Prognostic Impact of Deletions of Derivative Chromosome 9 on Patients (PTS) with Chronic Myelogenous Leukemia (CML) in Chronic Phase Treated with Nilotinib or Dasatinib.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2110-2110
Author(s):  
Alfonso Quintas-Cardama ◽  
Hagop M. Kantarjian ◽  
Susan O’Brien ◽  
Gautam Borthakur ◽  
Srdan Verstovsek ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Chromosome 9 ◽  
Myelogenous Leukemia ◽  
Fish Analysis ◽  
Prognostic Impact ◽  
Derivative Chromosome ◽  
2Nd Generation ◽  
Translocation Breakpoints

Abstract Background: Submicroscopic deletions of the derivative chromosome 9 [Del der(9)] mapping to regions adjacent to the translocation breakpoints occur in 9% to 15% of patients with CML. Del der(9) is a powerful prognostic indicator associated with unfavorable prognosis in patients treated with interferon-alpha (IFN-α)-based therapies. Imatinib is currently the standard treatment for patients with CML and it appears to overcome the adverse prognostic impact imparted by Del der(9). Methods: We investigated the prognostic impact of Del der(9) in 353 patients with CML treated at our institution with the 2nd generation tyrosine kinase inhibitors (TKIs) nilotinib (n=161) or dasatinib (n=192). The presence of Del der(9) prior to 2nd generation TKIs was investigated by FISH analysis using the LSI-BCR/ABL-(ES) probe (Vysis, Downers Grove, IL) in 245 patients. The median age was 53 years (range, 15–83) and the median follow-up was 24 months (range, 1–53). The primary endpoints evaluated were complete hematologic response (CHR), cytogenetic response, and survival. Results: Twenty-eight (11%) patients carried Del der(9) and 217 an intact der(9). Among patients with deletions, 22 were in chronic phase (CP), 4 in accelerated phase (AP), and 2 in blast phase (BP) at the start of nilotinib or dasatinib therapy. In the group of patients without deletions, 122 were in CP, 55 in AP and 40 in BP. Overall, 229 (93%) patients were assessable for response after a median of 25 months (range, 1–53) of therapy. The outcome by CML phase is shown in Table 1. CML phase Deletion der(9) No. CCyR (%) p EFS (12 mo) p OS (12 mo) p No 122 79 0.77 86 0.05 97 0.04 CP Yes 22 75 60 78 Not done 46 No 55 36 1.0 37 0.47 60 0.95 AP Yes 4 25 67 75 Not done 27 No 40 19 1.0 0 0.85 35 0.39 BP Yes 2 0 0 0 Not done 35 There was no difference in response rates among patients in CP, but those without Del der(9) had an improved EFS and OS at 24 months compared with those carrying Del der(9) (EFS: 86% vs 60%, p=0.05; OS: 97% vs 78%; p=0.04). Notably, whereas a trend towards worse EFS (p=0.05) and OS (p=0.12) was observed in patients in CP with Del der(9) treated with nilotinib, these outcomes were not significantly affected by Del der(9) in patients receiving dasatinib (EFS: p=0.47; OS: p=0.76). Conclusion: Our results suggest that, in contrast to what has been reported with imatinib therapy, patients with CML-CP carrying Del der(9) who failed imatinib may have a worse survival than their counterparts without deletions after treatment with 2nd generation TKI. This deleterious effect is more apparent among patients treated with nilotinib than among those receiving dasatinib.

Prognostic Impact of Deletions of Derivative Chromosome 9 on Patients (pts) with Chronic Myelogenous Leukemia (CML) in Chronic Phase Treated with Nilotinib or Dasatinib.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1955-1955
Author(s):  
Alfonso Quintás-Cardama ◽  
Hagop Kantarjian ◽  
Deborah Thomas ◽  
Charles Koller ◽  
Jenny Shan ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Prognostic Indicator ◽  
Chromosome 9 ◽  
Myelogenous Leukemia ◽  
Fish Analysis ◽  
Prognostic Impact ◽  
Derivative Chromosome ◽  
Significant Difference ◽  
Translocation Breakpoints

Abstract Background: Submicroscopic deletions of the derivative chromosome 9 [del der(9)] mapping to regions adjacent to the translocation breakpoints occur in 9% to 15% of patients with CML. Deletion of der(9) is powerful prognostic indicator associated with an unfavorable prognosis in patients treated with interferon-alpha (IFN-α)-based therapies. Imatinib is currently the standard treatment for patients with CML and it appears to overcome the adverse prognostic impact imparted by deletions of der(9). Methods: We tested the prognostic impact of the deletions of der(9) in 323 patients with CML treated at our institution with the 2nd generation tyrosine kinase inhibitors (TKIs) nilotinib (n=144) or dasatinib (n=179). The presence of deletions of der(9) was investigated by FISH analysis using the LSI-BCR/ABL-(ES) probe (Vysis, Downers Grove, IL) in 244 patients. The median age was 55 years (range, 15–83) and the median follow-up was 18 months (range, 1–44). The primary endpoints evaluated were survival, complete hematologic response (CHR) and cytogenetic responses. Results: Twenty-eight (12%) patients were found to have del der(9) and 216 an intact der(9). Among patients with deletions, 16 were in chronic phase (CP), 8 in accelerated phase (AP), and 4 in blast phase (BP) at the start of nilotinib or dasatinib therapy. In the group of patients without deletions, 112 were in CP, 54 in AP and 50 in blastic phase (BP). Overall, 222 (91%) of 244 patients were assessable for response. There was no significant difference between patients with or without deletions regarding the rate of CHR, major (MCyR) or complete (CCyR) cytogenetic responses, and event-free (EFS), and overall (OS) survival at 12 months for the total population. CML Phase deletion der(9) [No. Patients] CCyR (%) p EFS (12 months) p OS (12 months) p No (112) 72 1 84 0.2 97 0.01 Chronic Yes (16) 73 78 92 Not Done (30) No (54) 31 0.7 54 0.22 69 0.62 Accelerated Yes (8) 38 75 88 Not Done (27) No (50) 24 1 9 0.56 30 0.56 Blastic Yes (4) 25 25 25 Not Done (22) Among pts in CP there was no difference in response rate or EFS, but pts without del der(9) had an improved OS at 12 months compared with those carrying der(9) (97% vs 92%; p=0.01). There appears to be no significant difference between pts treated with nilotinib and those treated with dasatinib. Conclusion: Our results suggest that although the outcome of patients with CML treated in AP or BP with either nilotinib or dasatinib does not differ regardless of their deletion status, those in CP carrying del der(9) deletions may have a worse overall survival than their counterparts without deletions. This is in contrast to what has been reported with imatinib therapy. The reason for this difference is unclear.

Imatinib mesylate therapy may overcome the poor prognostic significance of deletions of derivative chromosome 9 in patients with chronic myelogenous leukemia

Blood ◽  
2005 ◽  
Vol 105 (6) ◽  
pp. 2281-2286 ◽  
Author(s):  
Alfonso Quintas-Cardama ◽  
Hagop Kantarjian ◽  
Moshe Talpaz ◽  
Susan O'Brien ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Imatinib Mesylate ◽  
Prognostic Significance ◽  
Chronic Phase ◽  
Response Duration ◽  
Cytogenetic Response ◽  
Chromosome 9 ◽  
Myelogenous Leukemia ◽  
Derivative Chromosome

AbstractDeletions of derivative chromosome 9 [der(9)] can be identified by fluorescence in situ hybridization (FISH) in 10% to 15% of patients with chronic myeloid leukemia (CML). Patients with der(9) deletions have been reported to have an adverse outcome when treated with chemotherapy, interferon, and possibly imatinib mesylate. We investigated the frequency and prognostic significance of der(9) deletions among 352 patients with CML treated with imatinib mesylate at our institution, in whom a deletion status of der(9) was determined. Thirty-three patients (9%; 95% CI 0.07, 0.13) (30 in chronic phase, 3 in accelerated phase) had der(9) deletions. The rates of major (82% vs 79%, P = 0.82) and complete cytogenetic response (76% vs 66%, P = .33) with imatinib mesylate therapy were similar in patients with and without der(9) deletions, respectively. After a median follow-up of 28 months, there was no difference in overall survival (P = .30) or response duration (P = .49) in patients with and without deletions. In a multivariate analysis, der(9) deletions had no significant impact on response, survival, or response duration. We conclude that treatment with imatinib mesylate overcomes the adverse prognostic significance of der(9) deletions in patients with CML.

Heterogeneous Prognostic Impact of 9q+ Deletions in Patients with Chronic Myelogenous Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2111-2111
Author(s):  
Sebastian Kreil ◽  
Katherine Waghorn ◽  
Markus Pfirrmann ◽  
Andreas Reiter ◽  
Rudiger Hehlmann ◽  
...  
Keyword(s):  
Blood Platelets ◽  
Univariate Analysis ◽  
Chronic Phase ◽  
Chromosome 9 ◽  
Myelogenous Leukemia ◽  
Prognostic Impact ◽  
Derivative Chromosome ◽  
German Studies ◽  
Reliable Technique ◽  
Significant Difference

Abstract Deletions at the ABL-BCR reciprocal breakpoint on the derivative chromosome 9 are seen in 10–15% of patients with CML and have been associated with a poor prognosis, at least for cases treated with hydroxyurea or interferon alpha (IFN). Studies to date have used different fluorescent-in-situ-hybridization (FISH) probe sets to determine deletion status and thus the results are not always directly comparable. Furthermore, information concerning the extent of deletions is limited and no studies have been performed in the context of a prospective randomised controlled clinical trial. To provide more accurate information about deletion status, we developed a rapid DNA-based screen based on multiplex ligation-dependent probe amplification (MLPA). Der(9) deletions were detected at dilutions of 60% or more MC3 cell DNA in non-deleted DNA, indicating that the method was suitable for analysis of samples with up to 40% normal cells. We then investigated 348 chronic phase (CP) patients that were treated with IFN based therapies in three consecutive prospective controlled German studies. The median duration of IFN-based treatment was 17 months (range, 1–115) with a median observation time of seven years (range, 0.3–16); 160 patients (46%) were alive at the date of analysis. Therapy subsequent to IFN included allogeneic stem cell transplantation (SCT; n=130) or imatinib mesylate (IM; n=62). DNA extracted at diagnosis was tested by MLPA and 9q+ deletions, defined as the loss of at least two consecutive markers, were found in 59/348 (17%) patients. Of these 59 deletions, 21 spanned the ABL-BCR breakpoint and 38 were either upstream only (n=20) or downstream only (n=18) of the breakpoint. Analysis of the baseline parameters age, spleen size, leukocyte count, % eosinophils, basophils and blasts in peripheral blood, platelets, hemoglobin, and prognostic scores according to Hasford and Sokal did not reveal any significant difference between patients with and without deletions. There was no significant difference in overall survival between patients with or without deletions and also no difference in survival when patients were censored at SCT in CP or IM treatment. Patients with large ABL-BCR deletions had a poorer survival compared to all other cases (5.7 vs 8.8 years; p=0.0025) but this fell below the level of significance using censored survival (p=0.08). Patients with low risk Sokal or Hasford scores with breakpoint spanning deletions had a significantly worse prognosis than other cases (p=0.01 and p=0.04, respectively). Patients with ABL-BCR deletions also showed a trend towards a less favourable survival after allogeneic SCT in CP-CML (p=0.06). Surprisingly, patients with deletions that did not span the breakpoint showed a superior outcome (p=0.02). Univariate analysis of baseline data revealed that patients with either ABL or BCR deletions only were younger, presented with more circulating blasts and a larger spleen at diagnosis. Patients with large deletions spanning the breakpoint had fewer additional chromosomal abnormalities. In conclusion, MLPA is a reliable technique for detection of der(9) deletions in CML. Our analysis indicates that only those deletions that span the reciprocal ABL-BCR breakpoint are associated with adverse prognosis but the effect is relatively weak.

Heterogeneous prognostic impact of derivative chromosome 9 deletions in chronic myelogenous leukemia

Blood ◽  
2007 ◽  
Vol 110 (4) ◽  
pp. 1283-1290 ◽  
Author(s):  
Sebastian Kreil ◽  
Markus Pfirrmann ◽  
Claudia Haferlach ◽  
Katherine Waghorn ◽  
Andrew Chase ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Cox Regression ◽  
Chronic Phase ◽  
Chromosome 9 ◽  
Myelogenous Leukemia ◽  
Prognostic Impact ◽  
Derivative Chromosome ◽  
German Studies ◽  
Cox Regression Analysis ◽  
Significant Difference

Abstract Derivative chromosome 9 deletions are seen in 10% to 15% of patients with chronic myelogenous leukemia and have been associated with a poor prognosis; however, no studies have been performed in the context of a randomized clinical trial. We developed a DNA-based deletion screen and investigated 339 chronic phase patients treated with interferon-α as first-line therapy in 3 controlled German studies with a median observation time of 7 years. Deletions were detected in pretreatment DNA of 59 of 339 (17%) patients. Of these, 21 spanned the ABL/BCR junction and 38 were centromeric (n = 20) or telomeric (n = 18) of the breakpoint. There was no significant difference in overall survival between deleted and nondeleted patients. Patients with breakpoint-spanning deletions had poorer survival compared with patients without deletions (4.7 versus 7.8 years; P = .003), but this was not significant when censored at allogeneic stem cell transplantation (n = 129) or imatinib (n = 62) treatment in the first chronic phase (P = .078). Unexpectedly, deletions that did not span the breakpoint were associated with improved survival compared with cases without deletions (P = .001). Multiple Cox regression analysis indicated that deletion status (P = .007), age (P = .018), and spleen enlargement (P < .001) were significant independent indicators of survival and confirmed that only deletions spanning the ABL/BCR breakpoint were associated with an adverse prognosis (P = .039).

scholarly journals Nilotinib therapy in an imatinib intolerant chronic myeloid leukemia patient with pulmonary severe hypertension

2015 ◽  
Vol 4 (2S) ◽  
pp. 17-20
Author(s):  
Mario Annunziata
Keyword(s):  
Side Effects ◽  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Chronic Myeloid Leukemia Patient ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Cutaneous Rash

Imatinib mesylate is a tyrosine kinase inhibitor that has significant efficacy in the treatment of chronic myelogenous leukemia. In general, hematologic and extrahematologic side effects of imatinib therapy are mild to moderate, with the large majority of patients tolerating prolonged periods of therapy. However, a minority of patients are completely intolerant of therapy, while others are able to remain on therapy despite significant side effects. Here, we describe a chronic phase CML patient with pulmonary arterial hypertension, mechanical hearth valve, who experienced extrahematologic adverse event (persistent grade III cutaneous rash, despite two discontinuations of imatinib and using of steroid). Necessitating switch to one of new tyrosine kinase inhibitors, nilotinib, has resulted in complete cytogenetic response and major molecular response, after 3 and 6 months, respectively. No cross-intolerance with imatinib was observed during nilotinib therapy. Besides, this clinical case suggests that warfarin and nilotinib can be used concurrently without the risk of increased anticoagulant effect.

Central nervous system (CNS) leukemia after imatinib mesylate therapy for chronic myelogenous leukemia (CML)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7042-7042
Author(s):  
M. M. Solh ◽  
H. Kantarjian ◽  
S. O'Brien ◽  
F. Giles ◽  
S. Faderl ◽  
...  
Keyword(s):  
Overall Survival ◽  
Kinase Inhibitors ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Leukemic Cells ◽  
Blast Transformation ◽  
Blast Phase ◽  
Cns Disease

7042 Background: Imatinib is the standard first line treatment for CML. Imatinib penetrates the CSF poorly. We examined the incidence and outcome of CNS disease in pts with CML treated with imatinib at our institution. Methods: The clinical data for pts with early or late chronic phase and accelerated phase CML treated with imatinib between 1999 and 2006 were reviewed. Pts who were started on imatinib elsewhere and progressed to blast phase were also included. CNS disease was defined as a pathologically proven enhancing lesion (leptomeningeal or parenchymal) or presence of CSF leukemic cells. Results: Nine hundred and ten pts with chronic or accelerated phase CML were treated with imatinib. Fifty five developed blast crisis while on imatinib; another 28 pts had blast transformation while receiving imatinib elsewhere, making up a total of 83 pts. At diagnosis, their median age was 51 yrs, median Hgb, WBC and PLT counts were 10.6 g/dl, 59.7×109/L and 307×109/L, respectively. Median time from diagnosis to starting imatinib was 45.4 mts and the median duration of imatinib therapy was 17.9 mts. Fifteen pts had achieved a complete cytogenetic response and 47 had a complete hematologic response before progressing to blast phase. Their median overall survival from diagnosis was 73.2 mts. Thirty pts developed extramedullary disease; they had similar baseline characteristics as the rest with a median survival of 68.3 mts. Fifteen pts developed CNS disease (5 leptomenigeal, 5 CSF, 3 parenchymal, and 2 spinal cord); 14 had concomitant medullary blast crisis. They had a statistically significant younger age at diagnosis (41.9 vs 52.4 yrs), lower platelet counts (186 vs 334×109/L), and shorter overall survival (66.7 vs 73.2 mts) compared to the other pts with blast phase. Conclusions: CNS disease occurs infrequently in pts receiving imatinib for CML but should be suspected in pts with relevant symptoms. Pts developing CNS leukemia had a worse prognosis; this may be secondary to an inherently worse disease, poor CSF penetration of imatinib, and subsequent difficulty in eradicating CNS disease using available therapies. More potent tyrosine kinase inhibitors, such as nilotinib and dasatinib, and new agents with the ability to cross the blood-brain barrier should be evaluated in this setting. No significant financial relationships to disclose.

Deletions of the Derivative Chromosome 9 Do Not Influence Response to Imatinib of Early Chronic Phase Chronic Myeloid Leukemia Patients (A GIMEMA Working Party Analysis).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2112-2112 ◽  
Author(s):  
Fausto Castagnetti ◽  
Giulia Marzocchi ◽  
Simona Luatti ◽  
Francesca Buontempo ◽  
Carmen Baldazzi ◽  
...  
Keyword(s):  
Chronic Phase ◽  
Working Party ◽  
Response Rates ◽  
Chromosome 9 ◽  
Fish Analysis ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Derivative Chromosome ◽  
Term Survival

Abstract Extensive submicroscopic deletions adjacent to the breakpoint on derivative chromosome 9 [der(9)] have been reported in a subset of Chronic Myeloyd Leukemia (CML) patients and have been associated with an adverse outcome with conventional drugs and α-interferon (α-IFN). Huntly et al (Blood.2003; 102.2205–12) reported 275 CML pts who were treated with imatinib in CP, suggesting that der(9) deletions were associated with lower response rates and a shorter time to progression. Different data were reported by Quintas-Cardama et al (Blood.2005; 105:2281–6), who did not find any difference related with der(9) deletions in other 320 patients treated with imatinib. In these 2 studies, some patients began imatinib in early CP (51 and 152, respectively) while many patients (224 and 168, respectively) were treated in late CP. To establish the relationship of der(9) deletions with the response to imatinib in early CP patients, we planned a prospective study involving 3 consecutive multicentric national studies of the GIMEMA (Gruppo Italiano Malattie Ematologiche dell’Adulto) CML Working Party. 421 CML patients in early chronic phase were enrolled between January, 2004 and January, 2006; Fluorescence in situ hybridization (FISH) analysis of bone marrow cells was performed using BCR/ABL extra-signal, D-FISH or dual-color dual-fusion probes. At diagnosis, 52 (12%) of them had der(9) deletion and 369 (88%) had not. The 2 groups, with/without deletions, were comparable (no difference in age, Sokal risk, imatinib dose). Median observation time is 12 months. At 3 months, the CHR rates in with/without deletions patients were 87%/92%. At 6 months, the complete cytogenetic response (0% Ph-pos; CCgR) rates were 80%/80%, with major molecular response (MMolR, defined as a Bcr-Abl/Abl x 100 ratio < 0.1%) rates of 52%/51%, respectively. At 12 months, CCgR rates were 89%/86% and MMolR 52%/61%. No difference is significant. We conclude that the presence of der(9) deletions at diagnosis do not constitute a negative factor for response to imatinib: the haematological, cytogenetic and molecular response rates resulted equal between the 2 groups of patients with and without der(9) deletions. This finding is relevant to the long term effect of imatinib treatment, since both the CCgR and the MMolR are important and established indicator of long term survival.

Deletions Adjacent to BCR and ABL Breakpoints Occur in a Substantial Minority of Chronic Myeloid Leukaemia Patients with Masked Philadelphia Rearrangements.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2929-2929
Author(s):  
Valeria A. De Melo ◽  
Paul Kotzampaltiris ◽  
Elisabeth Nacheva ◽  
David Marin ◽  
Jane F. Apperley ◽  
...  
Keyword(s):  
Chronic Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Kinase Inhibitors ◽  
Fusion Gene ◽  
Chronic Phase ◽  
Chromosome 9 ◽  
Significant Feature ◽  
Potential Side Effect ◽  
Translocation Breakpoints ◽  
Dual Colour

Abstract Chronic myeloid leukaemia (CML) results from the malignant transformation of haematopoietic stem cells by the BCR-ABL fusion gene, generated by a reciprocal translocation between chromosomes 9 and 22, the Philadelphia (Ph) translocation, or variations thereof. Common permutations of the Ph include translocations involving one or more additional chromosomes to 9 and 22 (“variant” Ph), and rearrangements resulting in cryptic insertion of chromosome 9 into chromosome 22, or vice versa, leaving apparently normal chromosomes 9 and 22 (“masked” Ph). Recently the development of new FISH techniques led to the identification of unexpected deletions at the Ph translocation breakpoints in approximately 15% of CML patients. The deletions, encompassing sequences 3′ of the BCR breakpoint and/or 5′ of the ABL breakpoint, were associated with a shorter duration of chronic phase and shorter survival in patients treated with interferon therapy, although their impact in patients treated with tyrosine kinase inhibitors is currently unclear. Interestingly, the incidence of deletions has been shown to vary for different cytogenetic subgroups of CML, with a significantly higher incidence of deletion in patients with a variant Ph translocation. The frequency of such events in patients with masked Ph rearrangements, however, has not yet been explored because of limitations inherent to the widely adopted dual-colour BCR-ABL FISH approach. We report the evaluation of 14 patients with masked Ph-positive CML for the presence of deletions extending 3′ from BCR and 5′ from ABL using two 3-colour BCR-ABL probes. Deletions were identified in 3 patients in total (21%), encompassing sequences 5′ to ABL in two of these and sequences 3′ to BCR in the remaining patient, thus demonstrating that the phenomenon is a significant feature of the masked Ph CML subgroup. Furthermore, our findings are consistent with the notion that loss of genomic material is a potential side effect of any DNA breakage event at the 9q34.1 and 22q11.2 chromosomal regions, regardless of the subsequent mechanism of chromosomal rearrangement.

scholarly journals Prognostic impact of deletions of derivative chromosome 9 in patients with chronic myelogenous leukemia treated with nilotinib or dasatinib

Cancer ◽  
2011 ◽  
Vol 117 (22) ◽  
pp. 5085-5093 ◽  
Author(s):  
Alfonso Quintás-Cardama ◽  
Hagop Kantarjian ◽  
Jianqin Shan ◽  
Elias Jabbour ◽  
Lynne V. Abruzzo ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Chromosome 9 ◽  
Myelogenous Leukemia ◽  
Prognostic Impact ◽  
Derivative Chromosome

scholarly journals Front-Line Therapy With Second-Generation Tyrosine Kinase Inhibitors in Patients With Early Chronic Phase Chronic Myeloid Leukemia: What Is the Optimal Response?

2011 ◽  
Vol 29 (32) ◽  
pp. 4260-4265 ◽  
Author(s):  
Elias Jabbour ◽  
Hagop M. Kantarjian ◽  
Susan O'Brien ◽  
Jianqin Shan ◽  
Alfonso Quintás-Cardama ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Second Generation ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Newly Diagnosed ◽  
Front Line ◽  
Line Therapy

Purpose The response definitions proposed by the European LeukemiaNet (ELN) are defined on the basis of imatinib front-line therapy. It is unknown whether these definitions apply to patients treated with second-generation tyrosine kinase inhibitors (TKIs). Patients and Methods One hundred sixty-seven patients with newly diagnosed chronic myelogenous leukemia (CML) in chronic phase were treated with second-generation TKIs in phase II trials (nilotinib, 81; dasatinib, 86). Median follow-up was 33 months. Event-free survival (EFS) was measured from the start of treatment to the date of loss of complete hematologic response, loss of complete or major cytogenetic response, discontinuation of therapy for toxicity or lack of efficacy, progression to accelerated or blastic phases, or death at any time. Results Overall, 155 patients (93%) achieved complete cytogenetic response (CCyR), including 146 (87%) with major molecular response (MMR; complete in 46 patients [28%]). According to the ELN definitions, the rates of suboptimal response were 0%, 2%, 1%, and 12% at 3, 6, 12, and 18 months of therapy, respectively. There was no difference in EFS and CCyR duration between patients who achieved CCyR with and without MMR across all the landmark times of 3, 6, 12, and 18 months. Conclusion The use of second-generation TKIs as initial therapy in CML induces high rates of CCyR at early time points. The ELN definitions of response proposed for imatinib therapy are not applicable in this setting. We propose that achievement of CCyR and partial cytogenetic response at 3 months should be considered optimal and suboptimal responses, respectively. The achievement of MMR offered no advantage over CCyR in defining long-term outcome in patients with newly diagnosed CML treated with second-generation TKIs.

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