Clinical Characteristics and Outcome of Patients (pts) with V299L BCRABL Kinase Domain (KD) Mutation after Therapy with Tyrosine Kinase Inhibitors (TKIs).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1105-1105
Author(s):  
Elias Jabbour ◽  
Hagop M. Kantarjian ◽  
Dan Jones ◽  
Elizabeth Burton ◽  
Jorge Cortes
Keyword(s):  
Kinase Inhibitors ◽  
Mutation Detection ◽  
Lymphoblastic Leukemia ◽  
Point Mutations ◽  
Cytogenetic Response ◽  
Experimental Models ◽  
Molecular Response ◽  
Primary Resistance ◽  
Secondary Resistance

Abstract Background. Point mutations of the BCR-ABL KD are the most frequently identified mechanism of resistance in pts with CML and Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) who fail TKI. Experimental models of in vitro drug sensitivity have shown that specific mutations may develop after incubation with second generation TKIs, albeit at a decreased frequency compared with imatinib. Some of the mutations are novel and not previously described after imatinib failure; in some instances they did not confer resistance to imatinib. One of them, V299L was rarely encountered after imatinib therapy but was reported to emerge after dasatinib exposure in induced mutagenesis models causing resistance to dasatinib by impairing its binding. Aims. We assessed the incidence and pattern of development of V299L in pts with TKI-resistant CML and Ph+ ALL at our institution, and the response following change of therapy. Results. V299L mutation was detected in 14 pts (12 CML, 2 Ph+ ALL): 1 occurred among 186 pts assessed for mutations (0.05%) after imatinib failure (1% of all mutation detected), 9 among 47 pts (19%) who developed mutations on dasatinib therapy, and 4 among 18 pts (22%) who developed mutations on bosutinib therapy (p<0.001); none of the 49 pts who developed mutations on nilotinib therapy acquired V299L. Median age was 55 years (range, 26–82 years). Seven pts were previously treated with interferon-alpha. One pt developed V299L after receiving imatinib for 26 months (mos). Nine pts developed V299L after being on dasatinib for a median of 14 mos (range, 1–30 mos); 7 received dasatinib after imatinib failure, 1 after imatinib and nilotinib failure; and 1 after failure of imatinib, INNO-406, and bosutinib. In 4 pts V299L appeared after receiving bosutinib as 3rd TKI after imatinib and dasatinib failure, for a median of 5 mos (range, 2–8 mos). None of the 11 evaluable pts treated with 2nd generation TKIs had V299L at start of therapy. The best response to TKI immediately preceding V299L (1 imatinib, 9 dasatinib, 4 bosutinib) was complete hematologic response only in 5 (36%, 4 dasatinib, 1 bosutinib), minor cytogenetic response in 2 (14%; 1 imatinib, 1 dasatinib), complete cytogenetic response in 4 (29%; 3 dasatinib, 1 bosutinib); no response in 3 pts (1 dasatinib, 2 bosutinib). The median duration of response was 14 mos. V299L was associated with primary resistance in 3 pts, and secondary resistance in 9. Two pts on dasatinib therapy remained in CHR and minor cytogenetic response, respectively, 3 months after the mutation detection. At the time the mutation was detected, 4 pts were in chronic (CP), 7 in accelerated (AP), 1 in blast phase (BP), and 2 with Ph+ ALL. 3 pts (1 CP, 1 AP, 1 BP) received nilotinib after V299L detection and 1 responded (major molecular response sustained for 16+ mos). One pt received INNO406 and did not respond. One pt with Ph+ ALL was refractory to allogeneic stem cell transplantation and acquired a T315I mutation. Two pts received homoharringtonine, did not respond, but had an eradication of the mutant clone. After a median follow-up of 8 mos (range, 3–29 mos), from the time V299L was detected, 4 died (1 CP, 1 BP, 2 ALL). The estimated 2-year survival from mutation detection was 74%. Conclusion. V299L occurs more frequently after dual Src/Bcr-Abl kinase inhibitors therapy, paralleling the findings of in vitro studies. TKIs showing in vitro activity against this mutation (e.g. nilotinib) may be good treatment options for pts with this mutation.

Characteristics and Outcome of Patients (pts) with V299L BCR-ABL Kinase Domain (KD) Mutation After Therapy with Tyrosine Kinase Inhibitors (TKIs).

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3428-3428
Author(s):  
Elias Jabbour ◽  
Hagop M. Kantarjian ◽  
Dan Jones ◽  
Yin Cameron ◽  
Elizabeth Burton ◽  
...  
Keyword(s):  
Research Funding ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Experimental Models ◽  
Molecular Response ◽  
Primary Resistance ◽  
Secondary Resistance ◽  
Abl Kinase

Abstract Abstract 3428 Point mutations of the BCR-ABL KD are the most frequently identified mechanism of resistance in pts with CML who fail TKI. Experimental models of in vitro drug sensitivity have shown that specific mutations may develop after incubation with second generation TKIs, albeit at a decreased frequency compared with imatinib. Some of the mutations are novel and not previously described after imatinib failure; in some instances they did not confer resistance to imatinib. One of them, V299L was rarely encountered after imatinib therapy but was reported to emerge after dasatinib exposure in induced mutagenesis models causing resistance to dasatinib by impairing its binding. We assessed the incidence and pattern of development of V299L in pts with TKI-resistant CML at our institution, and the response following change of therapy. V299L mutation was detected in 15 pts with CML: 1 occurred among 186 pts assessed for mutations (0.05%) after imatinib failure (1% of all mutation detected), 9 among 69 of the 170 evaluable (i.e., had abl sequencing) pts (13%) who developed mutations on dasatinib, and 5 among 19 of the 72 evaluable pts (26%) who developed mutations on bosutinib (p<0.001); none of the 51 pts who developed mutations on nilotinib (among 125 tested) acquired V299L. Median age for pts with V299L was 56 years (range, 26–82 years). Eight pts were previously treated with interferon-alpha. One pt developed V299L after receiving imatinib for 26 months (mos). The median time to development of V299L was 14 mos (range, 1–30 mos) for those treated with dasatinib (7 received dasatinib after imatinib failure, 1 after imatinib and nilotinib failure; and 1 after failure of imatinib, INNO-406, and bosutinib), and 13 mos (range, 2–48 mos) for those treated with bosutinib (after imatinib failure in 1, and as 3rd TKI after imatinib and dasatinib failure). The best response to TKI immediately preceding V299L (1 imatinib, 9 dasatinib, 5 bosutinib) was complete hematologic response only in 6 (40%, 4 dasatinib, 2 bosutinib), minor cytogenetic response in 2 (13%; 1 imatinib, 1 dasatinib), complete cytogenetic response in 4 (27%; 3 dasatinib, 1 bosutinib); no response in 3 pts (20%; 1 dasatinib, 2 bosutinib). The median duration of response was 17 mos. V299L was associated with primary resistance in 4 pts, and secondary resistance in 9. Two pts on dasatinib therapy remained in CHR and minor cytogenetic response, respectively, 3 months after the mutation detection. At the time the mutation was detected, 5 pts were in chronic (CP), 7 in accelerated (AP), and 3 in blast phase (BP). 3 pts (1 CP, 1 AP, 1 BP) received nilotinib after V299L detection and 1 in CPresponded (major molecular response sustained for 40+ mos). One pt received INNO406 and did not respond. One pt in BP was refractory to allogeneic stem cell transplantation and acquired a T315I mutation. Two pts received homoharringtonine, did not respond, but had an eradication of the mutant clone. After a median follow-up of 23 mos (range, 3–48 mos), from the time V299L was detected, 8 died (4 CP and 4 BP). In conclusion, V299L occurs more frequently after dual Src/Bcr-Abl kinase inhibitors therapy, paralleling the findings of in vitro studies. TKIs showing in vitro activity against this mutation (e.g. nilotinib) may be good treatment options for pts with this mutation if treated in chronic phase, but more data is need to evaluate the long-term benefit of this approach. Disclosures: Jabbour: BMS: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Cortes:Novartis: Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding.

Clinical Characteristics and Outcome of Patients (pts) with F317L BCR-ABL Kinase Domain (KD) Mutation after Therapy with Tyrosine Kinase Inhibitors (TKIs).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1949-1949
Author(s):  
Elias Jabbour ◽  
Hagop Kantarjian ◽  
Dan Jones ◽  
Susan O’Brien ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Mutation Detection ◽  
Point Mutations ◽  
Cytogenetic Response ◽  
In Vitro Mutagenesis ◽  
Molecular Response ◽  
Cell Transplant ◽  
Best Response

Abstract Background. Point mutations of the Bcr-Abl KD are the most frequently identified mechanism of resistance in pts with CML who failed TKI. The setting for outgrowth of different mutations and their subsequent response to different TKIs varies significantly. For example, mutations in codon 317, which would be predicted to impair dasatinib binding, have been generated during in vitro mutagenesis with dasatinib but not nilotinib, and the F317L, in particular, has been reported following treatment with dasatinib. Aims. We assessed the incidence and pattern of development F317L mutations in pts with TKI-resistant CML at our institution and responses following change in therapy. Results. F317L mutation was detected in 20 patients: 12 occurred among 99 pts (12%) after imatinib failure who had KD mutation assessment, and 8 among 16 pts (50%) who developed new mutations on dasatinib therapy (among 77 treated) (p=0.001). Median age for all pts with F317L was 49 years (range, 34–66 years). Pts had received imatinib for a median of 23 months (mo) (range, 2–69). Best response to imatinib was complete hematologic response in 11 and cytogenetic response in 8 (5 complete, 2 partial, 1 minor). One pt did not respond. At the time the mutation was detected, 8 pts were in chronic (CP), 6 in accelerated (AP) and 6 in blast phase (BP). Patients with F317L-mutated tumors developing on imatinib or dasatinib had similar characteristics as those who had KD mutations at other sites or no mutation detected. Among pts with F317L at start of 2nd TKI, 3 received dasatinib and all 3 had transient hematologic responses (best response) (1 partial -PHR-, 2 complete -CHR-) lasting 4, 12 and 19 mo;.4 were treated with nilotinib and 3 responded (1 CHR, 1 major molecular response-MMR-,1 complete molecular response -CMR-); 2 had imatinib dose escalation after appearance of F317L and both had a sustained complete cytogenetic response (CCyR) for 24+ and 26+ months; one pt received stem cell transplant and is in CMR 20 months after transplant; one pt did not respond to a combination of imatinib and farnesyl transferase inhibitor; and one pt was lost of follow-up with no further therapy. Among pts who developed F317L while on dasatinib (n=8), 4 never responded and 4 had an initial response to dasatinib (1 CHR, 3 CCyR) lost after a median of 15 months (range, 3 to 26); one pf these was then treated with nilotinib and achieved an ongoing CCyR for 3+ months and 2 received bosutinib after failing both nilotinib and dasatinib, achieving a transient CHR lasting 6 and 9 months, respectively. After a median follow-up of 29 months from treatment failure and 25 months from the detection of F317L, 10 pts (50%) are alive (7 CP, 2 AP, 1 BP at F317L). Median survival of pts with F317L from mutation detection was 19 mo. Survival of pts with F317L was similar to those with other mutations or without mutation when survival was dated from the time of treatment failure (p=0.51) or from mutation detection (p=0.92). Conclusion. F317L occurs more frequently after dasatinib therapy paralleling the findings of in vitro studies. TKIs showing differential in vitro activity against this mutation (e.g. nilotinib or INNO-406) may represent good candidates for treatment failure associated with F317L-mutated tumors.

For CML Patients in Chronic Phase Who Achieve a Cytogenetic Response to Imatinib the Finding of a BCR-ABL Mutation Predicts for Progression to Advanced Phase but It Has No Such Significance in Primary Resistance.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 323-323
Author(s):  
Hugues de Lavallade ◽  
Jamshid S. Khorashad ◽  
Dragana Milojkovic ◽  
Simon Wagner ◽  
Jaspal Kaeda ◽  
...  
Keyword(s):  
Adverse Effect ◽  
Genomic Instability ◽  
Direct Sequencing ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Primary Resistance ◽  
Secondary Resistance ◽  
Advanced Phase

Abstract We analysed outcome for 211 CML patients treated with imatinib in chronic phase (CP) (99 newly diagnosed and 112 late chronic phase) who were screened for BCR-ABL kinase domain (KD) mutations using direct sequencing regardless of the response status. When a mutation was found all available previous cDNA samples were analysed by pyrosequencing to establish the date of its first occurrence and subsequent kinetics. The median age of patients was 47.4 years. The Sokal risk score was ‘low’ in 57 patients, ‘intermediate’ in 82 and ‘high’ in 72. The median follow up from starting imatinib was 45 months (rage 6 to 89 months). A mutation was detected in 34 of the 211 patients (16%) at a median time of 27 months from starting imatinib. Twenty-two different mutations were identified, the most frequent being M244V (n=6) and F359V (n=3). When studied serially by pyrosequencing the size of the mutant subclone never exceeded 50% of total BCR-ABL transcripts in 8 patients, while in 17 patients it exceeded 90% on at least one occasion. 48 patients discontinued imatinib while still in CP and received either dasatinib, nilotinib or an allograft. The overall progression-free survival (absence of advanced phase) at 5 years was 73%. Major (MCyR) and complete (CCyR) cytogenetic responses were achieved by 153 and 123 patients respectively; 56 patients achieved major molecular response. 24% of the patient with up front cytogenetic resistance had a mutation while 40% of the patients with acquired cytogenetic resistance develop a mutation. In an-intention-to-treat analysis, patients harboring a mutant clone had a poorer PFS at 4 years (78% versus 57%, p=0.0014). The various mutations had no differential effects based on their known imatinib IC50. By multivariate analysis, factors associated with worse PFS were the presence of a KD mutation and failure to achieve CCyR (relative risks for PFS 2.6 and 8.7 respectively, p=0.002). Interestingly, the adverse effect of the presence of a KD mutation was restricted to the patients who achieved a MCyR (PFS 91% versus 62% at 5 years, p = 0.0006); it had no adverse impact on patients who failed to achieve a MCyR (PFS 42% and 49%, p=0.73). Similar results were found when the analysis was repeated according to the achievement of CCyR (data not shown). Surprisingly patients with a continuously low percentage (≤50%) of mutated vs wild type (>50%) clones fared worse than patients in whom the mutated clone became the predominant population (PFS 14% vs 69% respectively, p=0.0005). Comparable results were obtained when the patients were censored at the point of discontinuing imatinib, correcting for the effects of subsequent treatment, ie allografting (data not shown). The fact that the adverse effect of a mutation seems to be restricted to patients who had achieved cytogenetic response, the fact that mutations present at low level seemed to have a remarkable adverse effect and the fact that the in-vitro level of resistance to imatinib of the specific mutation did not affect the PFS could all be explained if the development of a mutation is only a reflection of the genomic instability of the disease that leads to secondary resistance to imatinib and eventually to transformation. Thus genomic instability may be less important in explaining primary resistance to imatinib and eventual transformation in patients with up-front resistance.

A New BCR-ABL1 Mutation (L248R) Is Highly Resistant to Imatinib, Bosutinib, Nilotinib and Dasatinib, but Can Be Inhibited by AP-24534 and DCC-2036.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3398-3398
Author(s):  
Sara Redaelli ◽  
Luca Mologni ◽  
Roberta Rostagno ◽  
Rocco Piazza ◽  
Michela Viltadi ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Novel Mutation ◽  
Clinical Sample ◽  
Tritiated Thymidine ◽  
Blast Crisis ◽  
Point Mutations ◽  
Molecular Response ◽  
Wild Type ◽  
Activity Profile

Abstract Abstract 3398 Chronic Myeloid Leukemia (CML) treatment was radically modified by the discovery of imatinib (IM), a selective inhibitor of the fusion kinase Bcr-Abl. Second generation ATP-competitive tyrosine kinase inhibitors (TKIs) bosutinib (BOS), nilotinib (NIL) and dasatinib (DAS) further improved CML therapy. However, resistance to TKIs occurs in a variable proportion of patients; it can arise from different mechanisms but in the majority of cases it is due to Bcr-Abl point mutations that alter directly or indirectly the drug-protein binding. Over 70 mutations have been described in patients, with T315I showing resistance to IM, NIL, BOS and DAS. Here we report the discovery of a new P-loop mutant (L248R) that is highly resistant to all currently available inhibitors. L248R was identified in a lymphoid Blast Crisis CML patient. The patient initially presented with an IM-resistant F359I mutation. A cytogenetic and molecular response was obtained with BOS, but after 1 year haematological relapse developed; at this point a F359I/L248R clone was identified. L248R was previously reported only in an in vitro during a mutagenesis screen involving IM (Bradeen et al. 2006) and in a study with the T315I inhibitor SGX393 (O'Hare et al. 2008). L248R was never isolated from a clinical sample. Activity profile of BOS, IM, DAS and NIL against L248R, F359I and F359I/L248R was performed (Table). Stable transfectant Ba/F3 cells were generated and the TKIs anti-proliferative activity was determined. The relative IC50 increase over wild type Bcr-Abl (Relative Resistance, RR) was calculated. We classified RR values in four categories: sensitive (RR≤ 2), moderately resistant (RR between 2.1 and 4), resistant (RR between 4.1 and 10) or highly resistant (RR>10). In all cases a RR >10 was obtained, for L248R. Recently new compounds were developed to overcome resistance generated by the T315I mutant. Among them AP-24534 (AP), a panBcr-Abl inhibitor (O'Hare et al. 2009) and the switch pocket inhibitor DCC-2036 (DCC) were reported as potently active against the T315I mutation. Both compounds showed activity against L248R (RR 6.2 and 0.4), although the activity against the double mutant F359I/L248R was reduced especially for AP (RR 17.7 and 1.0). The activity profile of AP and DCC against L248R and a panel of 26 mutated forms of Bcr/Abl covering the most common mutations is also presented (Table). Activity of BOS, IM, DAS and NIL is also reported for comparison. According to our data, only mutation E255V is classified as highly resistant to AP, in addition to F359I/L248R: 6/26 mutations are considered “resistant” to AP (L248R, G250E, G252H, E255K, F359V, H396R) and 3/26 to DCC (D276G, E279K, F317V). The huge difference in the IC50 values for AP between Bcr/Abl wild type (2.1 nM) and parental Ba/F3 cells (>1000 nM) could render some of the mutants with high RR values to AP still sensitive to this inhibitor. It is also important to note that, according to our data, every mutation analysed shows sensitivity to at least one of the tested TKIs. In conclusion we describe a novel mutation that is highly resistant to the commonly used Bcr-Abl TKIs but which is inhibited by AP and DCC. Modelling data on the L248R mutant in complex with different TKIs will also be presented IC 50 values are based on tritiated thymidine incorporation assay. Results are an average of at least 3 independent experiments Disclosures: Wise: Deciphera Pharmaceuticals: Employment. Flynn:Deciphera Pharmaceuticals: Employment. Gambacorti-Passerini:Pfizer pharmaceuticals: Research Funding.

ABCG2 and SLC22A1 Expression Are Associated with Imatinib Response in Chronic Myeloid Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1422-1422
Author(s):  
Douglas Vivona ◽  
Luciene Terezina Lima ◽  
Carolina Tosin Bueno ◽  
Rosario D C Hirata ◽  
Mario H Hirata ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Philadelphia Chromosome ◽  
Cytogenetic Response ◽  
Response To Treatment ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Primary Resistance ◽  
Secondary Resistance ◽  
Altered Expression ◽  
Complete Cytogenetic Response

Abstract Abstract 1422 Background: Imatinib Mesylate (IM) used in the treatment of CML, interacts with membrane efflux transporters such as ABCB1 and ABCG2, whereas the active uptake of IM into the cells is mediated by SLC22A1. The predictive value of these markers is still controversial. The altered expression of these genes could impact on intracellular concentration of IM and contribute to resistance. Aims: The aim of this study was to investigate ABCB1, ABCG2 and SLC22A1 gene expression as potential sources of resistance to imatinib in patients with CML Methods: One hundred and eighteen patients in chronic phase of CML, both genders with age range 18 to 80 were studied. All patients were initially treated with a standard dose of IM (400 mg/day) and divided in two groups according to response. The responder group comprised 70 patients who had a complete cytogenetic response within 18 months of treatment. The non-responder group comprised 48 patients who did not have a complete cytogenetic response with the initial dose (400 mg/day) of IM or who relapsed during treatment and were submitted to higher doses of 600 or 800 mg/day. Criteria of failed response to treatment were established by European LeukemiaNet. Patients with cytogenetic patterns other than the Philadelphia chromosome and patients with mutations in the BCR-ABL1 gene were excluded from this study. Major molecular response (MMR) was defined as a reduction of BCR-ABL1 transcripts levels to ≤ 0.1% in the peripheral blood standardized on the International scale. Complete molecular response (CMR) was defined as a reduction ≤ 0.032% BCR-ABL1 transcripts levels. Primary resistance and secondary resistance also were evaluated. Real-Time PCR was performed to evaluate the ABCB1, ABCG2 and SLC22A1 mRNA relative expression to control gene GAPDH. Results: Expression of ABCG2 in the non-responder group was higher than in the responder group (P=0.028). This result was influenced by patients with primary resistance (n= 34 p=0.029) but not secondary resistance (n=14 p=0.249) when compared with responders (n=70). ABCB1 and SLC22A1 expression were similar between responder and non-responder groups. Higher levels of SLC22A1 mRNA were found in patients who achieved MMR in the responder group (p=0.009). The elevated ABCG2 expression was also found in those who did not achieve MMR (p=0.027) when all patients were analyzed. None of studied genes was associated with CMR. Conclusions: The high expression of ABCG2 is related to primary resistance and SLC22A1 is positively associated with major molecular response to treatment with IM. Our data suggests that ABCG2 may be a mediator of IM resistance, whereas SLC22A1 could be a good predictor of response to IM therapy. Financing: Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP 2009/54184-0). Disclosures: No relevant conflicts of interest to declare.

scholarly journals Complete Molecular Response due to nilotinib as III line treatment in a patient with CML and F317L point mutation of the Bcr-Abl kinase domain

2015 ◽  
Vol 5 (5S) ◽  
pp. 21-25
Author(s):  
Maria Iovine ◽  
Giuseppe Monaco ◽  
Mario Troiano ◽  
Antonio Abbadessa
Keyword(s):  
Point Mutation ◽  
Kinase Inhibitors ◽  
Mutational Analysis ◽  
Point Mutations ◽  
Cytogenetic Response ◽  
Kinase Domain ◽  
Molecular Response ◽  
Abl Kinase ◽  
First Line Therapy ◽  
Complete Molecular Response

In 1997, a forty-three years old woman was diagnosed with CML and treated with alfa-Interferon, achieving complete haematological response (CHR). Three years later, patient was switched to hydroxiurea due to thyroid toxicity. For logistic reasons, therapy with imatinib 400 mg/die was initiated only in 2003, obtaining complete cytogenetic response (CCyR) and suboptimal molecular response in twelve months. CCyR and CHR were then lost three years later. Doubling imatinib dose to 800 mg/die gave no positive results. Mutational analysis performed in September 2007 showed F317L point mutation of the Bcr-Abl kinase domain. In October 2007 dasatinib was started and in April 2008 CCyR was reached with suboptimal molecular response. In March 2009 Bcr-Abl transcript progressively increased, and in August 2009 cytogenetic analysis showed loss of CCyR. Therapy with nilotinib 800 mg/die was started, and in October 2009 the patient obtained complete molecular response (CMR). Bcr-Abl kinase-domain point mutations, acquired during first line therapy, are a common cause of resistance to tyrosine kinase inhibitors. While several Bcr-Abl mutations have been identified, involvement of codon 317 has been reported in the literature following treatment with imatinib and dasatinib.

Characteristics and Outcome of Patients with Chronic Myeloid Leukemia (CML) and T315I Mutation Following Failure of Imatinib Mesylate Therapy.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1943-1943
Author(s):  
Elias Jabbour ◽  
Hagop Kantarjian ◽  
Dan Jones ◽  
Srdan Verstovsek ◽  
Alessandra Ferrajoli ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Cell Transplant ◽  
2Nd Generation ◽  
Hematologic Response ◽  
T315i Mutation

Abstract Background. T315I is an imatinib pocket binding mutation within the Bcr-Abl kinase domain that is highly resistant, both in vitro and in vivo, to imatinib and to 2nd generation tyrosine kinase inhibitors (TKIs). Several studies have suggested that patients with T315I have a poor outcome. Study Aims. The objectives of this study were to define the clinical characteristics of patients harboring the T315I mutation, and to assess their outcome after imatinib failure. Results. T315I was detected in 27 pts: 20 among a series of 186 pts assayed after imatinib failure (11% of all pts; 21% of all mutations detected) after a median of 37 months (mos) from start of imatinib, and 7 among 23 pts who developed new mutations after a median of 10 mos on therapy with a 2nd generation TKI. Median age was 52 years. Median time from diagnosis to T315I was 41 mos, and the median follow-up from the detection of mutation is 18 mos. At the time of T315I detection, 10 pts were in CP, 9 in AP, and 8 in BP. Fifteen pts (56%) had transformed to accelerated or blast phase at the time of T315I detection. Best response to TKI immediately preceding development of T315I (20 imatinib, 2 nilotinib, 2 dasatinib, 2 bosutinib, 1 INNO-406) was CHR in 13 (48%) and CyR in 9 (33%; complete in 6, partial in 1, minor in 2). The median duration of response was 44 mos. Except for the lack of response to a second TKI (p=0.001), there was no difference in pt characteristics between pts with or without T315I, other mutations, or no mutations. Among the 20 pts with T315I present prior to start of 2nd TKI, 5 responded, all hematologic (3 complete hematologic response -CHR-, 2 partial hematologic response -PHR-, 1 return to chronic phase); in contrast all 5 pts without T315I prior to 2nd TKI, responded (1 major molecular response -MMR-, 2 Minor cytogenetic response -CyR-, 1 CHR, 1 PHR); and among the 2 pts with unknown T315I status at start of 2nd TKI 1 had PHR and 1 complete cytogenetic response -CCyR-. Responses were usually transient but 3 pts had sustained responses for some time despite presence of T315I: 1 pt in AP harboring simultaneously F317L and G250E acquired a T315I mutation 5 mos after the start of nilotinib and achieved MMR that was sustained for 21 mos eventually lost to major CyR. A 2nd pt in AP treated with bosutinib acquired a T315I mutation 6 months after the start of bosutinib, but nonetheless achieved a minor CyR that has been sustained for more than 8 mos. A third patient with Y253H mutation developed T315I 1 mo after therapy with INNO-406 for CML AP; at the last follow-up, 4 months into therapy, he maintained a PHR. 4/14 pts (38%) treated with T315I-directed agents (aurora kinase inhibitors, homoharringtonine) responded. 4 pts received allogeneic stem cell transplant (ASCT) and 2 are alive: 1 in CMR 24+ months after ASCT and 1 in CCyR 9 months after ASCT, wit molecular relapse and recurrence of T315I. 11/27 pts with T315I (40%) died. Patients in CP had better outcome with 87% 2-year survival, compared to 45% in AP and 20% in BP. Survival of patients with T315I was similar to those with other mutations or without mutations (p=0.64). Conclusion. Altough T315I is a mutation highly resistant to conventional BCR-ABL TKI, occasional responses can be observed. Overall survival of patients with T315I mutations is mostly dependent on the stage of the disease.

scholarly journals "Secondary Chronic Myeloid Leukemia": Comparison between Patients Previously Exposed or Not to Chemo and/or Radiotherapy

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5437-5437
Author(s):  
Francesco Autore ◽  
Federica Sora ◽  
Patrizia Chiusolo ◽  
Mario Annunziata ◽  
Alessandra Iurlo ◽  
...  
Keyword(s):  
Median Time ◽  
Previous History ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Haematological Malignancies ◽  
Primary Resistance ◽  
Secondary Resistance ◽  
History Of ◽  
Group A ◽  
Group B

Abstract Introduction. Haematological malignancies related to previous chemo and/or radio-therapy for neoplasia have been well investigated. This subgroup was defined as therapy-related myeloid neoplasms by ELN. In the field of chronic myeloid leukaemia (CML) the diagnosis of a secondary neoplasia after CML diagnosis has been studied but the presence of 'secondary CML' has not been completely defined. In clinical practice we collected patients with a CML diagnosis who had a previous history of malignancy. Aim and methods. We reviewed our databases to collect the cases of 'secondary CML' in 4 hematological Italian centres. Results. We found 51 patients who were diagnosed with previous malignancies out of 617 CML patients (8.3%). We conducted the analysis on 48 patients, removing the other three patients who were diagnosed before the era of tirosine-kinase inhibitors (TKIs). We then subdivided patients in two groups according to the treatment they received for the previous neoplasia: patients treated by surgery (group A: 27 patients) and patients treated by chemotherapy and/or radiotherapy (group B: 21 patients). Clinical characteristics at diagnosis of the patients of the two groups were summarized in Table 1. The majority of the patients showed bcr-abl b3a2 (59% in group A and 62% in group B), no one showed additional cytogenetic abnormalities. The median time between the diagnosis of the primary neoplasia and CML were not different: 78 months (range 1-276) in the group A and 75 months (range 1-371) in the group B. Upfront treatment was Imatinib in 55.6% of the patients in group A and 81% in group B; the remaining patients were treated with Dasatinib in 22.2% and 14% of the patients, respectively, and Nilotinib 22.2% and 5% of the patients, respectively. All patients achieved haematological response after 1 month, 24 out of 27 patients (89%) of the group A achieved complete cytogenetic response after a median time of 3 months (range 3-28) and 20 out of 21 patients (95%) of the group B achieved complete cytogenetic response after a median time of 3 months (range 3-12). The median time of major molecular response was 9 months in 20 out of 27 patients (74%) of group A and in 19 out of 21 patients (90%) of group B. Patients in group A showed a higher number of events who determined a change in the treatment: 9 patients (33.3%) in group A changed TKI due to resistance (3 patients: 2 primary resistance and 1 secondary resistance) or intolerance (6 patients) versus 4 patients (19%) of the group B because of resistance (3 patients: 2 primary resistance and 1 secondary resistance) or intolerance (1 patient). We recorded 3 deaths: 2 in the group A not related to CML and 1 in the group B due to CML. The median overall survival was 53 months (range 8-228) in the first group and 51 months (range 4-196) in the second group. Unexpectedly we found a 12.5% of patients with a previous diagnosis of lymphoma in patients developing CML and this reached statistical significance (p=0.004) when compared to patients in A group. We also detected 3 out of 48 CML patients (6%) with a previous history of 2 neoplasia and all of them were treated with chemo and/or radiotherapy. Conclusion. Our research found that "secondary CML" occurred in 8.3% of newly diagnosed CML patients. Patients were comparable in terms of bcr-abl transcript, risk assessment, clinical and laboratory presentation. Cytogenetic and molecular response to TKIs as well as survival was similar to CML standard population. A significant fraction of patients with "secondary CML" received prior chemo and /or radiotherapy for an haematological malignancies and poses new questions in terms of either genetic predisposition and/or exposure to anticancer treatment. Disclosures No relevant conflicts of interest to declare.

Stem Cell Transplant (SCT) for Patients (pts) with Chronic Myeloid Leukemia (CML) Resistant to Tyrosine Kinase Inhibitors (TKI) with BCR-ABL Kinase Domain (KD) Mutation T315I.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2120-2120
Author(s):  
Nikolai Velev ◽  
Jorge Cortes ◽  
Richard Champlin ◽  
Hagop M. Kantarjian ◽  
Gabriela Rondon ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Kinase Domain ◽  
Cancer Center ◽  
Molecular Response ◽  
Cell Transplant ◽  
Best Response

Abstract Background: Resistance to TKI therapy is associated with development of KD mutations in approximately 50–60% of pts. Although many imatinib-resistant mutations respond well to second generation TKI, T315I is insensitive to all currently available TKI (imatinib, dasatinib, nilotinib) in vitro and in the clinic. SCT is frequently recommended for these pts but there is no available data about the efficacy of SCT in such pts. Aims: To investigate the efficacy and safety of SCT for patients with TKI-resistant CML with a T315I mutation. Methods: We reviewed the outcome of all pts with T315I that have received a SCT at MD Anderson Cancer Center. Results: Seven pts received 8 transplants. Their median age was 44 years (yrs) (range, 26 to 64 yrs). The median time from diagnosis to SCT was 42 months (mo) (range, 9–160 mo). All pts had become resistant to with imatinib; 5 received dasatinib and 1 nilotinib after imatinib failure, and 6 pts received other additional therapy prior to SCT. At the time of SCT 2 pts were in chronic phase (CP), both in partial cytogenetic response; 2 in accelerated (AP) with active disease; and 3 in second or greater CP from lymphoid blast phase (BP) (1 in minor cytogenetic response, 2 major molecular response, 1 complete molecular response –CMR-). Six transplants were from matched unrelated donors and 2 from cord blood. Best response after SCT was CCyR in 3 (2 AP, 1 BP), CMR in 4 (2 CP, 2 BP), and 1 unknown (died early). After a median follow-up of 11 months from SCT, 4 pts are alive; the 2 transplanted in CP are alive after 11 and 42 months after SCT and in CMR; 1 pt transplanted in AP has a sustained CCyR 20 mo after SCT with persistent T315I representing 94% of transcripts by pyrosequencing; and 1 in BP has a CMR sustained 6 mo after a second SCT (relapsed 5 months after first SCT) 3 pts have died: 1 AP and 2 BP, all with relapse. Conclusion: SCT appears to be an effective strategy for pts with CML with T315I, although longer follow up is needed. Results are significantly better when pts are transplanted in CP. Thus, SCT should be considered in pts with resistance to TKI once T315I is identified, ideally in CP.

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.

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