Imatinib Mesylate Discontinuation in Patients with Chronic Myelogenous Leukemia in Complete Molecular Remission: An Update Follow Up.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2154-2154 ◽  
Author(s):  
Francois-Xavier Mahon ◽  
Francoise Huguet ◽  
Gabriel Etienne ◽  
Delphine Réa ◽  
Jean-Michel Cayuela ◽  
...  
Keyword(s):  
Imatinib Mesylate ◽  
Chronic Myelogenous Leukemia ◽  
Kinase Inhibitor ◽  
Residual Disease ◽  
Quantitative Polymerase Chain Reaction ◽  
Leukemic Cell ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Molecular Remission

Abstract The BCR-ABL tyrosine kinase inhibitor imatinib mesylate (Gleevec) induces complete cytogenetic responses (CCR) in more than 85% of patients with chronic myelogenous leukemia (CML). However, patients in CCR relapse after imatinib interruption in case of detectable residual disease. In fact, less than 10% of patients achieve a molecular remission, defined by an undetectable residual disease using real time quantitative polymerase chain reaction (RTQ-PCR). We previously reported the outcome of CML patients in CCR after cessation of interferon-alpha during the pre-imatinib era. Seven (all with a negative PCR) out of 15 patients did not relapse (J Clin. Oncol.,20,2002:214–220). In the present study, we address the issue of the discontinuation of imatinib in CML with undetectable residual disease for more than 2 years in 15 patients. The median duration of RTQ-PCR negativity and imatinib therapy were respectively 32 months (24–46) and 45 months (32–56) before imatinib interruption. Eight patients displayed a molecular relapse with a detectable BCR-ABL transcript appearance between the first 6 months. Imatinib was then re-introduced and led to a novel molecular response in most patients. Seven other patients have still an undetectable level of BCR-ABL transcript after a median follow up of 20 months (9–24). With the assumption that the doubling time of a proliferative CML cell is 8 days, it will take a maximum of 6 months if only one leukemic cell persists and proliferates to reach 107 cells i.e corresponding to a residual disease detectable by RTQ-PCR. Relapses observed within 6 months may reflect the kinetic of undetectable dividing CML cells. Those cells may be eradicated or controlled in long term non relapsing patients described in our study.

Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years

Blood ◽  
2006 ◽  
Vol 109 (1) ◽  
pp. 58-60 ◽  
Author(s):  
Philippe Rousselot ◽  
Francoise Huguet ◽  
Delphine Rea ◽  
Laurence Legros ◽  
Jean Michel Cayuela ◽  
...  
Keyword(s):  
Imatinib Mesylate ◽  
Chronic Myelogenous Leukemia ◽  
Residual Disease ◽  
Quantitative Polymerase Chain Reaction ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Polymerase Chain ◽  
Kinetics Of

Abstract In the present study, we address the issue of the discontinuation of imatinib mesylate (Gleevec) in chronic myelogenous leukemia with undetectable residual disease for more than 2 years. Twelve patients were included. The median duration of real-time quantitative–polymerase chain reaction (RTQ-PCR) negativity and imatinib therapy were, respectively, 32 months (range, 24-46 months) and 45 months (range, 32-56 months) before imatinib interruption. Six patients displayed a molecular relapse with a detectable BCR-ABL transcript at 1, 1, 2, 3, 4, and 5 months. Imatinib was then reintroduced and led to a novel molecular response in most patients. Six other patients (50%) still have an undetectable level of BCR-ABL transcript after a median follow-up of 18 months (range, 9-24 months). We hypothesize that relapses observed within 6 months reflect the kinetics of undetectable dividing chronic myelogenous leukemia (CML) cells. Those cells may be eradicated or controlled in long-term nonrelapsing patients, as described in our study.

Loss of Major Molecular Response As a Trigger for Restarting Tyrosine Kinase Inhibitor Therapy in Patients With Chronic-Phase Chronic Myelogenous Leukemia Who Have Stopped Imatinib After Durable Undetectable Disease

2014 ◽  
Vol 32 (5) ◽  
pp. 424-430 ◽  
Author(s):  
Philippe Rousselot ◽  
Aude Charbonnier ◽  
Pascale Cony-Makhoul ◽  
Philippe Agape ◽  
Franck E. Nicolini ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Multicenter Observational Study ◽  
Tyrosine Kinase Inhibitor Therapy ◽  
Treatment Free Remission

Purpose More than half of patients with chronic-phase chronic myelogenous leukemia (CP-CML) in complete molecular response (CMR) experience molecular relapse after imatinib discontinuation. We investigated loss of major molecular response (MMR) as a criterion for resuming therapy. Patients and Methods A multicenter observational study (A-STIM [According to Stop Imatinib]) evaluating MMR persistence was conducted in 80 patients with CP-CML who had stopped imatinib after prolonged CMR. Results Median time from imatinib initiation to discontinuation was 79 months (range, 30 to 145 months);median duration of CMR before imatinib discontinuation was 41 months (range, 24 to 96 months); median follow-up after discontinuation was 31 months (range, 8 to 92 months). Twenty-nine patients (36%) lost MMR after a median of 4 months off therapy (range, 2 to 17 months). Cumulative incidence of MMR loss was estimated as 35% (95% CI, 25% to 46%) at 12 months and 36% (95% CI, 26% to 47%) at 24 months, whereas probability of losing CMR was higher. Fluctuation of BCR-ABL transcript levels below the MMR threshold (≥ two consecutive positive values) was observed in 31% of patients after imatinib discontinuation. Treatment-free remission was estimated as 64% (95% CI, 54% to 75%) at 12 and 24 months and 61% (95% CI, 51% to 73%) at 36 months. Median to time to second CMR was estimated as 7.3 months in re-treated patients. Conclusion Loss of MMR is a practical and safe criterion for restarting therapy in patients with CML with prolonged CMR.

Imatinib Mesylate Induces High Complete Cytogenetic and Molecular Response Rates in Children and Adolescents with Philadelphia Chromosome-Positive (Ph+) Chronic Myelogenous Leukemia (CML) in Chronic Phase (CP)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4273-4273
Author(s):  
Fiorina Giona ◽  
Maria Caterina Putti ◽  
Maria Luisa Moleti ◽  
Mauro Nanni ◽  
Anna Maria Testi ◽  
...  
Keyword(s):  
Children And Adolescents ◽  
Imatinib Mesylate ◽  
Kinase Inhibitor ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Real Time Quantitative Pcr

Abstract Imatinib mesylate (IM), a BCR-ABL tyrosine kinase inhibitor, is an effective therapy for CML in adults and has shown efficacy in children with Ph+ leukemias. The aim of this study was to evaluate the efficacy of IM in Ph+ CML patients (pts) in CP aged <18 years at diagnosis, previously untreated or resistant to Interferon (IFN). In all pts, IM therapy, started at a dose of 340 mg/m2/day, was modulated according to the hematologic parameters. Cytogenetic studies were performed on bone marrow (BM) cells at baseline and, during IM therapy, every 3 months (mo). Complete cytogenetic response (CCyR) was also confirmed by FISH. BCR-ABL transcripts were measured in the peripheral blood (PB) cells every mo and in the BM cells every 3 mo by real-time quantitative PCR (RQ-PCR). Molecular response (MolR) was defined as major in the presence of a BCRABL: ABL ratio <0.05% and as complete with a ratio <0.001. Between February 2001 and October 2007, 13 Ph+ CML pts (9 M and 4 F; median age 128/12 years) in CP were recruited from 2 pediatric centers (Rome and Padua). Eight of the 13 pts (7 M and 1 F; median age 11 years) received IM at diagnosis and 5 (3 F and 1 M; median age 146/12 years) after IFN therapy given at a mean dose of 6.000.000 UI/day for a median of 18 mo. All but 1 pt tolerated well IM treatment. The mean dose of IM administered was 326 mg/m2/day for untreated pts and 227 mg/m2/day for those resistant to IFN. The characteristics and followup of the pts are summarized in the Table: Sex/Age at diagn/Age at treat (yrs) IFN duration/%Ph+ IM mg/m2/day CCyR/time (mo) Max Bcr-Abl:Abl (%)/time (mo) (BM) Max Bcr-Abl:Abl (%)/time (mo) (PB) CCyR duration (mo) Follow-up .F/11/146/12 40 mo/100 193.5 4 0/60 0/4 +80 Alive CCyR, Bcr-Abl:Abl (%)BM 0 PB 0.0023 F/179/12/1810/12 9 mo/100 182 6 1.27/9 0.89/9 +7 Lost to follow-up in CCyR at + 13 mo M/91/12/117/12 26 mo/50 208 3 0/36 0/12 +65 Alive CCyR, Bcr-Abl:Abl (%)BM 0 PB 0 F/89/12/910/12 13 mo/50 350 3 0/44 0/66 +66 Alive CCyR, Bcr-Abl:Abl (%)BM 0.009 PB 0 M/172/12/189/12 18 mo/80 205 9 0.029/68 0.114/72 +82 Alive CCyR, Bcr-Abl:Abl (%)BM 0.05 PB 0.15 M/126/12 −/100 310 4 0/42 0/30 +66 Alive CCyR, Bcr-Abl:Abl (%): BM 0 PB 0 M/161/12 −/100 327 n.e. n.e. n.e. n.e. IM tox; alive CCyR after SCT (sibl) (+40 mo) M/144/12 −/100 291 4 0/42 0/24 +61 Alive CCyR, Bcr-Abl:Abl (%) BM 0 PB 0 M/811/12 −/100 357.5 6 0.044/9 0.057/9 CyRel/33 Alive CCyR after SCT (+ 8 mo) M/95/12 −/100 326 3 0.013/12 0.028/9 +12 Alive CCyR,Bcr-Abl:Abl (%) BM 0.013 PB 0.15 M/410/12 −/100 328.5 3 0.02/9 0/12 BMT/+13 SCT (sibl) in CCyR->Alive in CCyR +43 mo M/137/12 −/100 349 6 0.012/30 0.025/30 +32 Alive CCyR, Bcr-Abl:Abl (%) BM 0.012 PB 0.025 F/94/12 −/100 320 3 0.009/9 0.003/9 +7 Alive CCyR, Bcr-Abl:Abl (%) BM 0.02 PB 0.003 Twelve of the 13 pts (92%) achieved a CCyR after a median of 4 mo (range 3–9). Eleven of the latter 12 pts were evaluated for MolR: 11/11 (100%) pts achieved a MolR, 6 major (54.5%) and 5 complete (45.5%), on BM cells after a median of 36 mo (range 9–68) and 9/11 pts (82%) on PB cells, 4 major (44.4%) and 5 complete (55.6%), after a median of 12 mo (range 4–66). To date, 12 evaluable pts are alive in CCyR: 3 after a stem cell transplantation (SCT) and 9 still receiving IM for a median time of 68 mo (range 10–89). MolR persists on BM cells in 9/9 pts (100%), 4 complete (44%), and on PB cells in 7/9 pts (78%), 4 complete. Our experience indicates that IM is highly effective in children and adolescents with Ph+ CML in CP, capable also of inducing high and persistent CCyR and MolR rates also in pts resistant to IFN.

The Natural History of RTQ-PCR Levels After the Achievement of Complete Molecular Remission (CMR): Implications for ‘Stopping' Studies

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 605-605 ◽  
Author(s):  
Dragana Milojkovic ◽  
Gareth Gerrard ◽  
Christos Paliompeis ◽  
Marco Bua ◽  
Alistair Reid ◽  
...  
Keyword(s):  
Natural History ◽  
Kinase Inhibitor ◽  
Residual Disease ◽  
Chronic Phase ◽  
Molecular Response ◽  
First Line ◽  
Molecular Remission ◽  
Negative Results ◽  
History Of

Abstract Abstract 605 Variations in RTQ-PCR estimations of BCR-ABL1 transcript numbers between laboratories have resulted in recognised difficulties in interpreting results and have led to a global effort of harmonisation via an international reporting scale (IS). Currently this is achieved in a limited number of laboratories worldwide by exchange of samples and will hopefully be replaced by the production of internationally accredited reference reagents. Differences in the limits of sensitivity of assays in different laboratories pose particular problems in the definition and interpretation of molecular negativity, so-called complete molecular remission (CMR), leading some investigators to suggest distinctions between assays capable of detecting 4, 4.5 and 5 log reductions in tumour load and introducing the terms CMR4, CMR4.5 and CMR5. These definitions take on particular relevance when designing studies of de-escalation and/or stopping tyrosine kinase inhibitor (TKI) therapy. In the French STIM trial, criteria for stopping were relatively stringent in that patients were required to have at least 5 results of RTQ-PCR negativity in their local laboratory sustained over at least 2 years and confirmed on one further occasion in the centralised laboratory. Negative results of BCR–ABL 1 amplification were reported only if the RNA was of good quality and quantity (50 000 copies of normal ABL1). Subsequently several groups are designing similar studies. As our ability to stop treatment must in large part be determined by the level of residual disease at the time of cessation, it is important to have robust definitions of CMR. We maintain a comprehensive database of all our CML patients on TKI. For chronic phase this database now contains 521 patients (273 [52%] male) of median age 48 yrs (range 13–86). 212 patients received interferon prior to TKI therapy. The median follow up for surviving patients is 76 mths (range15-137). 88 (37 [42%] male) of these patients have achieved RTQ-PCR molecular negativity on more than one occasion and prompted us to identify the proportion that would satisfy entry criteria for a stopping study and hence the natural history of RTQ-PCR results in such patients. Confirmed complete molecular response (cCMR) was defined as two consecutive samples with no detectable transcripts at least 4 weeks apart with an ABL1 control >40,000 copies (median ABL1 control in the CMR samples was 84,000 copies). 64 patients met our criteria for cCMR, the remaining 24 patients had at least two negative results but never consecutively. 56 patients achieved cCMR on their first line TKI (imatinib in all but 2). Times from diagnosis to MMR and cCMR in this cohort were a median of 24 (range 3–77) and 46 mths (range 5–118) respectively. The median time from MMR to cCMR was 26 mths (range 0–89). Excluding 8 patients in whom follow-up since cCMR is less than 24 months the median duration from cCMR is 53 mths (range 24–113), Only one patient has subsequently lost MMR confirming the excellent prognosis of this cohort. However, only 10 patients (21%) have sustained RTQ-PCR negativity over a 2 year period that would deem them eligible for a STIM-equivalent study. If we were to define a less stringent CMR4.5 as a BCR-ABL ratio of 0.0032 in the international scale the number of eligible patients increases to 18/48 (37.5%). If we applied CMR4.5 to the 24 patients without consecutive RTQ-PCR results a further 3 patients would meet the criteria for a stopping study, total 21/88 (24%). In conclusion the numbers of patients eligible for stopping studies confined to sustained cCMR is relatively few although we cannot exclude the possibility that some patients were not entirely compliant. Although not proven, reducing the stringency of the definition of CMR is likely to lead to higher relapse rates in subsequent stopping studies than in the original STIM trial. This must be considered when interpreting the results of first-line second generation TKI where the rates of achievement of MMR and CMR may be higher than with imatinib. In these studies CMR may not be synonymous with a 50% chance of discontinuing treatment permanently and future studies might more appropriately consider strategies of de-escalation rather than cessation. Disclosures: Apperley: Novartis: Honoraria, Research Funding; Bristol Myers Sqibb: Honoraria; Ariad: Honoraria; Chemgenex: Honoraria; Genzyme: Honoraria.

scholarly journals Significance of Increasing Levels of Minimal Residual Disease in Patients With Philadelphia Chromosome–Positive Chronic Myelogenous Leukemia in Complete Cytogenetic Response

2009 ◽  
Vol 27 (22) ◽  
pp. 3659-3663 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Jianqin Shan ◽  
Daniel Jones ◽  
Susan O'Brien ◽  
Mary Beth Rios ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Kinase Inhibitors ◽  
Residual Disease ◽  
Quantitative Polymerase Chain Reaction ◽  
Philadelphia Chromosome ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Therapeutic Interventions ◽  
Molecular Response ◽  
Complete Cytogenetic Response

Purpose The aim of this study was to evaluate the clinical relevance of increases in quantitative polymerase chain reaction (QPCR) levels in patients with chronic myelogenous leukemia (CML) who are in complete cytogenetic response (CGCR) on therapy. Patients with Philadelphia chromosome (Ph)–positive CML receiving tyrosine kinase inhibitors (TKIs) are frequently monitored for response by QPCR studies for minimal molecular disease. The clinical significance of increasing levels of QPCR in patients in CGCR is uncertain. Patients and Methods One hundred sixteen patients in durable CGCR, and on imatinib therapy for at least 18 months, had increases in QPCR levels (documented at least twice consecutively) as defined by literature reports. These were further analyzed by the achievement of major molecular response (MMR) defined as QPCR ≤ 0.05%, as well as by the degree of increase in QPCR. Results Only 11 (9.5%) of 116 patients with increases in QPCR had CML progression; 10 of them were among 44 patients (23%) who either lost a MMR or never had a MMR, and had more than 1 log increase of QPCR. Conclusion Most patients with increases in QPCR remain in CGCR. Patients who lose a MMR or never achieve a MMR, and have more than 1 log increase of QPCR, should be monitored more closely, and may be evaluated for mutations of BCR-ABL kinase domain and considered for investigational therapeutic interventions.

Imatinib Mesylate Therapy in Late Ph+ Chronic Myeloid Leukemia Patients in Stable Complete Cytogenetic Response after Interferon-Alpha Results in a Very High Complete Molecular Response Rate.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2158-2158
Author(s):  
Giuliana Alimena ◽  
Massimo Breccia ◽  
Luigia Luciano ◽  
Fabrizio Quarantelli ◽  
Daniela Diverio ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Imatinib Mesylate ◽  
Copy Number ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Complete Cytogenetic Response ◽  
Complete Molecular Response

Abstract Imatinib mesylate was given to 26 Philadelphia positive (Ph+) chronic myeloid leukemia (CML) patients who were in late chronic phase (CP) and in stable complete cytogenetic response (CCR) after interferon-alfa (IFN-α), but showed persistent positive residual disease at PCR analysis under this treatment. At diagnosis median age was 40 years (range 21–64) and according to Sokal’s score, 18 patients were low risk and 8 were intermediate risk. Median IFN treatment was 88 mo.s (range 15–202) and median CCR duration was 73 mo.s (range 10–148). Imatinib was administered at the standard dose of 400 mg/die, after stopping IFN for 1 week. Residual disease was measured on bone marrow (BM) cells at baseline, before starting Imatinib, at 3, 6, 12, 18 mo.s and at the last follow-up (median 32 mo.s, range 21–49), by assaying BCR-ABL transcripts using quantitative PCR (RQ-PCR). The copy number (CN) of BCR/ABL and ABL transcript were derived by the interpolation of CT values to the appropriate standard curve, and the result, for each sample, was expressed as ratio of BCR/ABL mRNA copies to ABL mRNA x 100 (normalized copy number - NCN). Imatinib treatment resulted in a progressive and consistent decline of residual disease in all but one patient, from a median of 0.89 at baseline to 0.01 at the end of follow-up. Major molecular response (BCR/ABL levels <0.1) was reached in 20 patients (77%) and BCR/ABL transcripts were undetectable in 13 (50%). Achievement of molecular response was significantly correlated with post-IFN baseline transcript level (mean 1.194 for patients achieving complete molecular response vs 18,97 for those who did not; p<0.001), but not with other clinical/biological patient characteristics. In all patients, imatinib was well tolerated with no side effects requiring drug dose reduction or dose discontinuation. Albeit obtained from an unusual subset of selected patients with favourable prognosis, and likely particularly sensitive to imatinib, present results confirm the efficacy of combining Imatinib and IFN-α and further support investigating treatment approaches employing these two drugs.

Dasatinib (SPRYCEL®) Efficacy and Safety in Patients (pts) with Chronic Myelogenous Leukemia in Lymphoid (CML-LB) or Myeloid Blast (CML-MB) Phase Who Are Imatinib-Resistant (Im-r) or -Intolerant (Im-i).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 745-745 ◽  
Author(s):  
Giovanni Martinelli ◽  
A. Hochhaus ◽  
S. Coutre ◽  
J.F. Apperley ◽  
N. Shah ◽  
...  
Keyword(s):  
Median Duration ◽  
Kinase Inhibitor ◽  
Mutational Analysis ◽  
Blast Crisis ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Blast Phase ◽  
Phase Ii Studies ◽  
Grade 3

Abstract Pts with CML-LB or CML-MB have a poor prognosis with survival from onset of blast crisis of 3–6 months. Dasatinib (SPRYCEL®, formerly BMS-354825) is a multi-targeted kinase inhibitor of BCR-ABL and SRC, which results in complete hematologic and cytogenetic responses in pts with CML-LB or CML-MB who are Im-i, or who have disease that is Im-r. Between January and June 2005, 48 CML-LB pts were enrolled in the START-L trial, and 109 CML-MB pts in the START-B trial both of which were open label, multi-center, global phase II studies. As previously reported, with a minimum of 6-months follow up in the combined blast-phase pts, the major hematologic response (MHR) rate was 32% including 26% complete hematologic responses (CHR) and the major cytogenic response (MCyR) rate was 38%, including 31% complete cytogenetic responses (CCyR). The median duration of MHR had not been reached and the median progression-free survival (PFS) was 4.3 months (mo). In both studies, dasatinib was given orally, 70 mg twice daily (BID) with escalation to 100 mg BID for poor response or reductions to 50 mg and 40 mg BID for toxicity. Pts had weekly blood counts and monthly bone marrow exams, including cytogenetics. Mutation analysis was conducted at baseline and at end of study. Quantitative PCR was carried out at pretreatment and at the time of CCyR. Overall, among all blast-crisis pts in both studies, 90% were Im-r. Due to the small number of Im-i pts, data for all pts is presented. Among the 157 pts, 56% were male, with a median age of 54 years (range 17–81). The median time from diagnosis of CML was 45 mo (range 2–216). Prior therapy included Im &gt;600 mg/d in 50%, with Im for &gt;3 years in 36% and stem cell transplantation in 19% of the pts. At baseline, 57% of pts had WBC &lt;20,000/mm3, 69% had platelets &lt;100,000/mm3, and 17% had extramedullary disease outside of the spleen. In the 149 pts with baseline mutation data, Im-resistant BCR-ABL mutations were observed in 50%. With a minimum of 9 mo follow up on all pts, 19% pts remained on treatment with disease progression as the most common reason for discontinuation. Overall, doses were reduced in 33% of pts and interrupted in 59%, most commonly due to non-hematologic toxicities. Dasatinib dose was escalated in 43% of pts. The median duration of therapy was 3.4 mo (0.03–18) in all pts and was 14 mo (6–18) in pts still on treatment. The MHR rate was 34% including 27% CHR; the MCyR was 38% including 31% CCyR. Of the 73 pts with baseline mutations, the MHR rate was 32%. The median duration of MHR still has not been reached and the median PFS was 4.3 mo. Among all pts, grade 3–4 thrombocytopenia occurred in 17% and 68%, respectively and grade 3–4 neutropenia was observed in 17% and 63%, respectively. Most frequent non-hematologic toxicities included diarrhea in 37% (grade 3–4, 5%), pleural effusion in 27% (grade 3–4, 11%), vomiting in 22% (grade 3–4, 3%), nausea in 20% (grade 3–4, 3%), and fatigue in 21% (grade 3–4, 3%) of pts. Dasatinib has efficacy in pts with blast phase CML including some with substantial duration of response and PFS. Updated efficacy (including molecular response), safety, and mutational analysis data will be presented at the meeting.

Significance of Rising Levels of Minimal Residual Disease in Patients with Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia (Ph+ CML) in Complete Cytogenetic Response (CGCR)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 445-445 ◽  
Author(s):  
Hagop M Kantarjian ◽  
Jianqin Shan ◽  
Dan Jones ◽  
Susan O’Brien ◽  
Mary Beth Rios ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Residual Disease ◽  
Quantitative Polymerase Chain Reaction ◽  
Philadelphia Chromosome ◽  
Disease Status ◽  
Myelogenous Leukemia ◽  
Therapeutic Interventions ◽  
Imatinib Therapy ◽  
Molecular Response ◽  
Cell Transplant

Abstract Background . Patients with Ph+ CML receiving tyrosine kinase inhibitors (TKIs) are frequently monitored for response by quantitative polymerase chain reaction (QPCR) studies for minimal molecular disease. The clinical significance of rising levels of QPCR in CGCR is uncertain. Study Aims . To evaluate the relevance of increases of QPCR levels in patients with CML in CGCR on therapy. Study Group and Methods . Of 258 patients on imatinib therapy for newly diagnosed CML, 116 patients in durable CGCR on imatinib therapy for at least 18 months had significant QPCR increases (documented at least twice) as defined by literature reports. These were analyzed by the achievement of major molecular response (MMR; QPCR &lt; 0.05%), and by the degree of QPCR increase. Results. The outcome of patients by disease status (still in MMR vs. loss of MMR vs. never in MMR) and by the QPCR level increase are shown in the Table. Only 13 of 116 patients (11%) with significant QPCR increases had CML progression; 11 of them were among 44 patients (25%) who either lost a MMR or never had a MMR, and had &gt; 1 log increase of QPCR. The 5-year survival of all 116 patients was 92%, suggesting the minimal relevance of QPCR increases in patients in CGCR. Conclusion . Most patients with significant QPCR increases remain in CGCR. Patients who lose a MMR or never achieve a MMR, and have &gt; 1 log increase of QPCR, should be monitored more closely, and may be evaluated for mutations of BCR-ABL kinase domain and considered for investigational therapeutic interventions. Allogeneic stem cell transplant should not be considered in view of the excellent survival. Outcome of Patients in CGCR by QPCR Increases Disease Status QPCR Log increase No. Patients CML Progression Median follow-up from QPCR increase in months (range) Persistent MMR Any 28 0 36 (3–62) Loss of MMR &gt;0.5–1 12 0 34 (14–59) &gt;1–2 25 3 31 (6–52) &gt;2 11 4 45 (20–57) Not in MMR &lt;1 32 2 35 (10–70) &gt;1 8 4 25 (12–56)

Imatinib mesylate therapy in newly diagnosed patients with Philadelphia chromosome–positive chronic myelogenous leukemia: high incidence of early complete and major cytogenetic responses

Blood ◽  
2003 ◽  
Vol 101 (1) ◽  
pp. 97-100 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Jorge E. Cortes ◽  
Susan O'Brien ◽  
Francis Giles ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Imatinib Mesylate ◽  
Chronic Myelogenous Leukemia ◽  
Quantitative Polymerase Chain Reaction ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Interferon Α ◽  
Combination Regimens ◽  
Philadelphia Chromosome Positive

Abstract Fifty patients with Philadelphia chromosome–positive (Ph+) chronic myelogenous leukemia (CML) in early chronic phase received imatinib mesylate, 400 mg orally daily. After a median follow-up of 9 months, 49 patients (98%) achieved a complete hematologic response and 45 patients (90%) achieved a major cytogenetic response, complete in 36 patients (72%). Compared with similar patients who received interferon-α with or without hydroxyurea or other interferon-α combination regimens, those receiving imatinib mesylate had higher incidences of complete and major (Ph &lt; 35%) cytogenetic responses at 3 months (34% and 74% versus 1%-4% and 9%-24%, respectively), 6 months (52% and 80% versus 3%-7% and 11%-28%, respectively), and 9 months (60% and 77% versus 5%-11% and 14%-30%, respectively; P &lt; .001). Competitive quantitative polymerase chain reaction (QPCR) studies at 9 months showed a median QPCR value (ratio of BCR-ABL/ABL transcripts × 100) of 0.59% overall and of 0.24% (range, 0.001%-29.5%) for complete cytogenetic response.

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