Does pre-imatinib (IM) fluorescence in situ hybridization (FISH) predict myelosuppression and outcomes in chronic myeloid leukemia (CML)?

7071 Background: IM-associated myelosuppression occurs in 4–40% of CML patients (pts) vs. 1–16% in GIST. Selective inhibition of predominantly Philadelphia chromosome (Ph+) driven hematopoiesis may explain development of myelosuppression. In the absence of clinically applicable methods to quantitate Ph+/Ph- progenitor ratio, we hypothesized that the pre-IM percentage of BCR-ABL+ cells measured by FISH predicts myelosuppression. Methods: FISH pre-IM was available in 58 CML pts with chronic phase (CP, n=52), or advanced phase (AP, accelerated =3, blast =3) at 2 institutions. Grade >3 myelosuppression occurred < 60 days from starting IM in 9 pts (400 mg/d=6, > 600 mg/d=3), leading to dose reduction (4), discontinuation (1) or continuation same dose IM despite myelosuppression (4). Cryopreserved marrow CD34+/CD38- cells from 14 pts with (7) or without (7) post-IM myelosuppression were sorted using flow cytometry and subjected to FISH analyses. Results: Median FISH was higher for myelosuppression (90%) vs. no myelosuppression (80%) pts (p= 0.03), and in AP vs. CP (97 % vs. 80%, p=0.003). Results of FISH on CD34+/CD38- cells will be reported. Table summarizes outcomes of CP pts. Median follow-up was 14 and 45 months for myelosuppression and no myelosuppression AP pts, respectively. Myelosuppression AP pts expired (CML=2, GVHD=1); 1 after complete hematologic (CHR) and minor cytogenetic response (CTGR), 1 after partial HR, and 1 resistant disease. All 3 pts without myelosuppression achieved CHR with major CTGR, and 2 had partial molecular response. 1 died from GVHD. Conclusions: Higher FISH pre-IM identifies a group of CML pts who develop myelosuppression and are less likely to respond to IM. [Table: see text] No significant financial relationships to disclose.

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Initial treatment for patients with CML

Hematology ◽

10.1182/asheducation-2009.1.453 ◽

2009 ◽

Vol 2009 (1) ◽

pp. 453-460 ◽

Cited By ~ 18

Author(s):

John M. Goldman

Keyword(s):

Initial Treatment ◽

Myeloid Leukemia ◽

Kinase Inhibitor ◽

Philadelphia Chromosome ◽

Chronic Phase ◽

Cytogenetic Response ◽

Molecular Response ◽

Major Molecular Response ◽

Log Reduction ◽

Advanced Phase

AbstractFor adult patients who present with chronic myeloid leukemia (CML) in chronic phase it is now generally agreed that initial treatment should start with the tyrosine kinase inhibitor (TKI) imatinib at 400 mg daily. Five years after starting imatinib about 60% of these patients will be in complete cytogenetic response (CCyR), still taking imatinib; an appreciable proportion of these will have achieved a major molecular response, defined as a 3-log reduction in the level of BCR-ABL1 transcripts in their blood. The patients in CCyR seem to have a very low risk of relapse to chronic phase or of progression to advanced phase. Other patients may be resistant to imatinib or may experience significant side effects that require change of therapy. The best method of monitoring responding patients is to enumerate Philadelphia chromosome–positive marrow metaphases at 3-month intervals until CCyR and to perform RQ-PCR for BCR-ABL1 transcripts at 3-month intervals after starting imatinib. The recommendations for defining “failure” and “sub-optimal response” proposed by the European LeukemiaNet in 2006 have proved to be a major contribution to assessing responses in individual patients and are now being updated. Patients who fail imatinib may respond to second-generation TKIs, but allogeneic stem cell transplantation still plays an important role for eligible patients who fare badly with TKIs. Patients who present in advanced phases of CML should be treated initially with TKI alone or with TKI in conjunction with cytotoxic drugs, but their overall prognosis is likely to be much inferior to that of those presenting in early chronic phase.

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Results of Imatinib Dose Escalation After 36 Months of Follow-up in Chronic Myeloid Leukemia Patients with Failure or Sub-Optimal Response According to 2006 EuropeanLeukemia Net (ELN) Criteria.

Blood ◽

10.1182/blood.v114.22.3302.3302 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3302-3302

Author(s):

Massimo Breccia ◽

Fabio Stagno ◽

Roberto Latagliata ◽

Paolo Vigneri ◽

Laura Cannella ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Dose Escalation ◽

Myeloid Leukemia ◽

Conflicts Of Interest ◽

Standard Dose ◽

Acquired Resistance ◽

Chronic Phase ◽

Cytogenetic Response ◽

Molecular Response

Abstract Abstract 3302 Poster Board III-190 Introduction Imatinib mesylate (IM) given at a daily dose of 400 mg currently represents the gold standard of care for patients with chronic myeloid leukemia (CML) in chronic phase (CP). European LeukemiaNet (ELN) guidelines propose IM dose escalation to rescue those CML patients with either suboptimal response or drug resistance. We report on the long-term efficacy of IM dose escalation in 74 patients with CP-CML after suboptimal response or failure to IM conventional dose. Patients and methods Median age was 50 years (range 19-85), there were 52 males and 22 females. Thirteen patients were classified as hematologic failure (10 primary and 3 secondary), 57 patients as cytogenetic resistance (24 primary and 33 acquired). Three patients escalated the dose for cytogenetic suboptimal response and one patient for molecular suboptimal response at 18 months. Fifty-four received IM dose escalation from 400 to 600 mg and 20 patients from 400 to 800 mg. Results Overall, after a median follow-up of 36 months, 68/74 (91.8%) patients maintained or achieved a complete haematologic response (CHR); this was maintained in all patients who escalated the dose for cytogenetic failure or suboptimal response. A major cytogenetic response (MCyR) was achieved in 41 patients (72%) who escalated the dose for cytogenetic failure and in 6/13 (46%) patients who escalated imatinib for hematologic failure (p=0.002). Overall, complete cytogenetic responses (CCR) were achieved in 27 (37%) out of 74 CML patients: of the 13 hematologic failure patients, only 5 achieved CCyR: all patients had prior acquired resistance to imatinib. Of the 57 cytogenetic failure, 22 reached CCR: this response was obtained in 27% of the primary cytogenetic resistant, and in 50% of the acquired cytogenetic resistant patients (p=0.02). Three patients who escalated the dose for cytogenetic suboptimal response obtained CCR and complete molecular response (CMR), whereas one patient who escalated the dose for molecular suboptimal response at 18 months did not obtain CMR. Median time to cytogenetic response was 3.5 months. Cytogenetic responses occurred in 37/50 patients who escalated the dose to 600 mg and in 10/20 patients who escalated to 800 mg daily (p=0.234). CMR was obtained in 10 patients: in 7 patients who escalated the dose for cytogenetic failure and in 3 patients who escalated imatinib for suboptimal cytogenetic response. Estimated 2 year-progression free survival (PFS) and overall survival (OS) is 87% and 85% respectively. Sixteen patients (21.6%) experienced toxicities and had temporarily IM interruption. Conclusions Imatinib dose escalation can induce sustained responses in a subset of patients with cytogenetic resistance and a prior suboptimal cytogenetic response to standard-dose imatinib, whereas it appears less effective in haematologic failure patients or in molecular sub-optimal responders. The availability of second generation TKI should be taken into account in these letter categories of patients. Disclosures No relevant conflicts of interest to declare.

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Clinical Outcome of CML Patients with Philadelphia Chromosome Complex Variants.

Blood ◽

10.1182/blood.v116.21.4499.4499 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4499-4499

Author(s):

Santiago del Castillo ◽

Regina Garcia Delgado ◽

Laura Entrena ◽

Agustin M Hernandez ◽

Arturo Campos ◽

...

Keyword(s):

Conflicts Of Interest ◽

Philadelphia Chromosome ◽

Genetic Material ◽

Chronic Phase ◽

Cytogenetic Response ◽

Molecular Response ◽

Imatinib Treatment ◽

Current State ◽

Worse Prognosis

Abstract Abstract 4499 INTRODUCTION: The presence of translocation between chromosomes 9 and 22 that characterizes the chronic myeloid leukemia (CML) is occasionally accompanied by more complex variations involving additional exchange of genetic material with other chromosomes. This variants of Philadelphia chromosome have no worse prognosis than those others with the common translocation. MATERIAL: Since 1997 we have diagnosed in our hospital 5 CML patients who didn't show any of these variants. Three women 17, 23 and 76 years old and two men of 36 and 65. All of them diagnosed in chronic phase. Risk stage at diagnosis by Sokal were 1 high, 1 intermediate and 3 low. By Hasford 2 were intermediate end 3 low. Philadelphia chromosome variants involve a third chromosome in 4 cases (translocations 2;9;22, 9;22;12, 9;22;9 and 6;9;22) and in one case involving four chromosomes (translocation 1;2;9;22). Three patients diagnosed before the imatinib approval started treatment with IFN and Ara-C and subsequently changed to Imatinib treatment. Two others started treatment with imatinib directly. RESULTS: All patients had a good outcome with treatment being the current state of 2 patients in complete molecular response (105 and 60 months of follow-up) and 2 patients in Major Molecular Response (146 and 143 months). The 5th patient, a 17 years old woman, has been treated for three months with Imatinib and showed complete haematological response at first month and major cytogenetic response at third month. It is striking in this last patient the fact that two years earlier had been referred for study of myeloid moderate leukocytosis (20,000 leukocytes with circulating myeloid progenitors without anemia, thrombocytosis, or splenomegaly). The patient didn't come to clinic when Bone Marrow Test was cited and two years later resumes the visit continuing with the same leukocytosis in peripheral blood and without splenomegaly unchanged despite not having received any treatment. CONCLUSION: Our experience confirm that this type of patients with complex translocation variants have no worse prognosis than normal translocation under imatinib treatment and suggests that may have a more benign clinical behavior. Disclosures: No relevant conflicts of interest to declare.

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Clinical Efficacy and Safety Of Dasatinib For Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase In Japan

Blood ◽

10.1182/blood.v122.21.1493.1493 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1493-1493

Author(s):

Kohei Yamaguchi ◽

Kazunori Murai ◽

Shigeki Ito ◽

Tomoaki Akagi ◽

Kazuei Ogawa ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Cytogenetic Response ◽

Molecular Response ◽

Newly Diagnosed ◽

Efficacy And Safety ◽

Major Molecular Response ◽

Once Daily

Abstract Background Dasatinib is a second-generation BCR-ABL inhibitor that has a 325-fold higher potency than imatinib and a 16-fold higher potency than nilotinib in vitro. The previous report from the global DASISION trial showed dasatinib resulted in significantly higher and faster rates of complete cytogenetic response (CCyR) and major molecular response (MMR) compared with imatinib. We conducted a phase II study to evaluate the efficacy and safety of dasatinib in patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML-CP) in Japan. Methods Eighty newly diagnosed CML-CP patients were include in this study. Patients received dasatinib 100mg once daily. Treatment was continued until disease progression or unacceptable toxicity. Primary end point was the rate of major molecular response (MMR) by 12 months. MMR defined as a BCR-ABL transcript level of 0.1% or lower on the International scale by means of a real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) in peripheral blood. Secondary end points were the rate of complete cytogenetic response (CCyR) by 12 months, the rate of MR4.5 (either (i) detectable disease with <0.0032% BCR-ABL1 IS or (ii) undetectable disease in cDNA with >32,000 ABL1 transcripts in the same volume of cDNA used to test for BCR-ABL1) by 12 months and adverse events of dasatinib (UMIN #000006358). Results Eighty newly diagnosed CML-CP patients were included in this study. All except one patient administered dasatinib 100 mg once daily. One patient was withdrawal before administration of dasatinib. So far, there were 71 patients with 6 months follow-up and 51 patients with 12 months follow-up. The estimated MMR rates were 69.5 % (95%CI, 58.7-80.3 %) by 6 months and 82.7% (95%CI, 73.0-92.4 %) by 12 months. The estimated MR4.5 rates were 27.1 % (95%CI, 16.7-37.5 %) by 6 months and 48.9% (95%CI, 36.0-61.7 %) by 12 months. Only 6 patients were withdrawal because of adverse event (5 patients) and ineffectiveness (1 patient). Conclusion Dasatinib treatment results in higher rates of molecular responses in newly diagnosed CML-CP patients in Japan. Dasatinib as the first-line agent might be acceptable for CML-CP patients because of better clinical efficacy and less toxicity. Disclosures: No relevant conflicts of interest to declare.

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Predictive Value Of Early Molecular Responses In Outcomes Of Patients With Chronic Myeloid Leukemia Treated With Imatinib In First-Line Therapy

Blood ◽

10.1182/blood.v122.21.4941.4941 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4941-4941

Author(s):

Katia B. Pagnano ◽

Bruna Vergilio ◽

Eliana C M Miranda ◽

Marcia Torresan Delamain ◽

Maria Helena De Almeida ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Cytogenetic Response ◽

Molecular Response ◽

First Line ◽

Molecular Responses ◽

Advanced Phase ◽

Significant Difference ◽

The Impact

Abstract Several studies demonstrated the prognostic significance of an early molecular response in chronic myeloid leukemia (CML) patients (pts) treated with imatinib in first line or other tyrosine kinase inhibitors. Aims: The aim of this study was to evaluate the impact of early molecular responses, at 3 and 6 months after treatment with imatinib in CML pts and correlate these responses with CCR, MMR, overall survival (OS) and event free survival (EFS). Patients and Methods Between February 2006 and June 2012, 95 adult pts with newly diagnosed CML in chronic phase (CP) received imatinib 400mg/daily. CP was defined using WHO 2008 criteria. All pts received a short course of hydroxiurea until imatinib was available. Cytogenetic analysis was performed at diagnosis, 3, 6, 12 and 18 months after starting therapy and then every 12-24 months thereafter. BCR-ABL transcripts were measured in peripheral blood at 3-month intervals using quantitative RT-PCR (RQ-PCR). Results were expressed as BCR-ABL/ABL ratio, with conversion to the international scale (IS). Major molecular response (MMR) was defined as a transcript level ≤ 0.1% (IS). Statistical analysis: OS was measured from imatinib start until date of death or last visit. An event was defined as death from any cause. EFS was measured from imatinib start until the first event (loss of complete hematological response (CHR); complete cytogenetic response (CCR), progression to advanced phase, death or imatinib discontinuation) or last visit. OS and EFS rates were calculated using Kaplan-Meier method and log-rank test to compare its curves. The MMR probabilities according to molecular responses at 3 and 6 months were calculated by c2 method and cumulative incidence, considering as competitive event death or progression, before the event. Results 95 pts were analyzed, 57 (60%) male, with a median age of 47 years (17-79); Sokal score: high, intermediate and low was 30, 38.6 and 31.4% respectively; EUTOS scores was 81.5% low and 18.5% high. The median time from diagnosis until imatinib therapy was 1 month (0-5) and the follow-up was 39 month (3-89). Responses: 88% achieved CHR; 50% CCR and 53% MMR. One patient progressed to advanced phase during follow-up, while on imatinib treatment. 21 (22%) pts discontinued imatinib due to intolerance (47.6%); resistance (42.9%), death (4.8%) and Allo-HSCT (4.8%). At 3 months from the start of therapy, 30/64 (46.8%) achieved CCR, 15/64 (23.4%) partial cytogenetic response and 20/64 (31.2%) less than partial; by RQ-PCR, 72.3% (68/94) achieved at 3 months BCR-ABL transcripts ≤10% and 27.7% (26/94) > 10%. At 6 months 55.2% (48/87) had BCR-ABL transcripts ≤ 1% and 44.8% (39/87) >1%. The OS was 97% (95%CI: 95-99%) and EFS 63% (95%CI: 52-75%).There was no significant difference in OS and EFS in pts with RQ-PCR > 10% vs ≤ 10% at 3 months (figure 1), but pts with BCR-ABL transcripts > 10 and >1-10% at 6 months had an inferior EFS in comparison with pts with BCR-ABL transcripts ≤ 1% (41%,50%,89% respectively - p= 0.005), (figure 2). The CI showed that CCR pts at 3 months reached MMR earlier at 24 month (54% vs 18%, p=0.03), as well as CCR pts at 6 months, albeit no significance statistically (52% vs 37%, p= 0.16). For RQ-PCR at 3 months, pts with BCR-ABL transcripts 0-1% had a probability of 88% to achieve MMR, 1-10% had 52% and >10% 42%, p< 0.0001 (figure 3). In conclusion, our results show that early molecular responses are predictive of achieving MMR and BCR-ABL transcripts <1% at 6 months is predictive of EFS in CP-CML treated with imatinib. Disclosures: No relevant conflicts of interest to declare.

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Significant Reduction of BCR-ABL Transcripts after Switching to Imatinib Therapy in Patients with CML and Complete or Near-Complete Cytogenetic Responses to Interferon-Alpha (IFN).

Blood ◽

10.1182/blood.v108.11.2142.2142 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2142-2142

Author(s):

Susan Branford ◽

Timothy Hughes ◽

Steven Stylian ◽

Anthony P. Schwarer ◽

Chris Arthur ◽

...

Keyword(s):

Chronic Phase ◽

Progression Free Survival ◽

Cytogenetic Response ◽

Primary Objective ◽

Imatinib Therapy ◽

Molecular Response ◽

Log Reduction ◽

Advanced Phase ◽

Molecular Assessment

Abstract IFN confers a survival advantage for the minority of patients with CML who achieve a complete cytogenetic response. The 10-year survival rate was reported as 72%. In the IRIS trial only 3% of patients remained on IFN after randomization and 65% crossed-over to imatinib. Imatinib offered superior compliance and toxicity profiles and clear quality of life advantages. Furthermore, patients on first line imatinib with a major molecular response (MMR) by 12 months had a 100% progression free survival to advanced phase. An important clinical question of whether IFN-responsive patients can experience further improvements with imatinib has not been answered. We studied 23 chronic phase patients treated with IFN for a median of 4.5 years (r1.6–14.3) who had achieved a complete (n=15) or near-complete (n=8) cytogenetic response. IFN was ceased and 400mg imatinib commenced in a clinical trial with the primary objective of determining if switching to imatinib in IFN-responsive patients improves response when assessed at the molecular level. Molecular assessment was undertaken for the first 12 months of imatinib therapy by measurement of peripheral blood BCR-ABL levels by quantitative PCR at 3 month intervals. A subset of 10 patients had follow-up molecular assessment for 3.8 to 4.5 years after commencing imatinib. Prior to IFN cessation all patients had detectable BCR-ABL and 16 of 23 had not achieved a MMR, which is a 3 log reduction of BCR-ABL from a standardized baseline value for untreated patients. At a median of 3 months of imatinib (r3–12) these 16 patients achieved MMR. A significant reduction of BCR-ABL over the 12 month assessment was considered >50% and this occurred in 15 of these 16 patients (median 98.4% reduction, r94.4–99.8). In the sole patient without a significant reduction, BCR-ABL returned to the pre imatinib level after repeated dose interruptions of 93 days and decrease to 200mg imatinib due to thrombocytopenia. Of the 7 patients with a MMR prior to IFN cessation, all 7 maintained this level of response after switching to imatinib. Therefore, over the 12 month assessment all patients either achieved MMR (n=16) or maintained MMR (n=7). One patient withdrew consent after 83 days. The 10 patients with longer molecular follow-up of up to 4.5 years of imatinib all maintained MMR. The typical molecular response is illustrated in the figure, which plots the log reduction of BCR-ABL from the standardized baseline for 3 patients assessed at regular time-points before and after switching to imatinib. In conclusion, the data suggest that switching to imatinib leads to rapid and significant improvement in IFN-responsive patients in terms of achieving MMR, a response with established prognostic value with imatinib therapy. The study should help patients and their physicians make evidence-based decisions about the potential benefits and risks of switching to imatinib with prior response to IFN. Figure Figure

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Patients with Chronic Phase CML in the IRIS Study Who Receive Imatinib Mesylate (IM) 2nd Line after Prior IFN/Ara-C Have Sustained Complete Cytogenetic and Major Molecular Response Rates Similar to 1st Line IM Patients.

Blood ◽

10.1182/blood.v108.11.2139.2139 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2139-2139

Author(s):

Jaspal Kaeda ◽

Andreas Hochhaus ◽

Jerald Radich ◽

Susan Branford ◽

Charlene So ◽

...

Keyword(s):

Chronic Phase ◽

Response Rates ◽

Cytogenetic Response ◽

Progression Rate ◽

Molecular Response ◽

Major Molecular Response ◽

Real Time Quantitative Pcr ◽

Log Reduction ◽

Advanced Phase

Abstract The IRIS study compared IM and interferon+cytarabine (IFN/Ara-C) in patients (pts) with newly diagnosed CML-CP (n=553 per arm). IFN/Ara-C pts. could cross over to IM if they satisfied predetermined criteria for disease, either resistance/refractoriness (=resistance), or intolerance of or reluctance to continue the combination (=lack of resistance). Pts who received IM 1st line or 2nd line who achieved a complete cytogenetic response (CCyR) had BCR-ABL transcript levels measured serially by real-time quantitative PCR (RQ-PCR). Results were expressed as log reduction in BCR-ABL/BCR from a standardized baseline value for untreated pts. Yearly rates of 3 log reduction (Major Molecular Response, MMR) from IM treatment starting date were estimated by multiplying the CCyR rate by the MMR rate in CCyR pts at each time point. Overall, of 553 pts who received 1st line IM 82% achieved CCyR, an estimated 69% during the 1st year (yr) of treatment. Of 359 pts who received 2nd line IM, 80% achieved CCyR, 62% during the 1st yr; rates were lower in pts with resistance than in those without resistance to prior IFN/Ara-C (75% vs 85% overall, p=0.025, 56% vs 68% within first yr, p<0.01). Best observed and estimated molecular responses for CCyR pts. are summarized in the table. The median follow-up for BCR-ABL evaluation on 1st line vs 2nd line IM was 45 and 35 months, respectively. Molecular response on 1st- and 2nd-line IM in the IRIS study 1st-line IM 2nd-line IM after IFN/Ara-C All pts N = 553 All pts N = 359 Resistance N =174 Lack of resistance N =185 CcyR 454 (82%) 288 (80%) 131 (75%) 157 (85%) Pts with CCyR during treatment and PCR sample(s) N = 401 N = 211 N = 98 N = 113 –≥3 log reduction (MMR) 323 (81%) 154 (73%) 63 (64%) 91 (81%) –≥ 4 log reduction 216 (54%) 92 (44%) 35 (36%) 57 (50%) Estimated % of all pts who achieve CCyR and MMR by – 1 yr 36 24 19 28 – 2 yr 59 38 29 45 – 4 yr 67 67 58 72 – 5 yr 85 82 78 84 Overall response rates were similar between 1st and 2nd line IM pts, although responses in 2nd line IM pts may have occurred more slowly. However, the number of RQ-PCR samples between 1 and 2 yrs of 2nd line IM was limited as samples were not obtained routinely between Jan 2003 and Aug 2004. In pts who achieved CCyR, the estimated 5-yr progression rate to advanced CML phase was 3% for 1st line IM and 4% for 2nd line IM; using the broader definition of progression (including events such as CML-unrelated deaths and loss of MCyR/CHR) the progression rates were 9% and 8% respectively. In both 1st and 2nd line IM pts with CCyR who also achieved MMR, only an estimated 1% progressed to advanced phase within 5 yrs; the estimated broadly defined event rates were 5% and 4% respectively. In summary, for 1st line IM patients with a RQ-PCR follow-up of up to 5 yrs, an estimated 85% achieved MMR at 5 yrs compared with 59% at 2 yrs. Cytogenetic and molecular response rates were similar for 1st line and 2nd line IM pts, primarily due to responses in pts who crossed over for reasons other than resistance or refractoriness. For IM pts the rate of progression to advanced CML phase at 5 yrs was low in those with CCyR and even lower in pts who also achieved MMR.

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

Blood ◽

10.1182/blood-2007-01-070045 ◽

2007 ◽

Vol 110 (8) ◽

pp. 2991-2995 ◽

Cited By ~ 102

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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Results of Imatinib Therapy In Patients with Early and Late Chronic-Phase Chronic Myeloid Leukemia In a South Brazilian Cohort.

Blood ◽

10.1182/blood.v116.21.4487.4487 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4487-4487

Author(s):

Marcelo Capra ◽

Mariza Shaan ◽

Katia Fassina ◽

Mario Sérgio Fernandes ◽

Marco Antônio Schilling ◽

...

Keyword(s):

Myeloid Leukemia ◽

Chronic Phase ◽

Cytogenetic Response ◽

Molecular Response ◽

Imatinib Treatment ◽

Second Line Therapy ◽

Line Therapy ◽

Sokal Score ◽

Hasford Score

Abstract Abstract 4487 Background: Imatinib treatment for Chronic Myeloid Leukemia (CML) was first introduced in Brazil in 2001, initially used as second line therapy for patients resistant or intolerant to interferon (IFN). In 2008 imatinib was adopted as front-line therapy for chronic-phase (CP-CML) and clinical experience is improving since then, but little is known about the result of its introduction in our clinical practice. Aims: To evaluate the impact of imatinib treatment in the outcomes of a cohort of CP-CML and the prognostic significance of Sokal and Hasford scores and late-onset treatment. Methods: We conducted a retrospective study in a cohort of patients with CP-CML from a south Brazilian database. All patients received imatinib 400mg as first or second-line therapy. Patient evaluation and response criteria followed the European LeukemiaNet. The outcomes were response to treatment, event-free survival (EFS) and overall survival (OS). Results: We analyzed data from 185 pts with CP-CML diagnosed since 1990. The median age at diagnosis was 48 years (4 – 85). The median time from diagnosis to imatinib was 7 months (0 – 178) and 29% of pts had more than 12 months lapse. Prior therapy with IFN was used in 70% pts. All pts had a minimum follow-up of 12 months. At baseline, 57 pts (31%) were in complete hematological response (CHR) due to the use of previous treatment. Of the 127 pts not in CHR at baseline, 98% achieved CHR early during imatinib treatment. 177 pts had cytogenetic evaluation during treatment and 9 pts were in complete cytogenetic response (CCyR) due to the use of previous IFN. Of the 168 pts not in CCyR at baseline, 86,4% achieved a major cytogenetic response (MCyR) during imatinib treatment (84% had a CCyR and 2,4% had a partial cytogenetic response). The rate of pts achieving MCyR any point during treatment differed significantly in the low, intermediate and high risk Sokal score groups (97%, 81% and 78% respectively, P=0,04), but not in the Hasford score groups (90%, 85% and 72%, P=0,22). Minor cytogenetic response was seen in 3,6% of pts, minimal cytogenetic response in 6% and 9,5% had no cytogenetic response. The median time to a MCyR was 9 months, with 62% of pts achieving MCyR at 12 months. The rate of pts achieving MCyR in 12 months differed significantly between pts who start imatinib before 12 months from diagnosis (68%) and those late treated (47%, P=0,02). Evaluation of minimal residual disease at the molecular level was available for 155 pts: 25,5% of pts had a complete molecular response (CMR), 43% had a major molecular response (MMR) and 2 pts were in MMR at baseline due to previous IFN. The projected EFS and OS rates at 4 years were, respectively, 68% and 92% after a median follow-up time of 4 years. The rate of EFS differed significantly in the low, intermediate and high risk Sokal score groups (80%, 66% and 52% respectively, P=0,04), but not in the Hasford score groups (78%, 62% and 44%, P=0,09). During treatment with imatinib, 120 pts (65%) had a register of any grade hematologic adverse event (21% being grades 3 or 4) and 165 pts (90%) had a register of any grade nonhematologic adverse event (9,3% being grades 3 or 4). Of the 185 pts who received treatment, 134 (72%) continue to receive imatinib and 51 (28%) discontinued treatment. The reasons for discontinuation were: 11 (6%) pts had drug-related adverse events (3 [1,6%] hematologic and 8 [4,3%] nonhematologic), 17 (9,2%) had disease progression (5 [2,7%] loss of CHR, 10 [5,4%] loss of CCyR, 2 [1%] had progression to accelerate or blastic phase), 22 (11,9%) had treatment failure (3 [1,6%] had no CHR, 13 [7%] had no CCyR and 6 [3,2%] had no MMR), 1 pt (0,5%) discontinued due to comorbidity. For the 51 (100%) pts that discontinued imatinib, 31 (61%) switched to dasatinib, 17 (33%) to nilotinib, 1 (2%) to hydroxyurea, 1 (2%) to other treatment and 1 (2%) remained without treatment. Sixteen pts (8,6%) died during imatinib treatment or during long-term follow-up after discontinuation of imatinib. Conclusions: In our population of CP-CML pts treated with imatinib, a majority of patients achieved complete cytogenetic and major molecular responses, with a prolonged of OS and EFS and good safety profile. Sokal score showed better prognosis prediction than Hasford. Early onset of imatinib therapy led to better outcomes and justifies imatinib as front-line treatment of our patients. Disclosures: No relevant conflicts of interest to declare.

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Nilotinib for the frontline treatment of Ph+ chronic myeloid leukemia

Blood ◽

10.1182/blood-2009-07-232595 ◽

2009 ◽

Vol 114 (24) ◽

pp. 4933-4938 ◽

Cited By ~ 149

Author(s):

Gianantonio Rosti ◽

Francesca Palandri ◽

Fausto Castagnetti ◽

Massimo Breccia ◽

Luciano Levato ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Cytogenetic Response ◽

First Year ◽

Molecular Response ◽

Major Molecular Response ◽

Phase 2 Study ◽

Frontline Treatment

AbstractNilotinib has a higher binding affinity and selectivity for BCR-ABL with respect to imatinib and is an effective treatment of chronic myeloid leukemia (CML) after imatinib failure. In a phase 2 study, 73 early chronic-phase, untreated, Ph+ CML patients, received nilotinib at a dose of 400 mg twice daily. The primary endpoint was the complete cytogenetic response (CCgR) rate at 1 year. With a median follow-up of 15 months, the CCgR rate at 1 year was 96%, and the major molecular response rate 85%. Responses were rapid, with 78% CCgR and 52% major molecular response at 3 months. During the first year, the treatment was interrupted at least once in 38 patients (52%). The mean daily dose ranged between 600 and 800 mg in 74% of patients, 400 and 599 mg in 18% of patients, and was less than 400 mg in 8% of patients. Dose interruptions were mainly due to nonhematologic and biochemical side effects. Myelosuppression was irrelevant. One patient progressed to blastic crisis after 6 months; one went off-treatment for lipase increase grade 4 (no pancreatitis). Nilotinib is safe and very active in early chronic-phase CML. These data support a role for nilotinib for the frontline treatment of CML. This study was registered at ClinicalTrials.gov as NCT00481052.

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