Delayed Achievement of Molecular Responses Is Associated with Increased Risk of Progression among Patients (pts) with Chronic Myelogenous Leukemia (CML) In Chronic Phase (CP) Treated with Imatinib (IM).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 432-432 ◽  
Author(s):  
Alfonso Quintas-Cardama ◽  
Hagop M. Kantarjian ◽  
Dan Jones ◽  
Guillermo Garcia-Manero ◽  
Susan O’Brien ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
White Cell Count ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
P Value ◽  
High Dose ◽  
Molecular Response ◽  
Transcript Levels ◽  
Increased Risk ◽  
Risk Of Progression

Abstract Background: Achieving a cytogenetic (CG) response or a molecular response after imatinib therapy has been associated with improved event-free (EFS) and transformation-free survival (TFS). It is unclear whether achieving these responses earlier confers an advantage. A recent update of the IRIS trial suggests that achieving a major CG response (MCyR) at 12, 18 or 24 months (mo) confers a similar TFS advantage. Another report (J Clin Oncol2006;24:454) suggests that achieving a complete CG response (CCyR) at 12 or 24 mo confers equal prognosis to patients. Although some patients may indeed improve their response with continued therapy, a pt not in CCyR faces the competing possibilities of eventually achieving a CCyR vs progressing. Methods: We analyzed the risks of improving the CG response vs progressing for pts not in CCyR at different times to determine whether early responses confer an advantage. 258 pts with CML CP treated with IM were analyzed. Progression was defined as transformation to AP or BP, loss of CHR or major CG response, or a doubling of the white cell count to more than 20x109/L. Results: After 3 mo of IM therapy, 77 (74%) of 104 assessable pts for CG response had a CCyR whereas 17 (16%) progressed. These differences were consistently significant at 6 and 12 mo (p=0.04) (Table 1). We then analyzed the long term risk of progression vs the probability of achieving CCyR according to the molecular response at different time points (Table 2). Patients with Bcr-Abl/Abl transcript levels >1–10 after 3 mo of therapy had a 92% probability of achieving CCyR with continued therapy, similar to the 98% for those with ≤1. However, they have a significantly higher risk of eventual progression that is more similar to that of pts with values of >10. The risk of progression increases to 23% if transcript levels >10 at 6 mo. Conclusion: These results suggest that while the risk of progression may be similar for pts who achieve a CCyR regardless of the time at which that is attained, those who fail to obtain a CCyR within the first 12 mo of IM therapy have higher rates of disease progression. This risk is discernible as early as 3 mo into IM therapy and may provide a rationale for therapies that induce higher rates of early molecular response (e.g. high-dose imatinib, new tyrosine kinase inhibitors). Table 1 Time on imatinib No. not in CCyR No. with eventual outcome with continued therapy (%) CCyR Progression p value 3 months 104 77 (74) 17 (16) 6 months 47 28 (60) 12 (26) 0.04 12 months 26 16 (62) 8 (31) Table 2 % Probability Months %Bcr-Abl/Abl No. CCyR Progression p value ≤ 1 87 98 2 3 > 1–10 76 92 11 0.04 > 10 30 67 13 ≤ 1 140 99 4 6 > 1–10 34 91 9 0.005 > 10 13 62 23

Immune Modulation of Minimal Residual Disease (MRD) in Patients (pts) with Chronic Myelogenous Leukemia (CML) in Early Chronic Phase (CP): A Randomized Trial of Frontline High-Dose (HS) Imatinib Mesylate (IM) with or without Pegylated-Interferon (PEG-IFN) and GM-CSF.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2207-2207 ◽  
Author(s):  
Alfonso Quintas-Cardama ◽  
Hagop M. Kantarjian ◽  
Farhad Ravandi ◽  
Guillermo Garcia-Manero ◽  
Susan O’Brien ◽  
...  
Keyword(s):  
Liver Toxicity ◽  
Residual Disease ◽  
Single Agent ◽  
Chronic Phase ◽  
Dose Intensity ◽  
Myelogenous Leukemia ◽  
P Value ◽  
High Dose ◽  
Molecular Response ◽  
Gm Csf

Abstract Some studies suggest that HD IM renders higher molecular response rates than standard dose IM in CP CML. Yet, most patients have MRD detectable by PCR and in vitro studies suggest the CML stem cell is insensitive to IM. The efficacy of IFN in CML has been linked to its immunomodulatory properties and preclinical studies have shown synergy with IM. IFN may be used as adjunct for the management of MRD. IFN combined with GM-CSF is a potent dendritic cell stimulator. In this phase II study we investigated whether the addition of PEG-IFN to IM improves complete molecular response (CMR) rates and prolong remission duration in pts with early CP CML. Pts received IM 800 mg daily for 6 months (mo) before randomization to either continuing HD IM as single-agent or combined with PEG-IFN 0.5 mcg/kg/week and GM-CSF 125 mg/m2 three times weekly. Pts were monitored with real-time PCR and cytogenetics (CG) every 3 mo for 12 mo and every 6 mo thereafter. Ninety-four pts were randomized between Arm A (IM alone; 49 pts) and Arm B (IM+PEG-IFN+GM; 45 pts) and 91 (97%) were followed for at least 12 mo (2 pts in Arm A and 1 in Arm B did not start therapy). Ten pts randomized to Arm B did not start PEG-IFN (4 refused, 3 off study before 6 mo, 1 melanoma, 1 heart disease, 1 financial). The primary objective was to increase by 50% the rate of major molecular response (BCR-ABL/ABL ratio <0.05%) at 12 mo. Pt characteristics and response are shown in Table 1. Median follow-up for pts on study was 24 mo (range, 12 to 38) and 8 mo (range, 1 to 22) for those taken off-study. Toxicity in Arm A was similar to that reported in prior studies of HD IM. The most common grade 3–4 toxicities among 39 pts assessable in Arm B were fatigue (n=12, 31%), depression (n=3, 8%), pruritus (n=3, 8%), and headache (n=3, 8%) and were all significantly more frequent in Arm B than Arm A. PEG-IFN was discontinued in 43% of pts and GM-CSF in 45%, mainly due to fatigue, rash, and flu-like symptoms. Nine pts were taken off study in Arm A (3 resistant, 2 liver toxicity, 4 other) and 10 in Arm B (3 resistant, 2 financial, 1 liver toxicity, 4 other). Median IM dose intensity at 12 mo was 98% (range, 47% to 100%) in Arm A and 99% (range, 46% to 100%) in Arm B. By contrast, PEG-IFN dose intensity was only 45%, with 75% of pts receiving < 60% of the planned dose. We conclude that the combination of HD IM and PEG-IFN is associated with acceptable toxicity but does not impact significantly the achievement of molecular response after 12 mo of therapy at the dose schedule used in this study. The high drop-out rate observed in the PEG-IFN arm may have compromised any potential immunomodulatory benefit. Table 1 No. / No. evaluable (%) Overall IM alone IM+PEG-IFN+GM p value Median age (range), years 48 (19-79) 46 (19-73) 51 (19-79) Sokal (% low/int/high) 72/21/6 65/24/10 80/16/4 0.96 CG response at 12 mo partial 4/82 (4) 2/45 (4) 2/37 (5) 0.50 complete 76/82 (93) 41/45 (91) 35/37 (95) 0.09 Best molecular response         >0% - <0.05% 40/91 (45) 23/47 (49) 17/44 (39) 0.20         undetectable 15/91 (17) 8/47 (17) 7/44 (16) 0.29 Molecular response at 12 mo         >0% - <0.05% 23/91 (25) 10/47 (21) 13/44 (24) 1.00         undetectable 9/91 (10) 5/47 (11) 4/44 (9) 0.29

Basophilic Blast Phase (B-BP) of Chronic Myelogenous Leukemia (CML).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4562-4562
Author(s):  
Alfonso Quintás-Cardama ◽  
Hagop Kantarjian ◽  
Jorge Cortes
Keyword(s):  
Bone Marrow ◽  
Kinase Inhibitors ◽  
Hospice Care ◽  
White Cell Count ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Cancer Center ◽  
Unrelated Donor ◽  
Molecular Response ◽  
Karyotypic Analysis

Abstract Approximately 65% of patients with CMP BP exhibit a myeloid phenotype, 30% a lymphoid, and 5% of cases have and undifferentiated or mixed phenotype. Although basophilia is a common feature in both the peripheral blood and the bone marrow during the chronic phase of the disease, transformation to B-BP is a rare occurrence with only anecdotal cases reported. To evaluate the incidence and outcome of B-BP, we reviewed 410 patients with CML who underwent transformation to BP at M.D. Anderson Cancer Center between January 1999 and April 2007. Of them, only 2 (0.5%) cases were diagnosed as having B-BP. CASE 1: a 19-year-old woman with CML in accelerated phase (AP) failed allogeneic stem cell transplantation (allo-SCT), donor lymphocyte infusion (DLI), autologous SCT, IFN-α, splenectomy, and gemtuzumab. In 10/00 started imatinib therapy at 400 mg/d, achieving a complete hematologic response (CHR) that lasted until 04/03 when she transformed to BP. Gentuzumab was again administered and rendered a CHR, after which she immediately received SCT from her haploidentical mother, resulting in a complete molecular response (CMR) that lasted until 6/05. Therapy with imatinib 800 mg/d was unsuccessful. In 7/05 her white cell count (WBC) was 44x109/L with 25% blasts and 28% basophils. A bone marrow (BM) biopsy showed the presence of 36% blasts with coarse basophilic granules (negative for myeloperoxidase [MPO] and butyrate esterase) and 38% basophils. Flow cytometry demonstrated 65% blastic cells with positive markers of myeloid lineage (CD11c, CD13, CD33) without immaturity markers (CD34, HLA-DR, TDT) B or T lymphoid markers (CD10, CD19, CD20, CD22, CD2, CD3, CD5) or other myeloid markers (CD14, CD15, CD65, MPO). Cytogenetics revealed an isochromosome 17, +8, and t(9;22) in 19/20 metaphases. A b3a2 BCR-ABL1 (p210) transcript with no evidence of mutations within the kinase domain was detected. Given her critical condition the patient was received only supportive care and died shortly thereafter. CASE 2: a 39-year-old woman was diagnosed with CML in chronic phase (CP) in 12/04. She failed therapy with IFN-α, allo-SCT, DLI, imatinib 800 mg/d, PR1 vaccine, matched unrelated donor SCT, imatinib 800 mg/d in combination with tipifarnib, and nilotinib 600 mg twice daily, after which she progressed to BP. A CBC revealed a WBC of 21x109/L with 29% blasts and 66% basophils. A hypercellular BM biopsy revealed 44% blasts (MPO negative) with large cytoplasmic granules and 45% basophils. Blast exhibited an immunophenotype characterized by positivity of myeloid markers, negativity of MPO, B and T cell markers, and partial positivity of CD117. Karyotypic analysis showed that 16/19 metaphases carried t(9;22), −16, add(17)(p13). Molecular studies detected a e1a2 p190 BCR-ABL1 transcript. Therapy with dasatinib 70 mg twice daily for 16 weeks was ineffective and the patient was referred to hospice care. In conclusion, B-BP is a rare subtype of BP CML that exhibits high resistance to standard chemotherapy, allo-SCT, and targeted BCR-ABL kinase inhibitors.

scholarly journals Delayed achievement of cytogenetic and molecular response is associated with increased risk of progression among patients with chronic myeloid leukemia in early chronic phase receiving high-dose or standard-dose imatinib therapy

Blood ◽  
2009 ◽  
Vol 113 (25) ◽  
pp. 6315-6321 ◽  
Author(s):  
Alfonso Quintás-Cardama ◽  
Hagop Kantarjian ◽  
Dan Jones ◽  
Jianqin Shan ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Imatinib Therapy ◽  
High Dose ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Increased Risk ◽  
Risk Of Progression

AbstractPatients not in complete cytogenetic response (CCyR) continuously face the competing possibilities of eventually achieving a cytogenetic response versus progressing. We analyzed the probability of achieving a CCyR, major molecular response, and progression in 258 patients with chronic myeloid leukemia in early chronic phase at 3, 6, and 12 months from imatinib start. The initial imatinib dose was 800 mg/day in 208 (81%) and 400 mg/day in 50 (19%) patients. For patients not in CCyR, the probability of achieving CCyR (P = .002) or major molecular response (P = .004) significantly decreased, whereas the risk of progression increased (P = .16) at each time point. Patients with a BCR-ABL1/ABL1 ratio greater than 1% to 10% after 3 months of imatinib had a 92% probability of achieving CCyR with continued therapy, similar to the 98% for those with 1% or less, but their risk of progression (11%) was almost 3-fold that of patients with a BCR-ABL1/ABL1 transcript ratio of 1% or less (4%) and similar to that of patients with transcript levels more than 10% (13%). These results suggest that patients not in CCyR after 12 months on imatinib have a higher risk of progression. This risk is discernible as early as 3 months into imatinib therapy by molecular analysis and may provide the rationale to institute therapies that render higher rates of early response.

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.

Imatinib in Children with Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia (CP CML): AAML0123 COG Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2140-2140 ◽  
Author(s):  
Martin A. Champagne ◽  
Cecilia Fu ◽  
Myron Chang ◽  
Linda Cooley ◽  
Nyla A. Heerema ◽  
...  
Keyword(s):  
Liver Toxicity ◽  
White Cell Count ◽  
Phase 1 ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Minor Response ◽  
Complete Cytogenetic Response

Abstract Introduction. Our prior phase 1 study (P9973) established the safety profile and suggested efficacy of imatinib in children with CP CML at doses varying from 260–570 mg/m2. The purpose of this phase 2 study was to define the rates of response in children with previously untreated CP CML. Methods. Patients less than 22 years of age at study entry with newly diagnosed CP CML, with no prior therapy other than hydroxyurea, were eligible. Imatinib was administered orally at a dose of 340 mg/m2 daily, with courses defined as 28-day intervals. A hematological response (HR) was defined at the end of courses 1 and 2 as a reduction in the white-cell count to &lt;10 x 109/L and in platelet count to &lt;450 x 109/L, and was considered a complete response (CHR) when maintained for at least four weeks. Cytogenetic response is defined as follows, based on the absolute percent of Ph+ metaphase cells on marrow specimens: complete cytogenetic response (CCyR) 0% Ph+ cells; partial (PCyR)1–35%; minor 39–65%; minimal 66–95%; none 96–100%. Iterative cytogenetic analyses were performed every 3 months during therapy. Toxicities were reported prospectively using the NIH CTCv2.0 criteria. Results. 50 children (42% boys), with a median age of 11.8 years (range 2.3–19.1) completed more than one course of therapy and were evaluable for response. Median number of courses delivered was 22.5 (range 1–43), with a median follow-up of 795 days. 96% of the calculated dose was administered. Eleven patients experienced 14 non-hematological grade 2–4 adverse events, and one patient discontinued therapy because of toxicity. The HR and CHR rates were 78% and 12%, at the end of course 1, and 20% and 78%, respectively, at the end of course 2. Only one patient was reported as a hematologic non-responder at the end of course 2. At the end of the third course, 33 patients were evaluated for cytogenetic response. Twelve (36%) children were in CCyR; 10 (30%) in PCyR; 5 in minor response; 4 in minimal response; 2 with no cytogenetic response. Six patients did not have cytogenetic evaluation; while in 11 (33%) the study was not possible due to insufficient sampling. Overall, 33 (66%) CCyRs were documented, at a median time of 5.6 months (91% documented by 9 months). Only 1 patient achieved a CCyR after course 10. Thirty-three children were removed from protocol, of which 23 underwent stem cell transplantation. One patient progressed to blast phase while on therapy, while six additional patients had cytogenetic progression. Of the 3 remaining patients, two patients had difficulty with taking medications and one had grade 4 liver toxicity. At 1 year, the estimated event free and overall survivals are 96% and 98%, respectively. Conclusion. Imatinib is well tolerated in previously untreated children with CP CML and induces comparable rates of complete cytogenetic response to those observed in adults. Current evaluation of molecular response is being performed.

EUTOS Score Is Not Predictive for Survival and Outcome in Patients (pts) with Chronic Myeloid Leukemia in Early Chronic Phase (CML-CP) Treated with Tyrosine Kinase Inhibitors (TKIs) At MD Anderson Cancer Center (MDACC),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3769-3769
Author(s):  
Aziz Nazha ◽  
Elias Jabbour ◽  
Jorge E. Cortes ◽  
Susan O'Brien ◽  
Jenny Shan ◽  
...  
Keyword(s):  
Research Funding ◽  
Kinase Inhibitors ◽  
Standard Dose ◽  
Chronic Phase ◽  
Cancer Center ◽  
High Dose ◽  
Molecular Response ◽  
Phase Ii Trials ◽  
Free Survival ◽  
Eutos Score

Abstract Abstract 3769 Background: Until recently, prognosis of pts with CML treated with TKI was based on scores developed in the chemotherapy and interferon era. Hasford and colleagues [Blood. 2011;(118):686–692] have identified the EUTOS score, using the percentage of basophils and spleen size, as a significant tool to predict the probability of achieving 18-month complete cytogenetic response (CCyR) and progression-free survival in patients treated with imatinib. Aims: To validate the EUTOS score in an independent MDACC cohort of pts, with early CML-CP treated with standard-dose imatinib, high-dose imatinib, dasatinib, and nilotinib, and its ability to predict transformation-free survival (TFS), event-free survival (EFS) and overall survival (OS). Methods: 465 consecutive pts with newly diagnosed CML–CP (0 – 6 months from diagnosis to TKI treatment) were treated with imatinib 400 mg daily (n=71), imatinib 800 mg daily (n=208), and 2nd TKIs (n=186; dasatinib n=88, nilotinib n=98) in sequential phase II trials. Entry criteria were similar for all trials. EUTOS score = (7 x basophils %) + (4 x spleen cm BCM). A EUTOS score of >87 indicates high-risk and ≤87 low-risk. Results: 465 pts with CML-CP were assessed. Median age was 47 years (range, 15–85). Median time from diagnosis to TKI therapy was 1 month (range, 0 to 6). 319 (69%), 112 (24%), and 34 (7%) pts were in low, intermediate, and high-Sokal score category, respectively. Median basophils percentage at baseline was 3 (range, 0 to 19). Median splenomegaly size was 0 cm (range, 0 to 30). 118 pts (25%) received previous cytoreduction therapy. Median follow-up was 117 months (range, 16 to 130) for pts receiving standard-dose imatinib, 88 months (range, 4 to 118) for those receiving high-dose imatinib, and 30 months (range, 3 to 69) for those receiving 2nd TKI. The overall CCyR rates were 87%, 91%, and 95%, respectively. The 4-year EFS, TFS, and OS rates for the whole group were 84%, 94%, and 95%, respectively. Overall, of the 465 pts, 427 (92%) were in low EUTOS score category (Table 1). Pts with low EUTOS score had higher rates of CCyR at anytime compared to pts with high EUTOS score (93% versus 81%, p=0.02). This difference was mainly significant among pts receiving 2nd TKI (p=0.03) while it was not different among pts receiving imatinib (p=0.27). There was no difference in the rates of major molecular response (85% versus 81%, p=0.48) between pts with low and high EUTOS score. There was no difference in TFS, EFS, and OS rates between pts with low and high EUTOS score, overall and among specific therapy (Table 1). Conclusion: Eight percent of pts with CML-CP treated at MDACC are of high EUTOS score. In this population, the EUTOS score was not predictive for overall MMR, TFS, EFS, and OS. Disclosures: Cortes: BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.

Prediction for Sustained Deep Molecular Response of BCR-ABL Levels in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1224-1224
Author(s):  
Koji Sasaki ◽  
Hagop M. Kantarjian ◽  
Susan O'Brien ◽  
Farhad Ravandi ◽  
Marina Konopleva ◽  
...  
Keyword(s):  
Research Funding ◽  
Chronic Phase ◽  
High Dose ◽  
Molecular Response ◽  
Regression Equations ◽  
Transcript Levels ◽  
Deep Molecular Response ◽  
Best Fit ◽  
Time Point

Abstract Introduction Initial treatment with tyrosine kinase inhibitors (TKI) induces excellent response in the majority of patients with CML-CP. Current guidelines recommend periodic monitoring of BCR-ABL1 levels to monitor response. During the course of treatment, recognizing early predictors of deeper response and longer-term outcomes can help guide treatment. This is relevant not only at the specified fixed time point typically reported (i.e., 3, 6, 12 months) but at any other time point when an assessment is made. Achievement of sustained deep molecular response is a goal of increasing relevance as it opens the possibility of treatment discontinuation. The objective of this study is suggest optimal BCR-ABL transcript levels at any given time, and to suggest a prediction model for sustained molecular response 4.5 (MR4.5) (BCR-ABL ≤0.0032%) for at least 2 years according to BCR-ABL levels achieved within the first 12 months of TKI therapy. Methods Response data for 630 patients with newly diagnosed CML-CP in consecutive prospective clinical trials of frontline imatinib (n=73; NCT00048672), high-dose imatinib (n=208; NCT00038469 and NCT00050531), nilotinib (n=148; NCT00129740), dasatinib (n=150; NCT00254423), and ponatinib (n=51; NCT01570868) were analyzed. Real-time PCR analysis was performed at approximately 3 month intervals during the first year and 6 month intervals thereafter. The "best fit average" molecular response was defined by robust linear regression models, with which the estimated molecular level in patients with complete cytogenetic response (CCyR) within 1 year, major molecular response (MMR) within 1 year, and sustained MR4.5 at any point were defined. The acceptable molecular response was defined by quantile regression for the 95th percentile, with which the worst 5% BCR-ABL levels in patients with CCyR within 1 year, MMR within 1 year, and sustained MR4.5 at any point were identified. Results In 630 patients, 2512 data points of BCR-ABL levels within 1 year of TKI were identified. The median follow-up for the entire cohort was 106 months (range, 0.3-177.8). The regression equations for best fit average PCR for CCyR within 1 year was Log10(PCR) = -0.2159 x (Months) + 0.1957; for MMR within 1 year, Log10(PCR) = -0.2304 x (Months) + 0.1046; for sustained MR4.5 at any point, Log10(PCR) = -0.2154 x Months -0.1161. The regression equations for acceptable PCR for CCyR within 1 year was Log10(PCR) = -0.15796 x (Months) + 1.54839; for MMR within 1 year, Log10(PCR) = -0.20999 x (Months) + 1.54839; for sustained MR4.5, Log10(PCR) = -0.22476 x (Months) + 1.50516 (Figure 1). The best fit average PCR (i.e., estimated levels achieved by the average responder in each category) for CCyR within 1 year was 0.353%, 0.079%, 0.017%, and 0.004% at 3, 6, 9, and 12 months, respectively; for MMR within 1 year was 0.259%, 0.053%, 0.011%, and 0.002% at 3, 6, 9, and 12 months, respectively; for sustained MR4.5 at any point was 0.295%, 0.067%, 0.015%, and 0.003% at 3, 6, 9, and 12 months, respectively (Table 1). To achieve CCyR within 1 year, the acceptable PCR (i.e., levels achieved by 95% of all those who eventually reach the said endpoint) response was 11.872%, 3.987%, 1.339%, and 0.450% at 3, 6, 9, and 12 months, respectively; to achieve MMR within 1 year, 8.287%, 1.943%, 0.455%, and 0.107% at 3, 6, 9, and 12 months, respectively; to achieve sustained MR4.5 at any time, 6.774%, 1.434%, 0.304%, and 0.064% at 3, 6, 9, and 12 months, respectively. Of 289 patients who eventually achieved sustained MR4.5, 288 (99%) achieved CCyR within 1 year; 268 (93%), MMR within 1 year; 201 (70%), MR4 within 1 year; 162 (56%), MR4.5 within 1 year; 72 (25%), CMR within 1 year. Of 359 patients who achieved MMR within 1 year with a minimum follow-up of 48 months, 256 (71%) achieved sustained MR4.5; of 180 patients who achieved MR4.5 within 1 year, 151 (84%); of 72 patients who achieved CMR within 1 year, 65 (90%). Conclusion Proper interpretation of early transcript levels at any time during the course of therapy may help predict later response and outcome. Such models can be built to guide therapy for patients in a continuous basis. To achieve sustained MR4.5 for at least 2 years, deeper responses are required at each time point. Our model proposes optimal values that predict the highest probability of reaching such goal. At a minimum, CCyR within 1 year is required to achieve sustained MR4.5. Disclosures Kantarjian: Bristol-Myers Squibb: Research Funding; ARIAD: Research Funding; Amgen: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding. Ravandi:Seattle Genetics: Consultancy, Honoraria, Research Funding; BMS: Research Funding. Konopleva:AbbVie: Research Funding; Genentech: Research Funding. Wierda:Novartis: Research Funding; Abbvie: Research Funding; Acerta: Research Funding; Gilead: Research Funding; Genentech: Research Funding. Daver:Ariad: Research Funding; Karyopharm: Honoraria, Research Funding; Sunesis: Consultancy, Research Funding; BMS: Research Funding; Kiromic: Research Funding; Otsuka: Consultancy, Honoraria; Pfizer: Consultancy, Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy.

scholarly journals The natural history of vascular and other complications in patients treated with nilotinib for chronic myeloid leukemia

2019 ◽  
Vol 3 (7) ◽  
pp. 1084-1091 ◽  
Author(s):  
Adrian G. Minson ◽  
Katherine Cummins ◽  
Lucy Fox ◽  
Ben Costello ◽  
David Yeung ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Natural History ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Molecular Response ◽  
Increased Risk ◽  
History Of ◽  
Dose Modifications

Abstract Although second-generation tyrosine kinase inhibitors (TKIs) show superiority in achieving deep molecular responses in chronic myeloid leukemia in chronic phase (CML-CP) compared with imatinib, the differing adverse effect (AE) profiles need consideration when deciding the best drug for individual patients. Long-term data from randomized trials of nilotinib demonstrate an increased risk of vascular AEs (VAEs) compared with other TKIs, although the natural history of these events in response to dose modifications or cessation has not been fully characterized. We retrospectively reviewed the incidence of nilotinib-associated AEs in 220 patients with CML-CP at 17 Australian institutions. Overall, AEs of any grade were reported in 95 patients (43%) and prompted nilotinib cessation in 46 (21%). VAEs occurred in 26 patients (12%), with an incidence of 4.1 events per 100 patient-years. Multivariate analysis identified age (P = .022) and dyslipidemia (P = .007) as independent variables for their development. There was 1 fatal first VAE, whereas the remaining patients either continued nilotinib (14 patients) or stopped it immediately (11 patients). Recurrent VAEs were associated with ongoing therapy in 7 of 14 who continued (with 2 fatal VAEs) vs 1 of 11 who discontinued (P = .04). Nineteen of the 23 evaluable patients surviving a VAE ultimately stopped nilotinib, of whom 14 received an alternative TKI. Dose reduction or cessation because of VAEs did not adversely affect maintenance of major molecular response. These findings demonstrate that in contrast to other AEs, VAEs are ideally managed with nilotinib cessation because of the increased risk of additional events with its ongoing use.

High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome–positive chronic phase chronic myeloid leukemia

Blood ◽  
2004 ◽  
Vol 103 (8) ◽  
pp. 2873-2878 ◽  
Author(s):  
Hagop Kantarjian ◽  
Moshe Talpaz ◽  
Susan O'Brien ◽  
Guillermo Garcia-Manero ◽  
Srdan Verstovsek ◽  
...  
Keyword(s):  
Imatinib Mesylate ◽  
Quantitative Polymerase Chain Reaction ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
High Dose ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Complete Cytogenetic Response

Abstract Imatinib mesylate (STI571) is effective in chronic phase chronic myelogenous leukemia (CML). However, most patients treated with 400 mg imatinib daily have variable levels of residual molecular disease. We treated 114 patients with newly diagnosed chronic phase CML with 400 mg imatinib twice daily. Overall, 109 patients (96%) had a major cytogenetic response (Philadelphia chromosome [Ph] &lt; 35%), and 103 (90%) had a complete response (Ph 0%). With a median follow-up of 15 months, no patient has progressed to accelerated or blastic phase. The estimated 2-year survival rate was 94%. By quantitative polymerase chain reaction (QPCR) studies, 71 (63%) of 112 patients showed BCR-ABL/ABL percentage ratios decrease to less than 0.05%, and 31 (28%) to undetectable levels. Compared with standard-dose imatinib, high-dose imatinib was associated with significantly better complete cytogenetic response (P = .0005), major molecular response (QPRC &lt; 0.05%; P = .00001), and complete molecular response (undetectable BCR-ABL; P = .001). High-dose imatinib was well tolerated but resulted in more frequent myelosuppression; 82% of patients continue to receive 600 mg or more of imatinib daily. In conclusion, high-dose imatinib induced higher rates of complete cytogenetic response and of molecular response in patients with newly diagnosed chronic phase CML. (Blood. 2004; 103:2873-2878)

Efficacy of Nilotinib (AMN107) in Patients (Pts) with Newly Diagnosed, Previously Untreated Philadelphia Chromosome (Ph)-Positive Chronic Myelogenous Leukemia in Early Chronic Phase (CML-CP).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 29-29 ◽  
Author(s):  
Jorge Cortes ◽  
Susan O’Brien ◽  
Elias Jabbour ◽  
Alexandra Ferrajoli ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
P Value ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Major Molecular Response ◽  
Treatment Interruptions ◽  
Grade 3

Abstract Background: Nilotinib is a novel, oral tyrosine kinase inhibitor with increased selectivity against Bcr-Abl that is approximately 30-fold more potent than imatinib. High response rates have been reported with nilotinib therapy in CML after imatinib failure. Methods: We evaluated the efficacy of nilotinib as first line therapy in pts with newly diagnosed Ph-positive CML-CP. The primary objective was to estimate the proportion of pts attaining major molecular response (BCR-ABL/ABL ratio ≤0.05% in our lab) at 12 months (mo). Results: Thirty-two pts have been treated with nilotinib 400 mg orally twice daily for a median of 5 months (mo) (range, 1 to 31 mo). The median age was 47 years (yrs) (range, 24–73 yrs). The Sokal risk at pretreatment was low in 21 (70%) pts, intermediate in 6 (20%), and high in 3 (10%). The rate of complete cytogenetic response [CCyR] (Ph 0%) at 3, 6 and 12 mo compares favorably to those observed in historical controls treated with imatinib 400 mg or 800 mg daily: The median QPCR with nilotinib at 3, 6, and 12 months were, respectively, 0.52% (range, 0.0–29.5%), 0.03% (range, 0.0–9.13%), and 0.09% (range, 0.0–16.21%). At 3 mo follow-up, major molecular response (MMR; BCR-ABL/ABL ratio ≤0.05%) was observed in 3/22 patients (14%), 7/13 (54%) at 6 mo, and 5/11 (45%) at 12 mo. 12-mo rates of MMR for the historical imatinib groups treated at 400 mg and 800 mg were 24% and 47%, respectively (p=0.02). None of the molecular responses has been lost while on therapy. Grade 3–4 neutropenia was observed in 2 (7%) pts, and thrombocytopenia in 1 (3%). Other grade 3–4 adverse events included elevation of lipase (n=3, 9%), or bilirubin (n=2; 6%), and amylase elevation, back pain, and infection (1 each). Twelve pts had transient treatment interruptions (median 11 days), most frequently due to pain (n=3; musculoskeletal 2, abdominal 1), lipase elevation (n=2). Seven patients had their dose reduced to 400 mg daily, 2 to 200 mg twice daily, and 1 to 200 mg daily due to extramedullary toxicity. Three patients decided to change therapy after 4, 6 and 8 months; 2 switched to imatinib and 1 received SCT. Conclusion: Nilotinib 400 mg orally twice daily suggest significant efficacy manifested by complete cytogenetic responses in nearly all patients as early as 3 months after the start of therapy with a favorable toxicity profile. Percent with CCyR (No. evaluable) Months on Therapy Nilotinib Imatinib 400 mg Imatinib 800 mg P value 3mo 95 (22) 37 (49) 62 (202) < 0.0001 6mo 100 (13) 54 (48) 82 (199) <0.0001 12mo 100 (11) 65 (48) 86 (197) 0.0007

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