Long-Term Significance of Achieving a Major Cytogenetic Response (MCyR) without a Complete Hematologic Response (CHR) among Patients (pts) with Chronic Myeloid Leukemia (CML) in Advanced Phase Treated with Second Generation Tyrosine Kinase Inhibitors (TKI).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1944-1944
Author(s):  
Carmen Fava ◽  
Hagop M. Kantarjian ◽  
Elias Jabbour ◽  
Mary Beth Rios ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Survival Rates ◽  
Philadelphia Chromosome ◽  
Cytogenetic Response ◽  
Imatinib Resistance ◽  
Hematologic Response ◽  
Advanced Phase ◽  
Best Response ◽  
Imatinib Resistant ◽  
Complete Hematologic Response

Abstract The BCR-ABL TKI, dasatinib (D) and nilotinib (N), are effective in Philadelphia chromosome-positive (Ph+) leukemias, including all stages of imatinib-resistant CML and Ph+ ALL. For both dasatinib and nilotinib, the reported rates of MCyR are higher than the rates of CHR; that is, some pts achieve MCyR but may have cytopenias that make their hematologic response less than a CHR; this has been attributed to myelosuppression induced by TKI. At present it is not known whether pts with MCyR who do not have CHR have a similar outcome as those with a CHR. We studied 135 pts with accelerated (AP; n=84) or blast phase (BP; n=47) CML or Ph+ ALL (n=4) treated with D (59) or N (76) for imatinib resistance, to see whether the presence of cytopenias at the time of best response affected the prognosis. The median age was 55 yrs (range, 15 to 98) and 62 were female. 56 (41%) had bcr/abl mutations at the start of therapy. Overall 36 pts (27%) achieved MCyR. All the 36 pts who achieved a MCyR after treatment with N or D had received imatinib for an average time of 34 mos (range 4–78) and 24/36 pts had obtained a MCyR under imatinib. They started the new TKI 66 mos after first diagnosis (12–336). 2-yr survival rates for pts that achieved MCyR was 72% compared to 35% for those without MCyR (p<0.001). There was a trend for an inferior survival for those not having a concomitant CHR at the time of MCyR compared to those with CHR (2-yr survival 58% vs 82%; p=0.11). The rates of CHR and MCyR were 68% and 29%, respectively in AP; 32% and 21% in BP, and 50% and 50% in Ph+ ALL. Among pts in AP, 17/24 (70%) who achieved a MCyR, had a CHR at the time of best cytogenetic response; 6 of these 17 (35%) pts eventually failed (lost response or transformed), compared to 3/7 (43%) of those with no CHR at the time of MCyR (p=0.28). The results are similar when analyzing separately pts treated with N or D. 2-yr survival was 88% and 66% for those with and without concomitant CHR (p=0.29). Among the 10 pts in BP that achieved a MCyR, 5 had a CHR at the time of best cytogenetic response. Three (60%) of these pts eventually failed (lost response), compared to 4 failures among the 5 pts with no CHR at the time of MCyR (p=1.0). Survival rates at 2 yrs were 60% and 40% for those with and without concomitant CHR (p=0.29). Among the 2 patients with ALL that achieved MCyR, one had comcomitant CHR (treated with N) and the other did not have CHR (D); both of them failed. Of the 18 pts who failed after having achieved an MCyR, 7 had a mutation before starting treatment with a 2nd TKI (A433T, G250E, E355G, E459K, M244V, M315T, F317L), and 6 developed a new mutation after treatment (F317L, F311I, Y253H, G476C, E255K, H359V). Five of them occurred in pts with a concomitant CHR and 1 without a CHR. These results suggest that achievement of MCyR with residual cytopenias (ie, without a concomitant CHR) may not have the same favorable outcome as that of MCyR with concomitant CHR. Whether this is related to pt- or disease-related characteristics remains to be determined.

Dasatinib (BMS-354825) is active in Philadelphia chromosome–positive chronic myelogenous leukemia after imatinib and nilotinib (AMN107) therapy failure

Blood ◽  
2006 ◽  
Vol 109 (2) ◽  
pp. 497-499 ◽  
Author(s):  
Alfonso Quintas-Cardama ◽  
Hagop Kantarjian ◽  
Dan Jones ◽  
Claude Nicaise ◽  
Susan O'Brien ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Philadelphia Chromosome ◽  
Src Kinase ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Imatinib Resistance ◽  
Kinase Activation ◽  
Complete Hematologic Response

Abstract Developing strategies to counteract imatinib resistance constitutes a challenge in chronic myelogenous leukemia (CML). Therapy with the tyrosine kinase inhibitors nilotinib (AMN107) and dasatinib (BMS-354825) has produced high rates of hematologic and cytogenetic response. Src kinase activation has been linked to Bcr-Abl–mediated leukemogenesis and CML progression. In addition to binding Abl kinase with less stringent conformational requirements than imatinib, dasatinib is a potent Src kinase inhibitor. In the current study, we report on 23 patients with CML (19 of them in accelerated or blastic phases) treated with dasatinib after treatment failure with both imatinib and nilotinib. More than half (13; 57%) of 23 patients responded to dasatinib: 10 (43%) had a complete hematologic response (CHR), including 7 (30%) who had a cytogenetic response (2 complete, 4 partial, and 1 minor). These results suggest that dasatinib may be active in some patients after failure with both imatinib and nilotinib.

A Phase 1/2 Study of SKI-606, a Dual Inhibitor of Src and Abl Kinases, in Adult Patients with Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia (CML) or Acute Lymphocytic Leukemia (ALL) Relapsed, Refractory or Intolerant of Imatinib.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 168-168 ◽  
Author(s):  
Jorge Cortes ◽  
Hagop M. Kantarjian ◽  
Michele Baccarani ◽  
Tim H. Brummendorf ◽  
Delong Liu ◽  
...  
Keyword(s):  
Safety Profile ◽  
Phase 1 ◽  
Philadelphia Chromosome ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Dual Inhibitor ◽  
Hematologic Response ◽  
Complete Cytogenetic Response ◽  
Imatinib Resistant ◽  
Complete Hematologic Response

Abstract SKI-606 is an orally available, dual Src/Abl kinase inhibitor shown to be 200-fold more potent than imatinib as an inhibitor of Bcr-Abl phosphorylation in biochemical assays. BaF3 cell lines and primary cells from pts expressing different imatinib-resistant Bcr-Abl mutant proteins are sensitive to SKI-606 in vitro. Unlike imatinib and dasatinib, SKI-606 exhibits no significant inhibition of c-kit or PDGFR. This differential selectivity may result in clinical benefit by altering the safety profile. In the phase 1 portion of this phase 1/2 study, pts in chronic phase with imatinib relapsed or refractory disease were eligible for treatment with SKI-606 once-daily dosing. 18 pts [median age: 62 yrs (range 27 – 72); 14 male; 4 female; median CML duration: 5.8 yrs (range 0.9 – 11.1); and median time on imatinib (n=16): 3.9 yrs (range 0.8 – 6.5)] have been enrolled in the following dose cohorts (mg/day): 400 (3 pts), 500 (3 pts) and 600 (12 pts), and have been on treatment for 30 to 192 days. 17/18 pts remain on study; 1 pt discontinued with disease progression. The following SKI-606-related AEs have been reported (n=15, G1/2): diarrhea (87%), nausea (33%), vomiting (20%), abdominal pain (13%), rash (13%), asthenia (13%), and increased AST/ALT levels (7%). 2 pts treated at 600 mg experienced a G3 toxicity: rash and thrombocytopenia. 5 pts (4 pts at 600 mg and 1 pt at 500 mg) had dose reductions for rash, thrombocytopenia, diarrhea, fever and increased AST/ALT levels. No pleural effusion or pulmonary edema has been reported. Of the 7 pts who entered the study in hematologic relapse and have completed 1 month of treatment, all have achieved complete hematologic response. Of the 7 pts on treatment ≥ 12 weeks (time of first cytogenetic assessment), 3 pts have achieved complete cytogenetic response and 1 pt a minimal cytogenetic response. 6/7 pts who have achieved complete hematologic response had pre-treatment imatinib-resistant Bcr-Abl mutations: M351T; F359V; T315I; F359(V,F); and 2 pts with multiple mutations [L248(L,V) and H396(H,R); H396(H,P) and E286(E,G) and M351(T,M)]. The 3 pts with complete cytogenetic response had mutations: M351T; M244V; and H396(H,P), E286(E,G) and M351(T,M). Based on the emergence of 1 DLT of G3 rash, and additional G2 GI and dermatologic toxicities observed at 600 mg, 500 mg has been selected as the dose for the phase 2 portion of the study. Patients in all phases of CML and Ph+ ALL are now being enrolled. SKI-606 is well tolerated in pts with CML, with a primarily GI and dermatologic safety profile, and with encouraging evidence of clinical activity in imatinib-resistant patients with complete hematologic and cytogenetic responses.

Prior Response to Imatinib Predicts Response to Second Line Treatment with Nilotinib in CML Patients Resistant or Intolerant to Imatinib.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3297-3297
Author(s):  
Maya Koren-Michowitz ◽  
Philipp D. le Coutre ◽  
Justus Duyster ◽  
Christof Scheid ◽  
Panayiotis Panayiotidis ◽  
...  
Keyword(s):  
Prior Treatment ◽  
Imatinib Therapy ◽  
Study Entry ◽  
Imatinib Resistance ◽  
2Nd Generation ◽  
Advanced Phase ◽  
Best Response ◽  
Imatinib Resistant ◽  
Elevated Liver Enzymes ◽  
Grade 3

Abstract Abstract 3297 Poster Board III-185 Nilotinib is active in imatinib resistant or intolerant CML patients and was recently FDA and EMEA approved for these indications in chronic and accelerated phases. We report the efficacy and safety of 400mg BID nilotinib treatment in 88 CML patients (CP=58, AP=11, BP=19) treated within 2 phase II expanded access clinical trials (CAMN107AIL01 and ENACT). Median age of included patients was 60 years (range 23-85) and the median disease duration 44 months (range 2-200). Imatinib resistance was the reason for inclusion in 66 (75%) and intolerance in 22 (25%). Thirty-five percent were previously treated with α interferon, 18% with another 2nd generation TKI and 7.5% have undergone SCT. Twenty-six percent harbored ABL KD mutations at study entry. Overall 90% of patients responded to nilotinib therapy with best responses of CHR in 23 (27%), PCyR in 10 (12%), CCyR in 12 (14%), MMolR in 16 (19%), stable disease in 15 (18%) and return to CP in 1 patient (1%). In CP, CHR was newly achieved in 25/35 (71%), PCyR in 14/32 (44%), CCyR in 14/37 (38%) and MMolR in 8/41 (20%) of patients not having those responses at study entry, while the respective responses in advanced phase (AP+BP) were 58% (CHR), 30% (PCyR), 33% (CCyR) and 7.7% (MMolR). In imatinib resistant and imatinib intolerant patients, response rates were, respectively, 61% and 75% for CHR, 36% and 50% for PCyR, 29% and 47% for CCyR and 16% and 33% for MMolR with group comparisons NS in all cases. The best response achieved on imatinib therapy was predictive of the best response to nilotinib while imatinib resistance as defined in the study inclusion criteria was predictive of progression or lack of response to nilotinib therapy. Sixty-one percent of patients whom best response to imatinib was a CHR achieved a CHR as their best response to nilotinib while 83% of patients with at least a MCyR to imatinib have achieved at least a MCyR to nilotinb therapy (p=0.0025). Moreover, at the time of analysis, 32% of imatinib resistant patients have discontinued therapy due to lack of efficacy or disease progression compared to none of the imatinib intolerant patients (p=0.0012). Responses were not statistically different in patients with ABL KD mutations compared to those without mutations, patients with and without additional cytogentic abnormalities at study entry and patients with prior treatment with another 2nd generation tyrosine kinase inhibitor compared to those without prior treatment. Adverse hematological events during nilotinib treatment included thrombocytopenia in 27% and leucopenia in 18%, being grade 3-4 in 13% and 10%, respectively. Common biochemical abnormalities included hyperbilirubinemia (17%, [grade 3-4 2%]), elevated liver enzymes (14%, [1%]) hyperglycemia (7%) and elevated amylase or lipase (6%). The majority of the non-hematological events were mild, the common being rash (14%, [1%]), infection (9%, [1%]), bone pain (6% [1%]), headache (5%) and nausea and vomiting (4%). In summary, nilotinib treatment is an efficient and safe therapy for imatinib resistant or intolerant patients. Prior response to imatinib therapy is a predictor for response to nilotinib. Disclosures le Coutre: Novartis: Honoraria. Nagler:Novartis: Consultancy, Honoraria, Research Funding, paprticipating in Leadsummite .

Importance of Early Intervention with Dasatinib at Cytogenetic Rather Than Hematologic Resistance to Imatinib.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1036-1036 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Alfonso Quintas-Cardama ◽  
Susan O’Brien ◽  
Farhad Ravandi ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Early Intervention ◽  
Chronic Phase ◽  
Progression Free Survival ◽  
Cytogenetic Response ◽  
Imatinib Resistance ◽  
Free Survival ◽  
Hematologic Response ◽  
Complete Cytogenetic Response ◽  
Advanced Phase ◽  
Resistance Loss

Abstract Recent data for patients with chronic-phase (CP) CML indicate that development of resistance or intolerance to imatinib and treatment intervention following progression to advanced-phase disease are both associated with poor clinical outcome (with 3-year survival rates of 72% for chronic-phase disease, 30% for accelerated-phase CML, and 7% for blast-phase CML) (Kantarjian et al. Cancer2007;109:1556–60). Results also demonstrate that intervention with a second-generation tyrosine kinase inhibitor is more effective for individuals with chronic-phase CML than for those with advanced-phase disease. Of note, development of hematologic resistance (loss of a complete hematologic response [CHR]) was identified as an independent prognostic factor with a 3-year survival rate of 57% (compared with 92% for patients who experienced cytogenetic resistance [loss of a major cytogenetic response (MCyR)]). The objective of the current data analysis was to assess whether the development of hematologic resistance to imatinib would be a predictor of poor response to dasatinib (SPRYCEL®) relative to the development of cytogenetic resistance. Data from three Phase-II/III dasatinib clinical studies (CA180–013 [70 mg BID], CA180–017 [70 mg BID], and CA180–034 [100mg QD, 50 mg BID, 140 mg QD, 70 mg BID]) in patients with CP CML with resistance to prior imatinib were evaluated. Consistent with our earlier findings, significantly higher complete cytogenetic response (CCyR) rates were reported for patients who had developed secondary or acquried cytogenetic resistance to prior imatinib than for those with hematologic resistance. The improved rates of CCyR in patients with cytogenetic resistance to imatinib were associated with prolongation of progression-free survival compared to patients with hematologic resistance, thereby confirming the importance of early intervention in the event of imatinib resistance and the significance of achieving CCyR with dasatinib. Loss of MCyR Loss of CHR N n % N n % n = number of patients with [1] complete cytogenetic response or [2] progression Complete cytogenetic response [1] CA180–013 47 34 72 71 27 38 CA180–017 19 12 63 22 5 23 CA180–034     100 mg QD 28 21 75 14 2 14     50 mg BID 17 11 65 12 3 25     140 mg QD 18 9 50 16 8 50     70 mg BID 23 19 83 12 2 17 Progression-free survival at 1 year [2] CA180–013 47 3 95 71 15 84 CA180–017 19 1 94 22 3 85 CA180–034     100 mg QD 28 1 96 14 1 93     50 mg BID 17 0 100 12 6 58     140 mg QD 18 2 87 16 2 93     70 mg BID 23 2 95 12 4 69 These results confirm previous observations and emphasize the importance of close monitoring of treatment response to imatinib, and argue for early intervention in case of imatinib resistance. Late intervention, ie waiting for patients to lose a hematologic response, appears to significantly diminish the effectiveness of dasatinib.

Prognostic Significance of Prior Best Response to Imatinib in Patients (pts) with Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) Treated with Second Generation Tyrosine Kinase Inhibitors (TKIs).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1942-1942
Author(s):  
Elias Jabbour ◽  
Hagop Kantarjian ◽  
Jenny Shan ◽  
Susan O’Brien ◽  
William Wierda ◽  
...  
Keyword(s):  
Disease Burden ◽  
Second Generation ◽  
Cytogenetic Response ◽  
Event Free Survival ◽  
Free Survival ◽  
2Nd Generation ◽  
Hematologic Response ◽  
Best Response ◽  
Complete Hematologic Response ◽  
The Impact

Abstract Backgound. Imatinib mesylate therapy has significantly improved the prognosis of CML. A minority of pts in CP-CML are primary resistant to imatinib or develop resistance during treatment. Second generation TKIs such as dasatinib and nilotinib demonstrated efficacy in overcoming imatinib resistance, with high rates of hematologic and cytogenetic responses in CML post imatinib failure. Study Aims and Study Group. We assessed the impact of prior best response to imatinib on outcome of 120 pts in CP treated with new TKIs at our institution after imatinib failure: 75 (62%) received dasatinib and 45 (38%) recived nilotinib. Median age was 57 years (range, 21–83). The median duration of the disease was 67 months (range, 4–241). Pts have been followed for a median of 22 months (range, 1–44) from the start of 2nd generation TKIs. Results. Best response to imatinib was hematologic in 47 pts (40%) and cytogenetic in 60 (50%) (complete in 28, partial in 16, minor in 16). Five pts (4%) were primary refractory and 8 (6%) were intolerant. At the start of 2nd generation TKIs, 87 pts (73%) were in active CP with no complete hematologic response (CHR). Eighty-five (71%) harbored more than 90% Philadelphia-positive metaphases, and clonal evolution was noted in 28 pts (23%). Patients that had achieved a cytogenetic response at any time during their imatinib therapy had a better outcome than those who had only a hematologic response: CHR rates 98% vs 68%, p <0.001; major cytogenetic response (MCyR) rates 75% vs 26%, p<0.001; and complete cytogenetic response (CCyR) rates 68% vs 23%, p<0.001. This translated into an improved 12-month event-free survival (EFS) of 92% vs 68% (p<0.001) and a trend for better 12-month survival of 92% vs 89% (p=0.06) (Table1). Pts with CHR at the start of therapy with 2nd generation TKIs had higher rates of cytogenetic response than those not already in CHR (88% vs 64%; p=0.01). Low disease burden defined by Philadelphia-positive metaphases <90% was associated with higher rates of hematologic response (p=0.006), MCyR (p<0.001) and CCyR (p=0.003), with no impact on EFS. There was no difference in activity between the two 2nd generation TKIs with CHR rates of 89% and 80% (p=0.18), MCyR rates of 57% and 51% (p=0.57) and CCyR rates of 52% and 47% (p=0.71) for dasatinib and nilotinib, respectively. Conclusion. The probability of response to 2nd generation TKIs is highly dependent on prior response to imatinib and disease burden at the start of therapy. Table 1. % CG response % 12-Month Best response to imatinib N % CHR Major Complete EFS Survival EFS=Event-free survival; CG=Cytogenetic; CHR=complete hematologic response No CHR 4 80 40 40 80 80 CHR 32 68 26 23 68 89 Any CG response 59 98 75 68 92 92 P-value <0.001 <0.001 <0.001 <0.001 0.06

Correlation of Clinical Response to Dasatinib (BMS-354825) with BCR-ABL Mutation Status in Imatinib- Resistant Patients (pts) with Chronic Myeloid Leukemia (CML) Treated at MD Anderson Cancer Center (MDACC).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1091-1091 ◽  
Author(s):  
Elias Jabbour ◽  
Jorge Cortes ◽  
Moshe Talpaz ◽  
Dan Jones ◽  
Susan O’Brien ◽  
...  
Keyword(s):  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Kinase Domain ◽  
Cancer Center ◽  
Abl Kinase ◽  
Hematologic Response ◽  
Imatinib Resistant ◽  
Wide Range

Abstract Resistance to imatinib in CML occurs most frequently through mutations of the BCR-ABL kinase domain. Dasatinib is an orally available, dual SRC/ABL kinase inhibitor with 300-fold greater potency than imatinib, and with preclinical activity against all but one (T315I) type imatinib-resistant Bcr-Abl mutants. Dasatinib is currently used to treat pts with CML in chronic phase (CP), accelerated phase (AP), or blast phase (BP) or with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). We analyzed the response to dasatinib among pts with Bcr-Abl kinase mutations. Prior to therapy, peripheral blood samples were analyzed for mutation by DNA sequencing. 26 pts with 13 different imatinib-resistant point mutations in the Bcr-Abl kinase domain were treated (CP n=10, AP n=11, BP n=4, ALL n=1). The most common mutations were G250E/A (n=7, 27%), T315I (n=3, 12%), F317L (n=3, 12%), and E355G/A (n=3, 12%). 20 (77%) pts responded to therapy. Responses were: major molecular remission (MMR) in one pt (4%), complete cytogenetic response (CGCR) in 3 (12%), partial cytogenetic response (CGPR) in 5 (19%), complete hematologic response (CHR) in 6 (23%), partial hematologic response (PHR) in 3 (12%), and return to CP in 2 (8%). 6 pts did not respond: 3 of them were in AP (T315I, L364I, and G250E) and 3 in CP (2 T315I and F317L). Three pts (1 CP [F317L], 2 BP [M351T and E355G]) have lost their response (CGPR, CHR, and PHR) after a median of 3 months (range, 2–4 months) without developing any detectable new mutations. The median duration of response for the other 19 pts was 5+ months (range 1+–14+); 4 pts (1 CP [F486S], 3 AP [E255V and 2 G250E]) have a sustained response (1 MMR, 1 CGCR, and 2 CHR) beyond 6 months. Among 12 pts with P-loop mutations (2 in CP, 8 in AP, 2 in BP) 11 (92%) responded to therapy and their median survival since the start of therapy is 5+ months (range, 1+-11+ months). In 2 pts (CHR) subsequent analysis revealed persistence of mutations (E355G and E255V). In one pt G250E mutation occurred while patient was on treatment, but has remained in CHR. We conclude that clinical activity of dasatinib in imatinib-resistant CML is observed in pts with a wide range of imatinib-resistant Bcr-Abl kinase domain mutations. Pts harboring the T315I mutations are resistant to BMS-354825.

Response of ETV6-FLT3–positive myeloid/lymphoid neoplasm with eosinophilia to inhibitors of FMS-like tyrosine kinase 3

Blood ◽  
2011 ◽  
Vol 118 (8) ◽  
pp. 2239-2242 ◽  
Author(s):  
Christoph Walz ◽  
Philipp Erben ◽  
Michael Ritter ◽  
Adrian Bloor ◽  
Georgia Metzgeroth ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Clonal Evolution ◽  
Cytogenetic Response ◽  
Hematologic Response ◽  
Imatinib Resistant ◽  
Complete Hematologic Response ◽  
Heavily Pretreated ◽  
Tk Inhibitors ◽  
Male Patients ◽  
T Lymphoblastic Lymphoma

Abstract Imatinib-resistant tyrosine kinase (TK) fusions involving FGFR1, JAK2, or FLT3 are rare but recurrent in patients with eosinophilia-associated neoplasms. We report here 2 male patients with ETV6-FLT3+ myeloid/lymphoid neoplasms with eosinophilia who were treated with the multitargeted TK inhibitors sunitinib and sorafenib. Patient 1 achieved rapid complete hematologic response and complete cytogenetic response after 3 months of taking sunitinib. A secondary blast phase caused by clonal evolution was diagnosed after 6 months. He achieved a second complete hematologic response after taking sorafenib but relapsed 2 months later. An N841K point mutation within the TK domain of FLT3, previously reported in acute myeloid leukemia and potentially conferring resistance to sorafenib, was subsequently identified. Patient 2 was heavily pretreated according to the initial diagnosis of T-lymphoblastic lymphoma and died in sunitinib-induced pancytopenia. This report highlights the importance of a careful diagnostic workup for eosinophilia-associated neoplasms to evaluate the possibility of TK inhibitor therapy.

Second-line bosutinib (BOS) for patients (pts) with chronic phase (CP) chronic myeloid leukemia (CML): Final 10-year results of a phase 1/2 study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7009-7009
Author(s):  
Carlo Gambacorti-Passerini ◽  
Tim H. Brümmendorf ◽  
Dong-Wook Kim ◽  
Yeow Tee Goh ◽  
Irina S Dyagil ◽  
...  
Keyword(s):  
Phase 1 ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Dose Intensity ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Second Line ◽  
Prior Therapy ◽  
Kaplan Meier ◽  
Imatinib Resistant

7009 Background: BOS is approved for Philadelphia chromosome (Ph)+ CML resistant/intolerant to prior therapy and newly diagnosed Ph+ CP CML. In a phase 1/2 study, second-line BOS showed durable efficacy and manageable toxicity in pts with imatinib-resistant (IM-R) or -intolerant (IM-I) Ph+ CP CML. Methods: This final efficacy and safety analysis of the phase 1/2 study and extension study was based on ≥10 y of follow-up (FU). Ph+ CP CML pts who received BOS starting at 500 mg/d after prior treatment (Tx) with imatinib only were included. Results: 19% of pts were on BOS at y 10, and 13% were still on BOS at study completion after ≥10 y; 19% completed ≥10 y of FU. Median duration of Tx and FU were 26 and 54 mo, respectively. Median (range) dose intensity was 436 (87–599) mg/d. The most common primary reasons for permanent Tx discontinuation were lack of efficacy (unsatisfactory response or disease progression; 27%) and adverse events (AEs; 26%). In pts with a valid baseline assessment, cumulative complete cytogenetic response (CCyR), major molecular response (MMR) and MR4 rates (95% CI), respectively, were 50% (43–56), 42% (35–49) and 37% (30–44) (IM-R: 48% [41–56], 46% [37–55] and 39% [31–48]; IM-I: 53% [41–64], 36% [25–48] and 33% [22–45]). Responses were durable, with estimated probabilities of maintaining CCyR, MMR and MR4 > 50% after ≥10 y (Table). At 10 y, cumulative incidence of on-Tx progression/death was 24% and Kaplan-Meier (K-M) overall survival 72% (Table); 55 deaths (IM-R: n = 41; IM-I: n = 14) occurred on study, none BOS-related. Any grade Tx-emergent AEs (TEAEs) in ≥40% of pts were diarrhea (86%), nausea (46%) and thrombocytopenia (42%). Pleural effusion, cardiac and vascular TEAEs occurred in 13%, 12% and 11% of pts, respectively. 28% of pts had AEs leading to permanent Tx discontinuation; most common (≥2% of pts) were thrombocytopenia (6%), neutropenia (2%) and alanine aminotransferase increased (2%). Conclusions: These 10-y data are consistent with prior results of durable efficacy and manageable toxicity with second-line BOS and support long-term BOS use in CP CML pts after imatinib failure. Clinical trial information: NCT00261846 and NCT01903733. [Table: see text]

Early treatment decisions with interferon-alfa therapy in early chronic-phase chronic myelogenous leukemia.

1998 ◽  
Vol 16 (3) ◽  
pp. 882-889 ◽  
Author(s):  
S Sacchi ◽  
H M Kantarjian ◽  
T L Smith ◽  
S O'Brien ◽  
S Pierce ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Univariate Analysis ◽  
Group Analysis ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Interferon Alfa ◽  
Myelogenous Leukemia ◽  
Costal Margin ◽  
Hematologic Response

PURPOSE To determine, in patients with Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML) on interferon alfa (IFNalpha), whether combining pretreatment characteristics and early response profiles would distinguish patients with differential benefits that would allow better decisions on subsequent therapy. PATIENTS AND METHODS A total of 274 patients treated from 1982 through 1990 with IFNalpha regimens were analyzed. A second group of 137 patients treated with IFNalpha and low-dose cytarabine (ara-C) between 1990 and 1994 was later used to confirm the guidelines derived from the original study group analysis. Patients' pretreatment factors and response to IFNalpha therapy at 3, 6, and 12 months were analyzed in relation to subsequent achievement of major cytogenetic response. After univariate analysis of prognostic factors, a multivariate analysis selected, at 6 months, independent pretreatment factors that added to the response status in predicting subsequent outcome. The results were then applied at the 3- and 12-month periods and confirmed in the subsequent population. RESULTS Response to IFNalpha therapy at 3, 6, and 12 months was a significant predictor of later major cytogenetic response. The presence of splenomegaly > or = 5 cm below the costal margin (BCM) or thrombocytosis > or = 700 x 10(9)/L pretreatment added significant independent prediction to response. At 6 months, patients with a partial hematologic response (PHR) or resistant disease had a less than 10% chance of achieving a later major cytogenetic response, as were those in complete hematologic response (CHR) and who had pretreatment splenomegaly and thrombocytosis. Applying the model at 3 months showed that only patients with < or = PHR and pretreatment splenomegaly or thrombocytosis at 3 months had such a low major cytogenetic response rate. Finally, at 12 months, patients with CHR still had a 15% to 25% chance of having a major cytogenetic response later if they did not have pretreatment splenomegaly and thrombocytosis. CONCLUSION This analysis allows better selection of patients with Ph-positive CML on IFNalpha therapy for continuation of IFNalpha versus changing therapy early in the course of CML. For treatment programs that choose to change patients to other investigational therapies (eg, intensive chemotherapy and/or autologous stem-cell transplantation [SCT]), baseline outcome expectations are provided for patients continued on IFNalpha therapy, against which the results of new approaches can be compared.

scholarly journals Genetics and prognosis of ALL in children vs adults

Hematology ◽  
2018 ◽  
Vol 2018 (1) ◽  
pp. 137-145 ◽  
Author(s):  
Kathryn G. Roberts
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Lymphoblastic Leukemia ◽  
Diagnostic Testing ◽  
Survival Rates ◽  
Philadelphia Chromosome ◽  
Genetic Alterations ◽  
Tyrosine Kinase Signaling ◽  
Disease Biology ◽  
Long Term Prognosis

Abstract Acute lymphoblastic leukemia (ALL) is characterized by genetic alterations that block differentiation, promote proliferation of lymphoid precursor cells, and are important for risk stratification. Although ALL is less common in adolescents and young adults (AYAs) and adults than children, survival rates are inferior, and long-term prognosis for adults is poor. Thus, ALL remains a challenging disease to treat in the AYA and adult populations. A major contributing factor that influences prognosis in this population is the reduced prevalence of genetic subtypes associated with favorable outcome and a concomitant increase in subtypes associated with poor outcome. Recent advances in genomic profiling across the age spectrum continue to enhance our knowledge of the differences in disease biology between children and adults and are providing important insights into novel therapeutic targets. Philadelphia chromosome-like (Ph-like) ALL is one such subtype characterized by alterations that deregulate cytokine receptor or tyrosine kinase signaling and are amenable to inhibition with approved tyrosine kinase inhibitors. One of the greatest challenges now remaining is determining how to implement this breadth of genomic information into rapid and accurate diagnostic testing to facilitate the development of novel clinical trials that improve the outcome of AYAs and adults with ALL.

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