Incidence and outcomes of chronic myeloid leukemia (CML) patients (pts) treated with second-generation tyrosine kinase inhibitors (TKI) who develop other chromosomal abnormalities (OCA).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7090-7090
Author(s):  
Naveen Pemmaraju ◽  
Hagop M. Kantarjian ◽  
Elias Jabbour ◽  
Alfonso Quintas-Cardama ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Chromosomal Abnormalities ◽  
Philadelphia Chromosome ◽  
Initial Therapy ◽  
Adverse Impact ◽  
Trisomy 8 ◽  
Hematologic Disorders ◽  
2Nd Generation

7090 Background: Development of OCA has been reported among pts receiving imatinib as initial therapy for CML. Little is known about OCA development in CML pts treated with frontline 2nd generation TKI (dasatinib, nilotinib). Methods: OCA is defined as cytogenetic abnormality in non-Philadelphia chromosome positive clones as pts respond to TKI. Among pts treated with frontline dasatinib (n=99) or nilotinib (n=117), on parallel prospective single-arm phase II protocols at MDACC, 30 OCA ptswere identified, chronic (n=25) or accelerated phase (AP) (n=5). Results: 11 (11%) pts treated with dasatinib and 19 (16%) with nilotinib developed OCA; median follow-up 30 mo (range 0-71). Difference in OCA incidence with dasatinib and nilotinib was not statistically significant. At start of therapy, median age (years) of OCA pts was 53 (41-71) with dasatinib and 52 (37-82) with nilotinib, compared to those pts without OCA: 48 (18-83) with dasatinib and 49 (17-87) with nilotinib. Most common OCA was abnormality of chromosome 7 with 6 occurrences in 5 pts (1 pt with both inv(7) and +7) (inversion (n=1), 2 different translocations (n=2), deletions (n=2), and additions (n=1)). No pts developed trisomy 8 (historically most common OCA in imatinib-treated pts). Median time to first OCA: 9 mo (range 3-58) for all pts (12 mo (range 3-58) for dasatinib group and 9 mo (3-48) for nilotinib group). OCA disappeared spontaneously in 25 pts during follow-up. Outcomes for OCA versus non-OCA group (Table). For AP pts: 3/6 (50%) in dasatinib group and 2/17 (12%) in nilotinib group developed OCA. None of the OCA pts has developed AML or MDS. Conclusions: OCA is observed in 10-15% of pts receiving initial therapy with 2nd generation TKI. At median follow-up of 30 mo, occurrence of OCA confers no adverse impact on outcomes when compared to non-OCA pts treated with 2nd generation TKI and has not resulted in other hematologic disorders. [Table: see text]

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

Patients with Chronic Myeloid Leukemia with Variant Philadelphia Chromosome (Ph) Translocations Have a Similar Outcome as Those with Classic Ph When Treated with Imatinib or 2nd Generation TKI

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3228-3228 ◽  
Author(s):  
Nicolas Batty ◽  
Hagop Kantarjian ◽  
Gautam Borthakur ◽  
Farhad Ravandi ◽  
Susan O’Brien ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Initial Therapy ◽  
P Value ◽  
Limited Information ◽  
2Nd Generation ◽  
Chromosome Variant

Abstract Background: Variant Philadelphia chromosome (Ph) translocations frequently involving 1-2 additional chromosomes besides 9 and 22 and represent 5–10% of patients (pts) with chronic myeloid leukemia (CML). The European LeukemiaNet recommendations provide a warning for patients with variant translocations, although there is limited information about their outcome after therapy with tyrosine kinase inhibitors (TKI). Our prior analysis mostly among pts who had failed prior interferon suggested that these pts had similar outcome to those with classic Ph translocations when treated with imatinib (El-Zimaity et al; Br. J Haematol 2004). Aims: To explore the characteristics and outcome of patients with variant translocations treated with frontline imatinib or 2nd generation TKI (dasatinib or nilotinib) after imatinib failure. Methods: We reviewed the outcome of all pts with CML treated at our institution in 3 groups: early chronic phase (CP) receiving imatinib as initial therapy, and CP treated with 2nd generation TKI after Imatinib failure, accelerated phase (AP) treated with 2nd TKI after imatinib failure. Results of pts with variant Ph were compared to those with classic Ph. Results: Among 554 pts (278 CP frontline imatinib, 190 CP post imatinib failure, 86 AP post Imatinib failure) 33 (6%) had variant Ph (21[8%], 6[3%], 6[7%], in each of the 3 groups, respectively). Median follow up is 55 months (mo) (2 – 90), 24 (1 – 53) mo and 29 (5 – 46) mo, respectively, for the 3 groups. Results are summarized in the following tables: Frontline Imatinib Therapy Percentage Variant Ph Classic Ph P value N=21 N=255 MCyR 95 95 1 CCyR 86 89 0.49 2-yr EFS 83 93 0.93 2-yr TFS 94 96 0.7 2-yr OS 100 99 0.48 Second generation TKI Variant Ph Chromosome Variant Ph Classic Ph P value Chronic Phase N = 6 N = 78 MCyR 100 75 0.34 CCyR 100 72 0.34 2-yr EFS 100 80 0.27 2-yr OS 100 98 0.71 Accelerated Phase N=6 N=80 MCyR 33 38 1 CCyR 33 32 1 2-yr EFS 25 41 0.41 2-yr OS 100 89 0.44 Conclusion: Pts with variant Ph have a similar prognosis to those with classic Ph translocations when treated with imatinib as initial therapy or with 2nd generation TKI after imatinib failure. The warning category for these patients may no longer be needed in the era of TKI.

Incidence and Outcomes of Chronic Myeloid Leukemia (CML) Patients (pts) with Other Chromosomal Abnormalities (OCA) Treated with Second Generation Tyrosine Kinase Inhibitors (TKI)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4311-4311
Author(s):  
Naveen Pemmaraju ◽  
Hagop M. Kantarjian ◽  
Elias J. Jabbour ◽  
Alfonso Quintás-Cardama ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Research Funding ◽  
Chromosomal Abnormalities ◽  
Clonal Evolution ◽  
Philadelphia Chromosome ◽  
Group Versus ◽  
Chronic Phase ◽  
Initial Therapy ◽  
Chromosome 7 ◽  
2Nd Generation

Abstract Abstract 4311 Background: Development of OCA (i.e., chromosomal abnormalities in the Philadelphia chromosome negative metaphases) has been reported among patients receiving imatinib as initial therapy for CML. Little is known about incidence and outcomes of OCA in CML pts treated with frontline 2nd generation TKI (dasatinib, nilotinib). Objectives: We describe incidence of OCAs in CML pts treated with frontline 2nd generation TKI and determine the outcomes of pts who develop OCA events. Methods: We reviewed pts treated with frontline 2nd generation TKI, dasatinib (n=99) or nilotinib (n=117), treated on 2 parallel ongoing prospective single-arm Phase II protocols at our institution. An OCA was defined as a cytogenetic abnormality in one or more non-Philadelphia chromosome positive clones (different than clonal evolution). Pts were followed with cytogenetic analysis at 3 month (mo) intervals for the first year, then every 6–12 mo. 30 pts with OCA were identified. Pts in chronic (n=25) or accelerated phase (n=5) at diagnosis were included in the analysis. Results: With a median follow-up of 30 mo (range 0–71), 11 (11%) pts treated with dasatinib and 19 (16%) pts treated with nilotinib developed OCA. The difference in incidence of OCA with dasatinib and nilotinib was not statistically significant (p=0.280). At start of therapy, median age of pts developing OCA was 53 (41–71) with dasatinib and 52 (37–82) with nilotinib, compared to those pts without OCA: 48 (18–83 yrs) with dasatinib and 49 (17–87) with nilotinib. The most common OCA event overall was abnormality of chromosome 7 found in 5 pts (one pt with both inv(7) and +7) for total of 6 occurrences (including inversion (n=1), 2 different translocations (n=2), deletions (n=2), and additions (n=1) involving chromosome 7). The most common translocation event was t(6;13) in 2 pts. No pts developed trisomy 8 (historically most common OCA among imatinib treated pts). Median time to first appearance of OCA was 9 mo (range 3–58) for all 2nd generation TKI pts (12 mo (range 3–58) for dasatinib group and 9 mo (3–48) for nilotinib group). 9 pts had OCA on more than one occasion. OCA disappeared in 25 pts during course of follow-up. Outcomes for OCA group versus non-OCA group are shown in Table 1, and outcomes with focus on chronic phase pts only in Table 2. For pts in accelerated phase, 3/6 pts (50%) in dasatinib group and 2/17 pts (12%) in nilotinib group developed an OCA. None of the pts who developed OCA has developed AML or MDS. Conclusions: OCA are observed in 10–15% of pts receiving initial therapy with 2nd generation TKI. At median follow up of 30 mo, occurrence of OCA confers no statistically significant adverse impact on outcomes when compared to non-OCA pts treated with 2nd generation TKI and has not resulted in other hematologic disorders. Disclosures: Off Label Use: Dasatinib and Nilotinib originally used in investigational setting when trials were begun. Kantarjian:Novartis Pharmaceuticals Corp: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Research Funding. Jabbour:BMS: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Cortes:Novartis, BMS, ARIAD, Pfizer: Consultancy, Research Funding.

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.

Clinical Significance of Additional Chromosomal Abnormalities In Ph-Positive and Ph-Negative Cells In Patients with Chronic Myeloid Leukemia Treated by Tyrosine Kinase Inhibitors

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1683-1683
Author(s):  
Anna G. Turkina ◽  
Olga Vinogradova ◽  
Alexandra Vorontsova ◽  
Ekaterina Chelysheva ◽  
Olga Lazareva ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Research Funding ◽  
Kinase Inhibitors ◽  
Chromosomal Abnormalities ◽  
Cytogenetic Response ◽  
2Nd Generation ◽  
Risk Of Progression ◽  
Variant Chromosome ◽  
Additional Chromosomal Abnormalities

Abstract Abstract 1683 Introduction. Additional chromosomal abnormalities (ACA) in Ph'-positive (Ph'+) cells firstly described more than 30 years ago were associated with progression of chronic myeloid leukemia (CML) and often were founded in advanced stages of the disease. Prognostic significance of ACA in Ph'+ cells in the era of tyrosine kinase inhibitors (TKI) are not yet fully clarified. The ACA in Ph'-negative (Ph'-) cells seem to have no adverse prognostic impact, but it is not possible to exclude the development of myelodisplasia within the long lasting persistence of such clones. Long-term cytogenetic monitoring can better understand the biological aspects of CML. Aim. To estimate the clinical significance of ACA in Ph'+ and Ph'- cells in CML patients (pts) treated by TKI 1st and 2nd generation (TKI-1 or 2). Materials and methods. The complete peripheral blood count, morphological and cytogenetic examination of bone marrow (BM) cells have been done for 435 CML pts in different disease stages: chronic phase (CP)/accelerated phase (AP)/blast crisis (BC) pts were 336/78/21 respectively. The median (Me) age was 50 years (y) (16–61), Me follow-up- 97 months (mo) (5−265). Results and discussion. The ACA in Ph'+ cells were revealed by conventional cytogenetic study generally in 50 (11,5%) of 435 CML pts. ACA in Ph'+ cells were a rare event for CP and AP: 9% and 14% of pts respectively and more frequent for BC: 43% of pts. The most frequent ACA was the additional Ph'-chromosome (addPh'+) found in 50% of cases. 17pts had addPh'+ alone, while 13pts had also other ACA: trisomy 8 (8 cases), deletion or monosomy 7 (3 cases) and complex abnormalities (2 cases in CP & AP); dominated by male (M: F=23: 7). The duration of IM treatment in 16pts with addPh'+ was from 6mo to 5,5y. The follow-up duration of pts with addPh'+ was from 26 to 176 mo (Me 107 mo). All 16 pts have achieved complete hematological response (CHR) after 3 to 6mo of Imatinib (IM) treatment, but all pts with standard IM doses had primary cytogenetic resistance. Complete cytogenetic response (CCyR) was achieved in 56%pts without ACA, in 24% with ACA, and only in 7% with addPh'+. Due to IM resistance, 14 pts were switched to TKI-2 (Dasatinib – 10pts, Nilotinib – 3pts, Bosutinib – 1pt); 3 of these pts later progressed to AP; for 2 of them T315I mutation was found. All of the 11 pts still in CP have achieved CHR; partial cytogenetic response was founded in 45% and CCyR in 36% cases. At present, 43% pts with ACA died: 11% in CP, 82% in AP and all in BC. The 8-year overall survival (OS) for CML CP pts with ACA was 83%, no statistically significant (p>0,5) difference with the general CML CP pts group, treated by TKI. The assessment by multifactorial Cox model with variable risk factors revealed the increased probability of fatal outcome in CML CP more than 16 times higher in pts with ACA vs. patients without ACA. The variant chromosome abnormalities were rare: 13pts (3 %), but in 77% of them there was cytogenetic resistance pts and high risk of progression. ACA in Ph'- cells were founded in 13 (3%) pts only after the achievement of major cytogenetic response. 10 of them received IM 600–800mg daily; 3pts received 2nd generation of TKI. All those patients got the MCR only after 18–36 mo of treatment and 11 (85%) of 13pts achieved the CCyR. Ph'- clone was constantly founded only in 1 patient, in all other cases it was not constant but persisted from one analyses to other. No myelodisplastic changes were founded in the BM of 5 examined pts after IM treatment within 3–7y. All pts with ACA in Ph'- cells are alive. Conclusion. The durable persistence of Ph'+ cells in CML CP pts is a marker of therapy resistance but not all cases are associated with disease progression. The addPh'+ during IM treatment was associated with cytogenetic resistance. The dose escalation of IM was ineffective in the majority of cases, only TKI-2 therapy could restore Ph'- neg. hematopoiesis and suppressed addPh'+ clone more effectively. This finding should be tested in large-scale studies. The male predominance in pts with addPh'+ also needs further investigation. In contrast to other reported data, we founded that the prognosis for 77% of pts with the variant chromosome abnormalities was poor and associated with cytogenetic resistance and high risk of progression on TKI-1 and 2 therapy. In most pts with ACA in Ph'- cells a dose escalation of IM and switching to TKI-2 was needed but generally the disease prognosis was favorable. Disclosures: Turkina: Novartis: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau. Vinogradova:Novartis: Research Funding, Speakers Bureau; Bristol: Speakers Bureau. Chelysheva:Novartis: CML registry, Research Funding, Speakers Bureau; Bristol: Speakers Bureau. Lazareva:Novartis: CML registry, Research Funding, Speakers Bureau. Gusarova:Novartis: Honoraria, Speakers Bureau. Khoroshko:Novartis: Speakers Bureau; Bristol: Speakers Bureau.

scholarly journals Chromosomal Aberrations in Chronic Myeloid Leukemia: Response to Conventional TKIs and Risk of Blastic Transformation

2021 ◽  
Vol 6 (1) ◽  
pp. 35-39
Author(s):  
Shafaq Maqsood ◽  
Fatima Ali ◽  
Abdul Hameed ◽  
Neelam Siddiqui
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Chromosomal Abnormalities ◽  
Fusion Gene ◽  
Philadelphia Chromosome ◽  
Trisomy 8 ◽  
Additional Chromosomal Abnormalities

Background and Purpose: Chronic Myeloid Leukemia (CML) is a common hematological malignancy. The characteristic molecular abnormality is the presence of Philadelphia chromosome or BCR-ABL fusion gene which is the result of 9:22 translocation. Tyrosine kinase inhibitors (TKIs) form the main stay of treatment in CML with excellent responses. The purpose of this study was to determine the impact of additional chromosomal abnormalities on outcomes in CML.Methods: This is a retrospective chart review of all patients who were diagnosed with CML in chronic phase (CP) with additional chromosomal abnormalities (ACAs) over a period of 5 years from 2010 to 2015 at Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan. Results: A total of 283 patients were diagnosed with CML from January 2010 to January 2015. 31 patients out of these were found to have additional chromosomal abnormalities at the time of diagnosis in addition to BCR-ABL fusion gene or Philadelphia chromosome detection. Out of these 31 patients, 23 (74.2%) were males whereas 8 (25.8%) were females. 13 (41.9%) were in the age group of 31 to 50 years whereas the other two groups that is 18 to 30 years and 51 to 70 years had 9 patients each. After approval from the government which usually takes a standard 2-3 weeks’ time, these patients were started on tyrosine kinase inhibitors which was Imatinib in 30 (96.8%) and Nilotinib in 1 (3.2%) patient. Conventional cytogenetic analysis performed for each patient at the time of diagnosis revealed that 11 (35.5%) of patients had variant Philadelphia chromosome followed by 7 patients (22.6%) with trisomy 8. 5 patients (16.1%) had multiple chromosomal abnormalities including trisomy 8, deletion 1 and isochrome 17q. 2 patents each had isochrome 17q, inversion 3 and deletion 9 abnormalities. 1 patient had deletion 7 whereas 1 had variant Philadelphia chromosome with other chromosomal abnormalities. Conclusion: It was evident that frequently occurring ACAs In our CML population were Variant Philadelphia chromosome and trisomy 8.

Causes of Death for Patients with Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) Treated with Imatinib.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4279-4279
Author(s):  
Andrea Renata Dean ◽  
Hagop M. Kantarjian ◽  
Susan O'Brien ◽  
Mary Beth Rios ◽  
Alfonso Quintas-Cardama ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Causes Of Death ◽  
Kinase Inhibitors ◽  
Cytogenetic Response ◽  
Initial Therapy ◽  
Cardiac Complications ◽  
Time Of Death ◽  
Lost To Follow Up

Abstract Abstract 4279 Background Imatinib is the current standard initial therapy for patients with CML in CP. Over 80% of patients achieve a complete cytogenetic remission (CCyR), and the projected overall survival at 7 years is 89%. This survival probability is significantly better than the historical pre-imatinib era (approximately 50% at 5 years). Understanding the causes of death among patients treated with imatinib is needed to further improve the long-term results. Aim To determine cause of death in patients treated with imatinib as initial therapy for CP Philadelphia-chromosome positive CML. Methods We reviewed the records of all patients with CML in CP treated with imatinib (standard or high-dose) as initial therapy since 2000. Results A total of 281 patients were treated. The overall rate of major cytogenetic response (MCyR) was 94% and CCyR 89%. At 6 years the projected event-free survival was 83% and overall survival 91%. After a median follow-up of 5.6 years, 29 (10%) patients have died. The median age at diagnosis was 56 years (range, 20 to 84 years) and at the time of death 60 years (23 to 91 years). The median time from start of therapy to death was 3.9 years (6 months to 8 years). Initial imatinib dose was 400mg for 13 patients (out of 281, 26% treated at that dose) and 800mg for 16 patients (out of 281, 74% treated at 800mg). All patients had achieved a complete hematological response. Among those that eventually died, 24 (82%) pts achieved a MCyR with imatinib: 19 (65%) achieved CCyR and 5 (17%) partial cytogenetic response (PCyR). Two patients achieved a minor cytogenetic response and 2 had no cytogenetic response; one patient was lost to follow up soon after starting treatment. Causes of death included the following: CML (8), transplant-related complications (4), cardiac complications (3), cerebral vascular accident (2), motor vehicle accident (2), acute myeloid leukemia (1), suicide (1), sudden cardiac death (1), metastatic melanoma (1), metastatic renal cell carcinoma (1), and bowel obstruction (1). Four patients were lost to follow up and cause of death could not be determined. All eight patients that died from CML had lost their hematological response to imatinib; 7 transformed to blast phase. Three of these patients received treatment with second generation tyrosine kinase inhibitors and one achieved a transient MCyR. The four patients that died from transplant-related complications ranged in age from 20 to 48 years at diagnosis. Patients underwent transplant (2 in CP, 2 in 2nd CP) after failing treatment with imatinib and other therapies. Three patients where in CCyR at time of death and 1 had unknown cytogenetic response. Among the other 17 pts, 9 (53%) were in CCyR at the time of death. The 3 patients that died from cardiac complications had past medical histories of heart disease and all were in CP at time of death: 2 with CCyR and 1 with PCyR. These patients died from congestive heart failure, myocardial ischemia, or arrthymia, respectively. The 2 patients that died from cerebral vascular accidents had prior histories of stroke. Both patients were in CP: 1 in CCyR and 1 with PCyR. The 2 patients who died of car accidents were in CP at the time of death: 1 in CCyR and 1 with PCyR. The patients that died of acute myeloid leukemia, suicide, sudden cardiac death, metastatic renal cell carcinoma and bowel obstruction were all in CCyR prior to death. The patient who died from metastatic melanoma had unknown cytogenetics prior to death. Among the patients that died for reasons other than CML or transplant-related complications, all except three were treated with imatinib only. Two of the 4 patients lost to follow up underwent bone marrow transplants at other facilities and status at time of death is unknown. The other 2 patients lost to follow up discontinued imatinib due to side effects long before their death. Discussion The survival probability of CML CP patients treated with imatinib is excellent. Less than half of the deaths are related to CML or stem cell transplant. These deaths might be preventable if 2nd generation tyrosine kinase inhibitors are more effective as initial therapy. Other deaths result from co-morbidities, with no deaths attributed to the treatment with imatinib. Close monitoring of patients with predisposing factors for these events could improve their long-term outcome. Disclosures: Rios: BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau. Jabbour:Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau. Cortes:Novartis: Research Funding.

A Retrospective Evaluation of Clonal Cytogenetic Abnormalities in Ph Negative Clones in Patients with CP-CML on Therapy

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4277-4277
Author(s):  
Monique A Hartley ◽  
Bijal D. Shah ◽  
Sady Armada ◽  
Sara Tinsley ◽  
Javier Pinilla
Keyword(s):  
Kinase Inhibitors ◽  
Chromosomal Abnormalities ◽  
Treated Patient ◽  
Philadelphia Chromosome ◽  
Median Number ◽  
Disease Course ◽  
Trisomy 8 ◽  
Monosomy 7 ◽  
To Receive ◽  
In Cells

Abstract Cytogenetic clonal aberrations in CML are a well recognized indicator of transition to blast phase. However, it is unclear how to interpret such changes when they occur in cells not harboring a Philadelphia Chromosome (Ph-), considering that some of these changes are often seen in patients with MDS/AML. In this retrospective review of 208 cases, we sought to determine the frequency, onset, character, and general course among CML patients harboring clonal chromosomal abnormalities (ChA) in Ph- cells during treatment with tyrosine kinase inhibitors (TKI’s). In this cohort, we were able to identify 13 ChA among 11 patients (5% of initial cohort), with most cases demonstrating trisomy 8 (31%), monosomy 7 (23%), and loss/gain of chromosome Y (38%). The median number of treatments per patient was 2 (1–3), with a median followup of 77.5 months (18–196 mo) among these 11 patients. Of the 13 ChA, 9 occurred during Imatinib therapy, and 5 of these 9 resolved without a change in medication. Of the remaining 4 patients, 2 presented with ChA prior to therapy, and 2 developed ChA while on a second generation TKI (Nilotinib, Dasatinib). The ChA persisted in the patient taking Nilotinib and resolved in the Dasatinib treated patient without change in therapy. Among those with ChA prior to therapy, the ChA resolved in one after the addition of INNO-406 (a lyn-abl inhibitor), and in the other despite going untreated between interval marrow specimens (this patient later went on to receive Imatinib with no ChA over an 18 month followup). CML disease course in patients with ChA in Ph- clones does not appear to be more severe, with only one patient having gone on to receive bone marrow transplantation for accelerated phase disease, and one other not currently in cytogenetic remission. Ten patients have attained complete (6) and major (4) molecular responses. Seven patients demonstrated cytopenias at last followup. Accompanying marrow dysplasia was seen among 4 of these patients. Interestingly, cytopenias are most pronounced in those with persistence of the ChA, including one patient with 5q deletion and another with chromosome 7 deletion. In summary, while clonal cytogenetic changes in Philadelphia Chromosome positive cells are a well recognized marker of disease progression, their presence in cells lacking this translocation does not seem to reflect a similar disposition. However while cytopenias of varying severity are noted in the patients reported, there is no evidence of transformation to MDS/AML nor a more resistant disease course. Long term follow up still is needed to confirm these data.

Imatinib (IM) Treatment In Chronic Myeloid Leukemia (CML). Clinical Practice Limitations

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4454-4454
Author(s):  
Alicia Inés Enrico ◽  
Georgina Bendek ◽  
Maria Virginia Prates ◽  
Virginia Guerrero ◽  
Juan Jose Napal ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Blast Crisis ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Trisomy 8 ◽  
History Of ◽  
One Year

Abstract Abstract 4454 Introduction: CML represents 15% all of oncohematologic diseases in adults. IM changed the history of the disease. At one year of treatment, the emblematic IRIS study showed Major Cytogenetic Responses (MCyR) of approximately 87% and Complete Cytogenetic Responses (CCyR) of around 76%, with PFS to accelerated phase or blast crisis of 97.7% and 91.5%, respectively. Objective: To assess treatment characteristics and responses in a group of patients treated with IM in clinical practice. Materials and Method: 113 medical records of patients with CML diagnosed between 1998–2011 from two institutions in the Argentine Republic were retrospectively analyzed. Result: Mean population age was 46 years old (r 18–73) 65 male, 48 female. 97% in chronic phase, the rest in accelerated phase. 31% presented comorbidities at diagnosis. Cytogenetic abnormalities at diagnosis, in addition to the classic t(9:22), included: trisomy 8 and double Philadelphia chromosome in 4 tests. Only 7 patients had qualitative BCR/ABL determined at diagnosis. 25% had received interferon, patients received IM 400 mg and only 2% received 300 or 600 mg doses. 2.6% of patients did not achieve CHR. Cytogenetic responses assessed at any time of treatment were: Major: 12%, Minor 20%, Complete 51%, None 3%, 14% were not assessed. With a mean follow-up time of 46 months, the overall survival was 75%. 10% of patients progressed to BC/AP, 11 % of patients died due to disease-related causes or comorbidities. Conclusions: With a mean follow-up time of 46 months for chronic phase CML, treatment with IM achieved complete cytogenetic responses in 51% of patients, and progression occurred in 10% of patients. Disclosures: No relevant conflicts of interest to declare.

Chromosomal abnormalities in Philadelphia chromosome–negative metaphases appearing during imatinib mesylate therapy in patients with newly diagnosed chronic myeloid leukemia in chronic phase

Blood ◽  
2007 ◽  
Vol 110 (8) ◽  
pp. 2991-2995 ◽  
Author(s):  
Elias Jabbour ◽  
Hagop M. Kantarjian ◽  
Lynne V. Abruzzo ◽  
Susan O'Brien ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Progressive Disease ◽  
Chromosomal Abnormalities ◽  
Philadelphia Chromosome ◽  
Young Patients ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
High Dose ◽  
Newly Diagnosed

Abstract The development of chromosomal abnormalities (CAs) in the Philadelphia chromosome (Ph)–negative metaphases during imatinib (IM) therapy in patients with newly diagnosed chronic myecloid leukemia (CML) has been reported only anecdotally. We assessed the frequency and significance of this phenomenon among 258 patients with newly diagnosed CML in chronic phase receiving IM. After a median follow-up of 37 months, 21 (9%) patients developed 23 CAs in Ph-negative cells; excluding −Y, this incidence was 5%. Sixteen (70%) of all CAs were observed in 2 or more metaphases. The median time from start of IM to the appearance of CAs was 18 months. The most common CAs were −Y and + 8 in 9 and 3 patients, respectively. CAs were less frequent in young patients (P = .02) and those treated with high-dose IM (P = .03). In all but 3 patients, CAs were transient and disappeared after a median of 5 months. One patient developed acute myeloid leukemia (associated with − 7). At last follow-up, 3 patients died from transplantation-related complications, myocardial infarction, and progressive disease and 2 lost cytogenetic response. CAs occur in Ph-negative cells in a small percentage of patients with newly diagnosed CML treated with IM. In rare instances, these could reflect the emergence of a new malignant clone.

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