In the face of competing first-line treatment options for CML, early prediction of prognosis on imatinib is desirable to assure favorable survival or otherwise consider the use of a second-generation ...tyrosine kinase inhibitor (TKI). A total of 1303 newly diagnosed imatinib-treated patients (pts) were investigated to correlate molecular and cytogenetic response at 3 and 6 months with progression-free and overall survival (PFS, OS). The persistence of BCR-ABL transcript levels >10% according to the international scale (BCR-ABL(IS)) at 3 months separated a high-risk group (28% of pts; 5-year OS: 87%) from a group with >1-10% BCR-ABL(IS) (41% of pts; 5-year OS: 94%; P=0.012) and from a group with ≤1% BCR-ABL(IS) (31% of pts; 5-year OS: 97%; P=0.004). Cytogenetics identified high-risk pts by >35% Philadelphia chromosome-positive metaphases (Ph+, 27% of pts; 5-year OS: 87%) compared with ≤35% Ph+ (73% of pts; 5-year OS: 95%; P=0.036). At 6 months, >1% BCR-ABL(IS) (37% of pts; 5-year OS: 89%) was associated with inferior survival compared with ≤1% (63% of pts; 5-year OS: 97%; P<0.001) and correspondingly >0% Ph+ (34% of pts; 5-year OS: 91%) compared with 0% Ph+ (66% of pts; 5-year OS: 97%; P=0.015). Treatment optimization is recommended for pts missing these landmarks.
Treatment of chronic myeloid leukemia (CML) has been profoundly improved by the introduction of tyrosine kinase inhibitors (TKIs). Long-term survival with imatinib is excellent with a 8-year survival ...rate of ∼88%. Long-term toxicity of TKI treatment, especially carcinogenicity, has become a concern. We analyzed data of the CML study IV for the development of secondary malignancies. In total, 67 secondary malignancies were found in 64 of 1525 CML patients in chronic phase treated with TKI (n=61) and interferon-α only (n=3). The most common malignancies (n⩾4) were prostate, colorectal and lung cancer, non-Hodgkin's lymphoma (NHL), malignant melanoma, non-melanoma skin tumors and breast cancer. The standardized incidence ratio (SIR) for all malignancies excluding non-melanoma skin tumors was 0.88 (95% confidence interval (0.63-1.20)) for men and 1.06 (95% CI 0.69-1.55) for women. SIRs were between 0.49 (95% CI 0.13-1.34) for colorectal cancer in men and 4.29 (95% CI 1.09-11.66) for NHL in women. The SIR for NHL was significantly increased for men and women. An increase in the incidence of secondary malignancies could not be ascertained. The increased SIR for NHL has to be considered and long-term follow-up of CML patients is warranted, as the rate of secondary malignancies may increase over time.
Chronic myeloid leukemia (CML)-study IV was designed to explore whether treatment with imatinib (IM) at 400 mg/day (n=400) could be optimized by doubling the dose (n=420), adding interferon (IFN) ...(n=430) or cytarabine (n=158) or using IM after IFN-failure (n=128). From July 2002 to March 2012, 1551 newly diagnosed patients in chronic phase were randomized into a 5-arm study. The study was powered to detect a survival difference of 5% at 5 years. After a median observation time of 9.5 years, 10-year overall survival was 82%, 10-year progression-free survival was 80% and 10-year relative survival was 92%. Survival between IM400 mg and any experimental arm was not different. In a multivariate analysis, risk group, major-route chromosomal aberrations, comorbidities, smoking and treatment center (academic vs other) influenced survival significantly, but not any form of treatment optimization. Patients reaching the molecular response milestones at 3, 6 and 12 months had a significant survival advantage. For responders, monotherapy with IM400 mg provides a close to normal life expectancy independent of the time to response. Survival is more determined by patients' and disease factors than by initial treatment selection. Although improvements are also needed for refractory disease, more life-time can currently be gained by carefully addressing non-CML determinants of survival.
The finding of shortened telomeres in leukocytes from patients with aplastic anemia prompted a search for mutations in genes that maintain the structure of the telomerase complex. Mutations in
TERT,
...the gene encoding telomerase reverse transcriptase, were found in seven unrelated patients.
Mutations in
TERT
, the gene encoding telomerase reverse transcriptase, were found in seven patients who presented with acquired aplastic anemia. The mutations probably contribute to the cause of aplastic anemia.
In aplastic anemia, the bone marrow contains very few hematopoietic cells and consists mainly of fat. The disease can be acquired or constitutional.
1
In most acquired cases, the hematopoietic tissue is the target of an immune process dominated by oligoclonal expansion of type I cytotoxic T cells, which secrete interferon-γ and tumor necrosis factor α and cause hematopoietic cell death by apoptosis.
2
,
3
Acquired aplastic anemia can be successfully treated by allogeneic bone marrow transplantation or immunosuppressive therapy.
4
Fanconi's anemia and dyskeratosis congenita are the most common types of constitutional (congenital) aplastic anemia.
5
X-linked dyskeratosis congenita (Online Mendelian Inheritance in . . .
Purpose
This study assessed whether a cycle of “routine” therapeutic drug monitoring (TDM) for imatinib dosage individualization, targeting an imatinib trough plasma concentration (
C
min
) of ...1,000 ng/ml (tolerance: 750–1,500 ng/ml), could improve clinical outcomes in chronic myelogenous leukemia (CML) patients, compared with TDM use only in case of problems (“rescue” TDM).
Methods
Imatinib concentration monitoring evaluation was a multicenter randomized controlled trial including adult patients in chronic or accelerated phase CML receiving imatinib since less than 5 years. Patients were allocated 1:1 to “routine TDM” or “rescue TDM.” The primary endpoint was a combined outcome (failure- and toxicity-free survival with continuation on imatinib) over 1-year follow-up, analyzed in intention-to-treat (ISRCTN31181395).
Results
Among 56 patients (55 evaluable), 14/27 (52 %) receiving “routine TDM” remained event-free versus 16/28 (57 %) “rescue TDM” controls (
P
= 0.69). In the “routine TDM” arm, dosage recommendations were correctly adopted in 14 patients (median
C
min
: 895 ng/ml), who had fewer unfavorable events (28 %) than the 13 not receiving the advised dosage (77 %;
P
= 0.03; median
C
min
: 648 ng/ml).
Conclusions
This first target concentration intervention trial could not formally demonstrate a benefit of “routine TDM” because of small patient number and surprisingly limited prescriber’s adherence to dosage recommendations. Favorable outcomes were, however, found in patients
actually
elected
for target dosing. This study thus shows first prospective indication for TDM being a useful tool to guide drug dosage and shift decisions. The study design and analysis provide an interesting paradigm for future randomized TDM trials on targeted anticancer agents.
Early assessment of response at 3 months of tyrosine kinase inhibitor treatment has become an important tool to predict favorable outcome. We sought to investigate the impact of relative changes of ...BCR-ABL transcript levels within the initial 3 months of therapy. In order to achieve accurate data for high BCR-ABL levels at diagnosis, beta glucuronidase (GUS) was used as a reference gene. Within the German CML-Study IV, samples of 408 imatinib-treated patients were available in a single laboratory for both times, diagnosis and 3 months on treatment. In total, 301 of these were treatment-naïve at sample collection.
(i) with regard to absolute transcript levels at diagnosis, no predictive cutoff could be identified; (ii) at 3 months, an individual reduction of BCR-ABL transcripts to the 0.35-fold of baseline level (0.46-log reduction, that is, roughly half-log) separated best (high risk: 16% of patients, 5-year overall survival (OS) 83% vs 98%, hazard ratio (HR) 6.3, P=0.001); (iii) at 3 months, a 6% BCR-ABL(IS) cutoff derived from BCR-ABL/GUS yielded a good and sensitive discrimination (high risk: 22% of patients, 5-year OS 85% vs 98%, HR 6.1, P=0.002). Patients at risk of disease progression can be identified precisely by the lack of a half-log reduction of BCR-ABL transcripts at 3 months.
The production of blood cells during steady-state and increased demand depends on the regulation of hematopoietic stem cell (HSC) self-renewal and differentiation. Similarly, the balance between ...self-renewal and differentiation of leukemia stem cells (LSCs) is crucial in the pathogenesis of leukemia. Here, we document that the TNF receptor superfamily member lymphotoxin-β receptor (LTβR) and its ligand LIGHT regulate quiescence and self-renewal of murine and human HSCs and LSCs. Cell-autonomous LIGHT/LTβR signaling on HSCs reduces cell cycling, promotes symmetric cell division and prevents primitive HSCs from exhaustion in serial re-transplantation experiments and genotoxic stress. LTβR deficiency reduces the numbers of LSCs and prolongs survival in a murine chronic myeloid leukemia (CML) model. Similarly, LIGHT/LTβR signaling in human G-CSF mobilized HSCs and human LSCs results in increased colony forming capacity in vitro. Thus, our results define LIGHT/LTβR signaling as an important pathway in the regulation of the self-renewal of HSCs and LSCs.
There is limited and conflicting information on the prevalence of contamination of haematopoietic stem and progenitor cell products (HPCPs), and their optimal management remains unclear. The authors ...reviewed the microbial surveillance data of HPCPs collected between January 2002 and December 2019 for autologous transplantation at the study institution to determine the prevalence of microbial contamination and the potential infectious complications among recipients. Among 3935 HPCPs, 25 (0.6%) were contaminated. Ultimately, 22 patients received contaminated grafts, with pre-emptive antimicrobial therapy initiated in six of these patients. No patients developed subsequent infectious complications. These data suggest that microbial contamination of autologous HPCPs and associated adverse outcomes are rare.
The potential of cloning depends in part on whether the procedure can reverse cellular aging and restore somatic cells to a phenotypically youthful state. Here, we report the birth of six healthy ...cloned calves derived from populations of senescent donor somatic cells. Nuclear transfer extended the replicative life-span of senescent cells (zero to four population doublings remaining) to greater than 90 population doublings. Early population doubling level complementary DNA-1 (EPC-1, an age-dependent gene) expression in cells from the cloned animals was 3.5- to 5-fold higher than that in cells from age-matched (5 to 10 months old) controls. Southern blot and flow cytometric analyses indicated that the telomeres were also extended beyond those of newborn (<2 weeks old) and age-matched control animals. The ability to regenerate animals and cells may have important implications for medicine and the study of mammalian aging.
Dyskeratosis congenita is a cancer-prone bone marrow failure syndrome caused by aberrations in telomere biology.
We studied 65 patients with dyskeratosis congenita and 127 unaffected relatives. ...Telomere length was measured by automated multicolor flow fluorescence in situ hybridization in peripheral blood leukocyte subsets. We age-adjusted telomere length using Z-scores (standard deviations from the mean for age).
We confirmed that telomere lengths below the first percentile for age are very sensitive and specific for the diagnosis of dyskeratosis congenita. We provide evidence that lymphocytes alone and not granulocytes may suffice for clinical screening, while lymphocyte subsets may be required for challenging cases, including identification of silent carriers. We show for the first time using flow fluorescence in situ hybridization that the shortest telomeres are associated with severe variants (Hoyeraal-Hreidarsson and Revesz syndromes), mutations in DKC1, TINF2, or unknown genes, and moderate or severe aplastic anemia. In the first longitudinal follow up of dyskeratosis congenita patients, we demonstrate that telomere lengths decline with age, in contrast to the apparent stable telomere length observed in cross-sectional data.
Telomere length by flow fluorescence in situ hybridization is an important diagnostic test for dyskeratosis congenita; age-adjusted values provide a quantitative measure of disease severity (clinical subset, mutated gene, and degree of bone marrow failure). Patients with dyskeratosis congenita have accelerated telomere shortening. This study is registered at www.clinicaltrials.gov (identifier: NCT00027274).