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Background Resistance to proteasome inhibitors (PIs) is a major obstacle to the successful treatment of multiple myeloma (MM). Many mechanisms have been proposed for PI resistance; however, our mechanistic understanding of how PI resistance is inevitably acquired and reversed remains incomplete. Methods MM patients after bortezomib relapse, MM cell lines and mouse models were used to generate matched resistant and reversed cells. RNA sequencing and bioinformatics analyses were employed to assess dysregulated epigenetic regulators. In vitro and in vivo procedures were used to characterise PI-tolerant cells and therapeutic efficacy. Results Upon PI treatment, MM cells enter a slow-cycling and reversible drug-tolerant state. This reversible phenotype is associated with epigenetic plasticity, which involves tolerance rather than persistence in patients with relapsed MM. Combination treatment with histone deacetylase inhibitors and high-dosage intermittent therapy, as opposed to sustained PI monotherapy, can be more effective in treating MM by preventing the emergence of PI-tolerant cells. The therapeutic basis is the reversal of dysregulated epigenetic regulators in MM patients. Conclusions We propose an alternative non-mutational PI resistance mechanism that explains why PI relapse is inevitable and why patients regain sensitivity after a ‘drug holiday’. Our study also suggests strategies for epigenetic elimination of drug-tolerant cells.

MLL undergoes multiple distinct chromosomal translocations to yield aggressive leukemia with dismal outcomes. Besides their well-established role in leukemogenesis, MLL fusions also possess latent tumor-suppressive activity, which can be exploited as effective cancer treatment strategies using pharmacological means such as proteasome inhibitors (PIs). Here, using MLL-rearranged xenografts and MLL leukemic cells as models, we show that wild-type MLL is indispensable for the latent tumor-suppressive activity of MLL fusions. MLL dysfunction, shown as loss of the chromatin accumulation and subsequent degradation of MLL, compromises the latent tumor suppression of MLL-AF4 and is instrumental for the acquired PI resistance. Mechanistically, MLL dysfunction is caused by chronic PI treatment-induced epigenetic reprogramming through the H2Bub-ASH2L-MLL axis and can be specifically restored by histone deacetylase (HDAC) inhibitors, which induce histone acetylation and recruits MLL on chromatin to promote cell cycle gene expression. Our findings not only demonstrate the mechanism underlying the inevitable acquisition of PI resistance in MLL leukemic cells, but also illustrate that preventing the emergence of PI-resistant cells constitutes a novel rationale for combination therapy with PIs and HDAC inhibitors in MLL leukemias.

Objectives: Multiple myeloma (MM) often develops as a secondary primary malignancy (SPM). The retinoblastoma susceptibility gene (RB1) was the first tumour suppressor gene to be identified. We pooled and analyzed available data to compare the incidence of RB1 gene deletions and other cytogenetic abnormalities in patients with MM alone or as an SPM.Methods: We conducted a retrospective study of 475 patients. The experimental group comprised 18 patients with MM as an SPM, and the control group comprised 457 MM patients. We analyzed the baseline information in both groups, and used the odds ratio (OR), 95% confidence interval (CI), and forest plot to determine the incidence of SPMs with and without cytogenetic abnormalities.Results: The incidence of RB1 gene deletion was higher in the experimental group. There was no significant difference in other cytogenetic abnormalities.Conclusions: RB1 gene deletions appear to be associated with MM that develops as an SPM.

Objective:To assess the relevance between minimal residual disease (MRD) levels and disease recurrence and prognosis in patients with acute leukemia before and after hematopoietic stem cell transplantation (HSCT), and further to explore potential benefit based on pre-transplant MRD stratification. Methods: A total of 113 patients with newly diagnosed acute leukemia in Fujian Union hospital from April 2013 to April 2019 were retrospectively analyzed. 94 patients were complete remission (CR)( 50 cases of AML and 44 cases of ALL). 19 patients didn't achieve CR( 10 patients with AML and 9 patients with ALL). The median age was 26(1-56) years. 67 patients were male and 46 patients were female. The sources of hematopoietic stem cell include bone marrow, cord blood and peripheral blood stem cell. All patients underwent myeloablative conditioning before transplantation. Standard graft-versus-host disease (GVHD) prophylaxis was applied in all patients. MRD was measured by flow cytometry and real-time quantitative polymerase chain reaction(PCR). MRD values >10-4 or BCR-ABL were considered positive for minimal residual disease and compared with bone marrow morphological findings. Median follow time was 15.2 (2.2 to 70.5) months. Results: Among patients in CR, achieving pre-MRD negativity was associated with longer 2-year relapse-free survival (2-year RFS; 81.4% vs 49.1%; P=0.003) and 2-year overall survival (2-year OS; 84% vs 50.6%; P=0.012). Compared to pre-MRDneg patients, pre-MRDpos patients had a higher incidence of relapse (31.2% vs. 5.1%, P=0.001). There was no significant difference between OS and MRD level after transplantation (OS; post-MRDneg 82.9% vs. post-MRDpos 66.7%, P =0.468). In the second set of analyses, CR patients were classified into the MRDpos /MRDpos group, the MRDpos /MRDneg group, the MRDneg /MRDpos group, and the MRDneg /MRDneg group according to MRD dynamics. Compared to the other three groups, patients from the MRDpos /MRDpos group had higher cumulative incidences of relapse (MRDpos /MRDpos, 48.3%; MRDpos /MRDneg, 22.2%, MRDneg /MRDpos,40.0%; MRDneg /MRDneg, 2.7%; P Conclusion: MRD can be used as a sensitive indicator to evaluate disease prognosis. Patients who are in morphologic remission and have no evidence of MRD before the HSCT come to encouraging leukemia-free survival. Continuous regular dynamic observation is important for guiding disease recurrence and prognosis. Disclosures No relevant conflicts of interest to declare.

Objective: Invasive fungal disease (IFD) is a serious complication after allogeneic hematopoietic stem cell transplantation (HSCT). However, limited data is available on its clinical features after cord blood transplantation (CBT) for patients with hematological malignancies. Method: We retrospectively reviewed 63 patients who underwent myeloablative CBT at our institution between July 2013 and June 2019 with a median follow-up of 14 months. Micafungin, Voriconzole or Posaconazole was used for IFD prophylaxis. Results: Eight patients were identified as having an IFD, including 2 with proven IFD, 1 with probable IFD, and 5 with possible IFD. The most common prophylaxis regimen is micafungin (68.2%, 43/63). The incidence rate of IFD in the primary antifungal prophylaxis (PAP) and secondary antifungal prophylaxis (SAP) groups were 11.3% and 25% (P=0.488). The OS of day at +100, six months and +200 in the IFD and No IFD groups were 62.5% vs. 86.9% (P=0.1), 50 % vs.78.2% (P=0.07), and 50% vs.75.9% (P=0.094), respectively. The 3-year probabilities of overall survival (OS) in the IFD and No IFD groups were 50% and 60.5%, respectively (p=0.316). The incidence rate of Non-relapse Mortality in the IFD and No IFD groups were 42.9% and 30%, respectively (p=0.319). Conclusion: Antifungal prophylaxis could help to reduce the incidence of IFD after CBT for patients with hematological malignancies. Figure Disclosures No relevant conflicts of interest to declare.

Objective: To evaluate the efficacy and safety of the combination of haploidentical hematopoietic with low-dose ATG, PTCy and cord blood competitive transplantation for hematologic malignancies. Methods: This study was conducted as a retrospective review of medical records of 31 patients with hematologic malignancies who received a combination of haploidentical hematopoietic with low-dose ATG, PTCy and cord blood competitive transplantation at Fujian medical university union hospital, from November 2016 to April 2019. Results: Among the 31 patients with hematologic malignancies, the median age was 22 (6-52) years, of which 17 were CR patients and 14 were No CR patients. The conditioning was modified FABuCy+ low-dose ATG (total dose 5mg/kg) based regimen. Cord blood units were selected based on the results of HLA typing and cell doses evaluated before freezing. Units with at least 5/10 matched HLA loci became the candidates. Prophylaxis for graft-versus host disease(GVHD) was by CsA(cyclosporine), MMF (mycophenolate mofetil) plus PTCy(post-transplant cyclophosphamide). The median values of absolute total nucleated cell counts were 123.0 (49.0-258.8) × 107 / kg in The haploidentical grafts and 2.5 (1.1-13.0 × 107 / kg in the cord blood units,respectively. The median Doses of CD34+ cells infused were 70.0 (11.8-297.6) × 105 / kg in the haploidentical grafts and 1.4 (0.1-13.0) × 105 / kg in the cord blood units, respectively. All patients attained complete engraftment , of which 19 were haploidentical engraftment and 12 were cord blood engraftment. The median durations of myeloid engraftment were 14 (12-37) days and 14.5 (10-48) days for Platelets. With a cumulative platelet engraftment incidence of 90.3%. During a median follow-up of 8.5 (1.3-30.7) months, the incidence of grade II-IV acute GVHD at 100-day was 47.5%, grade III-IV acute GVHD was 13.8%, respectally. The incidence of limited chronic GVHD at 1-year was 35.1%, severe chronic GVHD was 14.6 %, respectively. The estimated 1-year OS was 76.1%,DFS was 68.5% ,GRFS was 60.6%, NRM was 18.5% , RM was 6.7% , respectively. The estimated 1-year OS of CR patients and No CR patients were 92.9% and 55.0%(p=0.114), DFS were 83.6% and 51.9%(p=0.053),NRM were 7.1% and 31.2%(p=0.132),relapse were 10.0% and 30.4%(p=0.131), respectively. Conclusion:The results suggested that the combination of haploidentical hematopoietic with low-dose ATG, PTCy and cord blood competitive transplantation may potentially improve the outcome of HSCT. It offers a transplant alternative for patients with hematologic malignancies who lack matching donors. Disclosures No relevant conflicts of interest to declare.

Bloodstream infection (BSI) caused by multidrug‐resistant bacteria (MDRB) or extensively drug-resistant bacteria (XDRB) in immunocompromised and neutropenic patients after hematopoietic stem cell transplantation (HSCT) is a global threaten. However, effective treatment regimen is still controversial and inadequate due to the rapid deterioration, the horrific evolution of bacteria and high mortality that the mortality related to BSI caused by carbapenem-resistant Enterobacteriaceae (CRE) is 51% in adult neutropenic patients[1]. Here, we presented four cases that CRE was detected in blood of severe agranulocytosis patients undergoing HSCT. All patients ranged from 2 to 50 years old were diagnosed as hematologic disease. CREs were detected within 1 month from the date of engraftment. In case 1, a 6-year-old boy with high-risk B-cell acute lymphocyte leukaemia received halpo-HSCT after chimeric antigen receptor T-cell therapy and the 20th chemotherapy, ultimately, he died from acute graft versus host disease and BSI that tienam and tigecycline showed little effect though the MIC value of tigecycline was less than 0.5ug/ml. The second patient is a 25-year-old female who was diagnosed as hemophagocytic syndrome with recurrent fever and a salvage haploidentical transplantation combining with a unit of umbilical cord blood stem cells was performed. Finally, she died from BSI caused by CRE although a combination therapy using polymyxin B, tigecycline and doubled-dose Tienam was given, which subsequently was changed to another therapeutic regimen using a higher dose tigecycline and fosfomycin and polymyxin B in light of the resistance of tienam. Patients in case 3 and case 4 received a combination therapy with tigecycline, polymyxin B, fosfomycin, and Tienam intravenously. For the 29-month-old boy diagnosed as acute monocytic leukemia with high expression of WT1 and abnormal karyotype and treated with cord blood stem cell transplantation in case 3, the tigecycline was given with a dose of 2.4mg/kg at the first time, followed by doses of 1.2mg per dose every 12 hours, and a dose of 2.0mg/kg at the first time, followed by doses of 1.25mg/kg per dose every 12 hours of polymyxin B, 0.15g/kg per every 12 hours of fosfomycin, as well as 30mg/kg per dose every 6 hours of imipenem were administrated. For the 50-year-old woman with multiple myeloma receiving an autologous hematopoietic stem cell transplantation (auto-HSCT) in case 4, the dose of tigecycline was 100mg at the first time, followed by doses of 1.2mg per dose every 12 hours. Fosfomycin with the dose of 8.0g was used every 12 hours, and the dose of imipenem was1.0g per dose every 6 hours, also, polymyxin B was administrated with a dose of 2.0mg/kg at the first time, followed by doses of 1.25mg/kg per dose every 12 hours. Consequently, patients in case 3 and case 4 were survival. Therefore, a strong combination therapy, as well as the emergency of new drugs might be considered in immunocompromised and neutropenic ill patients with BSI caused by MDRB or XDRB. Disclosures No relevant conflicts of interest to declare.

Background: Acute lymphoblastic leukemia (ALL) is a neoplastic cancer characterized by clonal expansion of leukemic cells in lymph organs and bone marrow. Lots of kinds of different chromosomal translocation can be found in those leukemic cells. However, the role of the abnormal chromosomals and genes in leukemogenesis is not yet fully understood. Identifying new chromosomal translocation can facilitate a better understanding of pathogenesis of this disease. Case presentation: We report a rare case of acute lymphocytic leukaemia with t(3;13)(q29,q21). The patient was diagnosed pre-B-ALL with no abnormal chromosomal or gene fusion and achieved complete remission (CR) after induction chemotherapy. Ten months later, she relapsed in the consolidation with cytogenetics test showing 46,XX,t(3;13)(q29,q21). Given no CR after 2 chemotherapy regimens, she received salvage cord blood transplantation. Regular intrathecal methotrexate was applied to prevent central nervous system leukemia. Good graft-versus-leukemia (GVL) effect was induced by daily injection of low dose of IL-2 two months post transplantation. Minimal residual disease (MRD) negativity was maintained until central nervous system leukemia was found 8 months after transplantation. A whole exome sequencing was performed. Nine driver mutation genes and seven tumor genes were found. Conclusions: We highly suspect that the relapse in central nervous system after transplantation is associated with the rare chromosomal translocation. Disclosures No relevant conflicts of interest to declare.

The NOTCH1 is a ligand dependent transcription factor that plays an important role in lymphocyte differentiation and apoptosis . NOTCH1 dysfunction is closely related to the proliferation, differentiation, and apoptosis of tumor cells in chronic lymphocytic leukemia (CLL). With the popularization of next-generation sequencing technology the relationship between NOTCH1 mutations and disease progression in CLL, has attracted increasing attention. Here, we investigated whether the loss of a 2 bp frame shift deletion mutation influences the NOTCH1 pathway and whether this mutation alters the NOTCH1 nuclear mechanism in CLL. The ICN plasmid was engineered by cloning the ICN coding sequence into a pmax-Clover vector. The c.7541-7542delCT mutation (CTdel) was generated by site-specific mutagenesis. The BaF3 cells were transfected with Amaxa Nucleofector technology then sorted. The NOTCH1 protein expression was evaluated by Western blotting using an anti-NOTCH1 antibody, which showed compatible with the ICN. The CTdel mutation resulted in a lower molecular weight band, consistent with the presence of a premature STOP codon. Results from qRT-PCR showed elevated mRNA expression of NOTCH1 in the groups transfected with ICN and CTdel genes. An immunofluorescence assay showed that NOTCH1 was distributed in both the nuclei and cytoplasm in the control cells, while it was located in the nucleus of the cells of the ICN and CTdel groups. Compared with the control group, the activity of the reporter genes in both the ICN and CTdel groups increased, with the highest increase in the CTdel group, as reported by the two-fluorescent enzyme reporting system assay. These results determine the presence or absence of a NOTCH1 mutation, the ICN protein is located in the nucleus, and show that the NOTCH1 pathway is enhanced and the function is more stable in the presence of a NOTCH1 mutation. From the RNA-seq results we found that RT-PCR showed transcription levels of CCL17 in the ICN and CTdel groups were higher than those in the control group, and that CCL17 in the CTdel group was significantly higher than in the ICN group. We collected the culture supernatant of CLL cells for an ELISA assay and found that CCL17 was significantly elevated in the CTdel group, but CCL17 was not detected in the control group and the ICN group. In order to verify the CCL17 function of in CLL with the NOTCH1 mutation, we performed a transwell experiment to detect the ability of mediating activated CD4+ T cell migration by CCL17. The results showed that the number of CD4+ T-cells in the CTdel group that migrated in response to CCL17 was more than in the ICN group. In order to verify that the NOTCH1 mutation changed the ICN binding function, we performed a CO-IP experiment. The results showed that ICN had an interaction with MTA2/HDAC1, but this interaction was weakened with CTdel. Mass spectrometry (MS) analysis suggested that ICN was combined with MTA2 while CTdel peptides were not detected in MTA2 samples. In order to verify the negative regulatory effect of MTA2 and HDAC1 on the NOTCH1 mutation induced by C-terminal truncation in CCL17 transcription, we conducted a CHIP experiment on the nuclear pyrolysis of ICN/CTdel.The results showed that the combination of MTA2/HDAC1 and the promoter of CCL17 and ICN/CTdel was weaker than that of the control group. Because of the multiple-point binding characteristics of transcription factors on gene expression regulation, it can be concluded that CTdel DNA binding is weaker than the binding of ICN. As a result, in the presence of the NOTCH1 protein C-terminal truncation, which has lost MTA2/HDAC1 binding, its inhibition is reduced and the CCL17 expression becomes significantly elevated. In conclusion, it is suggested that the NOTCH1 mutation found in CLL stimulates the NOTCH1 pathway, and is related to the high expression of CCL17. The chemokine CCL17 can cause the migration of CD4+ T-cells and change the microenvironment to favor tumor cell survival. ICN in the nucleus combines with CSL to form activating complexes or recruits transcription factor MTA2/HDAC1 to form inhibiting complexes, and constitutes the balance between the promotion and the inhibition for the downstream gene expression. The NOTCH1 mutation with CTdel could result in loss of this balance, and activate the expression of downstream genes, such as CCL17. Key words: chronic lymphocytic leukemia; NOTCH1; mutation; HDAC1; CCL17; chemokine Disclosures No relevant conflicts of interest to declare.

2-Methoxyestradiol (2-ME2) is an endogenous metabolite of 17beta-estradiol (E2) with estrogen receptor-independent anti-cancer activity. The current study sought to determine the mechanism of anti-cancer activity of 2-ME2 in human acute T lymphoblastic leukemia CEM cells. Results showed that 2-ME2 markedly suppressed proliferation of CEM cells in a time- and dose-dependent manner. 2-ME2-treated CEM cells underwent typical apoptotic changes. Exposure to 2-ME2 led to G(2)/M phase cell-cycle arrest, which preceded apoptosis characterized by the appearance of a sub-G(1) cell population. In addition, cytosolic cytochrome c release, increased procaspase-9 and -3 expressions, poly(ADP-ribose) polymerase (PARP) cleavage, and induced expression of caspase-8 were detected, suggesting that both the intrinsic apoptotic pathway and extrinsic apoptotic pathway were involved in 2-ME2-induced apoptosis. Moreover, the expression level of p21 protein was upregulated, whereas Bcl-2 and dysfunctional p53 protein were downregulated, which also contributed to 2-ME2-induced apoptosis. Our findings revealed that 2-ME2 might be a potent natural candidate for chemotherapeutic treatment of human acute T lymphoblastic leukemia when the precise effects of 2-ME2 were investigated further in other T leukemia cell lines and in primary T-cell leukemias.

CD40/CD40L interaction on high-grade aggressive lymphomas such as Burkitt lymphoma results in a decrease in proliferation, whereas a transient increase in proliferation and survival in vitro is seen with indolent lymphomas. In this study, cell growth inhibition on human Burkitt lymphoma cell lines CA46 and Raji were obtained with either srhCD40L or pyrrolidine dithiocarbamate (PDTC), a specific inhibitor of NF-kappaB, whereas converse effects on CD40 negative control. Moreover, S phase arrest was demonstrated on CA46 cells in the presence of srhCD40L, and also cell apoptosis following exposed to srhCD40L or PDTC. Furthermore, nuclear factor-kappaB (NF-kappaB) DNA binding activity of CA46 cell extracts was markedly suppressed with srhCD40L or PDTC by electrophoretic mobility shift assays (EMSAs). Thus, the growth inhibition and apoptosis-inducing activity of srhCD40L via CD40-CD40 ligand interaction on Burkitt lymphoma cells was confirmed, and these effects may be attributable to the suppression of NF-kappaB binding activity. Hence, srhCD40L may provide clinical benefits in the treatment of CD40 positive carcinomas including human Burkitt lymphoma.

The majority of patients with chronic lymphocytic leukemia (CLL) are not cured by traditional chemotherapy. One possible explanation for this is that the microenvironment protects CLL cells from both spontaneous- and cytotoxic-mediated apoptosis. The present study was designed to investigate the mechanisms accounting for these effects, since this information is crucial to understanding CLL physiopathology and identifying potential treatment targets. The CLL cell line L1210 and primary CLL cells were cultured under different conditions: With serum, cyclophosphamide (CTX), or with monolayers and conditioned medium (CM) from the stromal cell line HESS-5. Apoptosis, Hes family BHLH transcription factor 1 (HES-1) gene and protein expression, and histone H3K27me3 DNA demethylation were determined. Co-culture of L1210 cells with HESS-5 cells significantly inhibited serum deprivation- and CTX-induced apoptosis of leukemia cells, and resulted in a significant increase in short-term proliferation. Soluble factors in the CM from HESS-5 cells had a negligible effect. The HESS-5 cell-mediated inhibition of apoptosis of CLL cells was associated with increased HES-1 expression and hypomethylation of the H3K27me3 gene in the leukemia cells. These results indicate that stromal cells enhance the survival of CLL cells by regulating the HES-1 gene and protein expression, as well as H3K27me3 DNA demethylation, and suggest that specific interactions between stromal and leukemia cells may enhance the resistance of leukemia cells to chemotherapy.

NOTCH1 mutations occur in approximately 10% of patients with chronic lymphocytic leukemia (CLL). However, the relationship between the genetic aberrations and tumor cell drug resistance or disease progression remains unclear. Frameshift deletions were detected by gene sequencing in the NOTCH1 PEST domain in three naive CLL patients. These mutations were associated with chromosomal abnormalities including trisomy 12 or 13q deletion. Of note, one of the patients developed Richter’s transformation during FCR treatment. Immunofluorescent and western blot analyses revealed a markedly higher intracellular domain of NOTCH (ICN) expression in the mutated cells compared with their unmutated counterparts and normal CD19+ B lymphocytes (P

Chronic lymphocytic leukemia (CLL) is characterized by high heterogeneity in clinical features and outcomes in Western countries and China. In this study, the clinical and laboratory data of 210 CLL patients who were admitted to a single center in China between 2002 and 2011 were retrospectively analyzed. CLL patients had a median age of 60.2 years (range, 35–92 years) and CLL occurred more often in elderly female patients than in male patients (female:male, 1.2:1). The overall response rate [ORR, complete remission (CR) + partial remission (PR)] in the entire cohort of patients was 69.5% and the median overall survival (OS) was 67 months (95% CI, 57.88–76.11). In univariate analysis, an age of >60 years, chromosome 17p deletion (17p−) and elevated β2-MG were associated with a worse OS. Patients with all three poor prognostic factors had a worse outcome than patients with only one or two factors. Patients with 17p− had a significantly lower ORR (P=0.008) and shorter OS (P=0.001) than those without 17p−. Rituximab (R)-based treatment was able to overcome the poor prognosis associated with 17p−. Moreover, the addition of R to fludarabine (F) and cyclophosphamide (C) treatment significantly improved the OS (P=0.012) compared with FC alone in younger patients. However, there were no significant benefits for older patients (P=0.07). This implies that the age of a patient is important in their response to therapy and survival.

2-Methoxyestradiol (2-ME2) is an endogenous metabolite of 17beta-estradiol (E2) with estrogen receptor-independent anti-cancer activity. The current study sought to determine the mechanism of anti-cancer activity of 2-ME2 in human acute T lymphoblastic leukemia CEM cells. Results showed that 2-ME2 markedly suppressed proliferation of CEM cells in a time- and dose-dependent manner. 2-ME2-treated CEM cells underwent typical apoptotic changes. Exposure to 2-ME2 led to G(2)/M phase cell-cycle arrest, which preceded apoptosis characterized by the appearance of a sub-G(1) cell population. In addition, cytosolic cytochrome c release, increased procaspase-9 and -3 expressions, poly(ADP-ribose) polymerase (PARP) cleavage, and induced expression of caspase-8 were detected, suggesting that both the intrinsic apoptotic pathway and extrinsic apoptotic pathway were involved in 2-ME2-induced apoptosis. Moreover, the expression level of p21 protein was upregulated, whereas Bcl-2 and dysfunctional p53 protein were downregulated, which also contributed to 2-ME2-induced apoptosis. Our findings revealed that 2-ME2 might be a potent natural candidate for chemotherapeutic treatment of human acute T lymphoblastic leukemia when the precise effects of 2-ME2 were investigated further in other T leukemia cell lines and in primary T-cell leukemias.

Emerging evidence suggests that the three tyrosine kinase inhibitors currently approved for the treatment of patients with chronic myelogenous leukemia (CML) – imatinib, dasatinib, and nilotinib – have potential cardiotoxic effects. The mechanisms behind these events, and the relations between them, are largely unclear. For example, relative to dasatinib and nilotinib, severe congestive heart failure and left ventricular dysfunction are rare but prominent with imatinib treatment, particularly in patients receiving higher doses (>600 mg/day). In comparison with imatinib, prolongation of the QT interval is relatively common in patients treated with either dasatinib or nilotinib. In contrast to nilotinib, pericardial effusions are observed with both imatinib and dasatinib. It is suggested that these data, an evaluation of cardiac status, use of concomitant medications, and potential risk factors should be considered in the management of CML.

Indolent lymphoma (IL), the second most common lymphoma, remains incurable with chemotherapy alone. While R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) remains the standard frontline regimen for diffuse Large B –cell lymphoma, the optimal chemotherapy regimen for frontline therapy of advanced IL remains uncertain. FCR (fludarabine, cyclophosphamide, rituximab) has been shown to be better than fludarabine alone and fludarabine plus cyclophosphamide for IL. In FOLL05 trial, R-CHOP was compared with R-CVP (cyclophosphamide, vincristine, prednisone) and R-FM (fludarabine, mitoxantrone). The study showed that R-CHOP appears to have the best risk-benefit ratio for IL. The StiL NHL1 trial showed that BR (bendamustine, rituximab) has longer progression free survival and is better tolerated than R-CHOP. Long-term complications with secondary malignancies between the two regimens appear to be comparable. In this review, new combination regimens reported at 2012 ASCO annual meeting were evaluated for frontline and salvage therapy of indolent lymphoma.