed AML.

Successful treatment with low-dose decitabine in acute myelogenous leukemia in elderly patients over 80 years old: Five case reports

The incidence of acute myelogenous leukemia (AML) in patients over 80 years old is >20 times greater than that observed in younger patients. Previously, no standard treatment protocol for elderly patients with AML existed, however the development of hypomethylating agents, including decitabine, has brought about promising results in AML. In the present study, we report on the usage of a lower than routine dosage of decitabine in patients over 80 years old with AML. Since January 2010, 5 patients diagnosed with AML over the age of 80 years old received treatment with decitabine in our hospital. Decitabine was administered at a dose of 10–15 mg/m2 and repeated every other day for a total of 5 days. This cycle was repeated for ∼6 weeks. The 5 patients received a total of 19 cycles of treatment with decitabine. No patient achieved complete or partial remission. An antileukemic effect was observed in 25% of courses (3/12). An increase in platelet count of >20×109/l was observed in 26.3% (5/19) of cycles compared with previous treatment. An increase in hemoglobin concentration of >20 g/l was observed in 36.8% (7/19) of cycles in comparison to previous treatment, four of which achieved normal hemoglobin levels. One patient became red blood cell transfusion-independent. The median survival time was 19.8±4.8 months. Survival time from decitabine administration to mortality was 13.2±5.1 months. The main side-effect was bone marrow suppression with grade III–IV thrombocytopenia, grade III–IV leukocytopenia, grade III–IV neutropenia and anemia accounting for 94.7% (18/19), 47.4% (9/19), 89.5% (17/19) and 21.1% (4/19), respectively. Severe infection or bleeding was not observed and no patient stopped treatment due to adverse effects. In conclusion, extremely low-dose decitabine may be used safely in elderly patients and achieved longer survival times than reported previously in AML patients aged 80 and above. It is suggested that complete remission may not be the primary objective, while improvement of quality of life may be a better choice in AML patients over 80 years old. The cases observed in our study were limited, so more cases are required for further study.

Individualized fludarabine-based regimen in elderly patients with chronic lymphocytic leukemia/small lymphocytic lymphoma.

IntroductionThe aim of this study was to investigate the efficacy and safety of a fludarabine-based individualized regimen in elderly patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).MethodsSixteen patients were treated with the individual regimen of fludarabine combined with rituximab. Adverse reactions and efficacy of treatment were observed.ResultsSixteen patients received a total of 69 courses of immunochemotherapy, with an average administration of 275 mg fludarabine per person. The overall response rate was 81.3% (13/16), in which seven cases (43.8%) achieved complete remission, six cases (37.5%) achieved partial remission, two cases (12.5%) had stable disease, and one case (6.3%) developed disease progression. The most frequent side effect was myelosuppression. Two patients experienced grade 3–4 cytopenia, one case developed a grade 3 infection, and no treatment-related death was observed.ConclusionThe individual regimen of fludarabine combined with rituximab demonstrated marked clinical efficacy and acceptable toxicity in elderly patients with CLL/SLL.