Therapy For Chronic Myeloid Leukemia In Chronic Phase Research Articles

Importance of early and deeper responses to long-term survival in CML patients: Implications of BCR-ABL testing in management of CML in Indian setting.

The prognosis of patients with chronic myeloid leukemia (CML) has changed radically since the advent of imatinib mesylate, a selective inhibitor of BCR-ABL tyrosine kinase. Shortly thereafter, more potent BCR-ABL inhibitors (dasatinib and nilotinib) were introduced for use in patients resistant to or intolerant of imatinib. All three drugs are now approved for initial therapy for chronic phase CML. Response to tyrosine kinase inhibitor (TKI) treatment is assessed with standardized quantitative reverse transcriptase polymerase chain reaction (Q-RTPCR) and/or cytogenetics at 3, 6 and 12 months. Clinical trials have clearly demonstrated that early and deeper cytogenetic and molecular response to TKI therapy is associated with lower rate of disease progression and improved long-term outcomes. In recent times, molecular response as determined by BCR-ABL transcript levels at defined time points is rapidly gaining popularity as a predictive marker for subsequent outcomes in CML. Optimal response is defined as BCR-ABL transcript levels of ≤10% at 3 months, <1% at 6 months, and ≤0.1% from 12 months onward while >10% at 6 months and >1% from 12 months onward define failure. Patients who do not achieve molecular milestones at 3 or 6 months with 3 months being highly predictive are less likely to achieve cytogenetic responses eventually; early identification of such patients who have a low probability of achieving an adequate response are thus candidates for alternative treatment. Review of literature by electronic search of MEDline, Google Scholar was done using keywords and data was identified and systematically evaluated.

Significance of deeper molecular responses in patients with chronic myeloid leukemia in early chronic phase treated with tyrosine kinase inhibitors

Most patients with chronic myeloid leukemia (CML) in chronic phase (CP) treated with tyrosine kinase inhibitors (TKI) achieve complete cytogenetic response (CCyR). An increasing number of patients also achieve deep molecular responses (MR). We determined the frequency and significance of deep MR after TKI therapy for CML in CP. MR included: major molecular response (MMR), MR4, MR4.5, and undetectable transcripts (UND), i.e., BCR-ABL/ABL of ≤0.1, ≤0.01, ≤0.0032%, and undetectable transcripts, respectively. Four hundred eighty-three patients received imatinib 400 mg/day (IM400, 71, July 2000 to April 2001), imatinib 800 mg/day (IM800, 204, June 2001 to July 2005), nilotinib (106, July 2005 to date), or dasatinib (102, November 2005 to date). UND rates at 36 months were 18.1, 30.6, 29.2, and 28.6%, respectively. Patients achieving UND have superior transformation-free survival (TFS) and overall survival (OS) versus those obtaining ≤MMR, but not other MR levels. At the 18- and 24-month landmark analysis, patients achieving UND have no advantage in TFS and OS compared to those achieving a lesser degree of MR. Among patients achieving MR4.5, those who maintain it for ≥2 years (susMR4·5) have no additional benefit in TFS or OS. Most patients with early CP CML receiving TKI achieve MMR. BCR-ABL transcripts become undetectable in a significant fraction of them. Deeper MR at 18 or 24 months are not associated with a benefit in TFS or OS. Furthermore, achieving susMR4·5 does not appear to further reduce the risk of transformation or death.

Significance of Suboptimal Response to Imatinib, as Defined by the European LeukemiaNet, in Long-Term Outcome for Patients (Pts) with Chronic Phase (CP) Chronic Myeloid Leukemia (CML).

The European LeukemiaNet recently published recommendations for evaluating response to imatinib among pts with CML. Criteria for failure and suboptimal responses were proposed. The significance of failure is accepted and constitutes grounds for change in treatment. The prognostic implications of having a suboptimal response are less clear making treatment decisions less clear in this setting. We analyzed the outcome of 281 pts treated with imatinib as frontline therapy for CML in CP: 73 at initial dose of 400mg daily and 208 at 800mg daily. Their median age was 48 yrs (range, 15 to 84 yrs) and their median follow-up 48 months (mo) (2–79 mo). After 3 mo of therapy none of the 273 evaluable pts met definition of suboptimal response according to the European LeukemiaNet, while 3 of 273 (1%) met definition for failure. At 6 mo 10/259 (4%) evaluable had suboptimal response and 9 (3%) failure. At 12 mo 19/246 (8%) had suboptimal and 14 (6%) failure, and at 18 mo 91/224 (41%) had suboptimal and 21 (9%) had failure. The probability of having a suboptimal response at 6 and 12 mo was significantly higher for pts treated with a starting dose of 400mg than those treated at 800mg: at 6 mo [12% suboptimal at 400mg vs 1% at 800mg (p=0.002)] and at 12 mo [17% and 4%, respectively (p<0.001)]. The outcome at 24 months* by the response at specific times was as follows:TimeResponse% CCyR% MMR% Transf% Event6 moOptimal916026Suboptimal003050Failure002267P.001.001.001.00112 moOptimal946324Suboptimal5625016Failure002157P.001.001.001.00118 moOptimal988501Suboptimal933925Failure1501943P.001.001.001.001CCyR=Complete cytogenetic remission, MMR=Major molecular remission, Transf=Transformation to accelerated or blast phase, Event=loss of complete hematologic response, loss of major cytogenetic response, transformation, or death

Le traitement de la leucémie myéloïde chronique en 2007

The treatment of chronic myeloid leukemia (CML) has considerably evolved since imatinib mesylate has been introduced as a new therapeutic weapon for this disease. The 5-year updated results of the IRIS study confirmed that imatinib mesylate is the best first line therapy for chronic phase CML with an overall survival of 90%. Responses improve with time and complete cytogenetic and major molecular levels reach 87 and 70% respectively at 5 years. However, despite these remarkable improvements, new problems arise as sub-optimal responses, imatinib-resistances with recently identified BCR-ABL protein point mutations, responsible for a variety of therapeutic consequences : imatinib dose increase, alternative treatments with second generation tyrosine kinase inhibitors (TKIs : dastinib, nilotinib) or allogeneic stem cell transplantation. The treatment of accelerated and blastic phases relies on imatinib +/- conventional chemotherapy, ideally followed by allogeneic stem cell transplantation, as newly developed TKIs are currently evaluated within this frame. Finally, BCR-ABL(T315I) mutations remain a new therapeutic critical challenge as none of the three TKIs (imatinib, nilotinib, dasatinib) can efficiently control such diseases.

Medical Management of CML

Management strategies of patients with chronic-phase chronic myeloid leukemia (CML) have been revolutionized by the BCR-ABL-selective kinase inhibitor imatinib, which is substantially improving median survival. However, a proportion of patients suffer progressive disease on imatinib therapy. Importantly, patients who are particularly at risk for developing progressive disease can be identified with appropriate monitoring of disease burden. Many of these patients may benefit from alternative treatment strategies, including second-generation kinase inhibitors such as dasatinib. As a result of improvements in medical therapy, allogeneic stem cell transplantation is increasingly deferred despite its known curative potential. It is anticipated that outcomes with medical therapy will continue to improve with the availability of effective second- and third-generation kinase inhibitors, and the percentage of patients progressing to the advanced phase of the disease is projected to decline. The future of kinase inhibitor therapy for CML may involve combinations of ABL kinase inhibitors.

Sudden Blastic Transformation (SBT) in Patients (pts) with Chronic Myeloid Leukemia (CML) Treated with Imatinib Mesylate.

Imatinib has become standard therapy for pts with CML in chronic phase (CP). SBT has been reported in pts receiving IFN-α, at a rate of 0.5% to 2.5% during the first 3 years of therapy. There is little information on the occurrence of SBT among pts treated with imatinib. Here we report 3 pts who developed SBT, defined as occurring after being found in complete cytogenetic remission (CG CR). These 3 pts represent 0.5% of 557 pts who received imatinib at MD Anderson for chronic phase CML. The total population has been followed for a median of 33 months (range, 1 to 56). Pt #1 was a 54 yr old female with a variant Ph translocation, t(9;22;19;10) (q34;q11.2;p13.1;q22). Sokal risk was low. She started imatinib 400mg/day within 4 mos from diagnosis, achieved a CG CR within 3 mos and was still in CG CR after 9 mos with BCR-ABL/ABL 0.66%. On routine follow-up at 12 mos she was found in myeloid blast phase with 48,XX,+8,t(8;21)(q22;q22),t(9;22;19;10) (q34;q11.2;p13.1;q22), +der(22)t(9;22;19;10) in all 20 metaphases. She received standard induction chemotherapy followed by bone marrow transplantation and is alive and in CR after 24+ months. Pt #2 was a 51 yr old female initially treated with IFN-α. She achieved a CG CR but discontinued therapy because of toxicity after 18 mos. Fourteen mos after stopping IFN-α she had a CG recurrence (35% Ph-positive) and was started on imatinib 400mg/day. Three mos later she was in CG CR and BCR-ABL was undetectable by nested PCR; a similar result was found after 9 mos of therapy. 9 mos later (18 mos after start of imatinib) she had a lymphoid SBT (precursor B-cell). CG showed 45,XX,-8, t(9;22) (q34;q11.2), −20,+mar in one metaphase, and 11 metaphases were diploid. No ABL mutations were identified. She achieved CR with HCVAD + imatinib and is currently receiving a BMT. Patient #3 was a 27 yr old pt who received imatinib 800 mg/d as first line of therapy for CML in CP with intermediate Sokal risk score. Three mos after start of therapy he was in CG CR and repeated analyses showed continued CG CR up to mo 15, with the lowest BCR-ABL/ABL 0.12 at mo 6. On mo 18 he had a lymphoid SBT (precursor B phenotype) with 43–46,XY, −7, −8,i(9)(q10),t(9;22)(q34;q11.2), −13, −17, −21,+der(22)t(9;22),+mar in 13 metaphases and one diploid metaphase. No ABL mutations were identified. He was treated with HCVAD + imatinib and achieve a CR, becoming undetectable for BCR-ABL by nested PCR. He is undergoing a BMT. In pts 2 and 3, transformation was associated with a sudden drop in platelet counts. These isolated events should alert the physicians to continued monitoring of pts on imatinib and consider marrow studies in the event of late, unexpected peripheral blood count changes. Still, SBT is rare, probably less common that seen with IFN-α therapy.