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.
The Disabilities of the Arm, Shoulder and Hand (DASH) instrument was developed to assess the disability experienced by patients with any musculoskeletal condition of the upper extremity and to ...monitor change in symptoms and upper-limb function over time. The 30 items are scored on a 5-point rating scale. The Dutch-language version of the DASH instrument (DASH-DLV) has been examined with the classical test theory in patients with a humeral shaft fracture. This study aimed to examine the DASH-DLV with a more rigorous and extensive analysis by applying the Rasch model.
Data of 400 patients included in a multicenter, prospective study comparing operative and nonoperative treatment of adult patients with a humeral shaft fracture were used. The person-item map, item fit statistics, reliability, response category ordering, and dimensionality were examined. Raw data were converted to linear measures using the Rasch model.
The DASH-DLV showed a good fit to the Rasch model, except for item 26 (“Tingling pins and needles in your arm, shoulder or hand”). The person reliability was 0.92. In general, the category functioning of the 5-point rating scale was working well. Dimensionality analysis revealed that the DASH-DLV is a unidimensional scale. Differential item functioning for sex was not detected, and only item 26 exhibited differential item functioning as a function for age.
The DASH-DLV fits the stringent Rasch model in a clinical situation with a group of adult patients with a humeral shaft fracture. Adequate measurement for scientific research can be obtained to evaluate longitudinal intervention research.
In order to improve the molecular response rate and prevent resistance to treatment, combination therapy with different dosages of imatinib and cytarabine was studied in newly diagnosed patients with ...chronic myeloid leukemia in the HOVON-51 study.
Having reported feasibility previously, we hereby report the efficacy of escalated imatinib (200 mg, 400 mg, 600 mg or 800 mg) in combination with two cycles of intravenous cytarabine (200 mg/m(2) or 1000 mg/m(2) days 1 to 7) in 162 patients with chronic myeloid leukemia.
With a median follow-up of 55 months, the 5-year cumulative incidences of complete cytogenetic response, major molecular response, and complete molecular response were 89%, 71%, and 53%, respectively. A higher Sokal risk score was inversely associated with complete cytogenetic response (hazard ratio of 0.63; 95% confidence interval, 0.50-0.79, P<0.001). A higher dose of imatinib and a higher dose of cytarabine were associated with increased complete molecular response with hazard ratios of 1.60 (95% confidence interval, 0.96-2.68, P=0.07) and 1.66 (95% confidence interval, 1.02-2.72, P=0.04), respectively. Progression-free survival and overall survival rates at 5 years were 92% and 96%, respectively. Achieving a major molecular response at 1 year was associated with complete absence of progression and a probability of achieving a complete molecular response of 89%.
The addition of intravenous cytarabine to imatinib as upfront therapy for patients with chronic myeloid leukemia is associated with a high rate of complete molecular responses (Clinicaltrials.Gov Identifier: NCT00028847).
The consequences of radial nerve palsy associated with a humeral shaft fracture are unclear. The aim of this study was to examine the functional recovery of radial nerve palsy, at presentation or ...postoperatively, in patients with a humeral shaft fracture.
Data from patients who participated in the HUMeral shaft fractures: measuring recovery after operative versus non-operative treatment (HUMMER) study, a multicenter prospective cohort study including adults with a closed humeral shaft fracture Arbeitsgemeinschaft für Osteosynthesefragen (AO) type 12A or 12B, and had radial nerve palsy at presentation or postoperatively, were extracted from the HUMMER database. The primary outcome measure was clinically assessed recovery of motor function of the radial nerve. Secondary outcomes consisted of treatment, functional outcome (Disabilities of the Arm, Shoulder, and Hand and Constant–Murley Score), pain level, quality of life (Short Form-36 and EuroQoL-5D-3L), activity resumption, and range of motion of the shoulder and elbow joint at 12 months after trauma.
Three of the 145 nonoperatively treated patients had radial nerve palsy at presentation. One recovered spontaneously and 1 after osteosynthesis. Despite multiple surgical interventions, the third patient had no recovery after entrapment between fracture fragments. Thirteen of the 245 operatively treated patients had radial nerve palsy at presentation; all recovered. Nine other patients had postoperative radial nerve palsy; 8 recovered. One had ongoing recovery at the last follow-up, after nerve release and suture repair due to entrapment under the plate. At 12 months, the functional outcome scores of all patients suggested full recovery regarding functional outcome, pain, quality of life, activity resumption, and range of motion.
Radial nerve palsy in patients with a humeral shaft fracture at presentation or postoperatively functionally recovers in 94% and 89%, respectively.
Despite the revolutionary change in the prognosis of chronic myeloid leukemia (CML) patients with the introduction of imatinib, patients with resistant disease still pose a considerable problem. In ...this multicenter, randomized phase III trial, we investigate whether the combination of high-dose imatinib and intermediate-dose cytarabine compared to high-dose imatinib alone, improves the rate of major molecular response (MMR) in newly diagnosed CML patients. This study was closed prematurely because of declining inclusion due to the introduction of second generation tyrosine kinase inhibitors and only one third of the initially required patients were accrued. One hundred nine patients aged 18–65 years were randomly assigned to either imatinib 800 mg (
n
= 55) or to imatinib 800 mg in combination with two successive cycles of cytarabine 200 mg/m
2
for 7 days (
n
= 54). After a median follow-up of 41 months, 67 % of patients were still on protocol treatment. The MMR rate at 12 months was 56 % in the imatinib arm and 48 % in the combination arm (
p
= 0.39). Progression-free survival was 96 % after 1 year and 89 % after 4 years. Four-year overall survival was 97 %. Adverse events grades 3 and 4 were more common in the combination arm. The addition of intermediate-dose of cytarabine to imatinib did not improve the MMR rate at 12 months. However, the underpowering of the study precludes any definitive conclusions. This trial is registered at
www.trialregister.nl
(NTR674).
The HOVON cooperative study group performed a feasibility study of escalated imatinib and intravenous cytarabine in 165 patients with early chronic-phase chronic myeloid leukemia (CML). Patients ...received 2 cycles of intravenous cytarabine (200 mg/m2 or 1000 mg/m2 days 1-7) in conjunction with imatinib (200 mg, 400 mg, 600 mg, or 800 mg), according to predefined, successive dose levels. All dose levels proved feasible. Seven dose-limiting toxicities (DLTs) were observed in 302 cycles of chemotherapy, which were caused by streptococcal bacteremia in 5 cases. Intermediate-dose cytarabine (1000 mg/m2) prolonged time to neutrophil recovery and platelet recovery compared with a standard dose (200 mg/m2). High-dose imatinib (600 mg or 800 mg) extended the time to platelet recovery compared with a standard dose (400 mg). More infectious complications common toxicity criteria (CTC) grade 3 or 4 were observed after intermediate-dose cytarabine compared with a standard-dose of cytarabine. Early response data after combination therapy included a complete cytogenetic response in 48% and a major molecular response in 30% of patients, which increased to 46% major molecular responses at 1 year, including 13% complete molecular responses. We conclude that combination therapy of escalating dosages of imatinib and cytarabine is feasible. This study was registered at www.kankerbestrijding.nl as no. CKTO-2001-03.
Abstract 2208
Poster Board II-185
Hematologic and cytogenetic responses to first-line imatinib are high in patients with chronic myeloid leukemia (CML), but only a minority of patients proceeds to a ...complete molecular response (CMR). Persistent residual disease at the molecular level may be designated as molecular resistance and has been suggested to be accounted for by quiescent malignant stem cells. P-glycoprotein (P-gp), which is encoded by the ABCB1 multi drug resistance (MDR1) gene, has been demonstrated to mediate efflux of imatinib. As hematopoietic progenitor cells efficiently express P-gp, it was hypothesized that single nucleotide polymorphisms (SNPs) of the ABCB1 gene that account for differences in functional activity may possibly be involved in the probability of developing a molecular response to imatinib and molecular resistance. Methods: We set out to evaluate whether the 3 most prevalent MDR1 SNPs (C1236T; G2677T/A; C3435T) would be associated with molecular response in a cohort of 46 early chronic phase CML patients who received 800 mg of imatinib. Molecular response was assessed according to the International Scale. Results: Patient characteristics, including age and Sokal risk score, were distributed evenly among groups of patients, classified according to SNP-genotype. The median follow-up was 46 months (range, 32-60 months). Each of the 3 SNPs were in Hardy-Weinberg equilibrium. However, each combination of 2 SNPs was in strong linkage disequilibrium (P<.001). The overall cumulative incidences of a major molecular response (MMR) and CMR were 78% and 41%, respectively, at 2 years. Molecular responses proved to depend strongly on SNP-genotype. A cumulative incidence of MMR of 52% and 50% was observed in patients with genotype 1236CT or TT as compared to 92% in patients homozygous for 1236C (hazard ratio's (HR): 0.32 and 0.33, P=.02) in univariate analysis, which remained significant (P=.03) following multivariate analysis. Patients homozygous for allele 3435T showed a CMR rate of 10% versus a CMR of 50% at 1 year in patients homozygous for allele 3435C (HR: 0.24 (0.07-0.83, P=.04). Hazard ratio's with respect to CMR associated with C1236T and G2677T were: 0.27 (0.08-0.97, P=.01) for the 1236TT genotype versus the 1236CC genotype, and 0.23 (0.06-0.88, P=.05) for the 2677TT genotype versus the 2677GG genotype, indicating a 4-fold reduction of the probability to develop a CMR. Given the strong linkage disequilibrium, the response differences could not unequivocally be attributed to a single SNP. However, given the enhanced P-gp activity earlier associated with the 2677TT genotype, it is suggested that enhanced clearance of imatinib by the 2677TT genotype may account for the lower incidences of a MMR and CMR in those patients. Conclusions: Molecular resistance in CML patients receiving high-dose imatinib appeared strongly associated with ABCB1 genes SNPs, suggesting a role for P-gp mediated drug efflux in malignant hematopoietic progenitor cells, that may possibly account for persistent molecular residual disease in patients favourably responding to imatinib.
No relevant conflicts of interest to declare.
Abstract 3245
Poster Board III-182
Tyrosine kinase inhibitor (TKI) insensitivity of CML hematopoietic stem cells prevents eradication of the disease by these drugs and is presumably implicated in ...development of TKI resistance. Probably, improvement of treatment results will involve leukemic stem cell directed therapy. Therefore, more knowledge of stem cell specific targets would be instrumental. Previously, leukemic stem cells could only be identified indirectly by using culture techniques. We developed a new flowcytometric approach that enables to directly distinguish CML stem cells from their normal counterparts within single patient samples. In 24 newly diagnosed CML patients CML CD34+CD38- stem cells could be discriminated from normal stem cells by higher CD34 and CD45 expression and different forward/sideward light scatter properties, reflecting differences in size and granularity. In addition, aberrant expression of CD7, CD11b and CD56 was demonstrated on malignant stem cells, allowing clear discrimination from benign stem cells, that were always negative for these markers. Above all, in all tested CML patients we were able to demonstrate that high CD90 expression is a specific feature of CML stem cells, while CD90 expression is low on their normal counterparts. FISH analysis on FACS sorted cells proved that populations were BCR-ABL positive (in case of high CD34 and CD45 expression and high CD90 expression) or negative (in case of low CD34 and CD45 expression and low CD90 expression), while long term liquid culture assays with subsequent CFU assays and FISH analysis proved their malignant/normal stem cell character. Patients with a large proportion of non-leukemic stem cells had significantly lower clinical risk scores (Sokal, Euro) than patients with few remaining normal stem cells. This new technique will expand our possibilities to identify new CML stem cell specific targets and may improve efficacy assessment of CML treatment as well.
No relevant conflicts of interest to declare.
PDF
