Patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) not fit for intensive treatment need novel therapy options. Vascular endothelial growth factor (VEGF) receptor inhibition is one potential mechanism by which AML and MDS could be treated. The receptor tyrosine kinase inhibitor AZD2171 (cediranib) has activity against VEGF receptors KDR and FLT-1. This multicenter phase II study was designed to test cediranib's activity in patients with AML or high-risk MDS. The primary endpoint was confirmed disease response defined as a composite of complete remission, partial remission or hematologic improvement. The study enrolled 23 subjects in the AML cohort and 16 subjects in the MDS cohort. There were no confirmed responses in either group. Since the study met the stopping rule after the first stage of enrollment, the trial was closed to further accrual. Common adverse events in both cohorts included thrombocytopenia, neutropenia, anemia, fatigue, dyspnea, diarrhea, nausea and dehydration.
Myeloid leukemias and dysplasias; pharmacotherapeutics; signal transduction
AML; epigenetics; IDH1; IDH2; DNMT3A; molecular genetics
BAFF-R is the primary BAFF receptor that is responsible for promoting B-cell development and survival. Malignant B-cells exploit the BAFF/BAFF receptor system and high serum BAFF levels or genetic alterations in BAFF receptors have been found in B-cell cancers. BAFF signaling impacts pro-survival pathways, however, other than NF-κB2, little is known about the specific pathways activated by individual BAFF receptors. Using a novel BAFF-R expression model we now demonstrate that activation of BAFF-R, independent of TACI and BCMA, can induce phosphorylation of Akt and GSK3β. Expression of an activated form of BAFF-R also enhanced a pro-survival gene expression pattern, including the novel BAFF-regulated gene Pin1, whose expression was PI3K-dependent. Additionally, we show that TRAF6 is essential for mediating BAFF-R-dependent activation of Akt. Together these data describe a novel role for TRAF6 in BAFF-R-specific activation of the PI3K pathway and provide evidence suggesting a new role for Pin1 in BAFF-R signaling.
BAFF-R; BAFF; lymphoma; PI3-kinase
MOPP-Bleo (nitrogen mustard, vincristine, procarbazine, prednisone and bleomycin) induction therapy was given to 253 evaluable patients with Hodgkin lymphoma, stages IIIB, IIIs, or IV. Complete response (CR) occurred in 145 patients (57%) and partial response (PR) in 93 (37%). Of those 238 responders, 178 were randomized to consolidation therapy, and 164 were eligible and analyzable, including 114 CRs [55 patients randomized to ABVD and 59 to radiation therapy (RT)] and 50 partial responders (PRs) (25 each randomized to ABVD and RT). Among the 50 patients with PR, 34 (68%) converted to CR (16 with ABVD and 18 with RT). Therefore, of 253 patients, 182(72%) achieved CR and 56 (22%), PR. Median follow-up for all patients is 22.3 years and the estimated overall survival (OS) rate at 20 years is 48%. Of the 148 eligible, analyzable patients with CR, the estimated proportion remaining in CR at 20 years is 62%. OS at 20 years was significantly greater for patients receiving ABVD consolidation (66%) when compared with those who received RT consolidation (43%) (p = 0.002). Treatment toxicity was acceptable. After MOPP-Bleo induction for advanced Hodgkin lymphoma, ABVD provides better consolidation than local RT.
Hodgkin lymphoma; chemotherapy; radiation therapy; long-term follow-up
Few studies have examined the quality of life (QOL) in survivors of non-Hodgkin lymphoma (NHL). A total of 109 patients with NHL (58 aggressive [AGG], 51 indolent [IND]) completed two health-related QOL assessments using the Medical Outcomes Study 36-Item Short-Form Healthy Survey (MOS SF-36) and the Functional Assessment in Cancer Therapy – Fatigue (FACT-F). Scores between IND and AGG were compared using a two-sample t-test. Multiple linear regression was performed to account for any potentially explanatory variables. Overall, 70.6% had received chemotherapy and 55% had received immunotherapy. Some 17.6% of the IND group had received no therapy. The overall physical and mental component QOL scores of the SF-36 did not differ between survivors. Physical function in survivors of IND was significantly better when compared with that of AGG NHL. Our study reports a similar overall QOL between survivors of IND and AGG NHL. Physical function, however, may be more impaired in survivors of AGG NHL.
Quality of life; non-Hodgkin lymphoma; lymphoma; cancer survivorship
Despite vast improvements in treatment of Philadelphia chromosome–positive chronic myeloid leukemia (CML) in chronic phase (CP), advanced stages of CML, accelerated phase or blast crisis, remain notoriously difficult to treat. Treatments that are highly effective against CML-CP produce disappointing results against advanced disease. Therefore, a primary goal of therapy should be to maintain patients in CP for as long as possible, by (1) striving for deep, early molecular response to treatment; (2) using tyrosine kinase inhibitors that lower risk of disease progression; and (3) more closely observing patients who demonstrate cytogenetic risk factors at diagnosis or during treatment.
myeloid leukemias and dysplasias; tyrosine kinase inhibitor; drug resistance
Tyrosine kinase inhibitor (TKI) therapy has become the standard treatment for chronic myelogenous leukemia (CML). Off-target kinase inhibition has been implicated in the appearance of unique adverse effects, such as colitis and pleural effusions. In addition, some patients present oligoclonal expansions of large granular lymphocytes (LGLs). We sought to further investigate this phenomenon in 64 patients treated with 5 different TKIs. Clonal expansions of cytotoxic T lymphocytes (CTLs) were identified in all TKI-treated patient groups, but only in dasatinib-treated patients were these expansions characterized as LGLs. Survival factors known to be important in LGL leukemia (IL-15 transpresentation, plasma PDGF BB levels, NF-κB, and T-bet activation) were found to be associated with TKI-induced LGL expansions. Interestingly, patients with LGL expansions had increased cytotoxicity against non-transformed endothelial cells, which may play a role in observed autoimmune-like side effects. Our results indicate that CML patients treated with TKIs can develop T cell expansions, which can in certain cases be related with some adverse effects.
Chronic myeloid leukemia; tyrosine kinase inhibitors; large granular lymphocytes
FCR, the standard of care for frontline treatment of CLL patients, is associated with a high rate of neutropenia and infectious complications. GM-CSF reduces myelosuppression and can potentiate rituximab activity. We conducted a clinical trial combining GM-CSF with FCR for frontline treatment of 60 CLL patients. Eighty-six percent completed all 6 courses and 18% discontinued GM-CSF for toxicity; grade 3–4 neutropenia was observed in 30% of cycles, and severe infections in 16% of cases. ORR was 100%. Both median EFS and OS have not been reached. Longer EFS was associated with favorable cytogenetic. GM-CSF led to a lower frequency of infectious complications than the historical FCR group, albeit similar EFS and OS.
CLL; FCR; GM-CSF; neutropenia; infections
Most cases of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) occur <21 days after allogeneic hematopoetic stem cell transplantation (HCT). Rarely, however, VOD/SOS can occur later, and can be confused with other causes. We report the clinicopathologic features of 8 patients with advanced hematologic malignancies developing VOD/SOS >30 days after dose-escalated busulfan/fludarabine/alemtuzumab and HCT. Median time to diagnosis=52 days (range: 33–77). For 7 patients, VOD/SOS was confirmed by liver biopsies showing classical features including reticulin deposition within sinusoids, central vein occlusions, hepatocyte atrophy/necrosis, sinusoidal/perivenular hemorrhage, and sparing of portal tracts. VOD/SOS risk was directly related to higher busulfan plasma exposures. Two patients died from VOD/SOS, and in another two patients VOD/SOS was contributory to death. Late-onset VOD/SOS may be underrecognized and should be considered in the differential diagnosis of patients undergoing HCT, particularly after high dose busulfan. Liver biopsy should be entertained even late in the course if appropriate signs/symptoms exist.
veno-occlusive disease; sinusoidal obstruction syndrome; stem cell transplantation; late-onset; busulfan
Disease recurrence after allogeneic hematopoietic cell transplant (alloHCT) remains common, making improvements in conditioning regimens desirable. A dose-response relationship between busulfan exposure and outcome is known. Using individual real-time monitoring of the busulfan area under the curve (AUC), we aimed to determine the maximum-tolerated busulfan AUC in a conditioning regimen with fludarabine/alemtuzumab. Thirty-six patients with advanced hematologic malignancies were treated. Busulfan levels after a test dose and conditioning dose 1 allowed targeting of subsequent AUCs and dose-escalation above the starting AUC of 4800 μmol-min/L. Clearance of busulfan test doses was not always sufficiently predictive of treatment dose AUC and, on average, test dose clearance was faster than treatment dose clearance. When the study was modified to use conditioning dose 1 pharmacokinetics instead, accurately targeted treatment AUCs were achieved, and dose-escalation was possible. Severe, late-occurring sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) was the dose-limiting toxicity seen in 5/8 patients at an AUC level of 6800 μmol-min/L. The risk for SOS/VOD correlated with the highest observed AUC (AUCmax) rather than with the average cumulative AUC (AUCavg). Busulfan dose-escalation to a maximum-tolerated AUC of 5800 μmol-min/L—higher than that achieved by current standard busulfan regimens—was accurate and achievable using real-time pharmacokinetics monitoring of the first conditioning dose. This AUC is now being studied in phase II for patients receiving busulfan/fludarabine/alemtuzumab as alloHCT conditioning.
Clinical results; transplant toxicity; pharmacotherapeutics
We examined clofarabine pharmacokinetics and association with renal toxicity in 62 patients participating in a phase I–II study of clofarabine–melphalan–alemtuzumab conditioning for hematopoietic stem cell transplant (HSCT). Pharmacokinetic parameters, including clofarabine area under the concentration–time curve (AUC), maximum concentration and clearance, were measured, and patients were monitored for renal injury. All patients had normal pretreatment creatinine values, but over half (55%) experienced acute kidney injury (AKI) after clofarabine administration. Age was the strongest predictor of AKI, with older patients at greater risk (p = 0.002). Clofarabine AUC was higher in patients who developed AKI, and patients with the highest dose-normalized AUCs experienced the most severe grades of AKI (p = 0.01). Lower baseline renal function, even when normal, was associated with lower clofarabine clearance (p = 0.008). These data suggest that renal-adjustment of clofarabine dosing should be considered for older and at-risk patients even when renal function is ostensibly normal.
Clofarabine; pharmacokinetics; acute kidney injury; glomerular filtration rate
The incidence and pattern of secondary neoplasms in patients with acute promyelocytic leukemia (APL) treated with ATRA-containing regimens is not well-described. We compared secondary neoplasms in 160 patients with APL treated with ATRA plus idarubicin (n=54), or ATRA plus arsenic trioxide (ATO) (n=106) for tthe incidence of secondary cancers per unit time of follow-up. Median follow-up times for the two cohorts were 136 and 29 months, respectively. Nine patients developed secondary cancers in the chemotherapy group. These included two breast cancers, three myelodysplastic syndromes/acute myeloid leukemia, one vulvar cancer, one prostate cancer, one colon cancer and one soft tissue sarcoma. A melanoma and one pancreatic cancer developed in the ATO group. We conclude that treatment of patients with APL using the non-chemotherapy regimen of ATRA plus ATO is not associated with a higher incidence of secondary cancers (p=0.29) adjusted for unit time of exposure.
Secondary Neoplasm; Arsenic; Promyelocytic; Leukemia
It is thought that the low incidence of central nervous system (CNS) involvement in acute myeloid leukemia (AML) does not justify routine CNS prophylaxis, as high-dose cytarabine eliminates CNS disease. To test whether chemotherapy that does not include high-dose cytarabine increases the risk of CNS involvement, the medical records of 1,412 newly diagnosed AML patients were reviewed. In 1,370 patients, lumbar puncture (LP) was performed only if clinically indicated, and CNS disease was detected in 45 (3.3%) patients. Another 42 patients underwent routine LP as part of an investigational protocol, and in 8 (19%) CNS disease was detected (P<0.0001). Risk factors included high LDH, African-American ethnicity, and young age. Patients receiving high-dose cytarabine and those that did not had similar rates of CNS involvement. Disease free survival (DFS) and overall survival were shorter in patients with CNS involvement. It remains to be determined whether routine CNS prophylaxis would improve DFS.
Acute Myeloid Leukemia; Central Nervous System; Risk Factors; cytarabine; Lumber puncture
Although established risk factors such as immunodeficiency and viral infections may be responsible for a portion of non-Hodgkin lymphoma (NHL) cases, the vast majority of NHL cases remain unexplained. The role of dietary nitrate and nitrite in NHL risk is of interest since they are precursors of N-nitroso compounds and nitrosoureas have been shown to induce B and T-cell lymphomas in animal studies. However, few studies have evaluated the potential association between consumption of nitrate and nitrite intake and NHL by subtype or chromosomal translocation status, and the results of these studies have been inconsistent. We estimated the dietary intake of nitrate and nitrite using a food frequency questionnaire in a population-based, case-control study of 348 cases and 470 controls conducted in Nebraska in 1999–2002. A non-significant excess risk of NHL was found among women who reported an intake of nitrite in the highest quartile compared to the lowest quartile (OR = 1.6; 95% CI: 0.8–2.9), particularly nitrite from animal sources (OR=1.9; 95% CI: 1.0–3.4). No significant associations were observed for nitrate or nitrite by NHL subtype. Although there were some increases in risk that support the N-nitroso hypothesis, they were not significant and do not confer strong evidence of an association.
Non-Hodgkin lymphoma; nitrate; nitrite; diet
Increased body mass index (BMI) is associated with increased risk of treatment-related complications and inferior overall survival in children and adolescents with AML. The growing proportion of the general population who are obese raises the dilemma of whether the pharmacokinetic differences in obese patients necessitate chemotherapy dosage adjustments. This also poses the question of whether obese patients experience differing outcomes or toxicities with chemotherapy.
We are retrospectively evaluating the association between percentage of ideal body weight (IBW) and complete remission (CR) among newly diagnosed, previously untreated AML patients. We also describe secondary objectives including associations between IBW and overall survival (OS), platelet and neutrophil recovery, and incidence of grade 3-4 hematologic and nonhematologic toxic effects. Additionally, we characterize the dosing strategies used for induction chemotherapy in obese patients with AML at a single institution.
This is a retrospective study of obesity and its impact on outcome in 63 newly diagnosed, previously untreated adults with AML receiving standard induction chemotherapy with 7 + 3 from 2006 to 2010.
The median percentage of ideal body weight was 121% (range 86-246%). Thirty-five percent of patients were obese (≥ 130% IBW). Controlling for history of prior malignancies, FLT3-ITD status, and NPM1, obesity was not associated with CR (odds ratio [OR] = 0.97, p=0.88), OS (hazard ratio=0.48, p=0.52), platelet recovery by 30 days (OR=1.14, p=0.52), or neutrophil recovery by 30 days (OR=1.12, p=0.60). Among obese patients, CR rates were not significantly different comparing patients not dose adjusted to patients with obesity-related adjustments (CR=86% vs. 67%, p=0.55)
In this study population, obesity was not an independent prognostic factor of outcome or toxicity. Empiric dose reductions based on obesity did not result is significantly different CR rates.
acute myeloid leukemia; obesity; outcome
Patients with newly diagnosed AML (n=360) including 137 (38%) with normal karyotype (NK) were evaluated. Overall, 60 (16.6%) patients including 46 of the 137 (33.5%) NK patients had NPM1 mutation at baseline. Thirty nine patients (30 NK) had available NPM1 status at the time of CR and all (100%) were negative for mutated NPM1. Among the patients with mutated NPM1 at baseline, 10/39 overall (25%) and 7/30 NK (23%) patients relapsed. NPM1 status was available for 8 patients (6 with NK) at the time of relapse. Among them, 7/8 overall (87%) and 5/6 NK (83%) patients had mutated NPM1, while 1/8 overall (12%) and 1/6 NK (16%) patients remained NPM1 wild type. Among the 300 patients (including 91 with NK) with wild type NPM1 at diagnosis, none acquired a mutated NPM1 clone, either at CR or at relapse. We conclude that mutated NPM1 is a stable and reliable prognostic marker in AML and can be used to assess MRD.
AML; NPM1 mutations; minimal residual disease; MRD
Myeloma is characterized by a highly variable clinical outcome. Despite the effectiveness of high-dose therapy, 15% of patients relapse within 1 year. We show that these cases also have a significantly shorter post-relapse survival compared to the others (median 14.9 months vs. 40 months, p = 8.03 × 10− 14). There are no effective approaches to define this potentially distinct biological group such that treatment could be altered. In this work a series of uniformly treated patients with myeloma were used to develop a gene expression profiling (GEP)-based signature to identify this high risk clinical behavior. Gene enrichment analyses applied to the top differentially expressed genes showed a significant enrichment of epigenetic regulators as well as “stem cell” myeloma genes. A derived 17-gene signature effectively identifies patients at high risk of early relapse as well as impaired overall survival. Integrative genomic analyses showed that epigenetic mechanisms may play an important role on transcription of these genes.
Myeloma; gene expression profiling; risk; predictor
t(14;18)-positive cells can not only be detected in follicular lymphoma (FL) patients but also in healthy individuals (HI). We used epidemiological data and blood samples of the population-based Study of Health in Pomerania (SHIP) to analyze associations of FL risk factors and t(14;18)-positive cells in HI. Buffy coat samples from 4152 study participants were tested by real-time PCR for t(14;18)-positive cells. Out of 3966 evaluable subjects, 1526 were t(14;18)-PCR positive (38.5%, median 3.9 t(14;18)-positive per million nucleated cells, range 0.6 – 9299). In multivariable analyses age and sex but not parameters of smoking exposure were significantly associated with t(14;18)-prevalence (logistic regression, p < 0.001). Multivariable analyses of t(14;18)-frequency showed a positive association with age but not with sex or smoking. These age and sex associations in HI require careful control in future studies of t(14;18) as a potential biomarker of lymphoma risk.
Follicular Lymphoma; t(14;18); Lymphomagenesis; Healthy Individuals
Elevated levels of ubiquitin C-terminal hydrolase L1 (UCH L1) have been detected in a variety of malignancies, and recent studies show the oncogenic capacity of overexpressed UCH L1 in vivo in animal models. Here we demonstrate that expression of endogenous UCH L1 is significantly higher in B-lymphoma cells than in transformed cells of epithelial and fibroblastic origin. The specific hematopoietic transcription factor PU.1 induces UCH L1 expression through direct activation of the uch l1 promoter. Using chromatin immunoprecipitation (ChIP) assays and direct mutagenesis we identified PU.1 binding sites on the uch l1 promoter, at least three of which are involved in this activation. We also show that the viral transcriptional co-activator EBNA2 dramatically increases PU.1-dependent up-regulation of endogenous UCH L1 expression. Finally, inhibition of PU.1 expression with specific shRNA resulted in reduction of UCH L1 mRNA and protein levels in Epstein–Barr virus (EBV)-transformed B-cells. We propose that the ubiquitin-editing enzyme UCH L1 is a multifunctional pro-oncogenic factor involved in development and progression of certain lymphoid malignancies, including EBV-associated lymphomas.
Transcription factor PU.1; ubiquitin C-terminal hyrolase L1; lymphomas
Although chromosome 17p abnormalities and TP53 mutations are purported to be poor prognostic indicators in chronic lymphocytic leukemia (CLL), the significance of p53 expression in CLL has not been defined in patients uniformly treated with chemoimmunotherapy, nor has its utility in combination with other novel prognostic markers, such as IgVH mutation status (IgVH MS) or ZAP-70 expression, been evaluated. Therefore, we studied p53 expression by immunohistochemistry (IHC), using the bone marrow specimens from 222 CLL patients (pts) enrolled in the phase II evaluation of the fludarabine, cyclophosphamide and rituximab (FCR) regimen. ZAP70 expression and IgVH MS were assessed in 208 and 108 patients, respectively. 168 CLL pts had concurrent classical cytogenetic analysis. p53 expression correlated with abnormal karyotype (p=0.002) and adversely affected overall survival independent of ZAP70 expression and IgVH MS (p<0.001). p53(+)CLL pts were less likely to achieve complete remission, but patients who did achieve CR showed a durable response. In conclusion, p53 expression was an important determinant of complete remission and overall survival, but not remission duration, in CLL patients receiving chemo-immunotherapy.
Chronic lymphocytic leukemia; p53; prognostic factors
Thirty-three previously untreated patients with high risk CLL were treated before meeting standard criteria with alemtuzumab and rituximab. GM-CSF was added to the regimen to determine if it would improve treatment efficacy without increasing toxicity. High risk was defined as at least one of the following: 17p13-; 11q22.3-; unmutated IGHV (or use of VH3-21) together with elevated expression of ZAP-70 and/or CD38. Treatment was subcutaneous GM-CSF 250μg Monday-Wednesday-Friday for 6 weeks from day 1, subcutaneous alemtuzumab 3mg-10mg-30mg from day 3 and then 30 mg Monday-Wednesday-Friday for 4 weeks, and intravenous rituximab (375 mg/m2/week) for 4 weeks from day 8. Patients received standard supportive care and were monitored weekly for CMV reactivation. Using standard criteria, 31 (94%) patients responded to treatment with 9 (27%) complete responses (one with persistent cytopenia) and 9 (27%) nodular partial responses. Median progression free survival was 13.0 months and time to next treatment was 33.5 months. No patient died during treatment, seven (21%) had grade 3-4 toxicities attributable to treatment, and 10 (30%) had CMV viremia. Addition of GM-CSF to therapy with alemtuzumab and rituximab decreased treatment efficacy and increased the rate of CMV reactivation compared to a historical control.
Chronic lymphocytic leukemia; high risk; early treatment; alemtuzumab; rituximab; GM-CSF
The appropriate dose of antithymocyte globulin (ATG) been utilized in reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (alloHSCT) is yet unknown. We retrospectively compared patients who received 7.5 mg/kg (R-ATG – 39 patients) and 6 mg/kg (r-ATG- 97 patients). The cumulative incidences of acute graft-versus-host-disease (aGVHD) grade II–IV at 180 days were 46% and 41% and aGVHD grade III–IV were 11% and 18% in r-ATG and R-ATG, respectively (P>0.30). The respective estimated cumulative incidences at 24 months of cGVHD were 42% and 44% (P>0.3). There was no significant difference in non-relapse mortality (p=0.22), cumulative incidence of relapse (p=0.53), progression-free survival (p=0.69) or overall survival (p=0.95). In conclusion, a decreased ATG dose of 6 mg/kg was associated with a similar proportion of GVHD as 7.5 mg/kg ATG. Given the increasing number of RIC HSCT performed worldwide, the correct dose and preparation of ATG should be defined by prospective randomized trials.
Antithymocyte globulin; Allogeneic Transplantation; Reduce Intensity conditioning
Acute myeloid leukemia (AML) in the elderly is associated with several distinctive biological and clinical features compared to younger patients. Despite the advances in supportive care and the introduction of less intensive chemotherapy regimens, the overall outcome for this population remains poor. More importantly, the decision making process for choosing the appropriate treatment for individual patient, based on their comorbidities and the biological features of their disease, continues to be challenging for the treating physicians. Currently, a significant number of elderly patients with AML do not receive treatment above and beyond supportive care; several studies have suggested that patients who receive any therapy have a better outcome than patients who receive palliation alone. Furthermore, the development of novel, targeted, and less intensive therapies is providing new options suitable for older patients with multiple comorbidities and with high risk disease features. In this review, we will highlight the challenges that face the treating physicians when encountering elderly patients with AML and will describe some of the potential strategies under development for treating older AML patients and the available data from recent clinical trials.