Busulfan Exposure Decrease CCyR Rate On Imatinib Therapy - Impact On Recent Pretreatment

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4452-4452
Author(s):  
Irina Dyagil ◽  
Elza Lomaia ◽  
Kudrat Abdulkadirov ◽  
Elena Goryunova ◽  
Natalia Lazorko ◽  
...  
Keyword(s):  
Median Time ◽  
Death Rate ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Imatinib Therapy ◽  
Control Group ◽  
Study Group ◽  
Leningrad Region ◽  
Imatinib Treatment ◽  
Female Ratio

Abstract Abstract 4452 Imatinib (IM) is now used world-wide as a first line chronic myeloid leukemia (CML) treatment. Although some time lack may exist between diagnosis and IM treatment. Earlier (Blood 2009, 114: Abstract 4278) we have shown that in CML chronic phase (CP) pts with very long history of the disease(more than five years)the pretreatment by Busulfan was the adverse prognostic factor on Imatinib therapy. Now we extend our study by a population of pts recently and for rather short time pretreated by busulfan. Aim. To investigate the effect of busulfan pretreatment on survival and responses to imatinib in CML pts in late CML CP. Materials and methods. In retrospective study 85 pts with CML CP from St-Petersburg, Leningrad region (Russian Federation) and several Ukrainian centers were included. The main inclusion criteria were: CML late CP (the duration of the disease more than 6 mos before IM start), IM therapy in routine clinical practice at least 12 months. The median time of IM therapy was 42,9 mos (12–97 mos), the median age of pts at the IM start was 49,5 years (19–83), male/female ratio 31/54. 23 patients were pretreated with busulfan (the study group) and 62 were not (control group). These groups were equal by age, sex, the median time from diagnosis to the IM start (28,3 mos in the study group and 23,9 in the control group), Sokal risk groups. Median time of busulfan pretreatment was 3,9 mos (1–62 mos). Statistical analysis was performed with SPSS 17. Results. In the whole group of patients frequency of complete cytogenetic response (CCyR) was 60% (51/85), estimated overall survival (OS) by 5 years from IM start was 87% (death rate 7% - 6/85). In the study group CCyR rate was significantly lower, than in the control group: 34,8% (8/23) and 69,35% (43/62), respectively, p=0,038. Estimated OS by 5 years was 72% (death rate 17% - 4/23) for busulfan-pretreated pts and 95% (death rate 3% - 2/62) for the control group, p<0,01. Interestingly, that in the group of shortly busulfan-pretreated pts (the duration of pretreatment ≤6 mos), the lower CCyR rate has also been observed – 31% (4/13), although all other parameters were seemed equal to the control group (median time before IM start 28,3 mos). Conclusion. The pretreatment with busulfan impaired negatively the efficacy of imatinib treatment in CML late CP patients. Even short pretreatment (less than 6 mos) had adverse effect on CCyR. The mechanism is unclear. Busulfan pretreatment before imatinib therapy should not be used. Disclosures: No relevant conflicts of interest to declare.

6 Year Experience of Treatment by Imatinib in CML CP Patientsin 6 Million Population Region of Russia(Saint-Petersburg and Leningrad region)with Impact On Time and Kind of Pretreatment.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4278-4278
Author(s):  
Kudrat Abdulkadirov ◽  
Elza Lomaia ◽  
Vasiliy Shuvaev ◽  
Alla Abdulkadirova ◽  
Vera Udalieva ◽  
...  
Keyword(s):  
Overall Survival ◽  
Clinical Trials ◽  
Median Time ◽  
Conflicts Of Interest ◽  
Clonal Evolution ◽  
Leningrad Region ◽  
Imatinib Treatment ◽  
Saint Petersburg ◽  
Late Group ◽  
Early Late

Abstract Abstract 4278 Imatinib(IM) has become the “gold standard” for the treatment of CML CP. In clinical trials the majority of pts obtain complete hematologic (CHR) and complete cytogenetic (CCyR) responses. The aim of the study was to evaluate the results of treatment by IM in CML CP pts in general practice (outside clinical trials). Patients and methods There are 335 pts with CML in databases in Saint-Petersburg and Leningrad region. Most of them (283/335-84,5%) are ever treated with IM. Disease phases at the time of the start of IM therapy by ELN (from 268/283 evaluable pts) and MDACC (from 256/283 evaluable pts) criteria were: CP – 232 and 215, AP – 28 and 33, BP - 8 and 8 respectively. All 232 pts in CML CP (by ELN criteria) treated since 2001 by IM were included in the study. Before IM 91/232(39%), 114/232(49%) and 17/232 (7,3%) pts were pretreated by hydroxyurea, interferon-alfa with or without hydroxyurea and busulfan. 12/335(4%) pts were undergone alloSCT(6 alive, 6 dead due to progression or TRM) There were 134/232(58%) pts in early (duration before Im ≤ 12 mos) and 98/232(42%) pts in late CP (> 12 mos). In early and late CP, there were 49/123 and 50/89, 40/123 and 23/89, 34/123 and 16/89 evaluable pts with low, intermediate and high Socal score respectively. The predominance of low Sokal score in late CP pts could to be related to survival benefit before imatinib.. The median time before Im for the whole group, for early and late CP pts were 7,4 mos(from 7 days to 132 mons), 1,8 mons (form 7 days to 12 mons) and 39 mons (from 12,1 mos to 132 mos) respectively. Median time of Im therapy was 33 mos (1 - 75 mos) in whole group, 24mons (1 - 73mos) in early and 34mos(2 - 75mos) in late CP pts respectivel Results Estimated overall survival by 6 years was 94,2% in whole group, 97% and 87% in early and late CP pts resp. Only 14/228(6,1%) of evaluable patients died due to CML: 4/130(3%) in early and 10/98(10,2%) in late CP group. 4 pts, resistant to IM, were transplanted: 1 in early CP and 3 in BP. Deathes were due to TRM or disease progression. CHR was achieved by 3 mons in most cases: 82/110(74,5%) and 36/64(56%) pt, in early and late CP, resp. Patients (39 in hole group, 12 in early and 27 in late CP) with CHR before IM were excluded from these analyses. The probability of CCyR by 6 years was 98% in early CP and 82% in late CP (p=0.002). The rate of CCyR was 75% 80/107) vs 31% (14/75) in patients with or without CHR by 3 mons (p=0.00). The same differences were found in early and late CP. CCyR in patients with CHR before IM was the same as in patients with newly obtained CHR by 3 mons on IM. Thereafter we have divided group of pts with late CP according to its duration before IM (very early -<6mons, early late - 6-60 mons and very late ≥60 mons) and compared CCyR in early CP with different subgroups of late CP. Achievement of CCyR was higher in pts in very early(69.1%) and early –late(68.2%) than in very late group(34.6%)(p=0.09) Further subdivisions of the period of 6-60 mos did not reveal any differences. Moreover, when we deleted the patients pretreated with busulfan, the differences were found only between early and early-late phases. We have separately analyzed very late group, it appeared that pretreatment with busulfan severely decreases CCyR (22% vs 81% in with (12 pts) or without (7 pts) busulfan pretreatment, p=0,002. Probably, patients in very late CP is a specific group of patients with preformed very good prognosis. Clonal evolution before treatment (8 pts in early CP and 7 in late CP) did not influence CCyR achievement. The probability of progression to AP/BP was slightly higher in late (6%) than in early CP (3%) (p=0.05). The appearance of clonal evolution was higher in late than in early CP (p=0,0002). Progression to AP/BP was 1% vs 11% in pts with or without CHR by 3 mos resp. (p=0.003). Conclusions Imatinib is efficacious drug in general hematological practice with very high probability of overall survival, CCyR and low risk of progression to AP/BP. CHR is an early and very important predictor for further successful treatment. Achievement of CCyR strongly depends on CHR by 3 mons. Patients with CHR before imatinib have similar CCyR in patients with CHR by 3 mons on imatinib. Pretreatment period predispose patients to clonal evolution on imatinib treatment. Busulfan pretreatment severely decreases probability of CCyR. Disclosures: No relevant conflicts of interest to declare.

Dasatinib Efficacy in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) and Pre-Existing BCR-ABL Mutations

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 449-449 ◽  
Author(s):  
Martin C Müller ◽  
Jorge Cortes ◽  
Dong-Wook Kim ◽  
Brian J. Druker ◽  
Philipp Erben ◽  
...  
Keyword(s):  
Amino Acids ◽  
Median Time ◽  
Chronic Phase ◽  
Response Rates ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Imatinib Resistant ◽  
Dasatinib Treatment

Abstract Dasatinib (SPRYCEL®) is an effective BCR-ABL inhibitor that is 325-fold more potent than imatinib and 16-fold more potent than nilotinib in vitro against unmutated BCR-ABL. Across a series of phase II and III trials, dasatinib has demonstrated durable efficacy in patients with CML following resistance, suboptimal response, or intolerance to imatinib. BCR-ABL mutations are an important cause of imatinib failure and suboptimal response. Here, the efficacy of dasatinib in patients with CML-CP who had baseline BCR-ABL mutations following imatinib treatment was analyzed using data from three trials (CA180-013, -017, and -034). Mutational assessment of the BCR-ABL kinase domain was performed using RT-PCR and direct sequencing of peripheral blood cell mRNA. Hematologic, cytogenetic, and molecular response rates were reported after ≥24 mos of follow-up. Duration of response, progression-free survival (PFS), and overall survival (OS; in 013/034) were calculated using Kaplan-Meier analysis, and rates were estimated at the 24-mo time point. Of 1,150 patients with CML-CP who received dasatinib, 1,043 had a baseline mutational assessment and were analyzed further. Of these, 402 patients (39%) had a BCR-ABL mutation, including 8% of 238 imatinib-intolerant and 48% of 805 imatinib-resistant patients. Excluding known polymorphisms, 64 different BCR-ABL mutations were detected affecting 49 amino acids, with G250 (n=61), M351 (n=54), M244 (n=46), F359 (n=42), H396 (n=37), Y253 (n=26), and E255 (n=25) most frequently affected. Dasatinib treatment in patients with or without a baseline BCR-ABL mutation, respectively, resulted in high rates of major cytogenetic response (MCyR; 56% vs 65%), complete cytogenetic response (CCyR; 44% vs 56%), major molecular response (MMR; 33% vs 45%); PFS (70% vs 83%), and OS (89% vs 94%) (Table). After 24 mos, CCyRs in patients with or without a BCR-ABL mutation had been maintained by 84% vs 85%, respectively, of those achieving this response. Among patients with mutations who received dasatinib 100 mg once daily, which has a more favorable clinical safety profile, efficacy and durability were similar (MCyR: 55%; CCyR: 41%; MMR: 36%; PFS: 73%; OS: 90%). In general, high response rates and durable responses were observed in patients with different mutation types, including highly imatinib-resistant mutations in amino acids L248, Y253, E255, F359, and H396. When responses were analyzed according to dasatinib cellular IC50 for individual BCR-ABL mutations, dasatinib efficacy was observed in 44 patients who had any of 5 imatinib-resistant mutations with a dasatinib cellular IC50 &gt;3 nM (Q252H, E255K/V, V299L, and F317L, excluding T315I), including MCyR in 34%, CCyR in 25%, MMR in 18%, PFS in 48%, and OS in 81%. Among patients whose mutations had a dasatinib IC50 ≤3 nM (n=254) or unknown IC50 (n=83), responses and durability were comparable to patients with no BCR-ABL mutation. As expected, few patients with a T315I mutation (IC50 &gt;200 nM; n=21) achieved a response. Among 70 patients with &gt;1 mutation, a MCyR was achieved in 53% and a CCyR in 37%. Among patients with mutational analysis at last follow-up (n=162), 42 (26%) retained a BCR-ABL mutation (20 retained a mutation with IC50 &gt;3 nM), 42 (26%) lost a mutation (5 lost a mutation with IC50 &gt;3 nM), and 44 (27%) developed a new mutation (39 developed a mutation with IC50 &gt;3 nM), with some patients counted in more than one category. Overall, this analysis demonstrates that dasatinib has broad efficacy against all BCR-ABL mutations except for T315l. For patients with BCR-ABL mutations, dasatinib treatment is associated with durable responses and favorable long-term outcomes. Table Analysis by dasatinib IC50 No BCR-ABL mutation BCR-ABL mutation BCR-ABL mutation treated with 100 mg QD &gt;3 nM (excl. T315I) 3 nM* Unknown IC50** Some patients had &gt;1 mutation. *Excluding patients with a concurrent mutation with dasatinib IC50 &gt;3 nM. **Excluding patients with a concurrent mutation with known dasatinib IC50. Patients, n 641 402 49 44 254 83 Response rates (≥24 mos of follow-up), % CHR 93 90 90 82 94 96 MCyR 65 56 55 34 58 73 CCyR 56 44 41 25 47 54 MMR 45 33 36 18 34 43 Median time to MCyR, mos 2.8 2.9 2.8 5.7 2.9 2.8 Median time to CcyR, mos 3.0 5.3 3.0 5.7 5.4 3.4 24-mo PFS (95% CI), % 83 (79.8–86.5) 70 (65.3–75.2) 73 (60.1–86.3) 48 (31.2–64.7) 73 (66.6–78.9) 89 (82.3–96.3) 24-mo OS (95% CI), % 94 (91.4– 95.7) 89 (85.1– 92.1) 90 (81.2– 98.3) 81 (68.8– 93.8) 90 (85.8– 94.2) 96 (91.2–100)

Imatinib Plasma Levels and Its Correlation with Response in Chronic-Phase Chronic Myeloid Leukemia: Experience of One Centre.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4284-4284
Author(s):  
J. Valentin Garcia. Gutierrez ◽  
Jesús Odriozola ◽  
Pilar Herrera ◽  
Javier Lopez ◽  
Maria Calbacho ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Plasma Levels ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Plasma Concentrations ◽  
Chronic Phase ◽  
Control Group ◽  
Treatment Optimisation ◽  
Number Of Patients

Abstract Abstract 4284 Introduction Imatinib (IM), 400 mg/d. induces durable responses in chronic myeloid leukaemia (CML) in chronic phase (CP). However, although IM-biodisponibility is fairly good, its plasma levels are variable and can not be predicted. Recently, these plasma concentrations have been related both to the dose being administrated and to the cytogenetic and molecular responses. Thus, Imatinib pharmacokinetics could be an issue towards treatment optimisation in CML patients. Recent studies suggest that therapeutic IM plasma levels should be above 1040 ng/dl. Aims To evaluate the association between IM dose and throughout plasma levels with different clinical outcomes. Results In this study, we looked for an association between plasma concentrations and clinical outcomes in 16/86 CML chronic phase patients who did not achieve optimal responses following the European Leukemia Net guidelines (ELN) (table 1). Patients with optimal responses and treated with the same standard doses were also analysed as a control group. Patients receiving doses above 400 mg showed throughout plasma levels considered as appropriate. In 7 of 16 patients (47.5%) not achieving optimal responses (ELN criteria), plasma levels were below the supposed therapeutic ranges. We have found no evidence for a correlation between clinical risk factors at diagnosis and the measurement of optimal plasma levels. Conclusions IM plasma levels are well correlated with IM dose administrated in the patients studied. In almost 50% of patients who did not achieve optimal responses, IM plasma levels were under the ranges considered therapeutic. Probably these are the patients who may benefit of a dose increase. Obviously, to learn more about the practical value of these measurements a longer follow up with a larger number of patients is needed. Disclosures: No relevant conflicts of interest to declare.

Imatinib Meslylate Plasma Levels Predict Compliance in Patients with Chronic Myelogenous Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4274-4274 ◽  
Author(s):  
Sunggeun Lee ◽  
Courtney Johnson ◽  
Yanderi Sandoval ◽  
Gerry Gorospe ◽  
Allen S. Yang ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Response Rate ◽  
Trough Level ◽  
Medical Center ◽  
Plasma Concentrations ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Imatinib Therapy ◽  
P Value ◽  
Imatinib Treatment

Abstract Abstract 4274 INTRODUCTION Imatinib mesylate, an inhibitor of the BCR-ABL fusion protein, serves as the current standard of care in the treatment of chronic myeloid leukemia (CML). Since its introduction, significant improvements have been seen in both the course and prognosis of CML. Although imatinib is highly effective in treating CML, recent studies have demonstrated that approximately 30% of patients discontinue imatinib for at least 30 days during their first year of therapy. Clinically, treatment non-adherence is a common reason patients experience suboptimal outcomes and it has therefore become important to establish methods to predict compliance. Based on the association of treatment response with adherence, plasma imatinib levels can be used to predict compliance. METHODS A retrospective analysis was conducted on 19 CML patients (female 5, male 14; median age= 45.3) who received imatinib treatment at LAC+USC Medical Center. Patient charts, laboratory reports and physical examination reports were assessed and plasma concentrations were measured: 1) using liquid chromatography and 2) tandem mass spectrometry. A comparison was then made between Imatinib levels and CCyR. Compliance with imatinib therapy was assessed by chart review and patient history. RESULT: Nineteen patients were analyzed in this study: 1(5%), 17 (90%), and 1 (5%) were treated with 300, 400 and 600 mg imatinib daily, respectively. Fifteen (79%) were Hispanic, 4(21%) were previously treated with interferon, most patients (95%) were in chronic phase when they were diagnosed except one who was in accelerated phase. The median duration of imatinib therapy at the time of plasma imatinib testing was 37 months. The mean and SDs of trough plasma imatinib level was 1362 ng/ml and789 ng/ml, respectively. We found that the imatinib trough concentration was higher in our analysis compared to those reported in the IRIS study and the French group studies, 969 ng/ml and 1058 ng/ml respectively. The patients were divided into two groups (Q1–Q2) based on their imatinib trough level. The average of trough level of the first group (Q1) was 780 ng/ml (±230) (n=9), and that of the second group (Q2) was 1885 ng/ml (±746) (n=10). In total 67% (6 out of 9) of the patients in the first group (Q1) and 20% (2 out of 10) of patients in the second group (Q2) had poor compliance, demonstrating a significantly better compliance in the Q2 (P=0.0001). In terms of their response rate to treatment, Of the 17 patients, a total of 11 achieved a CCyR at 18 months (65%): 63% (5 out of 8) in Q1; 67% (6 out of 9) in Q2. There was no significant correlation between plasma imatinib level and response rate. However, there was a significant correlation between the compliance and the response rate. 80% (8 out of 10) of patients who were adherent to the treatment had CCyR at 18 months, compared to only 43% (3 out of 7) of patients who had CCyR at 18 months in the non-adherent group. (P value=0.0001). Conclusions: Non-adherence to imatinib therapy is common in CML patients and is associated with suboptimal response. Non-compliance should be considered as a possible reason for a patient's poor response to imatinib, prior to considering the patient as imatinib-resistant. Plasma imatinib level can be used as one of the tools to predict compliance. By examining patients' plasma imatinib level, it was shown that high imatinib plasma levels point to a higher likelihood of compliance, and low levels predict a lower likelihood of compliance. Disclosures: Gorospe: Novartis: Honoraria, Speakers Bureau. Yang:Novartis: Honoraria, Research Funding.

Finding of Kinase Domain Mutations at Diagnosis IN PATIENTS with Chronic PHASE Chronic Myeloid Leukemia (CP-CML) MAY Identify Those at High RISK of Disease Progression.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4251-4251
Author(s):  
Angelo Michele Carella ◽  
Gabriella Cirmena ◽  
Gioacchino Catania ◽  
Gianmatteo Pica ◽  
Germana Beltrami ◽  
...  
Keyword(s):  
High Risk ◽  
Conflicts Of Interest ◽  
Prognostic Significance ◽  
Chronic Phase ◽  
Kinase Domain ◽  
Imatinib Treatment ◽  
Intermediate Risk ◽  
High Risk Patients ◽  
Risk Patients ◽  
Kinase Domain Mutations

Abstract Abstract 4251 Kinase domain (KD) mutations are associated with resistance to Imatinib in CP-CML but their incidence and prognostic significance before any treatment are unclear. To assess if KD mutations at diagnosis may have prognostic significance, we have recently reviewed (before treatment with Imatinib) the mutation status of 45 patients,of whom low risk: 24 patients; intermediate risk: 8 patients; high risk: 13 patients, according to Sokal/Euro. We found that a) no patient with low and intermediate risk showed KD mutations at diagnosis; b) 4/13 high risk patients showed the following mutations at diagnosis: S265R, E255K, F359Y and E255V/E258V; other 5 patients developed mutations during Imatinib treatment (E255V, T315I, E255V/E258V, H396R and D248-274). All patients with low-intermediate risk are alive and well at a median of 44 months (range, 15-71 months). On the contrary, 3/4 high risk patients with KD mutations at diagnosis progressed and died of blastic evolution at 23, 33 and 69 months despite Nilotinib and Dasatinib therapy. Other 3/5 high risk patients who developed mutations under Imatinib, died of blastic evolution at 22, 23 and 43 months despite Nilotinib and Dasatinib treatment. Seven high risk patients are alive under Imatinib between 4 and 51 months. In conclusion, the KD mutations at diagnosis were frequent in high Sokal/Euro risk group supporting the concept that such mutations could be related to the basic biology of the disease. These data, if confirmed, could modify our approach to high risk patients with KD mutation at diagnosis, i.e. utilizing second/third TKI generation earlier during the disease and, in selected cases, reconsidering allografting earlier before leukemic evolution make such procedure useless. Disclosures: No relevant conflicts of interest to declare.

Impact of Imatinib Dose Escalation in Chronic Myeloid Leukemia Patients in Chronic Phase with Sub-Optimal Response or Failure with Imatinib 400 Mg.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3289-3289
Author(s):  
Katia BB Pagnano ◽  
Marcia T Delamain ◽  
Eliana C.M. Miranda ◽  
Vagner O Duarte ◽  
Brunna Eulálio Alves ◽  
...  
Keyword(s):  
Median Time ◽  
Dose Escalation ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Dose Increase ◽  
Free Survival ◽  
Optimal Response ◽  
Hematological Response

Abstract Abstract 3289 Poster Board III-1 Imatinib dose escalation has been used in sub-optimal response and therapeutic failure to imatinib in conventional doses. The aim of this study was to evaluate the efficacy of imatinib dose increase in CML patients in CP who did not achieve the best response to imatinib 400 mg QID. Patients and methods: All CML patients in CP treated in our institution with imatinib 400mg between March 2002 and December 2008 were evaluated. Imatinib was escalated to 600–800mg in cases with sub-optimal response or failure, according to Leukemia Net or IRIS Trial criteria. All survival curves were calculated from date of dose increase: overall survival (OS) until death or last follow-up, event free survival (EFS) until loss of complete hematological response (CHR) or major cytogenetic response (MCyR), progression to accelerated phase (AP) or blast crisis (BC) or death from any cause. Transformation free survival (TFS) was calculated from dose increase until progression to AP, BC or death. Results: 137 patients in CP were treated with imatinib 400 mg. Dose was escalated in 55 (40%) patients due to loss or failure to achieve CRH (13 = 24%); progression to BC (2 = 3.5%); no CCR (11 = 20%); loss of RCC (5 = 9%); CCR without major molecular response (MMR) after 18 months of imatinib (24 = 43.5%). Males: 37, females 18 cases. Median age: 44 (16–74) years. Twenty-eight patients (49%) were treated with imatinib as first line therapy and 51% had used IFN previously. Median time between diagnosis and imatinib start was 4.5 (0–94) months. Responses: 94% achieved CHR; 58% CCR and 34% MMR. After dose increase, 31 (56%) responded: 58% of the patients with previous sub-optimal molecular response achieved MMR. Among those who benefited from dose increase, only 3 cases lost the response: one with hematological resistance and two with cytogenetic resistance (2 lost CCR and one CHR). Seven out of 16 patients who increased dose due to cytogenetic failure (loss of response, failure and sub-optimal response) achieved response: one had partial cytogenetic response (PCyR) and 6 CCR. Five patients with hematological failure presented response: CHR (2), CCR (1), PCyR (1) and MMR (1). Patients with BC (2 cases) did not respond to dose escalation. TFS was 89% and 67% in 2 and 5 years, respectively. EFS was 71% and 64% in 2 and 5 years respectively. When stratified by the type of failure, EFS was 100%, 49% and 34% in the group with molecular sub-optimal response with median time of 22 (4–41) months, cytogenetic 17 (1.2–42) and hematological failure 7.7 (0.2–57), respectively (P<0.03). Conclusions: imatinib dose escalation was successful in molecular sub-optimal response. However, the patients who do not achieve MMR might be candidates to second line treatment. Patients who did not achieve cytogenetic or hematological response did worse with imatinib dose escalation. Disclosures: No relevant conflicts of interest to declare.

ABL Mutations In Early Chronic Phase Chronic Myeloid Leukemia (CP-CML) Are Associated with a Greater Likelihood of Progression and Shorter Survival

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4458-4458
Author(s):  
A. M. Carella ◽  
A. Garuti ◽  
G. Cirmena ◽  
G. Catania ◽  
G. Pica ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Acquired Resistance ◽  
Chronic Phase ◽  
Kinase Domain ◽  
Imatinib Treatment ◽  
Cycle Sequencing ◽  
Advanced Phase ◽  
Blastic Phase ◽  
The Status ◽  
Risk Patients

Abstract Abstract 4458 Acquired resistance to Imatinib in advanced phase of CML has been associated with mutations in the kinase domain (KD) of BCR-ABL. We have recently reviewed the status of the mutations in 52 patients with early CP-CML on the samples collected at diagnosis. Mutations were identified by direct sequency (DS) with BidDye Terminator V1.1. cycle sequencing kit and analyzed with a 3130 AB capillary electrophoresis system. Twenty-eight patients had low risk, 10 intermediate risk and 14 high risk, according to Sokal/Euro. Ten out of 14 high Sokal risk patients showed the following mutations: Y253C, S265R, E255K, F359Y, N374S, E255V, E255V, E255V, R332L, E334G. Three of these patients progressed during Imatinib and second-line TKIs and died of blastic phase CML at 23, 33 and 69 months. Curiously, S265R and N374S mutations disappeared during Imatinib treatment but were substituted during follow-up by other two mutations: E255L and H396R. The patient carrying E255L mutation died in blastic phase at 33 months and the one with mutation H396R was well controlled by Nilotinib and he is now alive in CMR 26 months after. Only one out of the 10 intermediate Sokal risk carried KD mutations at diagnosis (D363G). This patient is alive in MMR at 26 months after diagnosis under Imatinib. None of the 28 low Sokal risk patients carried KD mutations at diagnosis and no patients developed cytogenetic evolution while on treatment. In conclusion, the fact that KD mutations were more present in patients with high Sokal risk supports the hypothesis that the probability developing a mutation is related to the basic biology of the disease rather than being merely a random event. Disclosures: No relevant conflicts of interest to declare.

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.

Moderate/ Severe Pleural Effusion As a Side Effect in Very Old Chronic Myeloid Leukemia (CML) Patients Undergoing Imatinib Treatment

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4445-4445
Author(s):  
Dario Ferrero ◽  
Roberto Latagliata ◽  
Malgorzata Monika Trawinska ◽  
Francesco Cavazzini ◽  
Gabriele Gugliotta ◽  
...  
Keyword(s):  
Pleural Effusion ◽  
Side Effect ◽  
Chronic Phase ◽  
Fluid Retention ◽  
Imatinib Therapy ◽  
Imatinib Treatment ◽  
Pleural Effusions ◽  
Old Patients ◽  
Very Old ◽  
Very Old Patients

Abstract Abstract 4445 Imatinib advent has provided for old CML patients too a chance for an effective treatment, aimed at complete cytogenetic and major molecular response. Indeed, a few studies reported in patients more than 65 year old a response rate comparable to that observed in younger ones. However, fluid retention, a common side effect of imatinib therapy, seems to occur more frequently in elderly patients. Indeed, periorbital and ankle oedema are common patients’ complaints, whereas pleural effusions have not been usually observed in imatinib-treated patients. Conversely, pleural effusions (usually mild to moderate) occur in about 14% of patients treated with the second generation tyrosine-kynase inhibitor (TKI) dasatinib at the optimal dosage of 100 mg by single daily administration. We conducted a retrospective survey of 181 Italian CML patients, above the age of 75, treated with imatinib for chronic phase CML. Among sixty-five patients who were more than 80 year old we observed 5 cases (7.7%) who displayed a severe (grade 3: 4 patients) or moderate (grade 2: 1 patient) pleural effusion. Conversely, such a side effect was not observed in any of the 101 slightly younger (75–80 year old) patients. The 5 patients displaying a pleural effusion were all males, 80.3 – 88.7 year old at the time of imatinib start. One patient was in late chronic phase, and had received hydroxyurea for more than 2 years before imatinib start, whereas the other 4 started imatinib therapy within 2 months from diagnosis. All 5 patients had at least one cardiovascular co-morbidity. Pleural effusion developed after 3–8 months of imatinib therapy. Pericardial effusion and peripheral oedema were also evident in two and one of the 5 patients, respectively. Imatinib was definitely discontinued in 2 patients (one of them had cytogenetically resistant disease) whereas the drug could be resumed, after a few months of interruption, in the other 3, in one case after intolerance to second generation TKI nilotinib. Three patients died: two of myocardial infarction and one for CML blastic phase at 45, 31 and 54 months, respectively, from diagnosis. Two patients are alive, one in major cytogenetic response with resumed imatinib treatment, at 12 and 30 months from diagnosis. Our survey evidenced a significant percentage of very old patients who developed a pleural effusion during imatinib treatment. Although our casistic of patients with pleural effusion is small, some differences are evident, compared to the more common dasatinib-induced pleural effusions. In the case of dasatinib, most of pleural effusions are mild, unrelated to peripheral oedema, and may have an immune-related aetiology. In our imatinib-treated patients pleural effusions were more severe and frequently accompanied by pericardial involvement. Moreover, they were restricted to very old patients and possibly correlated to cardio-vascular co-morbidities. In conclusion, although imatinib still represents the best CML treatment for most of very old patients too, these should be strictly monitored for fluid retention and possible appearance of a pleural and or pericardial effusion. Disclosures: Russo Rossi: Novartis: Honoraria; Bristol Myers Squibb: Honoraria. Rosti:Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Research Funding; Novartis: Honoraria; Bristol Myers Squibb: Honoraria.

scholarly journals Complications and residual pleural thickening after intrapleural instillation of streptokinase with pigtail catheter drainage of tuberculous pleural effusion

2019 ◽  
Vol 7 (1) ◽  
pp. 1
Author(s):  
Sandeepa H. S. ◽  
Narendra U. ◽  
Gajanan S. Gaude ◽  
Supriya Sandeepa
Keyword(s):  
Pleural Effusion ◽  
Total Duration ◽  
Control Group ◽  
Study Group ◽  
Pigtail Catheter ◽  
Catheter Drainage ◽  
Female Ratio ◽  
Tuberculous Pleural Effusion ◽  
Pleural Thickening

Background: Tuberculosis is the most common cause of exudative lymphocytic pleural effusion in India. Residual pleural thickening (RPT) is observed in about 50 percent of patients even after proper treatment with ATT. Pleural fluid drainage either with simple aspiration or with intercostal drainage and addition of corticosteroids along with antitubercular drugs have not shown to influence the incidence of RPT. The present study was undertaken to study the complications and residual effects of tubercular pleural effusion on the patients during the follow up period following intrapleural streptokinase instillation.Methods: Clinical profile, hospital course and outcome of tuberculous pleural effusion patients at the end of six months of anti-tubercular treatment of 50 patients from January 2009 to June 2010 were analyzed. These patients were randomly divided into two groups. One group (n=25) received intrapleural streptokinase via pigtail catheter and the other group (n=25) received intercostal drainage without intrapleural streptokinase instillation. All the patients received standard daily anti TB regimen of 2HERZ/4HR for a total duration of six months. All the patients were followed up for a total duration of 1 year for evidence of any residual pleural thickening.Results: Majority of the patients were above 40 years of age (60%). The male to female ratio was 2.3:1. The major symptoms of the patients were, fever in 44 patients (88%), cough in 42 patients (84%), breathlessness in 33 patients (66%), loss of appetite in 25 patients (50%) and chest pain in 25 patients (50%). Most of the patients had ADA levels between 40-70IU/L (48%) and only 6% had ADA levels below 40IU/L. The incidence of residual pleural thickening in the study group was less as compared to the control group (2.36±0.49mm vs 9.28±1.50mm) (p <0.0001).Conclusion: Intrapleural streptokinase instillation with pigtail catheter drainage less number of complications associated with study group and is successful with the decreased incidence of residual pleural thickening during the follow up period.

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