Philadelphia Chromosome (Ph’) Secondary Clones in Chronic Myeloid Leukemia (CML) Are Not Indicative of Resistance to IFNa- or Imatinib-Based Treatment Regimens.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4806-4806
Author(s):  
Lorenzo Falchi ◽  
Paolo Prontera ◽  
Debora Luzi ◽  
Viola Festuccia ◽  
Rita Emili ◽  
...  
Keyword(s):  
Real Time ◽  
Small Sample Size ◽  
Clonal Evolution ◽  
Philadelphia Chromosome ◽  
Small Sample ◽  
Molecular Response ◽  
Molecular Remission ◽  
Trisomy 8 ◽  
Real Time Quantitative Pcr ◽  
Treatment Regimens

Abstract The rate of complete karyotypic remission (CKR) and complete molecular remission (undetectable BCR/ABL specific transcript by real-time quantitative-PCR (Gabert J et al. Leukemia: 2003; 17: 2318–57) and NESTED/real-time-PCR (Guo JQ et al.; Leukemia: 2002; 15:2447–53)) to various therapies was analysed in 35, of the 114 CML patients observed in our institution, who showed cytogenetic clonal evolution. Overall, 52 karyotypic abnormalities additional to Ph’ were documented at the time of diagnosis (early clonal evolution) or late in the course of the disease (late clonal evolution). Seven of 12 patients with early clonal evolution achieved one (5 pts) or more (2 pts) CKRs, for a total number of 9, in response to IFNα (2 CKRs), IFNα plus ARA-C (1 CKR), imatinib (5 CKRs) or imatinib-IFNα combination (1 CKRs). Six of the 23 patients with late clonal evolution achieved one or more CKRs during the course of their disease after treatment with IFNα (2), IFNa plus ARA-C (1) or imatinib (5). In addition, 7 of the 13 CK responders reached a complete molecular remission in response to IFNa (1), IFNa plus ARA-C (1) imatinib (1), or imatinib plus IFNa (4). The 5 complete molecular remissions documented in patients with early clonal evolution, were observed following treatment with IFNα plus ARA-C (1), imatinib (1), or imatinib plus IFNα (3). Two patients with late clonal evolution obtained complete molecular remission in response to IFNα and imatinib plus IFN therapy, respectively. Cytogenetic and molecular response rates were higher in patients with early (58%, 57%) than in patients with late secondary clones (26%, 33%), while there were no significant differences in time to achieve cytogenetic (2–20 months vs 1–25 months) or molecular (3–26 months vs 13–52 months) remission and the duration of response (11 months, range 4–42 vs 10 months, range 7–46 and 2–19 vs 3–13+ months, respectively) between the two groups. Finally, no relationship was evident between the type of additional karyotypic anomalies and sensitivity to treatment. In fact, clones bearing complex translocations (2), isoPh’ (2), trisomy 8 (2), translocations other than Ph’ (2), partial chromosome monosomy (11-q, 1) or loss of chromosome Y alone (1) or associated with other anomalies (−6 and −14 or −21 or isoPh’) (3) all responded to therapy. In conclusion, although the small sample size, these findings suggest that the presence of karyotypic abnormalities additional to Ph’ in CML is not associated to disease resistance to therapy.

Persistent Molecular Remission in Patients Treated with Imatinib-IFNa Combination or Imatinib Monotherapy.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4784-4784
Author(s):  
Monica Schippa ◽  
Enrico Gottardi ◽  
Debora Luzi ◽  
Lorenzo Falchi ◽  
Rita Emili ◽  
...  
Keyword(s):  
Real Time ◽  
Small Sample Size ◽  
Philadelphia Chromosome ◽  
Small Sample ◽  
Molecular Response ◽  
Second Line ◽  
Molecular Remission ◽  
Second Line Therapy ◽  
Line Therapy ◽  
Line Of Therapy

Abstract INTRODUCTION. Continously improving results have been obtained during the last two decades in the control of Philadelphia chromosome (Ph’) positive chronic myeloid leukemia (CML). However, the final goal of molecular remission remains difficult to be obtained, even in the imatinib era. AIMS: Evaluation of the rate of long lasting molecular remission (undetectable p210 transcript at RQ-PCR confirmed by NESTED/RT-PCR in at least two subsequent tests performed over a period of 12 months or more) in response to imatinib or to imatinib-IFNa combination employed as first, second or subsequent line of therapy. PATIENTS. Imatinib alone or in combination with IFNa was given as first, second or subsequent line of therapy to a total of 47 patients. In particular, twenty-one patients were treated at the time of diagnosis with imatinib alone (18,G1) or imatinib-pegilated IFN combination (3,G2). Twenty-three additional patients (G3) received imatinib as second line therapy. Finally, 11 patients were treated with the imatinib-IFNa combination as second (5,G4) or third (6,G5) line therapy. In details, G4 consisted of three patients in cytogenetic relapse (3) or no response (2) after first line imatinib (1)or IFNa-ARA-C(1)therapy. All six patients included in G5 were complete kariotypic, but not molecular responder to imatinib given as second line treatment. METHODS. Molecular response was evaluated by NESTED/real-time-PCR (Guo JQ et al.; Leukemia : 2002; 15:2447–53) and real-time quantitative-PCR (Gabert J et al. Leukemia : 2003; 17: 2318–57) time intervals of 3–6 months from the beginning of therapy. RESULTS. A complete molecular remission lasting 12 months or more was obtained in 11 of 42 evaluable patients(therapy duration ≥ 18 mths).The response rate was higher in patients receiving the imatinib-IFNa combination(6/14) than in those given imatinib in monotherapy (5/36).In details, 4/14 and 1/3 patients respectively receiving early imatinib or imatinib-IFNa combination achieved a stable molecular remission. Two to four consecutive negative tests were documented in all five cases over a period ranging from 12 to 19 mths with 4 patients still in continous remission. Furthermore, 1/22 and 5/11 patients obtained a complete molecular response to imatinib given as second line therapy or imatinib-IFNa combination employed as second (4) or third (1) line therapy. Five negative tests were documented over a period of 12 mths in the patient responsive to imatinib monotherapy. Three to 7 negative consecutive tests were obtained during a period of 12 to 36 mths in the remaining five cases while receiving the imatinib-IFN-a combination. At the present time, 5 of these 6 patients are in continous molecular remission. In all molecularly responsive patients, stable molecular remission was usually preceded by a period of fluctuating negative-positive results of NESTED-PCR tests. CONCLUSIONS. It is not possible to achieve any firm conclusion regarding the effect of the imatinib-INFa combination on molecular response because of the small sample size of treated patients. However, our findings suggest an additive effect of imatinib and IFNa in Ph’ clone control as indicated by the improvement of the quality of remission in long lasting kariotypically, but not molecularly responsive patients when this combination therapy was utilized.

Molecular remission to imatinib-IFN-alpha combination or imatinib monotherapy in chronic myeloid leukemia (CML) patients

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 17512-17512
Author(s):  
A. Liberati ◽  
M. Schippa ◽  
D. Luzi ◽  
L. Falchi ◽  
R. Emili ◽  
...  
Keyword(s):  
Philadelphia Chromosome ◽  
Small Sample ◽  
Molecular Response ◽  
Second Line ◽  
Rt Pcr ◽  
Molecular Remission ◽  
Second Line Therapy ◽  
Line Therapy ◽  
Remission Duration ◽  
Line Of Therapy

17512 Background: Continously improving results have been obtained in the control of Philadelphia chromosome (Ph’) positive CML. However, the final goal of molecular remission remains difficult to be obtained, even in the imatinib era. Evaluation of the rate of complete molecular remission (undetectable p210 transcript at RQ-PCR confirmed by NESTED/RT-PCR in at least two subsequent tests over a period of 3 mths or more) to imatinib or to imatinib-IFNa combination as first, second or subsequent line of therapy. Imatinib alone or in combination with IFNa was given as first, second or subsequent line of therapy to a total of 47 patients. In particular, 21 patients were treated at the time of diagnosis with imatinib alone (18,G1) or imatinib-pegilated IFN combination (3,G2). Twenty-three additional patients (G3) received imatinib as second line therapy. Finally, 13 patients were treated with the imatinib-IFNa combination as second (7,G4) or third (6,G5) line therapy, but in two cases IFNa was discontinuated after one month because of intolerance to treatment. Methods: Molecular response was evaluated by NESTED/RT-PCR (Guo JQ et al.; Leukemia:2002;15:2447–53) and RQ-PCR (Gabert J et al. Leukemia:2003;17:2318–57) at time intervals of 3–6 months from the beginning of therapy. Results: Complete molecular remission lasting 3 months or more (range 3–34) was obtained in 15 of 44 evaluable patients (therapy duration = 11 mths, range 11–73).The response rate was higher in patients receiving imatinib- IFNa combination given as first or second line therapy (5/13) than in those given imatinib monotherapy (9/37). In 7 of the 15 complete responders, remission duration lasted more than 12 mths (range 12–34) with 6/7 pts still continuous remission. In further 6 cases continuous remission duration ranged from 3–8 mths while in one case fluctuating negative-positive NESTED/RT-PCR tests have been observed over a period of 65 months. Conclusions: It is not possible to draw any firm conclusion regarding the effect of the imatinib-INFa combination on molecular response because of the small sample size of treated patients. However, our findings suggest an additive effect of imatinib and IFNa in Ph’positive clone control. No significant financial relationships to disclose.

Survival Outcomes for Patients (Pts) with Chronic Myeloid Leukemia (CML) with Clonal Evolution (CE) Treated with 2nd Generation Tyrosine Kinase Inhibitors (TKI) after Imatinib Failure.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2949-2949 ◽  
Author(s):  
Dushyant Verma ◽  
Hagop Kantarjian ◽  
Zeev Estrov ◽  
Guillermo Garcia-Manero ◽  
Charles Koller ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Chromosomal Abnormalities ◽  
Clonal Evolution ◽  
Philadelphia Chromosome ◽  
Cytogenetic Response ◽  
Chromosome 17 ◽  
Trisomy 8 ◽  
2Nd Generation ◽  
Molecular Events ◽  
Number Of Patients

Abstract Background: CE has been considered a criterion for accelerated phase (AP) CML, particularly when it appears during the course of therapy, when it is associated with a poor prognosis. CE may involve a variety of chromosomal abnormalities and may signal resistance to imatinib. The 2nd generation TKI (2nd TKI) dasatinib and nilotinib are effective in patients with AP after failure to imatinib, including those with CE. However, it is unclear whether different chromosomal abnormalities constituting CE may have the same outcome after therapy with 2nd TKI. Methods: We analyzed the outcome after 2nd TKI therapy of 61 pts with CML with CE who had failed prior imatinib therapy. Results: The median age was 55 years (range 23–76); the median follow-up after start of 2nd TKI was 18.9 months (mo) (range 5.3–39.3), and median CML duration 67.9 mo (0.4–206.6). Thirty-five pts had CE alone and 26 had CE with other AP features. At the time of this report 59 patients are evaluable for response: 30 treated with dasatinib and 29 with nilotinib. The accompanying table summarizes the findings. Conclusion: CE constitutes a heterogeneous entity with variable outcome with 2nd TKI. Regardless of the percentage of metaphases with CE, those with trisomy 8 or with abnormalities in chromosome 17 may have the worse outcome. In all cases, the presence of other features of AP further worsens the outcome. The molecular events behind this worse outcome and potential therapeutic approaches directed at them need to be defined. Characteristics (n=59) CCyR n/no. evaluable(%) p EFS % (12mo) p OS % (12mo p CCyR: Complete Cytogenetic Response, EFS: Event Free Survival, OS: Overall Survival, Chr: Chromosome, Ph+: Philadelphia chromosome positive, n: number of patients % Cellls with CE <16 3/12(25) 62 77 16-35 4/10(40) 60 68 36-99 9/15(60) 73 80 100 7/22(32) 0.24 60 0.96 78 0.85 Other AP features No 18/34(53) 80 89 Yes 5/25(20) 0.02 40 <0.001 60 0.005 Double Ph+ No 9/28(32) 55 69 Yes 14/31(45) 0.42 71 0.93 84 0.72 Trisomy 8 No 21/49(43) 72 84 Yes 2/10(20) 0.29 20 <0.001 40 <0.001 Chr 17 Abnormalities No 19/45(42) 74 83 Yes 4/14(29) 0.53 29 0.003 56 0.02 Other Translocations No 20/42(48) 61 75 Yes 3/17(18) 0.04 69 0.71 82 0.81 Other abnormalities No 15/37(41) 62 81 Yes 8/22(36) 0.79 65 0.45 70 0.93

scholarly journals Directly Exploring the Neural Correlates of Feedback-Related Reward Saliency and Valence During Real-Time fMRI-Based Neurofeedback

2021 ◽  
Vol 14 ◽  
Author(s):  
Bruno Direito ◽  
Manuel Ramos ◽  
João Pereira ◽  
Alexandre Sayal ◽  
Teresa Sousa ◽  
...  
Keyword(s):  
Real Time ◽  
Visual Motion ◽  
Task Complexity ◽  
Small Sample Size ◽  
Brain Activity ◽  
Small Sample ◽  
Neurofeedback Training ◽  
Feedback Processing ◽  
Positive Valence ◽  
Feedback Valence

Introduction: The potential therapeutic efficacy of real-time fMRI Neurofeedback has received increasing attention in a variety of psychological and neurological disorders and as a tool to probe cognition. Despite its growing popularity, the success rate varies significantly, and the underlying neural mechanisms are still a matter of debate. The question whether an individually tailored framework positively influences neurofeedback success remains largely unexplored.Methods: To address this question, participants were trained to modulate the activity of a target brain region, the visual motion area hMT+/V5, based on the performance of three imagery tasks with increasing complexity: imagery of a static dot, imagery of a moving dot with two and with four opposite directions. Participants received auditory feedback in the form of vocalizations with either negative, neutral or positive valence. The modulation thresholds were defined for each participant according to the maximum BOLD signal change of their target region during the localizer run.Results: We found that 4 out of 10 participants were able to modulate brain activity in this region-of-interest during neurofeedback training. This rate of success (40%) is consistent with the neurofeedback literature. Whole-brain analysis revealed the recruitment of specific cortical regions involved in cognitive control, reward monitoring, and feedback processing during neurofeedback training. Individually tailored feedback thresholds did not correlate with the success level. We found region-dependent neuromodulation profiles associated with task complexity and feedback valence.Discussion: Findings support the strategic role of task complexity and feedback valence on the modulation of the network nodes involved in monitoring and feedback control, key variables in neurofeedback frameworks optimization. Considering the elaborate design, the small sample size here tested (N = 10) impairs external validity in comparison to our previous studies. Future work will address this limitation. Ultimately, our results contribute to the discussion of individually tailored solutions, and justify further investigation concerning volitional control over brain activity.

Chromosomal Abnormalities in Philadelphia Chromosome (Ph)-Negative Metaphases Appearing during Imatinib Mesylate (IM) Therapy in Patients (pts) with Newly Diagnosed Chronic Myeloid Leukemia (CML) in Chronic Phase.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1090-1090 ◽  
Author(s):  
Elias Jabbour ◽  
Hagop Kantarjian ◽  
Susan O’Brien ◽  
Srdan Verstovsek ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Chromosomal Abnormalities ◽  
Philadelphia Chromosome ◽  
Chromosome 7 ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Trisomy 8 ◽  
Chromosome Y ◽  
Cytogenetic Abnormalities

Abstract The development of chromosomal abnormalities in the Ph-negative metaphases during IM therapy of CML has been recognized mostly in pts who failed prior therapy. Prior exposure to cytarabine has been suggested to be a predisposing factor. This phenomenon has not been yet assessed to date in patients with newly diagnosed CML and treated with IM. This is different from clonal evolution where the abnormalities are observed in the Ph-positive metaphases. We assessed the frequency and the significance of this event among 258 newly diagnosed pts with CML receiving IM (800 mg/d n=207, 400 mg/d n=51) as first line of therapy between March 2001 and April 2005. After a median follow-up of 30 months (range, 6–48 months), 19 pts (7%) developed 21 chromosomal abnormalities in Ph-negative metaphases. Thirteen (62%) of these abnormalities have been seen in 2 or more metaphases. The median time from the start of IM to appearance of abnormalities was 18 months (range, 3–36 months). The most common cytogenetic abnormalities were: loss of chromosome Y (n=7, 33%), trisomy 8 (n=3, 14%), and deletion of chromosome 7 (n=2, 10%). Excluding loss of chromosome Y abnormalities, the incidence was 5%. All pts achieved a major (Ph &lt; 35%) cytogenetic (CG) response (complete cytogenetic response [CCGR] in 17 [89%] pts). Major molecular response (BCR-ABL/ABL ratio &lt;0.05) was observed in 13 (68%) pts (including 2 with complete molecular response). In all but 4 pts these events have been transient and disappeared after a median of 4 months (range, 3–9 months). In 4 pts (loss of chromosome Y n=3, trisomy 8 n=1), they persisted for a median of 13+ months (range, 6+–24+ months). One pt developed acute myeloid leukemia (associated with -7); none of the other pts has any feature of myelodysplasia. After a median follow-up of 13 months (range, 1–42 months), 17 of the 19 pts are alive. One pt died after allogeneic stem cell transplantation, and one died after 6 months of CCGR from myocardial infarction. One pt lost response to IM. The remaining 16 pts are in major CG response at the last follow-up. We conclude that: 1) cytogenetic abnormalities occur in Ph-negative cells in a small fraction of patients (7%; 5% if loss of Y excluded) in newly diagnosed CML on IM; 2) in the majority of cases, they are transient with no clear clinical consequences; 3) in rare instances (loss of chromosome 7 only in our study) they could reflect the emergence of a new malignant clone necessitating and a close follow-up.

Loss of the Y Chromosome in Philadelphia-Positive Cells Predicts a Poor Response of CML Patients to Imatinib Mesylate Therapy.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2117-2117 ◽  
Author(s):  
Eric Lippert ◽  
Sophy Laibe ◽  
Marie-Joelle Mozziconacci ◽  
Carine Gervais ◽  
Stéphane Girault ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Imatinib Mesylate ◽  
Y Chromosome ◽  
Kinase Inhibitor ◽  
Clonal Evolution ◽  
Statistical Significance ◽  
Philadelphia Chromosome ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Diagnostic Characteristics

Abstract Loss of the Y chromosome (-Y) in bone marrow cells frequently occurs in elderly patients. It is thus unclear whether loss of the Y chromosome, when found in Philadelphiapositive cells, should be overlooked, or whether it represents a clonal evolution (a criterion of cytogenetic acceleration of the disease) or an additional cytogenetic abnormality (ACA), considered of little importance in patients treated with imatinib mesylate (IM). We have collected diagnostic characteristics, clinical, cytogenetic and molecular evolution data from 29 patients diagnosed with CML from 1991 to April 2007 in 6 participating centres, who presented a loss of the Y chromosome at diagnosis (n=20) or during evolution (n=9) and who were treated with imatinib in first (n=19) or second (n=10) line. They were compared to patients with a Philadelphia chromosome as sole anomaly, diagnosed at similar dates in the same centres, thus benefitting from the same management. Age and Sokal score at diagnosis were similar. In both -Y and control groups, two thirds of patients had received prior treatment (mostly interferon, hydroxyurea and aracytine). Median follow-ups were respectively 54 months (range: 7–146) and 58 months (range: 13–149), censored if therapy was changed for a second generation tyrosine-kinase inhibitor or bone marrow transplantation. The time to achieve complete cytogenetic remission (CCR) (22 months vs 7, p=0.02) and major molecular response (MMR) (not reached vs 30 months, p=0.0015) were significantly higher in -Y patients. Acceleration (8/29 vs 1/29, p=0.003), acutisation (4/29 vs 1/29, p=0.1) and death (3/29 vs 1/29) were more frequent in the -Y group, but owing to the rare occurrence of these events, statistical significance was clear for acceleration only. Interestingly, prognosis (time to CCR, MMR and occurrence of acceleration) was worse if loss of the Y chromosome was present in a subclone (suggesting a clonal evolution) rather than all mitoses (ACA) and also when it was observed at diagnosis rather than during the evolution of the disease. Consequently, survival was significantly reduced (55 months vs not reached, p=0.009) in those patients for whom -Y was present in a subclone at diagnosis. In conclusion, loss of the Y chromosome in Philadelphia-positive cells is an important finding since it affects the prognosis of CML patients, especially, but not exclusively, when present at diagnosis in a subclone. In this case, loss of the Y chromosome even predicts a decreased survival after imatinib treatment.

Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia Showing Complete Molecular Response Following Imatinib (Glivec®) - combined chemotherapy

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3971-3971
Author(s):  
Inas Ahmed Asfour ◽  
Shereen Ahmed El Shazly
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Molecular Level ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Treatment Strategies ◽  
Normal Karyotype ◽  
Molecular Response ◽  
Molecular Remission ◽  
Complete Molecular Response

Abstract The Philadelphia (Ph) chromosome is the result of a reciprocal translocation between chromosomes 9 and 22 [t (9; 22)] and is characterized at the molecular level by expression of the BCR-ABL fusion gene. It is the most frequent genetic aberration in adult acute lymphoblastic leukemia (ALL), being detectable in 30–40%of patients with B-precursor ALL. In our initial work we report two cases of grossly negative (Ph) ALL, that showed a complete molecular response after an imatinib based chemotherapy. In the first case we report a 17-year-old male who was admitted because of bony aches and fever. A diagnosis of acute lymphoblastic leukemia was made on the basis of a 95% infiltration of leukemic cells in his bone marrow. Standard G-banding chromosome analysis of bone marrow cells revealed a normal karyotype. And subsequent fluorescent in situ hybridization (FISH) examination showed a 20% positivity for the Philadelphia chromosome. As for the second case we report a 19 years old male patient who was presented with complaints of recurrent epistaxis and bony aches. He was also found to have acute lymphoblastic leukemia due to bone marrow infiltration with 55% blasts that showed a normal karyotype using the G- banding, and a positive Philadelphia chromosome-using FISH method - in 31 % of the examined cells. Both patients received combination chemotherapy incorporating imatinib mesylate; Glivec® in a dose of 400 mg/day continuously all through the induction, consolidation and subsequent re-enforcement courses. They both achieved complete hematological, cytogenetic as well as molecular remission that was maintained-thus far- for a total period of 20 and 11 months respectively. We postulated that there might have been two clones, both a Ph-positive clone and Ph-negative clone, with subsequent sensitivity of this Ph positive clone to the incorporated targeted treatment, as was evidenced by disappearance of the Ph-positive cells in subsequent FISH analysis and the negativity of the real time quantitative polymerase chain reaction (RT-QPCR) for BCR/ABL gene. Several investigators have studied the role of Hematopoeitic stem cell transplantation (HSCT) in the context of Ph+ ALL patients, which showed superior results when compared to conventional chemotherapy in means of remission induction as well as relapse rates, Dombret et al.2002. The highly successful introduction of the first ABL-kinase inhibitor imatinib into the treatment of Philadelphia chromosome positive chronic myeloid leukemia (CML) has led to clinical testing of imatinib in Ph+ALL. It has recently been approved for Ph+ALL in Europe and Japan. Given the much more aggressive nature of Ph+ALL when compared with chronic or even accelerated phase CML, a variety of imatinib-based treatment strategies have been explored in ALL(Ottman et al.,2007). Yet thus far the exploration of these treatment modalities in the very rare entity of gross normal karyotype and molecular level cytogenetic aberrations remains to be elucidated. Conclusion: Molecular remission on tyrosine kinase inhibitors in patient with ALL Ph +ve may open the door to revising the treatment strategies offered thus far for that subset of patients, as a new stratifying factor. Our work offers a unique protocol for utilizing imatinib as an integral part of the chemotherapy protocols normally offered for these patients, but yet at a lower dose, and raises the question of whether they should be transplanted in accordance with the current guidelines and if so when? More patients experience and controlled randomized trials are needed and eagerly awaited.

Second Report of Arab Leukemia Net (ALN) Registry for Chronic Myeloid Leukemia (CML) in the Middle East &North Africa Region (AFME). Epidemiology of CML and Additional Chromosomal Abnormalities (ACAs) in Egypt, Multicenter Results

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5539-5539 ◽  
Author(s):  
Mohamed osman Azzazi ◽  
Omar Fahmy ◽  
Mervat Mattar ◽  
Ashraf El Ghandour ◽  
Manal El Sorady ◽  
...  
Keyword(s):  
Disease Incidence ◽  
Clonal Evolution ◽  
Response Rates ◽  
Reliable Data ◽  
Arab Countries ◽  
Low Risk ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Gene Promoters ◽  
Trisomy 8

Abstract Little is known about burden of CML in Arab countries. The first ALN report demonstrated that age-specific rates for CML in Egypt and Arab nations are lower by at least two decades compared to western populations (Azzazi and Mattar ELN newsletter 2013). Lack of reliable data concerning geographic and ethnic variations and response rates to therapy contribute to the variability of incidences among CML registries. Studies underestimate the true age of CML patients as access to medical services show great diversity in AFME region. ACAs were reported in 5% of CML patients, considered at diagnosis by ELN as a “warning” requiring careful patient monitoring.(Baccarani et al Blood 2013), ACAs emerging during treatment are considered by WHO classification as accelerated phase (AP). There occurrence indicates that the leukemia has become BCR-ABL1 independent by secondary genetic acquisitions. Some ACAs are poor prognostic factors such as the acquisition of additional Ph‏ chromosome (ch) that increases the kinase activity of BCR-ABL1; the isochromosome 17q i(17q) which leads to inactivation of the tumor suppressor gene p53 and impedes the response to Imatinib; the extra 8 which lead to c-Myc over expression that enhances the transformation of leukemic cells and the extra 19 which hinder Imatinib activity via silencing gene promoters. Objectives 1) To Release 5 year follow-up data of second ALN report of CML epidemiology in Egypt. 2) To investigate the low age of CML in Egypt. 3) To evaluate ACAs role in disease and clonal evolution. 4) To build a reliable data base -the ALN- as information / support services. Method We analyzed data of 578 (302 male and 276 female) CML patients (followed-up for 5 years). Data collected according to ELN (Baccarani et al Blood 2013) GIMEMA and EUTOS recommendations via a multicenter web based data registry portal, the ALN. (www.aln-afme.com). To insure lack of bias an independent server for data storage and processing was established in Masaryk University, Institute of Biostatistics and Analyses, in Prague, Czech Republic, other logistics are managed by DMC Healthcare Inc. HQ in Toronto, Canada. Chromosome banding analysis and FISH were performed, for Y-ch, trisomy 8, duplication of Ph, i(17q), trisomy 19, and Deletion of der(9) ch (Luatti et al Blood 2012). Results Patients Median age was 43y, (40y for males, 41y for females), The age specific rates were highest for the age group of 30-35 years. Female patients presented with lower hemoglobin, higher platelet counts and smaller spleen size (P<0.0001). 98% of patients achieved CH respone, 89% PCYR, 87% CCYR, and 83% MMR. At diagnosis 87% patients were in chronic phase (CP) CML, 8.1% in accelerated, and 4.9% in blastic phase. Sokal score: Low risk 57.8% Intermediate 24.5% and High in 17.7%. EURO (Hasford) score (59% Low risk, 28.4%Intermediate risk and 12.6%High risk). 42% of patients received imatinib, 34% nilotinib 20% dasatinib and 4% needed therapies plus TKI). Transplantation rate was 19%, PFS and OS were equal in female and male patients. ACAs were found in 62 (11%) patients, they had lower cytogenetic and molecular response rates and longer response time to TKI and inferior outcome. ACAs were more frequent in younger, imatinib resistant patients, and in blast phase. We identified loss of Y ch in 18 patients (29%), trisomy 8 in 7 (11%), trisomy 19 in12 (19%), i(17q) in 12 (19%), other different single abnormalities in 8 patients (13%), complex karyotype with double ACAs in only 5 patient (8%). Four patient showed variant Ph ch: t(9;22;22)(q34;q11;q11). Deletion of der(9) ch in 17 cases (27%): (10 cases with loss of Y ch, 4 case with del(20)(q11q13), and 3 case with t(X;13) (q13;q32)). The cytogenetic and molecular response rates were uniformly lower in patients with ACAs, overall CCgR and MMR rates were significantly lower in patients with ACAs (68% vs 89% and 55% vs 86% respectively), responses were significantly slower in patients with ACAs, 54 patients presented with ACAs at diagnosis while 8 patients developed ACAs while on treatment. Conclusions: The importance of ethnicity and gender differences in relation to disease incidence, and prognosis are major health policy focus. To investigate the low mean age of CML in Egypt and evaluate role of ACAs on disease and clonal evolution, Data from 10 Centers in Egypt showed a much lower mean age of CML and more frequent (11%) ACAs, they adversely affected time and response rates to Imatinib treatment. Disclosures No relevant conflicts of interest to declare.

Uncommon Mutations in PML-RARα Associated with Poor Outcome after First Relapse in APL.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4248-4248
Author(s):  
Esther Schachter-Tokarz ◽  
Bruno Cassinat ◽  
Charikleia Kelaidi ◽  
Christine Chomienne ◽  
Claude Gardin ◽  
...  
Keyword(s):  
Small Sample Size ◽  
Extra Chromosome ◽  
Dose Schedule ◽  
Small Sample ◽  
Phase Iii ◽  
Patient Treatment ◽  
Trisomy 8 ◽  
Poor Outcome ◽  
Resistant Disease ◽  
First Relapse

Abstract Background. Mutations in the RARα-region ligand binding domain (LBD) of PML-RARα were detected in 30 – 40% of patients (pts) tested after first relapse from ATRA-chemotherapy (CT) regimens in 2 North American Phase III trials. However, no follow-up data were reported to assess whether this affected subsequent outcome. Methods. In the current study, 8 relapse pts were tested by previously-published techniques for PML-RARα LBD mutations after relapse from ATRA-CT regimens of the EAG. Treatment was according to the APL2000 protocol: randomization to induction with ATRA+DNR with AraC (arm-A) or no AraC (arm-B) followed by 2 consolidation courses with DNR with (A) or without (B) AraC and then 2 years maintenance with ATRA for 15 days every 3 months, as well as, 6MP and MTX (Ades, et al, J Clin Oncology24, 5703, 2006); 1 off-protocol (OP) pt was treated according to APL-93, which is similar to APL2000-A (Fenaux, et al, Blood94, 1192, 1999). Results. Patient Treatment Days to Relapse Days ATRA Maintenance Days Off ATRA PML-RARα LBD Mutation Status Post-Relapse 1-Au APL2000-B 1037 120 173 No CR2 2-An OP like-A 1072 120 210 No CR2 3-Ho APL2000-A 1194 105 529 No CR2 4_Ge APL2000-B 557 90 0 del/ins & R276W Rel1→Dead 5-Lu OP like-93 1249 0 ~1200 No Dead in CR2 6-Ro OP like-A + VP16 992 0 ~950 No CR2 7-Ka APL2000-B 530 45 0 ΔK227→S229/ M227 Rel3→Dead 8-Ma APL2000-B + AraC 406 45 0 R272W & N298S Rel2→CR3 Mutations were observed in the reported incidence range: 3/8 pts (37.5%). However, the findings were unusual, since 2/3 mutations were deletion mutations, while only 2/30 reported mutations were deletions, and since 2/3 pts harbored 2 mutant subclones, while only 1/30 such cases has been reported. Also, the nature of the mutations was unusual. In pt 7, the ΔK227∅S229/M227 mutation was atypically located in the amino-region of the LBD. In pt 4, a very atypical deletion/insertion (del/ins) mutation began in the hinge RARα-region at S157, extending 630 nt to R367, and was associated with a 547 nt insertion from the beginning of intron 4 that changed the translational reading frame, encoding a truncated protein lacking the entire LBD. Most notably, the 3 pts harboring these uncommon mutations either failed to achieve a second complete remission (CR) or suffered subsequent relapses, leading to death in 2 pts from resistant disease (pts 4 & 7), while 0/5 non-mutant pts relapsed (pt 5, death in CR2 was treatment-related). Discussion. With such a small sample size, it is not possible to determine whether the uncommon mutations occurred by chance or related to some unrecognized element in the EAG pts. No readily apparent basis could be identified: the modest treatment dose-schedule differences from other Phase III studies using common therapeutic agents seems an improbable cause; one each of the mutant/non-mutant pts had an extra chromosome (trisomy 8); 2 of the non-mutant cases had treatment-related APL. Although further study is needed to determine whether the poor outcome in 3 pts was related to the uncommon nature of their mutations, these results suggest that testing for PML-RARα mutations at first relapse may be of prognostic and potential therapeutic value.

Imatinib Plasma Levels Correlate with Molecular Response in CML Patients

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4268-4268
Author(s):  
Sarka Rozmanova ◽  
David Friedecky ◽  
Adriana Polynkova ◽  
Edgar Faber ◽  
Peter Rohon ◽  
...  
Keyword(s):  
Real Time ◽  
Quantitative Pcr ◽  
Plasma Levels ◽  
Response To Therapy ◽  
Time Interval ◽  
Molecular Response ◽  
Electrophoretic Method ◽  
Real Time Quantitative Pcr ◽  
Co Morbidity ◽  
One Year

Abstract Measurement of imatinib plasma levels is recommended for CML patients on Glivec therapy with suboptimal response or failure. Recently, reports suggesting that imatinib plasma levels correlate both with cytogenetic and molecular response of the patient and may be used for routine management of the treatment were published. We have introduced the examination of imatinib plasma levels into our laboratory follow-up of CML patients in 2007. All patients have signed informed consent before sampling. New capillary electrophoretic method was developed for determination of imatinib plasma levels. Plasma samples were deproteinated by methanol, evaporated, resuspended and directly analyzed. Separation was performed in buffer consisting of 50 mmol/L citrate adjusted with γ-amino-n-butyric acid to pH 4.0. Imatinib was quantified by UV detection in the range 250 – 270 nm (limit of detection is 10 nmol/L). BCR-ABL transcript levels were monitored by TaqMan-based real-time quantitative PCR, the baseline value of BCR-ABL/ABL% was 60%. Here we report comparison of plasma drug levels in CML patients with optimal and suboptimal molecular response. Total 238 samples from 100 CML patients were examined. Patients with major and complete molecular response (n = 68) and patients with suboptimal molecular response (n = 35) were chosen for the final comparison. The actual sample was eligible for analysis providing patient had been treated with standard dose 400 mg daily for at least one year, there was no other evident cause of the suboptimal response (presence of additional cytogenetic abnormalities or BCR/ABL mutation) and the sample was taken 24±6 hours after the ingestion of the drug. Other medication, the actual duration of the therapy (providing it was longer than one year), time interval between the dose and the meal ingestion, weight, body-mass index, body surface area and co-morbidity of patients were not taken into the account. All patients in the suboptimal group have achieved the complete cytogenetic response. Three patients in the suboptimal group have progressed, while there were any such patients in the optimal group. The results showed considerable inter-individual variability between the patients. However, the imatinib plasma levels found in the optimal group significantly higher (median of 2.34 umol/l; range of 0.46 – 6.23) than in the suboptimal group (median of 1.75 umol/l; range of 0.84 – 4.63) p &lt; 0.003. Moreover, patients with negativity in real-time quantitative PCR testing showed a trend for even higher drug plasma levels (median of 3.18 umol/l; range of 0.46 – 6.23, n = 36) p &lt; 0.001. We can conclude that higher imatinib plasma levels are associated with better molecular response to therapy and laboratory measurements may be used for modification of the imatinib dosage.

Sign in / Sign up

Export Citation Format

Share Document