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The accumulating evidence of a casual relationship between obesity and enhanced cancer risk has promoted us the introduction of a new term ‘‘adiponcosis’’, derived from the fusion of the words ‘‘adiposis’’ and ‘‘oncosis’’. Increased incidence of hematologic tumors is strongly associated with obesity. However, it is unknown whether leukemia incidence is, for instance, directly increased by obesity or rather by other genetic or socio-economic factors or lifestyle. It has emerged that, across many populations, there is an association between acute lymphoblastic leukemia (ALL) risk and obesity, although it is still not known why this occurs. It was observed that obesity can directly accelerate the progression of ALL in mice; older obese mice had accelerated ALL onset and higher leptin, insulin, and IL-6 levels than controls, all obesity-related hormones with potential roles in leukemia pathogenesis. Past observational studies had showed higher prevalence of overweight and obese individuals among adult survivors of ALL than among adults in the general population. More recently, studies were extended to childhood cancer survivors. In particular, following treatment for ALL, these patients tend to be less active and at greater risk for obesity than their healthy peers. This study, which assessed cases prospectively over a 12-month period during the early phases of treatment, extends prior reports by demonstrating that these outcomes are evident at an early stage in treatment. Indeed, a pilot study demonstrated that home exercise intervention during ALL maintenance therapy is feasible and has promise for efficacy. In an attempt to determine if weight gain, early in therapy, is predictive of obesity at the end of treatment, Withycombe et al. suggested that monitoring weight trends during childhood ALL induction therapy may be useful in identifying which patients are at highest risk for obesity development so that early intervention strategies may be implemented. Furthermore, another study showed that obese or underweight patients at diagnosis and for 50% or more of the time between end of induction and start of maintenance therapy had inferior event-free survival (EFS). Normalization of weight during that period was related to a mitigation of this risk comparable to never being obese or underweight. Obese or underweight status at start of each treatment phase was significantly associated with specific patterns of treatment-related toxicity. Of note, these authors very recently described the association between obesity and the key prognostic marker of minimal residual disease (MRD) in the bone marrow in pediatric B-precursor ALL. This study shows that obesity during induction was associated with both a significant greater risk for persistent MRD and with poorer EFS irrespective of end-induction MRD. This is important since it links obesity also with leukemia relapse; however, the limitations of this study are due to a selected population (Hispanic children who are prone to obesity) and the fact that heterogeneity of drug induction therapy cannot be excluded. However, another recent work published on Haematologica, performed on a cohort of newly diagnosed Dutch pediatric patients with ALL, although confirming that underweight patients have a similar overall survival and event-free survival as compared to patients with normal weight or who are overweight, shows that patients who are underweight have an increased risk of relapse. In addition, this study further extends our knowledge since it demonstrates that patients with loss of body mass index during the first 32 weeks of treatment had a similar risk of relapse and event-free survival, but a decreased overall survival compared to patients without a loss of body mass index. Indeed, loss of body mass index during treatment seems to mainly consist of a loss of lean body mass. These authors, in line with previous studies, agree on the importance of the physical exercise programs early during pediatric ALL treatment and suggest that pediatric ALL patients could benefit from interventions that enhance lean body mass in addition to the commonly used interventions. What comes out from the literature is that the ‘extremes’ concerning body weight status matter, and although the authors of this study were not able to associate obesity with survival, the comment should be made that outcome of overweight patients may be compromised due to a deficient immune response because of higher inflammation parameters, and that they have an increased risk of comorbidities related to being overweight. It is currently believed that a positive correlation between obesity and cancer is driven by white adipose tissue. Adipocytes secrete factors that play roles in cancer cell proliferation, migration, and metastasis. SDF-1α secretion induces ALL cells to migrate into adipose tissue; however, the precise mechanisms whereby adipocytes may contribute to ALL relapse are still not known. Numerous epidemiological studies revealed that chronic inflammation, that is associated with enlarged body fat mass, predisposes to different types of tumors. In the microenvironment of most neoplastic tissues, an inflammatory component related with obesity is finely orchestrated by NF-κB and Stat3. Anti-inflammatory effects have been proposed among other plausible biological mechanisms, as being the basis of the possible association between physical activity and hematologic cancers. However, there is still insufficient epidemiological evidence for this. In conclusion, the emerging studies strongly support the ‘obesity-leukemia’ link. Thus, the term “adiponcosis” can find an application also in hematologic tumors, and although the mechanisms of this connection remain largely unknown, we believe that the majority of people are unaware that obesity and overweight can increase also the risk of leukemia. The molecular mechanisms at the basis of the obesity-cancer link must be explored in order to provide new ways of prevention and treatment.
Developing optimal radiation-free central nervous system prophylaxis is a desirable goal in acute lymphoblastic leukemia, to avoid the long-term toxicity associated with cranial irradiation. In a randomized, phase II trial enrolling 145 adult patients, we compared intrathecal liposomal cytarabine (50 mg: 6/8 injections in B-/T-cell subsets, respectively) with intrathecal triple therapy (methotrexate/cytarabine/prednisone: 12 injections). Systemic therapy included methotrexate plus cytarabine or L-asparaginase courses, with methotrexate augmented to 2.5 and 5 g/m(2) in Philadelphia-negative B- and T-cell disease, respectively. The primary study objective was the comparative assessment of the risk/benefit ratio, combining the analysis of feasibility, toxicity and efficacy. In the liposomal cytarabine arm 17/71 patients (24%) developed grade 3-4 neurotoxicity compared to 2/74 (3%) in the triple therapy arm (P=0.0002), the median number of episodes of neurotoxicity of any grade was one per patient compared to zero, respectively (P=0.0001), and even though no permanent disabilities or deaths were registered, four patients (6%) discontinued intrathecal prophylaxis on account of these toxic side effects (P=0.06). Neurotoxicity worsened with liposomal cytarabine every 14 days (T-cell disease), and was improved by the adjunct of intrathecal dexamethasone. Two patients in the liposomal cytarabine arm suffered from a meningeal relapse (none with T-cell disease, only one after high-dose chemotherapy) compared to four in the triple therapy arm (1 with T-cell disease). While intrathecal liposomal cytarabine could contribute to improved, radiation-free central nervous system prophylaxis, the toxicity reported in this trial does not support its use at 50 mg and prompts the investigation of a lower dosage. (clinicaltrials.gov identifier: NCT-00795756).
To evaluate the effect of first-line and subsequent therapies, the outcome of 1,558 patients with chronic lymphocytic leukemia from five prospective phase II/III trials conducted between 1999 and 2010 was analyzed. The 3-year overall survival rate was higher after first-line treatment with chemoimmunotherapies such as fludarabine/cyclophosphamide/rituximab (87.9%) or bendamustine/rituximab (90.7%) compared to chemotherapies without an antibody (fludarabine/cyclophosphamide: 84.6%; fludarabine: 77.5%; chlorambucil: 77.4%). Furthermore, the median overall survival was longer in patients receiving at least one antibody-containing regimen in any treatment line (94.4 months) compared to the survival in patients who never received an antibody (84.3 months, P<0.0001). Univariate Cox regression analysis demonstrated that patients who did receive antibody treatment had a 1.42-fold higher risk of death (hazard ratio, 1.42; 95% confidence interval: 1.185-1.694). Therapies administered at relapse were very heterogeneous. Only 55 of 368 patients (14.9%) who started second-line treatment >24 months after first-line therapy repeated the first-line regimen. Among 315 patients requiring treatment ≤24 months after first-line therapy, cyclophosphamide/doxorubicin/vincristine/prednisone with or without rituximab as well as alemtuzumab were the most commonly used therapies. In these early relapsing patients, the median overall survival was shorter following therapies containing an anthracycline and/or three or more cytotoxic agents (e.g. cyclophosphamide/doxorubicin/vincristine/prednisone or fludarabine/cyclophosphamide/mitoxantrone, 30.0 months) compared to single agent chemotherapy (e.g. fludarabine; 39.6 months) and standard chemoimmunotherapy (e.g. fludarabine/cyclophosphamide/rituximab: 61.6 months). In conclusion, the analysis confirms the superior efficacy of chemoimmunotherapies in patients with chronic lymphocytic leukemia. Moreover, the use of aggressive chemo(immuno)therapy combinations in patients with an early relapse does not offer any benefit when compared to less intensive therapies. Trial identifier: NCT00281918, ISRCTN75653261, ISRCTN36294212, NCT00274989 and NCT00147901.
RNA interference (RNAi) has been suggested to represent a promising therapeutic approach in different disease settings. Primary effusion lymphoma (PEL) is a plasmablastic lymphoma consistently expressing B lymphocyte-induced maturation protein 1 (Blimp-1), a pivotal transcriptional regulator during terminal differentiation of B cells into plasma cells. Here we report, for the first time, that transient knockdown of the BLIMP1 gene (also known as PR Domain Containing 1 with ZNF Domain, or PRDM1) using small interfering RNA (siRNA) delivered by liposomes, induced remarkable killing in PEL cell lines. Furthermore, in a murine model of PEL, significantly prolonged survival was achieved by intraperitoneal treatment with such anti-BLIMP1 lipoplexes, while no vector-induced toxicity was observed. This effective and safe RNAi strategy, based on liposomal siRNA targeting a master transcription factor of post-germinal center B cells, may indeed be a potential treatment against plasmablastic lymphom
Nilotinib is a second-generation tyrosine kinase inhibitor that has been approved for the first-line treatment of chronic-phase chronic myeloid leukemia, based on the results of a prospective randomized study of nilotinib versus imatinib (ENESTnd). Apart from this registration study, very few data are currently available on first-line nilotinib treatment. We report here the long-term, 6-year results of the first investigator-sponsored, GIMEMA multicenter phase 2, single-arm trial with nilotinib 400 mg twice daily as first-line treatment in 73 patients with chronic-phase chronic myeloid leukemia. Six-year overall survival and progression-free survival rates were 96%, with one death after progression to blast phase. At 6 years, 75% of the patients were still on nilotinib. The cumulative incidence of major molecular response was 98%; only one patient had a confirmed loss of major molecular response. The cumulative incidence of deep molecular response (MR 4.0) was 76%. Deep molecular response was stable (≥ 2 years) in 34% of these patients. Cardiovascular adverse events, mainly due to arterial thrombosis, occurred in 11/73 patients (15%), after 24 to 76 months of therapy. They were more frequent in elderly patients, and in those with baseline cardiovascular risk factors. None was fatal, although there was a relevant morbidity. This is the study with the longest follow-up of a high dose of nilotinib (400 mg twice daily): it highlights the high efficacy and the cardiovascular toxicity of the drug (CTG.NCT.00481052).
Shwachman-Diamond syndrome is a congenital bone marrow failure disorder characterized by debilitating neutropenia. The disease is associated with loss-of-function mutations in the SBDS gene, implicated in ribosome biogenesis, but the cellular and molecular events driving cell specific phenotypes in ribosomopathies remain poorly defined. Here, we established what is to our knowledge the first mammalian model of neutropenia in Shwachman-Diamond syndrome through targeted downregulation of Sbds in hematopoietic stem and progenitor cells expressing the myeloid transcription factor CCAAT/enhancer binding protein α (Cebpa). Sbds deficiency in the myeloid lineage specifically affected myelocytes and their downstream progeny while, unexpectedly, it was well tolerated by rapidly cycling hematopoietic progenitor cells. Molecular insights provided by massive parallel sequencing supported cellular observations of impaired cell cycle exit and formation of secondary granules associated with the defect of myeloid lineage progression in myelocytes. Mechanistically, Sbds deficiency activated the p53 tumor suppressor pathway and induced apoptosis in these cells. Collectively, the data reveal a previously unanticipated, selective dependency of myelocytes and downstream progeny, but not rapidly cycling progenitors, on this ubiquitous ribosome biogenesis protein, thus providing a cellular basis for the understanding of myeloid lineage biased defects in Shwachman-Diamond syndrome.
In chronic lymphocytic leukemia the balance between the pro-apoptotic and anti-apoptotic members of the bcl-2 family is involved in the pathogenesis, chemorefractoriness and clinical outcome. Moreover, the recently proposed anti-bcl-2 molecules, such as ABT-199, have emphasized the potential role of of bcl-2 family proteins in the context of target therapies. We investigated bax/bcl-2 ratio by flow cytometry in 502 patients and identified a cut off of 1.50 to correlate bax/bcl-2 ratio with well-established clinical and biological prognosticators. Bax/bcl-2 was 1.50 or over in 263 patients (52%) with chronic lymphocytic leukemia. Higher bax/bcl-2 was associated with low Rai stage, lymphocyte doubling time over 12 months, beta-2 microglobulin less than 2.2 mg/dL, soluble CD23 less than 70 U/mL and a low risk cytogenetic profile (P<0.0001). On the other hand, lower bax/bcl-2 was correlated with unmutated IGHV (P<0.0001), mutated NOTCH1 (P<0.0001) and mutated TP53 (P=0.00007). Significant shorter progression-free survival and overall survival were observed in patients with lower bax/bcl-2 (P<0.0001). Moreover, within IGHV unmutated (168 patients) and TP53 mutated (37 patients) subgroups, higher bax/bcl-2 identified cases with significant longer PFS (P=0.00002 and P=0.039). In multivariate analysis of progression-free survival and overall survival, bax/bcl-2 was an independent prognostic factor (P=0.0002 and P=0.002). In conclusion, we defined the prognostic power of bax/bcl-2 ratio, as determined by a flow cytometric approach, and highlighted a correlation with chemoresistance and outcome in chronic lymphocytic leukemia. Finally, the recently proposed new therapies employing bcl-2 inhibitors prompted the potential use of bax/bcl-2 ratio to identify patients putatively resistant to these molecules.
doi:10.3324/haematol.2015.13203