A real-world study of infectious complications of venetoclax combined with decitabine or azacitidine in adult acute myeloid leukemia.

PURPOSE: The purpose of this study was to identify the incidence, sites and main pathogens, and risk factors for infectious complications occurring in patients with adult acute myeloid leukemia (AML) during the first course of venetoclax combined with decitabine or azacitidine. METHODS: A retrospective cohort analysis was performed of 81 patients with AML older than 14 years who received the first cycle of venetoclax combined with a hypomethylating agent (HMA) between March 2018 and March 2021 at our institution. Infectious complications, if any, were documented. RESULTS: Among a total of 81 cases of AML, 59 (72.8%) patients occurred infections, including fever without an identifiable source (28.8%), clinically documented infections (40.7%), and microbiologically documented infections (30.5%). The most commonly isolated organism in culture was Candida albicans, followed by Klebsiella pneumonia, and Pseudomonas aeruginosa. The 4-week and 8-week mortality rates were 3.7% and 7.4%, respectively. In multivariate analysis, a high proportion of blasts in bone marrow, decreased hemoglobin level, and fever with or without a documented infection at baseline were significant independent risk factors for infectious complications. CONCLUSION: Compared with conventional chemotherapy, the incidence of infectious complications of venetoclax combined with decitabine or azacitidine significantly decreased. Pretreatment high leukemia burden and fever were independent risk factors for infections.

Synchronous diagnosis and treatment of acute myeloid leukemia and chronic lymphocytic leukemia: Two case reports.

BACKGROUND: The concurrence of acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) is rare. Previous reports of such cases have focused mainly on clinical diagnosis and characteristics, so the mechanism remains unclear, and therapy options have been poorly explored. CASE SUMMARY: Here, we report two cases of synchronous AML and CLL. Flow cytometry revealed two distinct abnormal cell populations (myeloblasts and lymphoid cells) according to scatter characteristics. CD5-positive B cell lymphoma with myeloid leukemia invasion was observed on lymph node biopsy. Chemotherapy regimens indicated for both AML and CLL were used in our patients, and our patients achieved complete response after chemotherapy. Next-generation sequencing of 88 genes was performed. CONCLUSION: We conclude that early mutation and dysregulation at the hematopoietic stem cell stage and the accumulation of multiple rearrangements may cause the concurrence of CLL and AML. The treatment of infection and combination therapy aimed at the CLL component are significant in the management of patients with concurrent CLL and AML.

Case Report: The First Report of NUP214-ABL1 Fusion Gene in Acute Myeloid Leukemia Patient Detected by Next-Generation Sequencing.

The NUP214-ABL1 fusion gene is a constitutively active tyrosine kinase that can be detected in 6% of T-cell acute lymphoblastic leukemia (T-ALL) patients, and it can also be found in B-cell acute lymphoblastic leukaemia (B-ALL). However the NUP214-ABL1 fusion in acute myeloid leukemia (AML) has not yet been reported. Up to now, the sensitivity of NUP214-ABL1-positive patients to tyrosine kinase inhibitor (TKI) is still controversial. Here we report the first case of an AML patient carrying NUP214-ABL1 fusion gene. The conventional AML chemotherapy regimen for the patient was successful. Identification of additional AML patients with NUP214-ABL1 fusion gene will provide treatment experience and prognostic evaluation.

Commutators of PAR-1 signaling in cancer cell invasion reveal an essential role of the Rho-Rho kinase axis and tumor microenvironment.

We recently reported that proteinase-activated receptors type I (PAR-1) are coupled to both negative and positive invasion pathways in colonic and kidney cancer cells cultured on collagen type I gels. Here, we found that treatments with the cell-permeant analog 8-Br-cGMP and the soluble guanylate cyclase activator BAY41-2272, and Rho kinase (ROK) inhibition by Y27632 or a dominant negative form of ROK lead to PAR-1-mediated invasion through differential Rac1 and Cdc42 signaling. Hypoxia or the counteradhesive matricellular protein SPARC/BM-40 (SPARC: secreted protein acidic rich in cysteine) overexpressed during cancer progression also commutated PAR-1 to cellular invasion through the cGMP/protein kinase G (PKG) cascade, RhoA inactivation, and Rac1-dependent or -independent signaling. Cultured primary cancer cells isolated from peritoneal and pleural effusions from patients with colon cancer or other malignant tumors harbored PAR-1, as shown by RT-PCR and FACS analyses. These malignant effusions also contained high levels of activated thrombin and fibrin, and induced a proinvasive response in HCT8/S11 human colorectal cancer cells. Our data underline the essential role of the tumor microenvironment and of several commutators targeting cGMP/PKG signaling and the RhoA-ROK axis in the control of PAR-1 proinvasive activity and metastatic potential of cancer cells in distant organs and peritoneal or pleural cavities. We also add new insights into the mechanisms linking the coagulation mediators thrombin and PAR-1 in the context of blood coagulation disorders and venous thrombosis often observed in cancer patients, as described in 1865 by Armand Trousseau.

Homoharringtonine-induced apoptosis of human leukemia HL-60 cells is associated with down-regulation of telomerase.

Homoharringtonine (HHT), first isolated from the Chinese evergreen Cephalotaxus Harringtonia, has been shown inhibiting activity in leukemia in initial studies in China and in later studies in the US, but the detailed mechanism of action is still unclear. The goal of the experiments shown here is to explore the effect of HHT on the telomerase activity and apoptosis of human leukemia HL-60 cells. The telomerase activity of HL-60 cells was examined by the telomeric repeat amplification protocol (TRAP)--an enzyme-linked immunosorbent assay (ELISA). Apoptosis was analyzed by morphological observation, DNA agarose gel electrophoresis, flow cytometry (FCM), and TdT-mediated dUTP-biotin nick end labeling (TUNEL). After treatment with HHT at 5-500 microg/l for 48 hours, the level of telomerase activity in HL-60 cells decreased in a dose-and time-dependent manner. Simultaneously, HL-60 cells underwent apoptosis. In conclusion, our data suggest that HHT can inhibit the telomerase content of HL-60 cells effectively and induce apoptosis.

[Study on unrelated donor allogeneic bone marrow transplantation with Bu-CY2 conditioning regimen for myelodysplastic syndrome].

OBJECTIVE: To evaluate the efficacy and safety of Bu-CY(2) conditioning regimen on allogeneic bone marrow transplantation (BMT) with unrelated donor for myelodysplastic syndrome. METHODS: Six patients received chemotherapy regimen of busulfan (Bu) and cyclophosphamide (CY) before allogeneic BMT (Bu 4 mg . kg(-1) . d(-1), -7 d - -4 d, CY 60 mg . kg(-1) . d(-1), -3 d - -2 d). Mycophenolate mofetil combined with cyclosporin A and methotrexate was used for prevention of acute graft-versus-host disease after transplantation. Lipo prostaglandin E(1)was used in prophylactic regimen for hepatic veno-occlusive disease. RESULT: Neutrophil count began to be higher than 0.5 x 10(9)/Lat the 18th day after BMT. Platelet count began to be higher than 20 x 10(9)/Lat the 21st day after BMT. Disease-free survival in the six patients was 27 months. CONCLUSION: Bu-CY(2) conditioning regimen on allogeneic bone marrow transplantation with unrelated donor is an effective therapy for patients with myelodysplastic syndrome.

[Itraconazole for secondary prophylaxis of invasive fungal infection in patients undergoing chemotherapy and stem cell transplantation].

OBJECTIVE: To evaluate the efficacy and safety of itraconazole for secondary prophylaxis of previous proven or probable invasive fungal infection (IFI) in patients undergoing chemotherapy or allogeneic hematopoietic stem cell transplantation (HSCT) in agranulocytosis state. METHODS: A phase IV prospective, open-label, multicenter trial was conducted to evaluate itraconazole (200 mg q12h intravenously d1-2, 200 mg/d) as secondary antifungal prophylaxis in patients (18-65 years old) undergoing chemotherapy or HSCT with previous proven or probable IFI. Itraconazole was started when patients' neutrophils＜1.5 × 109/L, and stopped when chemotherapy patients' neutrophils ＞0.5 × 109/L and stem cell transplant recipients' neutrophils＞1.0 × 109/L. The primary end-point of the study was the incidence of proven, probable or possible IFI. RESULTS: Seventy one patients from November 2008 to September 2010 were enrolled in the trial. The median duration of itraconazole prophylaxis was 14 (4-35) days. No patients died of drug-related toxicity within trial. Five cases occurred IFI during the trial. The cumulative incidence of invasive fungal disease was 7.0%. One patient was withdrawn from the study due to treatment-related adverse events (liver malfunction and severe phlebitis). CONCLUSION: Itraconazole appears to be safe and effective for secondary prophylaxis of systemic fungal infection after chemotherapy and allogeneic HSCT. The observed incidence of 7.0% is considerably lower than the relapse rate reported in historical controls, suggesting that itraconazole is a promising prophylactic agent in this population.

Clinical characteristics and outcome of isolated extramedullary relapse in acute leukemia after allogeneic stem cell transplantation: a single-center analysis.

Isolated extramedullary relapse (EMR) of acute leukemia (AL) is a rare occurrence. However, it appears to be more common after allogeneic stem cell transplantation (allo-SCT). To characterize what has been observed in isolated EMR, we investigated 287 consecutive AL patients (144 acute myeloid leukemia; 138 acute lymphocytic leukemia; 5 acute mixed-lineage leukemia) who underwent allo-SCT. Twelve cases experienced relapse at extramedullary sites without concomitant involvement of the bone marrow (BM). The onset to relapse after allo-SCT was longer in extramedullary sites than in the BM (median, 10 months versus 5.5 months). EMR sites varied widely and included the central nervous system, skin, bone, pelvis and breasts. Univariate analysis demonstrated that cytogenetic abnormalities were correlated significantly with the onset of isolated EMR (P=0.001). The prognosis for patients who develop EMR remained poor but was relatively better than that after BM relapse (overall survival, 10 versus 18 months). Compared with local or single therapy, patients treated with systemic treatment in combination with local treatment could yield a favorable prognosis. In conclusion, we observed a significant number of isolated cases of EMR in AL patients after allo-SCT, cytogenetic abnormalities were correlated significantly with the onset of isolated EMR. We found that intensive approaches combining local and systemic therapy could produce favorable responses which may cure a proportion of these patients.

Prognostic values of various clinical factors and genetic subtypes for diffuse large B-cell lymphoma patients: a retrospective analysis of 227 cases.

AIM: To analyze the significance of different clinical factors for prognostic prediction in diffuse large B-cell lymphoma (DLBCL) patients. METHODS: Two hundred and twenty-seven DLBCL patients were retrospectively reviewed. Patients were managed with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen or rituximab plus the CHOP (RCHOP) regimen. RESULTS: Lactate dehydrogenase (LDH), ß2- microglobulin (ß2-M), B symptoms, Ann Arbor stage and genetic subtypes were statistically relevant in predicting the prognosis of the overall survival (OS). In the CHOP group, the OS in patients with germinal center B-cell- like (GCB)(76.2%) was significantly higher than that of the non-GCB group (51.9%, P=0.032). With RCHOP management, there was no statistical difference in OS between the GCB (88.4%) and non-GCB groups (81.9%, P=0.288). CONCLUSION: Elevated LDH and ß2-M levels, positive B symptoms, Ann Arbor stage III/IV, and primary nodal lymphoma indicate an unfavorable prognosis of DLBCL patients. Patients with GCB-like DLBCL have a better prognosis than those with non-GCB when treated with the CHOP regimen. The RCHOP treatment with the addition of rituximab can improve the prognosis of patients with DLBCL.

Role of CT-guided percutaneous lung biopsy in diagnosis of pulmonary fungal infection in patients with hematologic diseases.

The goal of our study is to evaluate the efficiency and safety of CT-guided percutaneous lung biopsy for the diagnosis of pulmonary fungal infection in patients with hematologic disease. Medical records were retrospectively reviewed for 16 patients with hematologic diseases, who were initially suspected to have pulmonary fungal infection clinically and underwent further diagnostic methods including blood culture, sputum culture and percutaneous lung biopsy. Of the 16 patients, 10 were diagnosed fungal infection (8 aspergillus, 2 mold fungus), 4 chronic organizing pneumonitis, 1 tuberculosis, and 1 Pneumocystis carinii through histological examination after percutaneous lung biopsy. However, the results of blood culture and sputum culture were negative. CT-guided biopsy showed 100% overall accuracy and 62.5% (10/16) fungal infection rate. The biopsy-induced complications encountered were pneumothorax in 3/16 (18.75%) and hemoptysis in 1/16 (6.25%). No serious complication was found in this series. In conclusion, CT-guided percutaneous lung biopsy is an effective and safe method for the diagnosis of pulmonary fungal infection in patients with hematologic diseases.

[Tandem autotransplants of peripheral blood stem cells following sequential high-dose CHOEP chemotherapy for aggressive lymphoma].

The purpose of this study was to evaluate the effecacy and safety of CHOEP mobilization regimen, and the effect and tolerance of sequential chemotherapy combined with tandem autotransplants of peripheral blood stem cells for aggressive lymphoma. The clinical data of 5 patients with recurrent, aggressive lymphoma treated with of sequential chemotherapy combined with tandem autotransplants were analyzed retrospectively. The patients included 1 HD and 4 NHL. Mobilization regimen was CHOEP combined with G-CSF 5 microg/(kg x d). The conditioning regimen for the tandem transplantation was high-dose CHOEP. The interval of the tandem autotransplantation was 9 (5 - 31) weeks. In tandem autotransplant, the cell number of MNC transfused was 3.05 (1.91 - 4.14) x 10(8)/kg and 3.55 (2.23 - 6.0) x 10(8)/kg; CD34(+) cells were 4.11 (2.59 - 4.94) x 10(6)/kg and 5.70 (2.77 - 10.6) x 10(6)/kg; CFU-GM was 2.96 (2.01 - 4.54) x 10(5)/kg and 2.44 (1.78 - 2.9) x 10(5)/kg respectively (P > 0.05). The results showed that all patients gained prompt and sustained hemotopoietic reconstitution. The interval of ANC >or= 0.5 x 10(9)/L was 10 (8 - 12) days and 10.5 (9 - 12) days; Pt >or= 2.0 x 10(9)/L was 11 (10 - 14) days and 12.5 (10 - 15) days respectively (P > 0.05). Four patients survived, three patients among them were alive in disease-free for median of 46 (9 - 88) months. The overall survival was 80%, and the disease-free survival was 60%. In conclusion, the method of sequential high-dose CHOEP chemotherapy combined with autotransplants of peripheral blood stem cells in tandem for aggressive lymphoma is probably safe and effective.

[Treatment of childhood leukemia with unrelated donor allogeneic bone marrow transplantation].

OBJECTIVE: Allogeneic bone marrow transplantation has been established as a standard method for the treatment of a range of malignant and non-malignant hematologic diseases in children. Unfortunately, fewer than 30% of patients have a human leukocyte antigen (HLA)-matched sibling. Advances in our understanding of the HLA system and the development of large international donor registries encourage the increasing use of unrelated donors as an alternative source of stem cells. The purpose of this study was to evaluate the clinical efficacy and safety of unrelated donor allogeneic bone marrow transplantation (URD-BMT) for the treatment of childhood leukemia. METHODS: Six patients with leukemia received URD-BMT. Two of them suffered from chronic myeloid leukemia (CML), 3 suffered from acute lymphocytic leukemia (ALL) and 1 suffered from acute promyelocytic leukemia (APL) (CR2). All cases were facilitated by Tzu Chi Marrow Donor Registry (TCTMDR). The high resolution DNA test for classIand II was carried out in HLA typing of all donor-receiver pairs. HLA allele matched in three cases, mismatched with one locus in two cases and with two loci in one case. All patients were prepared with cyclophosphamide (CY) 60 mg/kg/day for 2 days (total dose 120 mg/kg) and busulfan (Bu) 1 mg/kg x 4/day for 4 days (total dose 16 mg/kg). Mycophenolate mofetil (MMF), CsA and MTX were given to prevent acute graft-versus-host-disease (aGVHD). CsA of 3 mg/kg/d was continuously given by i.v. infusion, and then 6mg/kg/d by oral. The blood CsA concentration was 200 - 300 ng/ml. MTX was given at the dosage of 15 mg/m(2) on d 1 and 10 mg/m(2) on d 3, 6,9 or 11. MMF was given at the dosage of 0.25 - 0.5 g/d from day 0 to day 120. Prostaglandin E1 was given to prevent the hepatic veno-occlusive disease (VOD), Ganciclovir was used to prevent CMV infection until the CMV antigenemia became negative. RESULTS: Analysis of DNA short tandem repeats showed total engraftment of donor marrow after transplantation in all cases. The median time when granulocyte exceeded 0.5 x 10(9)/L was 14.5 (13 - 18) days, platelets exceeded 20 x 10(9)/L was 16 (14 - 23) days. The acute GVHD grade II-IV occurred in 2 of 6 (33.3%) patients. There were 3 cases with chronic GVHD and none of them developed with the extensive chronic GVHD. All patients were alive in disease-free situation now with median follow-up 412 (187 - 1338) days. CONCLUSION: URD-BMT is an effective method for the treatment of childhood leukemia.

[A comparison of clinical outcomes between HLA allele matched and 1 - 2 alleles mismatched unrelated allogeneic bone marrow transplantations].

OBJECTIVE: To compare the clinical outcomes between HLA allele matched (HLA-M) and 1 approximately 2 alleles disparity mismatched (HLA-mis) unrelated allogeneic bone marrow transplantation (URD-BMT). METHODS: Thirty-nine patients received HLA-M and 21 received HLA-mis URD-BMT for the treatment of acute leukemia, chronic myeloid leukemia in chronic phase (CP) and myelodysplastic syndromes (MDS) in our hospital between November 1998 and December 2002. Conditioning regimen was Bu 16 mg/kg plus CTX 120 mg/kg, and mycophenolate mofetil (MMF), CsA and MTX were given to prevent aGVHD. RESULTS: Thirty-eight of the HLA-M group and 18 of the HLA-mis group were engrafted successfully. The median follow-up duration was 11 (2.5 - 52.0) months for HLA-M group and 9 (2 - 46) months for HLA-mis group. The 3-year probabilities of disease-free survival (DFS) for HLA-M and HLA-mis group were (79.2 +/- 7.1)% and (45.8 +/- 15.5)%, respectively (P < 0.05). Grade II - IV aGVHD occurred in 10 (26.3%) patients in HLA-M group and 6 (33.3%) in HLA-mis group, respectively (P > 0.05). CONCLUSION: URD-BMT is an effective modality for the treatment of leukemia and MDS. The outcome after URD-BMT can be optimized by matching the HLA-A, B and DR alleles between the donor and recipient.