Hodgkin's lymphoma is one of the most common lymphoid neoplasms in young adults, but the low abundance of neoplastic Hodgkin/Reed-Sternberg cells in the tumour hampers the elucidation of its ...pathogenesis, biology, and diversity. After an incidental observation that genomic aberrations known to occur in Hodgkin's lymphoma were detectable in circulating cell-free DNA, this study was undertaken to investigate whether circulating cell-free DNA can be informative about genomic imbalances in Hodgkin's lymphoma.
We applied massive parallel sequencing to circulating cell-free DNA in a prospective study of patients with biopsy proven nodular sclerosis Hodgkin's lymphoma. Genomic imbalances in Hodgkin/Reed-Sternberg cells were investigated by fluorescence in-situ hybridisation (FISH) on tumour specimens.
By non-invasive prenatal testing, we observed several genomic imbalances in circulating cell-free DNA of a pregnant woman, who was subsequently diagnosed with early-stage nodular sclerosis Hodgkin's lymphoma stage IIA during gestation. FISH on tumour tissue confirmed corresponding genomic imbalances in Hodgkin/Reed-Sternberg cells. We prospectively studied circulating cell-free DNA of nine nodular sclerosis Hodgkin's lymphoma cases: eight at first diagnosis and one at first relapse. Seven patients had stage IIA disease and two had stage IVB disease. In eight, genomic imbalances were detected, including, among others, gain of chromosomes 2p and 9p, known to occur in Hodgkin's lymphoma. These gains and losses in circulating cell-free DNA were extensively validated by FISH on Hodgkin/Reed-Sternberg cells in biopsy samples. Initiation of chemotherapy induced normalisation of circulating cell-free DNA profiles within 2-6 weeks. The cell cycle indicator Ki67 and cleaved caspase-3 were detected in Hodgkin/Reed-Sternberg cells by immunohistochemistry, suggesting high turnover of Hodgkin/Reed-Sternberg cells.
In early and advanced stage nodular sclerosis Hodgkin's lymphoma, genomic imbalances in Hodgkin/Reed-Sternberg cells can be identified by massive parallel sequencing of circulating cell-free DNA at diagnosis. The rapid normalisation of circulating cell-free DNA profiles on therapy initiation suggests a potential role for circulating cell-free DNA profiling in early response monitoring. This finding creates several new possibilities for exploring the diversity of Hodgkin's lymphoma, and has potential implications for the future clinical development of biomarkers and precision therapy for this malignancy.
KU Leuven-University of Leuven and University Hospitals Leuven.
Abstract Background Tyrosine kinase inhibitors treatment in responding chronic myeloid leukaemia (CML) patients is generally continued indefinitely. In this randomised phase II trial, we investigated ...whether CML patients in molecular response4.5 (MR4.5 , quantitative reverse-transcription polymerase chain reaction (RQ-PCR)) after previous combination therapy with imatinib and cytarabine may discontinue imatinib treatment safely. Patients and methods Thirty-three patients from the HOVON 51 study with an MR4.5 for at least 2 years who were still on imatinib treatment were randomised between continuation of imatinib (arm A, n = 18) or discontinuation of imatinib (arm B, n = 15). Results After a median follow up of 36 months since randomisation, 3 patients (17%) in arm A and 10 patients (67%) in arm B had a molecular relapse. All 3 relapsing patients in arm A had also stopped imatinib after randomisation. All but one relapsing patient relapsed within 7 months after discontinuation of imatinib. The molecular relapse rate at 12 and 24 months after randomisation was 0% and 6% (arm A) and 53% and 67% (arm B) respectively. As-treated analysis revealed 56% and 61% relapses at 1 and 2 years since cessation in patients who discontinued imatinib, in contrast to 0% of patients who continued imatinib. All evaluable patients remained sensitive to imatinib after reinitiation and regained a molecular response. Conclusion Our data suggest that discontinuation of imatinib is safe in patients with durable MR4.5.
Myelodysplastic syndromes (MDS) represent a heterogeneous group of neoplastic hematopoietic disorders. Several recurrent chromosomal aberrations have been associated with MDS, but the genes affected ...have remained largely unknown. To identify relevant genetic lesions involved in the pathogenesis of MDS, we conducted SNP array-based genomic profiling and genomic sequencing in 102 individuals with MDS and identified acquired deletions and missense and nonsense mutations in the TET2 gene in 26% of these individuals. Using allele-specific assays, we detected TET2 mutations in most of the bone marrow cells (median 96%). In addition, the mutations were encountered in various lineages of differentiation including CD34+ progenitor cells, suggesting that TET2 mutations occur early during disease evolution. In healthy tissues, TET2 expression was shown to be elevated in hematopoietic cells with highest expression in granulocytes, in line with a function in myelopoiesis. We conclude that TET2 is the most frequently mutated gene in MDS known so far.
The proteasome inhibitor bortezomib was initially approved for the treatment of relapsed mantle-cell lymphoma. We investigated whether substituting bortezomib for vincristine in frontline therapy ...with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) could improve outcomes in patients with newly diagnosed mantle-cell lymphoma.
In this phase 3 trial, we randomly assigned 487 adults with newly diagnosed mantle-cell lymphoma who were ineligible or not considered for stem-cell transplantation to receive six to eight 21-day cycles of R-CHOP intravenously on day 1 (with prednisone administered orally on days 1 to 5) or VR-CAP (R-CHOP regimen, but replacing vincristine with bortezomib at a dose of 1.3 mg per square meter of body-surface area on days 1, 4, 8, and 11). The primary end point was progression-free survival.
After a median follow-up of 40 months, median progression-free survival (according to independent radiologic review) was 14.4 months in the R-CHOP group versus 24.7 months in the VR-CAP group (hazard ratio favoring the VR-CAP group, 0.63; P<0.001), a relative improvement of 59%. On the basis of investigator assessment, the median durations of progression-free survival were 16.1 months and 30.7 months, respectively (hazard ratio, 0.51; P<0.001), a relative improvement of 96%. Secondary end points were consistently improved in the VR-CAP group, including the complete response rate (42% vs. 53%), the median duration of complete response (18.0 months vs. 42.1 months), the median treatment-free interval (20.5 months vs. 40.6 months), and the 4-year overall survival rate (54% vs. 64%). Rates of neutropenia and thrombocytopenia were higher in the VR-CAP group.
VR-CAP was more effective than R-CHOP in patients with newly diagnosed mantle-cell lymphoma but at the cost of increased hematologic toxicity. (Funded by Janssen Research and Development and Millennium Pharmaceuticals; LYM-3002 ClinicalTrials.gov number, NCT00722137.).
The treatment of acute myeloid leukemia (AML) in first relapse is associated with unsatisfactory rates of complete responses that usually are short lived. Therefore, a clinically useful prognostic ...index can facilitate therapeutic decision making and evaluation of investigational treatment strategies at relapse of AML.
A prognostic score is presented based on the multivariate analysis of 667 AML patients in first relapse among 1,540 newly diagnosed non-M3 AML patients (age 15 to 60 years) entered onto three successive Dutch-Belgian Hemato-Oncology Cooperative Group and the Swiss Group for Clinical Cancer Research Collaborative Group trials.
Four clinically relevant parameters are included in this index (ie, length of relapse-free interval after first complete remission, cytogenetics at diagnosis, age at relapse, and whether previous stem-cell transplantation was performed). Using this stratification system, three risk groups were defined: a favorable prognostic group A (overall survival OS of 70% at 1 year and 46% at 5 years), an intermediate-risk group B (OS of 49% at 1 year and 18% at 5 years), and a poor-risk group C (OS of 16% at 1 year and 4% at 5 years).
The prognostic index estimates the outcome of AML patients in first relapse using four commonly applied clinical parameters and might identify patients who are candidates for salvage and investigational therapy.
Temsirolimus, a specific inhibitor of the mammalian target of rapamycin kinase, has shown clinical activity in mantle cell lymphoma (MCL). We evaluated two dose regimens of temsirolimus in comparison ...with investigator's choice single-agent therapy in relapsed or refractory disease.
In this multicenter, open-label, phase III study, 162 patients with relapsed or refractory MCL were randomly assigned (1:1:1) to receive one of two temsirolimus regimens: 175 mg weekly for 3 weeks followed by either 75 mg (175/75-mg) or 25 mg (175/25-mg) weekly, or investigator's choice therapy from prospectively approved options. The primary end point was progression-free survival (PFS) by independent assessment.
Median PFS was 4.8, 3.4, and 1.9 months for the temsirolimus 175/75-mg, 175/25-mg, and investigator's choice groups, respectively. Patients treated with temsirolimus 175/75-mg had significantly longer PFS than those treated with investigator's choice therapy (P = .0009; hazard ratio = 0.44); those treated with temsirolimus 175/25-mg showed a trend toward longer PFS (P = .0618; hazard ratio = 0.65). Objective response rate was significantly higher in the 175/75-mg group (22%) compared with the investigator's choice group (2%; P = .0019). Median overall survival for the temsirolimus 175/75-mg group and the investigator's choice group was 12.8 months and 9.7 months, respectively (P = .3519). The most frequent grade 3 or 4 adverse events in the temsirolimus groups were thrombocytopenia, anemia, neutropenia, and asthenia.
Temsirolimus 175 mg weekly for 3 weeks followed by 75 mg weekly significantly improved PFS and objective response rate compared with investigator's choice therapy in patients with relapsed or refractory MCL.
While commonly accepted in poor-risk acute lymphoblastic leukemia (ALL), the role of allogeneic hematopoietic stem cell transplantation (allo-SCT) is still disputed in adult patients with ...standard-risk ALL. We evaluated outcome of patients with ALL in first complete remission (CR1), according to a sibling donor versus no-donor comparison. Eligible patients (433) were entered in 2 consecutive, prospective studies, of whom 288 (67%) were younger than 55 years, in CR1, and eligible to receive consolidation by either an autologous SCT or an allo-SCT. Allo-SCT was performed in 91 of 96 patients with a compatible sibling donor. Cumulative incidences of relapse at 5 years were, respectively, 24 and 55% for patients with a donor versus those without a donor (hazard ratio HR, 0.37; 0.23-0.60; P < .001). Nonrelapse mortality estimated 16% (± 4) at 5 years after allo-SCT. As a result, disease-free survival (DFS) at 5 years was significantly better in the donor group: 60 versus 42% in the no-donor group (HR: 0.60; 0.41-0.89; P = .01). After risk-group analysis, improved outcome was more pronounced in standard-risk patients with a donor, who experienced an overall survival of 69% at 5 years (P = .05). In conclusion, standard-risk ALL patients with a sibling donor may show favorable survival following SCT, due to both a strong reduction of relapse and a modest nonrelapse mortality. This trial is registered with http://www.trialregister.nl under trial ID NTR228.
An urgent need for new treatment modalities is emerging in elderly patients with acute myeloid leukemia (AML). We hypothesized that targeting VEGF might furnish an effective treatment modality in ...this population. Elderly patients with AML were randomly assigned in this phase 2 study (n = 171) to receive standard chemotherapy (3 + 7) with or without bevacizumab at a dose of 10 mg/kg intravenously at days 1 and 15. In the second cycle, patients received cytarabine 1000 mg/m2 twice daily on days 1-6 with or without bevacizumab. The complete remission rates in the 2 arms were not different (65%). Event-free survival at 12 months was 33% for the standard arm versus 30% for the bevacizumab arm; at 24 months, it was 22% and 16%, respectively (P = .42). The frequencies of severe adverse events (SAEs) were higher in the bevacizumab arm (n = 63) compared with the control arm (n = 28; P = .043), but the percentages of death or life-threatening SAEs were lower in the bevacizumab arm (60% vs 75% of SAEs). The results of the present study show that the addition of bevacizumab to standard chemotherapy does not improve the therapeutic outcome of older AML patients. This trial is registered as number NTR904 in The Nederlands Trial Register (www.trialregister.nl).
Treatment failure in acute myeloid leukemia is probably caused by the presence of leukemia initiating cells, also referred to as leukemic stem cells, at diagnosis and their persistence after therapy. ...Specific identification of leukemia stem cells and their discrimination from normal hematopoietic stem cells would greatly contribute to risk stratification and could predict possible relapses.
For identification of leukemic stem cells, we developed flow cytometric methods using leukemic stem cell associated markers and newly-defined (light scatter) aberrancies. The nature of the putative leukemic stem cells and normal hematopoietic stem cells, present in the same patient's bone marrow, was demonstrated in eight patients by the presence or absence of molecular aberrancies and/or leukemic engraftment in NOD-SCID IL-2Rγ-/- mice. At diagnosis (n=88), the frequency of the thus defined neoplastic part of CD34+CD38- putative stem cell compartment had a strong prognostic impact, while the neoplastic parts of the CD34+CD38+ and CD34- putative stem cell compartments had no prognostic impact at all. After different courses of therapy, higher percentages of neoplastic CD34+CD38- cells in complete remission strongly correlated with shorter patient survival (n=91). Moreover, combining neoplastic CD34+CD38- frequencies with frequencies of minimal residual disease cells (n=91), which reflect the total neoplastic burden, revealed four patient groups with different survival.
Discrimination between putative leukemia stem cells and normal hematopoietic stem cells in this large-scale study allowed to demonstrate the clinical importance of putative CD34+CD38- leukemia stem cells in AML. Moreover, it offers new opportunities for the development of therapies directed against leukemia stem cells, that would spare normal hematopoietic stem cells, and, moreover, enables in vivo and ex vivo screening for potential efficacy and toxicity of new therapies.
Fatigue is a common and distressing symptom in cancer patients, especially in lymphoma patients. One hypothesized mechanism in the etiology of fatigue is a vicious circle between fatigue, physical ...inactivity, and deconditioning. However, the natural evolution of physical activity and physical fitness over the course of treatment is unknown. Therefore, the aim of this longitudinal study was to assess fatigue, physical activity, and physical fitness in lymphoma patients before, during, and after treatment. Fatigue was measured with the EORTC-QLQ-C30, physical activity with an accelerometer, and physical fitness with a maximal incremental cycle ergometer test, 6-min walking distance test, and muscle strength measurements. Differences between the three measurement moments and baseline differences between Hodgkin lymphoma and non-Hodgkin lymphoma, early and advanced disease, were analyzed. Twenty-nine patients were included. Functional exercise capacity and quadriceps force were impaired before the start of treatment (86 ± 15 and 82 ± 16 % of predicted value, respectively). Over the course of treatment, significant declines were found in hemoglobin, quadriceps force, handgrip force, and maximal oxygen uptake, while patients reported more fatigue (
p
values < 0.016). Fatigue was significantly correlated with hemoglobin (
r
= −0.49), physical activity (
r
= 0.81), and physical functioning (
r
= −0.44). Large interindividual variations were found. The present study partially confirmed the hypothesized vicious circle between fatigue, physical inactivity, and deconditioning. Further research with larger samples and longer follow-up is needed to identify factors associated with individual variation in the evolution of fatigue, physical activity, and physical fitness.
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