scholarly journals Treatment of chronic myeloid leukemia with Generic Imatinib in patients from Northeastern part of India

2019 ◽  
Vol 10 (4) ◽  
pp. 3107-3113 ◽  
Author(s):  
Siddharth Samrat ◽  
Lalit Prashant Meena ◽  
Jaya Chakravarty ◽  
Madhukar Rai
Keyword(s):  
Side Effect ◽  
Therapeutic Response ◽  
Blast Crisis ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Hematological Toxicity ◽  
Molecular Response ◽  
One Year

Imatinib is now used as the first-line drug to treat CML patient. However, the emergence of resistance to Imatinib in CML patient, the side effect of bone marrow suppression, fluid overload and gastritis are a major limitation of the use of Imatinib in the treatment of CML. This study was conducted to see the therapeutic response and side effect profile of generic Imatinib Mesylate in newly diagnosed CML patients. All cases of CML were given generic Imatinib and followed prospectively with a minimum follow-up of 6 months. They were followed at an interval of 2 weeks till complete hematologic response, thereafter at an interval of 6 to 8 weeks. Cytogenetic and molecular response at the end of one year also evaluated. Among 36 CML patients, 33 were in chronic phase 2 in accelerated phase and 1 in blast crisis while 35 were Philadelphia+ve and 1 was ph–ve at initial presentation. Minimum duration to achieve CHR was 2 week with a mean of 5 weeks. At 3 month except one 35 patients achieved CHR (97%). Out of 36 patients, 27 were subjected for Philadelphia chromosome at one year which shown 23 patients (85.18%) achieved a major cytogenetic response. 8 (38%) patients achieved a major molecular response and one patient (4.76%) was having a complete molecular response at one year. 8 (22.22%) patients developed hematological toxicity to Imatinib with Pancytopenia most common. In conclusion, Generic Imatinib is having an excellent therapeutic response in CML patients although higher response rate may be due to smaller sample size and lesser duration of follow up.

Early Optimization of Imatinib Therapy in Patients Newly Diagnosed with Chronic-Phase Chronic Myeloid Leukemia (CP-CML). A Study of the Spanish PETHEMA Group.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1113-1113
Author(s):  
Francisco Cervantes ◽  
Pilar López-Garrido ◽  
María-Isabel Montero ◽  
Fermín Jonte ◽  
Jesus Martinez ◽  
...  
Keyword(s):  
Chronic Phase ◽  
Cytogenetic Response ◽  
Hematological Toxicity ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Intention To Treat ◽  
Number Of Patients ◽  
Grade 3 ◽  
One Year

Abstract Abstract 1113 Poster Board I-135 Currently, imatinib (IM) 400 mg daily is the frontline therapy for patients with CP-CML. In an attempt to improve the therapeutic response to IM, the Spanish collaborative PETHEMA group undertook a study of early optimization of therapy, in which 210 adult patients newly diagnosed with CP-CML (< 3 months from diagnosis) were included. Median age was 44 (range: 18-71) years and distribution by Sokal groups: low risk 56%, intermediate risk 28%, and high risk 16%. Hydroxyurea was permitted before IM. Patients initially received IM 400 mg daily for 3 months and then those failing to achieve a complete hematologic response (CHR) had the dose increased (to 600 and then 800 mg daily), while the remainder were maintained on 400 mg daily for three more months. At 6 months, depending on cytogenetic response, patients were kept on IM 400, if they had achieved a complete cytogenetic response (CCyR), or randomized to receive higher IM doses (600 and then 800 mg) or IM 400 plus low dose interferon (IFN, 3 million units 3 times a week) in case that a CCyR had not been attained by that time. In patients already in CCyR at 6 months, the IM dose was increased if a major molecular response (MMolR) according to the international scale had not been achieved at 18 months, whereas in patients not in CCyR and randomized at 6 months, a switch to a second generation TKI (dasatinib or nilotinib) was permitted if a CCyR was not achieved at one year of randomization. At standard intervals, cytogenetic response was assessed in bone marrow by chromosome banding analysis and molecular response determined in peripheral blood by RT-Q-PCR performed in three reference laboratories. At the time of the analysis, median follow-up was 48.3 (range: 1.2-73) months. Median time from diagnosis to IM start was 0.5 (range: 0-2.8) months; 72% of patients started IM within one month from diagnosis. At 3 months of treatment, 4 patients had not achieved a CHR; two of them failed to achieve a favorable response following the increase in the IM dose. At 6 months, a CCyR was obtained in 79% of patients; of the 41 patients not in CCyR, 9 could not be randomized because of toxicity (n= 3) or withdrawal of consent (n=6), 17 were assigned to higher IM dose, and 15 to IM 400 + IFN, but only 9 of the latter actually started IFN. Due to the scarce number of patients randomized, no comparison could be established between the two arms. Overall, cumulative incidence of response at 3 years was: CHR 98.6%, CCyR 90%, and MMolR 82%. Based on an intention-to-treat analysis, CCyR was 70% at 18 months. With current follow-up, only 5 patients have died and 9 have progressed to the accelerated or blastic phases (AP/BP). At 5 years, overall survival rate is 97.5%, survival free from AP/BP 95.5%, survival free from failure (including death, progression to AP/BP and the lack of achievement or the loss of a previously obtained CHR and CCyR) 82%, and event-free survival (including the above plus the permanent IM discontinuation for any reason) 80%. Twenty-seven patients (12.8% of the overall group) had grade 3-4 hematological toxicity and 26 (12.4%) grade 3-4 nonhematological side effects, in most cases during the first year of treatment. The presentresults show the benefit of prompt institution and early optimization of IM therapy in patients with newly diagnosed CP-CML. Disclosures Cervantes: Novartis: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau.

Clinical Outcome of CML Patients with Philadelphia Chromosome Complex Variants.

Blood ◽  
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.

Switching patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) with residual disease on long-term imatinib (IM) to nilotinib (NIL): ENESTcmr 24-mo follow-up.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7053-7053
Author(s):  
Nelson Spector ◽  
Brian Leber ◽  
Jeffrey Howard Lipton ◽  
Carmino De Souza ◽  
Beatriz Moiraghi ◽  
...  
Keyword(s):  
Residual Disease ◽  
Blast Crisis ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Molecular Responses ◽  
The Difference ◽  
Treatment Free Remission

7053^ Background: The 12-mo results of ENESTcmr demonstrated that switching pts on IM with sustained BCR-ABL positivity to NIL leads to faster, deeper molecular responses (MRs)vs remaining on IM. These deeper molecular responses (MR4.5 [BCR-ABL ≤ 0.0032%IS] or greater) are a prerequisite to enter most treatment-free remission studies. Here, we report 24-mo f/u of ENESTcmr. Methods: Philadelphia chromosome–positive CML-CP pts (N = 207) who achieved a complete cytogenetic response, but had detectable BCR-ABL transcripts after ≥ 2 y on IM, were randomized to receive NIL 400 mg twice daily (BID; n = 104) or continue their IM dose (400/600 mg once daily [QD]; n = 103). Results: By 24 mo, significantly more pts achieved confirmed undetectable BCR-ABL (by RQ-PCR with ≥ 4.5 log sensitivity in 2 consecutive samples) with a switch to NIL vs continuing IM (22.1% vs 8.7%; P = .0087). The increase in the rate of undetectable BCR-ABL from mo 12 to 24 was higher for pts on NIL vs IM (9.6 vs 2.9 percentage points). In pts without MR4.5 at baseline (BL), MR4.5 was achieved by 24 mo in 42.9% vs 20.8% of pts (NIL vs IM; P = .0006). In pts without major molecular response (MMR; ≤ 0.1%IS) at BL, MR4.5 was achieved by 24 mo in 29.2% vs 3.6% of pts (P = .016). No progressions to accelerated phase/blast crisis or deaths occurred on study since the 12-mo f/u. Event-free survival at 24 mo was 96.6% vs 92.8% in the NIL and IM arms, respectively. Discontinuations due to adverse events occurred in 11.5% and 2.9% of pts in the NIL and IM arms. The NIL safety profile was consistent with prior switch studies. Conclusions: By 24 mo, significantly more pts achieved deeper responses (MR4.5and undetectable BCR-ABL) with switch to NIL vs remaining on IM, and the difference between arms in these endpoints increased between 12 and 24 mo. Clinical trial information: NCT00760877. [Table: see text]

Imatinib (IM) Treatment In Chronic Myeloid Leukemia (CML). Clinical Practice Limitations

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4454-4454
Author(s):  
Alicia Inés Enrico ◽  
Georgina Bendek ◽  
Maria Virginia Prates ◽  
Virginia Guerrero ◽  
Juan Jose Napal ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Blast Crisis ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Trisomy 8 ◽  
History Of ◽  
One Year

Abstract Abstract 4454 Introduction: CML represents 15% all of oncohematologic diseases in adults. IM changed the history of the disease. At one year of treatment, the emblematic IRIS study showed Major Cytogenetic Responses (MCyR) of approximately 87% and Complete Cytogenetic Responses (CCyR) of around 76%, with PFS to accelerated phase or blast crisis of 97.7% and 91.5%, respectively. Objective: To assess treatment characteristics and responses in a group of patients treated with IM in clinical practice. Materials and Method: 113 medical records of patients with CML diagnosed between 1998–2011 from two institutions in the Argentine Republic were retrospectively analyzed. Result: Mean population age was 46 years old (r 18–73) 65 male, 48 female. 97% in chronic phase, the rest in accelerated phase. 31% presented comorbidities at diagnosis. Cytogenetic abnormalities at diagnosis, in addition to the classic t(9:22), included: trisomy 8 and double Philadelphia chromosome in 4 tests. Only 7 patients had qualitative BCR/ABL determined at diagnosis. 25% had received interferon, patients received IM 400 mg and only 2% received 300 or 600 mg doses. 2.6% of patients did not achieve CHR. Cytogenetic responses assessed at any time of treatment were: Major: 12%, Minor 20%, Complete 51%, None 3%, 14% were not assessed. With a mean follow-up time of 46 months, the overall survival was 75%. 10% of patients progressed to BC/AP, 11 % of patients died due to disease-related causes or comorbidities. Conclusions: With a mean follow-up time of 46 months for chronic phase CML, treatment with IM achieved complete cytogenetic responses in 51% of patients, and progression occurred in 10% of patients. Disclosures: No relevant conflicts of interest to declare.

Nilotinib versus imatinib in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): ENESTnd 4-year (y) update.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7052-7052 ◽  
Author(s):  
Richard A. Larson ◽  
Andreas Hochhaus ◽  
Giuseppe Saglio ◽  
Dong-Wook Kim ◽  
Saengsuree Jootar ◽  
...  
Keyword(s):  
Blast Crisis ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Once Daily ◽  
Risk Of Progression ◽  
Peripheral Arterial ◽  
To Receive

7052^ Background: In the 3-y follow-up (f/u) of ENESTnd, NIL demonstrated superior rates of molecular response and reduced progression to accelerated phase/blast crisis (AP/BC) vs IM. Here, we report results with a minimum f/u of 4 y. Methods: 846 adults with newly diagnosed Philadelphia chromosome–positive CML-CP were randomized to receive NIL 300 mg twice daily (BID; n = 282), NIL 400 mg BID (n = 281), or IM 400 mg once daily (QD; n = 283). Results: NIL continued to demonstrate higher rates of major molecular response (MMR; ≤ 0.1% BCR-ABLIS), MR4 (≤ 0.01%IS), and MR4.5 (≤ 0.0032%IS) vs IM (Table). No new progressions have occurred on treatment on any arm since the 2-y analysis. NIL had significantly lower rates of progression to AP/BC on treatment (n = 2, 3, and 12 on NIL 300 mg BID, 400 mg BID, and IM, respectively) and when including f/u after discontinuation (n = 9, 6, and 19 on NIL 300 mg BID, 400 mg BID, and IM, respectively) and higher overall survival (OS) vs IM. By 4 y, half as many pts acquired new BCR-ABL mutations on study with NIL vs IM (n = 12, 11, and 22 on NIL 300 mg BID, 400 mg BID, and IM, respectively). Since the 3-y analysis, 2 new mutations (1 pt with T315I on NIL 300 mg BID; 1 pt with F317L on IM) were reported. Safety profiles of both drugs were consistent with previous ENESTnd analyses. By 4 y, peripheral arterial occlusive disease (PAOD) events were reported in 4 and 5 pts in the NIL 300 mg BID, and 400 mg BID arms, respectively. No pt in the IM arm had a PAOD event. Conclusions: ENESTnd 4-y data continue to demonstrate the superiority of NIL over IM for achieving deeper responses with lower risk of progression, supporting the use of NIL as frontline therapy in CML-CP. Clinical trial information: NCT00471497. [Table: see text]

scholarly journals Efficacy and Safety of Radotinib Compared with Imatinib in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia Patients: 12 Months Result of Phase 3 Clinical Trial

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 476-476 ◽  
Author(s):  
Jae-Yong Kwak ◽  
Hawk Kim ◽  
Jeong A Kim ◽  
Young Rok Do ◽  
Hyeoung Joon Kim ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Research Funding ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Phase 3 ◽  
Grade 3

Abstract Background Radotinib is a second generation BCR-ABL1 tyrosine kinase inhibitor (TKI) developed by IL-YANG Pharm. Co., Ltd (Seoul, South Korea) and approved by the Korea FDA for the treatment of chronic phase chronic myeloid leukemia (CML-CP) patients who have failed prior TKIs. We conducted the randomized, open-label, phase 3 study to assess the efficacy and safety of radotinib, as compared with imatinib, for the first-line treatment of newly diagnosed CML-CP. Methods Based on baseline demographics and Sokal risk score, 241 patients were randomized 1:1:1 to radotinib 300 mg twice daily (bid) (n=79), radotinib 400 mg bid (n=81), or imatinib 400 mg once daily (qd) (n=81). The primary endpoint was the rate of major molecular response (MMR) by 12 months and molecular response was assessed by RQ-PCR at baseline and every 3 months. Secondary endpoints were the rate of complete cytogenetic response (CCyR), MR4.5 by 12 months, and the rate of progression to accelerate phase or blast crisis. Results All three study groups were well balanced with baseline age, gender, race and Sokal risk score. With minimum follow-up of 12 months, the proportions of patients receiving a study drug were 86.3% (69/79) in radotinib 300 mg bid group, 71.6% (58/81) in radotinib 400 mg bid group, and 81.5% (66/81) in imatinib 400 mg qd group. By 12 months, rates of MMR were significantly higher in patients receiving radotinib 300 mg bid (51.9%, P = .0044) and radotinib 400 mg bid (45.7%, P = .0342) compared with imatinib (29.6%). The median time to MMR among responders were shorter on radotinib 300 mg bid (5.7 months) and radotinib 400 mg bid (5.6 months) than imatinib group (8.2 months). The MR4.5 rates by 12 months were also higher for both radotinib 300 mg bid (15.2%) and 400 mg bid (13.6%) compared to imatinib (8.6%). The CCyR rates by 12 months were also higher for radotinib 300 mg bid (91.1%, P = .0120) compared with imatinib (76.5%). There was no progression to accelerated phase or blast crisis in all groups by 12 months. Discontinuation due to adverse events (AEs) or laboratory abnormalities occurred in 7 (8.8%), 16 (19.8%), and 5 (6.2%) patients for radotinib 300 mg bid, radotinib 400 mg bid and imatinib, respectively. Grade 3/4 thrombocytopenia occurred in 16.5% of patients receiving radotinib 300 mg bid, in 13.6% for radotinib 400 mg bid, and in 19.8% receiving imatinib. And grade 3/4 neutropenia occurred in 19.0%, 23.5%, and 29.6% for radotinib 300 mg bid, 400 mg bid and imatinib, respectively. The most common any grade non-laboratory AEs were skin rash (35.4% and 33.3%), nausea/vomiting (22.8% and 23.5%), headache (19.0% and 30.9%), and pruritus (19.0% and 30.0%) in radotinib 300 mg bid and radotinib 400 mg bid, respectively; AEs in the imatinib group were edema (34.6%), myalgia (28.4%), nausea/vomiting (27.2%), and skin rash (22.2%). Overall, grade 3/4 non-laboratory AEs were uncommon in all groups. Conclusions With minimum 12 months follow-up, radotinib demonstrated significantly higher and faster rates of CCyR and MMR than imatinib in patients with newly diagnosed CML-CP. The safety profiles of the radotinib and imatinib were different, and most AEs were manageable with optimal dose reduction. The results of this trial support that radotinib can be one of the standard of care in newly diagnosed CML-CP. Table. Baseline Characteristics, Molecular and Cytogenetic Response Rates Radotinib 300mg BID Radotinib 400mg BID Imatinib 400mg QD (N=79) (N=81) (N=81) Age, median (range), years 45 (20-75) 43 (18-84) 45 (18-83) Gender, n (%) Male 52 (65.8) 47 (58.0) 52 (64.2) Female 27 (34.2) 34 (42.0) 29 (35.8) Sokal risk, n (%) Low 21 (26.6) 22 (27.2) 22 (27.2) Intermediate 38 (48.1) 38 (46.9) 39 (48.2) High 20 (25.3) 21 (25.9) 20 (24.7) MMR by 12 months, % 51.9 45.7 29.6 P = .0044 P = .0342 Cumulative Incidence of MMR by 12 months¢Ó, % 57.0 58.0 35.0 P = .0040 P = .0037 MR4.5 by 12 months, % 15.2 13.6 8.6 CCyR by 12 months, % 91.1 81.5 76.5 ¢Ó Kaplan-Meier estimates of MMR Disclosures Kim: IL-YANG Pharm. Co. Ltd: Research Funding. Kim:Alexion Pharmaceuticals: Research Funding. Chung:Alexion Pharmaceuticals: Research Funding. Choi:Alexion Pharmaceuticals: Research Funding.

Sustained Durability of Responses Plus High Rates of Cytogenetic Responses Result in Long-Term Benefit for Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia (CML-CP) Treated with Imatinib (IM) Therapy: Update from the IRIS Study.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 21-21 ◽  
Author(s):  
Francois Guilhot
Keyword(s):  
Blast Crisis ◽  
Chronic Phase ◽  
Transcript Level ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Major Molecular Response ◽  
First Line

IM has proven to be superior to IFN+Ara-C for newly diagnosed pts with CML-CP (O’Brien et al, NEJM, 2003). At 30-months of follow-up, 79% of pts randomized to IM remain on IM with 83% of them now treated for > 24 months. Therefore, this analysis is focused on first-line IM pts (n=553). Evaluation included complete hematologic response (CHR), major/complete cytogenetic response (MCyR/CCyR), major molecular response (≥3 log reduction in BCR-ABL/BCR vs. pooled diagnostic samples) time to progression (TTP) - defined as loss of CHR/MCyR or evolution to accelerated phase/blast crisis [AP/BC] or death, time to AP/BC, and overall survival. Median follow-up for first-line IM pts is 31.1. Summary of results are the following: 1st-line imatinib * 95% CI Best observed CHR/MCyR/CCyR (%) 95/87/79 Estimated major molecular response at 12 mos. (%) 40 Estimated cumulative MCyR % at 30 mos. 90 Estimated cumulative CCyR % at 30 mos. 82 Estimated % free of progression at 30 mos. 88 (85–91)* Estimated % free of AP/BC at 30 mos. 95 (93–97)* Estimated % survival at 30 mos. 95 (93–97)* The additional follow-up confirmed durable responses with first-line therapy while also demonstrating the effect of cytogenetic response on long-term outcomes. The estimated rate of confirmed responders remaining in response after achieving a CCyR at 30 months is >92%. Similarly, the estimated rate of patients still in response at 30 months after achieving either a MCyR or CHR is also >92% for both groups. Only 2% of pts with a confirmed loss of MCyR and 1% of the pts with a confirmed loss of CCyR subsequently progressed to AP/BC. Of these pts, 3 of 5 benefited from a dose increase to 600 or 800 mg of IM, while only 1 of 7 pts with a confirmed loss subsequently achieved a MCyR without a dose escalation. A total of 75 pts received a marrow transplant (BMT) after discontinuation from the study; 30 in the IM arm (2 after crossover from IFN) and 45 pts who were randomized to IFN (21 after crossover to IM). There was no difference in survival after BMT between pts who received first-line IM treatment (8 deaths, 1 after crossover) and pts who had received IFN+Ara–C (7 deaths) or IFN+Ara–C followed by IM (7 deaths) (p=0.78). The estimated survival at 12 months after BMT is 70%, 75%, and 68% respectively in the three groups. A landmark analysis showed that for 407 pts who achieved MCyR within 6 months, their estimated rate free of AP/BC at 30 months is 97% vs. 89% for the 124 pts who did not achieve this level of response at 6 months (p<0.001). Additionally, the estimated survival at 30 months for the same pts is 97% vs. 92% (p=0.0162). The achievement of a major molecular response at 12 months was also associated with improved progression-free survival. For patients who had achieved CCyR and a reduction in BCR-ABL transcript level ≥ 3 log at 12 months, the probability of remaining progression free was 100% at 30 months compared to 93% for such patients with reduction in BCR-ABL transcript level < 3 log and 82% for patients who were not in CCyR at 12 months (p<0.0001). These results will be further updated using a data cut-off of 31-July-04 to reflect additional 12-months of data (i.e., 42-month follow-up).

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 &lt;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 &lt;0.05% and as complete with a ratio &lt;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-&gt;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.

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

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 7071-7071
Author(s):  
L. Lima ◽  
S. E. Assouline ◽  
D. Saxe ◽  
K. Mann ◽  
M. McLemore ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Selective Inhibition ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Resistant Disease ◽  
Advanced Phase

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.

Safety and durability of ponatinib in patients with Philadelphia chromosome-positive (Ph+) leukemia: Long-term follow-up of an ongoing phase I study.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7063-7063
Author(s):  
Michael J. Mauro ◽  
Jorge E. Cortes ◽  
Hagop M. Kantarjian ◽  
Neil P. Shah ◽  
Dale Bixby ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Phase I Study ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Heavily Pretreated

7063 Background: Ponatinib is a potent oral pan–BCR-ABL tyrosine kinase inhibitor (TKI) that is active against native and mutated forms of BCR-ABL. The safety and anti-leukemic activity of ponatinib in patients (pts) with chronic myeloid leukemia (CML) or Ph+ acute lymphoblastic leukemia (ALL) were evaluated in a phase I clinical trial. Methods: Pts (N=81) with resistant/refractory hematologic malignancies were enrolled in this ongoing, open-label, dose escalation, phase I study. Ponatinib was dosed once daily (2–60 mg). 65 pts had Ph+ leukemia and are included in the present analysis (data as of 9 Nov 2012). Median follow-up was 25 (0.5–44) mos. Results: The median age of pts was 55 yrs; median time since diagnosis was 6.5 yrs. Pts were heavily pretreated (94% had received ≥2 prior TKIs, 62% ≥3). 65% had baseline BCR-ABL mutations. 46% (67% chronic phase [CP] CML) of pts remained on study. Progression and adverse events (AEs) were the most common reasons for discontinuation (17% each). The most common treatment-related AEs were rash (42%), thrombocytopenia (34%), arthralgia (20%), and increased lipase (20%). Significant anti-leukemic activity was observed (Table). Responses (major cytogenetic response [MCyR] for CP-CML or major hematologic response [MaHR] for accelerated phase [AP] CML, blast phase [BP] CML, or Ph+ ALL) were observed against the following mutations detected in >1 pt at baseline: 14/19 T315I, 4/7 F317L, 2/4 G250E, 2/2 M244V, 2/2 M35IT, and 1/2 F359V. Among CP-CML pts, 73% with complete cytogenetic response (CCyR) and 63% with major molecular response (MMR) are estimated to maintain response at 2 yrs (Kaplan-Meier). Of 28 CP-CML pts with CCyR, 25 remained on study (19 with continuous CCyR); of 22 pts with MMR, 21 remained on study (15 with continuous MMR). Updated data will be presented. Conclusions: Significant and durable responses were observed in heavily pretreated CP-CML pts, regardless of mutation status, and ponatinib was generally well tolerated. Clinical trial information: NCT00660920. [Table: see text]

Sign in / Sign up

Export Citation Format

Share Document