Chromosomal Abnormalities In Philadelphia Chromosome (Ph)-Negative Metaphases Appearing During Second Generation Tyrosine Kinase Inhibitors (2nd TKI) Therapy In Patients (pts) with Chronic Myeloid Leukemia (CML).

Abstract Abstract 1232 The development of chromosomal abnormalities in the Ph-negative metaphases during IM therapy of CML has been recognized in pts with CML. This is different from clonal evolution where the abnormalities are observed in the Ph-positive metaphases. This phenomenon has not yet been systematically assessed to date in patients treated with 2ndTKIs such as dasatinib, nilotinib and bosutinib. By definition, this phenomenon is evaluable only among pts who achieve at least a minor cytogenetic response. We assessed the frequency and the significance of this event among 453 pts with CML treated with 2nd TKIs either after imatinib failure (n=299; 124 pts treated with dasatinib, 116 pts treated with nilotinib, and 59 pts treated with bosutinib) or as frontline therapy (n=154; 76 pts treated with dasatinib, and 78 pts treated with nilotinib) between June 2003 and August 2010. After a median follow-up of 37 months (range, 12–67 months), 41 pts (9%) 35 in chronic phase, 2 accelerated phase, and 4 in blast phase) receiving dasatinib (n=11), nilotinib (n=21) or bosutinib (n=9) developed 72 chromosomal abnormalities in Ph-negative metaphases. 32 (44%) of these abnormalities have been seen in 2 or more metaphases. The median time from the start of the 2nd TKI to appearance of abnormalities was 8 months (range, 2 – 57 months). The most common cytogenetic abnormalities were: –Y (n=7, 10%), trisomy 8 (n=6, 8%), and del20q (n=5, 7%). Excluding loss of chromosome Y abnormalities and abnormalities observed in only one metaphase, the incidence was 4%. At the time abnormalities were detected, 33 pts were in major cytogenetic response (complete in 26) and 8 in minor cytogenetic response. In all but 14 pts, these events have been transient and disappeared after a median of 3 months (range, 1 – 42 months). In14 pts (+8 n=3, -Y n=3, and del20q n=2), they persisted for a median of 10+ months (range, 3+-60+ months). One pt on dasatinib developed refractory anemia with ringed sideroblasts (associated with trisomy 8); she had CML for 16 years, failed prior therapy with interferon, imatinib, and nilotinib, and achieved a complete cytogenetic response on dasatinib for 24 months, lost her response, progressed and died of multiple organ failure. None of the other pts had any features of myelodysplasia. At the last follow-up, all but 7 pts are alive: 29 in major cytogenetic response (complete in 24), 1 in minor cytogenetic response, and 4 alive with disease. Causes of death included stem cell transplant related morbidities (n=2), multisystem organ failure related to sepsis (n=2), and unknown causes (n=3). We conclude that cytogenetic abnormalities occur in Ph-negative cells in a small fraction of pts (9%; 4% if loss of Y and abnormalities in one metaphase are excluded) treated with the 2nd TKIs. These are frequently transient and usually have no clinical significance, but in rare instances they could signal the emergence of a new malignant clone. Disclosures: Jabbour: Novartis: Honoraria; BMS: Honoraria. Kadia:Novartis: Consultancy. Cortes:Novartis: Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding.

Download Full-text

Chromosomal Abnormalities in Philadelphia Chromosome (Ph)-Negative Metaphases Appearing during Novel Tyrosine Kinase Inhibitors (NTKI) Therapy in Patients (pts) with Chronic Myeloid Leukemia (CML) after Imatinib-Failure.

Blood ◽

10.1182/blood.v108.11.2115.2115 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2115-2115 ◽

Cited By ~ 1

Author(s):

Elias Jabbour ◽

Hagop Kantarjian ◽

Lynne Abruzzo ◽

Francis Giles ◽

Mary Beth Rios ◽

...

Keyword(s):

Chromosomal Abnormalities ◽

Clonal Evolution ◽

Philadelphia Chromosome ◽

Chronic Phase ◽

Cytogenetic Response ◽

The Other ◽

Refractory Anemia ◽

Trisomy 8 ◽

Cytogenetic Abnormalities

Abstract The development of chromosomal abnormalities in the Ph-negative metaphases during IM therapy of CML has been recognized in pts with CML. This is different from clonal evolution where the abnormalities are observed in the Ph-positive metaphases. This phenomenon has not been yet systematically assessed to date in patients treated with NTKIs such as dasatinib and nilotinib. By definition, this phenomenon is evaluable only among pts who achieve at least a minor cytogenetic response. We assessed the frequency and the significance of this event among 107 pts with CML after imatinib failure receiving dasatinib (=70) or nilotinib (n=37) therapy between June 2003 and March 2006. After a median follow-up of 13 months (range, 3–32 months), 12 pts (11%) (chronic phase n=6, accelerated phase n=6) receiving dasatinib (n=6) or nilotinib (n=6), developed 21 chromosomal abnormalities in Ph-negative metaphases. Ten (48%) of these abnormalities have been seen in 2 or more metaphases. The median time from the start of the NTKI to appearance of abnormalities was 7 months (range, 0–15 months). The most common cytogenetic abnormalities were: trisomy 8 (n=3, 14%) and del 20q (n=3, 14%). Excluding loss of chromosome Y abnormalities and abnormalities observed in only one metaphase, the incidence was 5%. At the time, abnormalities were detected, 8 pts were in major cytogenetic response (complete in 6) and 4 in minor cytogenetic response. In all but 4 pts these events have been transient and disappeared after a median of 4 months (range, 3–9 months). In 4 pts (+8 n=2, −Y n=1, and add1q, del10q, and del20q n=1), they persisted for a median of 5+ months (range, 3+ – 9+ months). One pt on dastinib developed refractory anemia with ringed sideroblasts (associated with trisomy 8); he had CML for 16 years, failed prior therapy with interferon, imatinib, and nilotinib, and achieved a complete cytogenetic response on dasatinib; none of the other pts has any feature of myelodysplasia. At the last follow-up, all pts are alive: 2 pts lost their response; one of them underwent allogeneic stem cell transplantation and achieved a major molecular remission. The other 10 pts remained in major cytogenetic response (complete in 8). We conclude that cytogenetic abnormalities occur in Ph-negative cells in a small fraction of patients (11%; 5% if loss of Y and abnormalities in one metaphase excluded) treated with the NTKIs. These are frequently transient and usually have no clinical significance, but in rare instances they could signal the emergence of a new malignant clone.

Download Full-text

Chromosomal Abnormalities in Philadelphia Chromosome (Ph)-Negative Metaphases Appearing during Imatinib Mesylate (IM) Therapy in Patients (pts) with Newly Diagnosed Chronic Myeloid Leukemia (CML) in Chronic Phase.

Blood ◽

10.1182/blood.v106.11.1090.1090 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1090-1090 ◽

Cited By ~ 1

Author(s):

Elias Jabbour ◽

Hagop Kantarjian ◽

Susan O’Brien ◽

Srdan Verstovsek ◽

Guillermo Garcia-Manero ◽

...

Keyword(s):

Myeloid Leukemia ◽

Chromosomal Abnormalities ◽

Philadelphia Chromosome ◽

Chromosome 7 ◽

Molecular Response ◽

Newly Diagnosed ◽

Trisomy 8 ◽

Chromosome Y ◽

Cytogenetic Abnormalities

Abstract The development of chromosomal abnormalities in the Ph-negative metaphases during IM therapy of CML has been recognized mostly in pts who failed prior therapy. Prior exposure to cytarabine has been suggested to be a predisposing factor. This phenomenon has not been yet assessed to date in patients with newly diagnosed CML and treated with IM. This is different from clonal evolution where the abnormalities are observed in the Ph-positive metaphases. We assessed the frequency and the significance of this event among 258 newly diagnosed pts with CML receiving IM (800 mg/d n=207, 400 mg/d n=51) as first line of therapy between March 2001 and April 2005. After a median follow-up of 30 months (range, 6–48 months), 19 pts (7%) developed 21 chromosomal abnormalities in Ph-negative metaphases. Thirteen (62%) of these abnormalities have been seen in 2 or more metaphases. The median time from the start of IM to appearance of abnormalities was 18 months (range, 3–36 months). The most common cytogenetic abnormalities were: loss of chromosome Y (n=7, 33%), trisomy 8 (n=3, 14%), and deletion of chromosome 7 (n=2, 10%). Excluding loss of chromosome Y abnormalities, the incidence was 5%. All pts achieved a major (Ph < 35%) cytogenetic (CG) response (complete cytogenetic response [CCGR] in 17 [89%] pts). Major molecular response (BCR-ABL/ABL ratio <0.05) was observed in 13 (68%) pts (including 2 with complete molecular response). In all but 4 pts these events have been transient and disappeared after a median of 4 months (range, 3–9 months). In 4 pts (loss of chromosome Y n=3, trisomy 8 n=1), they persisted for a median of 13+ months (range, 6+–24+ months). One pt developed acute myeloid leukemia (associated with -7); none of the other pts has any feature of myelodysplasia. After a median follow-up of 13 months (range, 1–42 months), 17 of the 19 pts are alive. One pt died after allogeneic stem cell transplantation, and one died after 6 months of CCGR from myocardial infarction. One pt lost response to IM. The remaining 16 pts are in major CG response at the last follow-up. We conclude that: 1) cytogenetic abnormalities occur in Ph-negative cells in a small fraction of patients (7%; 5% if loss of Y excluded) in newly diagnosed CML on IM; 2) in the majority of cases, they are transient with no clear clinical consequences; 3) in rare instances (loss of chromosome 7 only in our study) they could reflect the emergence of a new malignant clone necessitating and a close follow-up.

Download Full-text

Survival Outcomes for Patients (Pts) with Chronic Myeloid Leukemia (CML) with Clonal Evolution (CE) Treated with 2nd Generation Tyrosine Kinase Inhibitors (TKI) after Imatinib Failure.

Blood ◽

10.1182/blood.v110.11.2949.2949 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2949-2949 ◽

Cited By ~ 1

Author(s):

Dushyant Verma ◽

Hagop Kantarjian ◽

Zeev Estrov ◽

Guillermo Garcia-Manero ◽

Charles Koller ◽

...

Keyword(s):

Kinase Inhibitors ◽

Chromosomal Abnormalities ◽

Clonal Evolution ◽

Philadelphia Chromosome ◽

Cytogenetic Response ◽

Chromosome 17 ◽

Trisomy 8 ◽

2Nd Generation ◽

Molecular Events ◽

Number Of Patients

Abstract Background: CE has been considered a criterion for accelerated phase (AP) CML, particularly when it appears during the course of therapy, when it is associated with a poor prognosis. CE may involve a variety of chromosomal abnormalities and may signal resistance to imatinib. The 2nd generation TKI (2nd TKI) dasatinib and nilotinib are effective in patients with AP after failure to imatinib, including those with CE. However, it is unclear whether different chromosomal abnormalities constituting CE may have the same outcome after therapy with 2nd TKI. Methods: We analyzed the outcome after 2nd TKI therapy of 61 pts with CML with CE who had failed prior imatinib therapy. Results: The median age was 55 years (range 23–76); the median follow-up after start of 2nd TKI was 18.9 months (mo) (range 5.3–39.3), and median CML duration 67.9 mo (0.4–206.6). Thirty-five pts had CE alone and 26 had CE with other AP features. At the time of this report 59 patients are evaluable for response: 30 treated with dasatinib and 29 with nilotinib. The accompanying table summarizes the findings. Conclusion: CE constitutes a heterogeneous entity with variable outcome with 2nd TKI. Regardless of the percentage of metaphases with CE, those with trisomy 8 or with abnormalities in chromosome 17 may have the worse outcome. In all cases, the presence of other features of AP further worsens the outcome. The molecular events behind this worse outcome and potential therapeutic approaches directed at them need to be defined. Characteristics (n=59) CCyR n/no. evaluable(%) p EFS % (12mo) p OS % (12mo p CCyR: Complete Cytogenetic Response, EFS: Event Free Survival, OS: Overall Survival, Chr: Chromosome, Ph+: Philadelphia chromosome positive, n: number of patients % Cellls with CE <16 3/12(25) 62 77 16-35 4/10(40) 60 68 36-99 9/15(60) 73 80 100 7/22(32) 0.24 60 0.96 78 0.85 Other AP features No 18/34(53) 80 89 Yes 5/25(20) 0.02 40 <0.001 60 0.005 Double Ph+ No 9/28(32) 55 69 Yes 14/31(45) 0.42 71 0.93 84 0.72 Trisomy 8 No 21/49(43) 72 84 Yes 2/10(20) 0.29 20 <0.001 40 <0.001 Chr 17 Abnormalities No 19/45(42) 74 83 Yes 4/14(29) 0.53 29 0.003 56 0.02 Other Translocations No 20/42(48) 61 75 Yes 3/17(18) 0.04 69 0.71 82 0.81 Other abnormalities No 15/37(41) 62 81 Yes 8/22(36) 0.79 65 0.45 70 0.93

Download Full-text

Outcome After Failure to Second Generation Thyrosine Kinase Inhibitors(TKI) Treatment as Frontline Therapy for Patients with Chronic Myeloid Leukemia (CML) In Chronic Phase(CP).

Blood ◽

10.1182/blood.v116.21.3442.3442 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3442-3442

Author(s):

Alireza Eghtedar ◽

Hagop Kantarjian ◽

Elias Jabbour ◽

Susan O'Brien ◽

Alfonso Quintas-Cardama ◽

...

Keyword(s):

Stem Cell ◽

Research Funding ◽

Stem Cell Transplant ◽

Cytogenetic Response ◽

Initial Therapy ◽

Subsequent Treatment ◽

Cell Transplant ◽

2Nd Generation ◽

Frontline Therapy

Abstract Abstract 3442 Background: Imatinib has been the standard frontline therapy for patients with CML in early CP. 2nd generation TKIs (nilotinib, dasatinib) have been reported to be more effective than imatinib as frontline therapy in rates of response and transformation. Nilotinib has received regulatory approval for this indication and others (dasatinib, bosutinib) may come soon. Although fewer patients are expected to experience failure to therapy with the use of these agents, these patients will represent a management challenge. The characteristics, management and outcome of patients who fail therapy with 2nd generation TKI used as initial therapy has not been reported. Aim: To analyze the characteristics of patients who fail therapy with 2nd generation TKI used as initial therapy, their management, and outcome after failure to initial therapy. Methods: Two parallel studies of 2nd generation TKI as initial therapy for CML early CP are being conducted at MDACC, one with nilotinib and one with dasatinib. The study with nilotinib includes also patients in accelerated phase (AP) that have received no other prior therapy. The records of all patients who were taken off therapy from these trials were reviewed to investigate the reasons for failure, subsequent management and outcome. Results: A total of 172 pts have been treated with dasatinib (n=82) or nilotinib (n=90; 9 in AP) since 2005. After a median follow-up of 18.9 months, 23 pts (14%) have discontinued therapy: 13 (16%) pts in the nilotinib study (2 of them treated in AP), and 10 (12%) in the dasatinib study. Their median age 48 years (range:19–73) and they had received therapy with nilotinib or dasatinib for a median of 5.2 (0.03-48) months. Reasons for nilotinib treatment discontinuation include: toxicity 4 pts (elevated lipase, acute pancreatitis + atrial fibrillation, pericardial effusion and acute renal failure, one each), transformation to blast phase (BP) 3 pts (2 of them treated in AP), and other reasons 6 pts (2 each for insurance issues, patient request and non-compliance). Reasons for discontinuation of dasatinib include: toxicity 5 pts (2 pleural effusion, 1 prolonged thrombocytopenia, 1 bone pain, 1 congestive heart failure), 2 pts for loss of response, and 3 pts for pts' choice. Best response to frontline treatment with nilotinib or dasatinib was 6 (26%) pts major molecular response, 6 (26%) pts complete cytogenetic response, 1 (4%) pt partial cytogenetic response, 3 (13%) pts minor cytogenetic response, 1 (4%) pt with no response and 6 (26%) pts nonevaluable. At the time of failure 18 pts were in CP, 4 pts in BP (one pt transformed shortly after discontinuation) and 1 AP. At the time of treatment interruption, 14 pts had BCR-ABL sequencing and 2 were found to have mutations (F359C, Y253H); 3 pts had new additional chromosomal abnormalities (ie, clonal evolution). Subsequent treatment after failure to initial therapy include: imatinib in 8 pts, nilotinib in 2 pts, dasatinib 1 pt, Hyper CVAD with dasatinib 1 pt, Hyper CVAD with imatinib 1 pt, stem cell transplant 2 pts, bafetinib 1 pt, and unknown 4 pts (lost to follow-up). One pt died shortly after failure without further therapy. Best response to subsequent therapies were 1 pt with CMR (after stem cell transplant), 7 pts with MMR (3 pts after imatinib, 1 pt after dasatinib, 1 pt after nilotinib, 1 pt after Hyper CVAD with imatinib and 1 pt after stem cell transplant), 1 pt CHR, 1 pt minor CyR, 3 pts without response, and 8 pts were not evaluable. Of the 5 pts that achieved MMR with subsequent TKI, all were in CP and had discontinued initial therapy because of toxicity (4 pts) or personal reasons (1pt). Median duration of ongoing subsequent treatment is 8 months (range 1.7–25). The survival rate after a median follow-up of 3.9 months since failure to frontline therapy is 87%. Conclusion: Failure after frontline therapy with second generation TKI is an uncommon event, most frequently associated with toxicity or patient preference. Most of these patients respond well to alternative TKI. This adequate response should alleviate the fear of not having available effective therapy if patients fail to respond to 2nd generation TKI when used as frontline therapy. Disclosures: Kantarjian: BMS: Research Funding; NOVARTIS: Research Funding. Cortes:BMS: Research Funding; NOVARTIS: Research Funding; Pfizer: Consultancy, Research Funding.

Download Full-text

Incidence and Outcomes of Chronic Myeloid Leukemia (CML) Patients (pts) with Other Chromosomal Abnormalities (OCA) Treated with Second Generation Tyrosine Kinase Inhibitors (TKI)

Blood ◽

10.1182/blood.v120.21.4311.4311 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4311-4311

Author(s):

Naveen Pemmaraju ◽

Hagop M. Kantarjian ◽

Elias J. Jabbour ◽

Alfonso Quintás-Cardama ◽

Gautam Borthakur ◽

...

Keyword(s):

Research Funding ◽

Chromosomal Abnormalities ◽

Clonal Evolution ◽

Philadelphia Chromosome ◽

Group Versus ◽

Chronic Phase ◽

Initial Therapy ◽

Chromosome 7 ◽

2Nd Generation

Abstract Abstract 4311 Background: Development of OCA (i.e., chromosomal abnormalities in the Philadelphia chromosome negative metaphases) has been reported among patients receiving imatinib as initial therapy for CML. Little is known about incidence and outcomes of OCA in CML pts treated with frontline 2nd generation TKI (dasatinib, nilotinib). Objectives: We describe incidence of OCAs in CML pts treated with frontline 2nd generation TKI and determine the outcomes of pts who develop OCA events. Methods: We reviewed pts treated with frontline 2nd generation TKI, dasatinib (n=99) or nilotinib (n=117), treated on 2 parallel ongoing prospective single-arm Phase II protocols at our institution. An OCA was defined as a cytogenetic abnormality in one or more non-Philadelphia chromosome positive clones (different than clonal evolution). Pts were followed with cytogenetic analysis at 3 month (mo) intervals for the first year, then every 6–12 mo. 30 pts with OCA were identified. Pts in chronic (n=25) or accelerated phase (n=5) at diagnosis were included in the analysis. Results: With a median follow-up of 30 mo (range 0–71), 11 (11%) pts treated with dasatinib and 19 (16%) pts treated with nilotinib developed OCA. The difference in incidence of OCA with dasatinib and nilotinib was not statistically significant (p=0.280). At start of therapy, median age of pts developing OCA was 53 (41–71) with dasatinib and 52 (37–82) with nilotinib, compared to those pts without OCA: 48 (18–83 yrs) with dasatinib and 49 (17–87) with nilotinib. The most common OCA event overall was abnormality of chromosome 7 found in 5 pts (one pt with both inv(7) and +7) for total of 6 occurrences (including inversion (n=1), 2 different translocations (n=2), deletions (n=2), and additions (n=1) involving chromosome 7). The most common translocation event was t(6;13) in 2 pts. No pts developed trisomy 8 (historically most common OCA among imatinib treated pts). Median time to first appearance of OCA was 9 mo (range 3–58) for all 2nd generation TKI pts (12 mo (range 3–58) for dasatinib group and 9 mo (3–48) for nilotinib group). 9 pts had OCA on more than one occasion. OCA disappeared in 25 pts during course of follow-up. Outcomes for OCA group versus non-OCA group are shown in Table 1, and outcomes with focus on chronic phase pts only in Table 2. For pts in accelerated phase, 3/6 pts (50%) in dasatinib group and 2/17 pts (12%) in nilotinib group developed an OCA. None of the pts who developed OCA has developed AML or MDS. Conclusions: OCA are observed in 10–15% of pts receiving initial therapy with 2nd generation TKI. At median follow up of 30 mo, occurrence of OCA confers no statistically significant adverse impact on outcomes when compared to non-OCA pts treated with 2nd generation TKI and has not resulted in other hematologic disorders. Disclosures: Off Label Use: Dasatinib and Nilotinib originally used in investigational setting when trials were begun. Kantarjian:Novartis Pharmaceuticals Corp: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Research Funding. Jabbour:BMS: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Cortes:Novartis, BMS, ARIAD, Pfizer: Consultancy, Research Funding.

Download Full-text

Additional Chromosomal Abnormalities in Philadelphia Chromosome-Negative Metaphases Appearing during Therapy with Imatinib, Dasatinib, Nilotinib and Ponatinib in Patients with Newly Diagnosed Chronic Myeloid Leukemia

Blood ◽

10.1182/blood.v126.23.1577.1577 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1577-1577 ◽

Cited By ~ 1

Author(s):

Ghayas C. Issa ◽

Hagop M. Kantarjian ◽

Elias Jabbour ◽

Gautam Borthakur ◽

Srdan Verstovsek ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Clinical Outcomes ◽

Myeloid Leukemia ◽

Research Funding ◽

Chromosomal Abnormalities ◽

Philadelphia Chromosome ◽

Cytogenetic Response ◽

Banding Technique ◽

First Year ◽

Additional Chromosomal Abnormalities

Abstract Background Additional chromosomal abnormalities (ACAs) in the Philadelphia chromosome (Ph)-negative metaphases that emerge as patients with chronic myeloid leukemia (CML) are treated with tyrosine kinase inhibitors (TKIs) have been reported during treatment with imatinib. It has been suggested that these might be associated with an inferior outcome and in rare instances lead to the emergence of a new malignant clone resulting in myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) (Jabbour et. al, Blood 2007). This phenomenon has not been well characterized when other TKIs are used. We conducted a retrospective analysis of patients treated on imatinib, dasatinib, nilotinib, and ponatinib frontline trials to assess the frequency and prognostic impact of ACAs appearing during the treatment after achieving cytogenetic response. Patients and Methods A total of 524 patients with CML were evaluated with a median age at diagnosis of 48 years (range 15 to 86). These included 236 patients treated with imatinib, 125 with nilotinib, 118 with dasatinib and 45 with ponatinib. All the patients were treated in clinical trials approved by the institutional board review and signed an informed consent in accordance with institutional guidelines and in accordance with the declaration of Helsenki. Conventional cytogenetic analysis was done in bone marrow cells using standard G-banding technique at baseline, every 3 months during the first year, then every 6-12 months. Clonal ACAs were identified as abnormalities present in ≥2/20 metaphases or, if only one metaphase, present in ≥2 consecutive assessments. Results After a median follow-up of 83.8 months (range 0.3-176.6 months) 13% (72/524) patients had ACAs, of which 7% (41/524) were clonal. ACAs were seen in 11% (27/236) of patients on imatinib compared to 11% (13/118, p=0.9) on dasatinib, 19 % (24/125, p= 0.04) on nilotinib, and 17% (8/45, p=0.2) on ponatinib. Six patients had both clonal evolution (CE) and ACAs at different times. The median number of metaphases containing ACAs was 5/20 (range 1 to 20) with an average of 7/20. Most appeared within the first year of the start of the TKI (median 6 months, range 3-72 months); they first appeared after 12 months of therapy in 21 of the 72 (29%) patients. ACAs were transient and were detected in 2 or less time points in 52 of the 72 (72%) cases. The most common clonal ACAs were - Y (13/41) and +8 (4/41). The rates of cytogenetic and molecular responses were similar for patients with and without clonal ACAs (CCyR: 88% vs 91%; p=0.55) (MMR: 78% vs 86%, p=0.20). Having clonal ACAs did not affect the rate of deep molecular response either (MR4.5 71% vs 67%; p =0.65). There was no significant difference in EFS and OS (5y EFS 73% vs 86%; p=0.19) (5y OS 77% vs 93%; p=0.06) although there was a trend for lower rates for both. Responses and clinical outcomes were similar between different TKIs for patients with and without clonal ACAs. One patient with -7 treated with ponatinib developed MDS. Monosomy 7 appeared 9 months from the start of treatment in 9/20 metaphases and persisted. He was taken off ponatinib because of pancytopenia. He subsequently received bosutinib, achieved and maintained a CCyR. A high-risk MDS was documented approximately 1 year after appearance of the -7 clone. He was started on decitabine and achieved a partial cytogenetic response for MDS. Another patient in the imatinib cohort with -7 developed secondary AML (CCyR for CML) and died from a multiple organ failure after allogeneic stem cell transplant from a one antigen-mismatched unrelated donor. There was a third patient with -7 that later had CE and developed Ph+ CML blast phase. Conclusion ACAs are rare and mostly transient events that appear during the treatment of CML with TKIs. These changes do not affect responses or clinical outcomes, independent of what TKI is used. A small subset of patients with -7 may develop AML or MDS warranting close monitoring of patients with changes that are reminiscent of those diseases. Molecular analysis after appearance of ACAs could help identify mutations driving the Ph-clone into AML or MDS. Disclosures Pemmaraju: Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Cortes:BerGenBio AS: Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Teva: Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy.

Download Full-text

Chromosomal abnormalities in Philadelphia chromosome–negative metaphases appearing during imatinib mesylate therapy in patients with newly diagnosed chronic myeloid leukemia in chronic phase

Blood ◽

10.1182/blood-2007-01-070045 ◽

2007 ◽

Vol 110 (8) ◽

pp. 2991-2995 ◽

Cited By ~ 102

Author(s):

Elias Jabbour ◽

Hagop M. Kantarjian ◽

Lynne V. Abruzzo ◽

Susan O'Brien ◽

Guillermo Garcia-Manero ◽

...

Keyword(s):

Myeloid Leukemia ◽

Progressive Disease ◽

Chromosomal Abnormalities ◽

Philadelphia Chromosome ◽

Young Patients ◽

Chronic Phase ◽

Cytogenetic Response ◽

High Dose ◽

Newly Diagnosed

Abstract The development of chromosomal abnormalities (CAs) in the Philadelphia chromosome (Ph)–negative metaphases during imatinib (IM) therapy in patients with newly diagnosed chronic myecloid leukemia (CML) has been reported only anecdotally. We assessed the frequency and significance of this phenomenon among 258 patients with newly diagnosed CML in chronic phase receiving IM. After a median follow-up of 37 months, 21 (9%) patients developed 23 CAs in Ph-negative cells; excluding −Y, this incidence was 5%. Sixteen (70%) of all CAs were observed in 2 or more metaphases. The median time from start of IM to the appearance of CAs was 18 months. The most common CAs were −Y and + 8 in 9 and 3 patients, respectively. CAs were less frequent in young patients (P = .02) and those treated with high-dose IM (P = .03). In all but 3 patients, CAs were transient and disappeared after a median of 5 months. One patient developed acute myeloid leukemia (associated with − 7). At last follow-up, 3 patients died from transplantation-related complications, myocardial infarction, and progressive disease and 2 lost cytogenetic response. CAs occur in Ph-negative cells in a small percentage of patients with newly diagnosed CML treated with IM. In rare instances, these could reflect the emergence of a new malignant clone.

Download Full-text

Genetic Response to Lenalidomide in the Circulating Progenitor Cell Compartment of MDS Cohort. Preliminary Results of the Multicenter German LE-MON-5 Study

Blood ◽

10.1182/blood.v118.21.1721.1721 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1721-1721

Author(s):

Katayoon Shirneshan ◽

Ulrich Germing ◽

Friederike Braulke ◽

Julie Schanz ◽

Uwe Platzbecker ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Cytogenetic Response ◽

Response To Therapy ◽

Fish Analysis ◽

Trisomy 8 ◽

Advisory Committees ◽

Clone Size ◽

Observation Period

Abstract Abstract 1721 Introduction: LE-MON-5 is a multicenter German phase-II study to verify the safety of monotherapy with lenalidomide (LEN) in MDS patients (pts) with IPSS low or Int-1 and isolated del(5q). We report our cytogenetic results after a monitoring period of sixteen months since start of the trial. Methods: For sequential and frequent survey of LEN-treated pts we applied FISH on enriched CD34+ stem cells from peripheral blood (CD34+ pb) every 2–3 months using a panel of 8 to 13 probes. Karyotyping and FISH on bone marrow aspirates was performed at initial screening and every six months. The median number of analyzed metaphases was 25 (4–30) and FISH analyzing was based on 200 interphase nuclei. Results: We have already screened 94 pts and could confirm isolated del(5q) in 76 (81%). Due to our cytogenetic results demonstrating additional changes in 18/94 (19%) pts, these were registered as screening failures and thus excluded from the study. Until now cytogenetic follow-up data for 40 pts is available. After a median follow-up of 9 months (2–16 months) we have observed a significant impact of LEN on the reduction of the clone size (p < 0.05) by FISH-monitoring. Based on cytogenetic remission, we have separated the cohort into three groups: Fast responders (14/40 (35%) pts) showed a very rapid cytogenetic response to therapy with >50% reduction of 5q- clone size within two months. In the second group, the slow responders, we observed >50% reduction of clone size in 9/40 (22.5%) after > two months. However, two pts showed an increase of 5q- clone after 12 and 13 months respectively after initial response in the sense of a relapse. In the third group, the non responders, (11/34 (27.5%)) we could not observe any cytogenetic response during the as yet limited observation period. In six cases (15%) we detected a reduction of the 5q- clone during follow-up, but the emergence of additional aberrations were also observed such as: 1. trisomy 8 in 6.7% of metaphases after 8 months and is reduced to 3.6% after 12 months, 2. trisomy 4 in 6.7% of metaphases after 6 months and is disappeared after 12 months, followed by emergence of trisomy 8 in 8% of interphase cells, 3. finally, two cases showed loss of Y-chromosome after 4 months in 6% and 19% of CD34+ pb cells, respectively. In CD34+ pb cells of another case, trisomy 8 was detectable after two months in 3.5% of cells. All these new secondary abnormalities occurred in cells with normal chromosomes 5 and were slightly above or below our laboratory thresholds (3 times standard variation). In only one case, a new abnormality emerged in the 5q- clone: In this case additional del(20q) occurred after 2 months in 46% of CD34+ pb cells. In this case no reduction of 5q- cells after 4 months of treatment was observed. However, FISH analysis after 6 months of treatment showed a 14% reduction for both aberrations. To date we could not identify any pts who acquired complex anomalies while treated with LEN. Conclusion: FISH analysis of CD34+ pb cells allows a reliable frequent and relevant genetic monitoring of treatment response to LEN. Our results confirm the positive and rapid effects of LEN on clones with del(5q): Thus, already after 2 months, we could observe up to 90% reduction in the 5q- clone size in 35% of pts. In general, remission rates increased with duration of therapy. We suspect that trisomy 4, 8 and Y-loss are fluctuant “mini clones” without any clinical relevance. Inclusion of additional pts and prolonged observation period will help us to better evaluate the clinical response to LEN. Disclosures: Off Label Use: lenalidomide for MDS del(5q) provided by Celgene for this clinical study. Germing:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Braulke:Celgene: Honoraria, Research Funding. Schanz:Celgene: Honoraria, Research Funding. Giagounidis:Celgene: Honoraria. Götze:Celgene: Honoraria. Haase:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Download Full-text

The patient's BCR-ABL1 Kinase Domain Mutation History Is Important for Decisions Regarding Tyrosine Kinase Inhibitor Therapy

Blood ◽

10.1182/blood.v120.21.1692.1692 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1692-1692

Author(s):

Wendy T Parker ◽

Alexandra L Yeoman ◽

Bronte A Jamison ◽

David T Yeung ◽

Hamish S Scott ◽

...

Keyword(s):

Mutation Analysis ◽

Research Funding ◽

Direct Sequencing ◽

Cytogenetic Response ◽

Kinase Domain ◽

Cell Transplant ◽

Hematopoietic Cell Transplant ◽

Advisory Committees ◽

Imatinib Resistant

Abstract Abstract 1692 Introduction. BCR-ABL1 kinase domain mutations are the most common known cause of resistance to tyrosine kinase inhibitors (TKIs) in CML. Some imatinib resistant mutations also confer resistance to second generation TKIs nilotinib and/or dasatinib. Therefore, it is recommended that mutation analysis be performed before changing therapy. However, BCR-ABL1 mutant clones are often de-selected upon TKI cessation or change of therapy, and may become undetectable (Hanfstein et al, Haematologica 2011). It is not known whether treatment discontinuation or long term alternative TKI therapy leads to eradication of these mutant clones. If mutant clones persist at sub-clonal levels they have the potential to be re-selected and expand clonally given favorable conditions, such as change to a TKI for which they confer resistance. We examined longitudinal data of patients with imatinib resistant mutations that became undetectable by direct sequencing to determine whether these “long dormant” mutations could reappear, and the circumstances related to reappearance. Method. All chronic phase patients who had been monitored at our institution since starting imatinib, and had mutations detectable by sequencing during imatinib therapy were analyzed; 49 patients, median follow up since starting imatinib was 4.3 years (range 0.6–11.6 years). Sensitive mutation analysis using mass spectrometry (detection limit 0.2% mutant) was performed at selected times when the mutations became undetectable by direct sequencing (detection limit 10–20%). Results. Of the 49 patients with mutations detected by sequencing during imatinib therapy, mutations became undetectable by sequencing in 21 patients (29 mutations), at a median of 2 months after changing therapy (range 1–20 months). This was associated with increased imatinib dose (3 mutations), stopping imatinib (2), hematopoietic cell transplant (6), chemotherapy (1), switching to nilotinib (3), or switching to dasatinib (14). All mutations that became undetectable by sequencing when the patient switched to nilotinib or dasatinib were those known to be sensitive to the inhibitor received (e.g. F359V in a patient treated with dasatinib). In 16 of the 21 patients whose mutations became undetectable by direct sequencing, the mutations have not been detected again with 0.1 to 6.9 years of follow up since the mutations were last detected (median 1.1 years). Of these 16 patients, 15 maintained a stable complete cytogenetic response and 1 lost a major cytogenetic response. In the other 5 patients, the same mutations as those originally detected (identical nucleotide exchange) became detectable by sequencing between 1.7 and 5.4 years after last detection (median 4.4 years), Figure. The original mutations in 4 of these patients confer resistance to nilotinib as well as imatinib (Y253H and F359V), and their reappearance was associated with initiation of nilotinib therapy, Figure. Three of these 4 patients died of their disease, and 1 lost a major cytogenetic response. Sensitive mutation analysis could detect the mutation in 1 of these patients during the time of “dormancy” and before nilotinib therapy. The 5th patient received an autologous hematopoietic cell transplant upon detection of F359V, and the mutation became undetectable by sequencing. The patient subsequently received dasatinib for 3 years and the mutation remained undetectable. Dasatinib therapy was stopped due to intolerance and F359V rapidly reappeared while the patient was off TKI therapy, having been undetectable for 4.8 years. Using sensitive mutation analysis, F359V could be detected at low levels after the transplant, suggesting that the mutant clone had not been eradicated. Conclusion. The data suggest that some BCR-ABL1 mutations may persist at sub-clonal levels for many years after changing therapy. This could lead to clonal expansion under the selective pressure of a TKI for which the mutation confers insensitivity. Alternatively, the reappearance of the mutation could be a new occurrence of the same mutation. The study highlights the importance of knowing the mutation history of individual patients to enable informed therapy choices. Disclosures: Yeung: Novartis Pharmaceuticals: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Hughes:Ariad: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Branford:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cepheid: Consultancy.

Download Full-text

Discontinuation of Tyrosine Kinase Inhibitors (TKIs) in Philadelphia Chromosome-Positive (Ph+) Acute Lymphoblastic Leukemia (ALL)

Blood ◽

10.1182/blood-2019-127499 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3819-3819 ◽

Cited By ~ 2

Author(s):

Bachar Samra ◽

Hagop M. Kantarjian ◽

Koji Sasaki ◽

Marina Y Konopleva ◽

Rita Khouri ◽

...

Keyword(s):

Board Of Directors ◽

Median Duration ◽

Research Funding ◽

Kinase Inhibitors ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

Cell Transplant ◽

Advisory Committees ◽

Tki Discontinuation

Background: Treatment of Ph+ ALL has significantly improved since the addition of TKIs to chemotherapy, with improvement in complete molecular remission (CMR) and overall survival (OS) rates. However, the optimal duration of TKI is not yet established and the common practice is to continue indefinitely unless allogeneic stem cell transplant (ASCT) is performed. In pediatric setting, when TKIs were discontinued after 2 years of maintenance, high rates of relapse were seen, fortunately salvaged with ASCT and other approaches (Slayton WB et al; JCO. 2018 and Schultz KR; Leukemia 2014). In chronic myeloid leukemia, patients (pts) who achieve deep and sustained molecular remissions on TKI may be able to stop therapy successfully. Herein, we reviewed outcome of pts with Ph+ ALL treated with chemotherapy + TKI without ASCT who later discontinued TKI mainly due to adverse events. Methods: We reviewed 240 pts treated at our institution on sequential protocols with Hyper-CVAD chemotherapy + TKI (dasatinib [n=100], ponatinib [n=84], or imatinib [n=56]) between 2001 and 2019. We identified 9 pts (4%) in whom TKI was discontinued, 4 (44.5%) post dasatinib therapy, 4 (44.5%) post imatinib therapy, and 1 (11%) post ponatinib. We analyzed their characteristics and outcomes including molecular relapse rates and treatment-free remission (TFR). Pts were closely monitored with monthly PCR for the first 3 months, then every other month for 3 months, then every 3 months thereafter. Molecular relapse was defined as the loss of MMR (PCR>0.1%) or positivity of PCR at two assessments within a 2-week period. TKI was resumed upon molecular relapse. TFR was defined from the date of TKI discontinuation to molecular relapse or last-follow-up. Kaplan-Meier method was used for survival analysis. Results: Baseline characteristics are summarized in table 1. The median follow up from the time of diagnosis was 138 months (range: 40-190). The median age at diagnosis was 60 years (range: 20-80). Transcript type was p190 BCR-ABL1 in 7 pts (78%). Median time to CMR was 3 months (range: 0.4-120). Median duration of TKI therapy prior to discontinuation was 70 months (range: 23-143). Median duration of CMR before TKI stop was 52 months (range: 22-141). Reasons for stopping TKI were side effects in 8/9 pts, and physician's choice in 1 pt (after completing 2+ years of maintenance). At the time of TKI stop, 8 pts were in CMR, and 1 pt with low positive transcript level (0.01%). Median follow-up post TKI discontinuation was 37 months (range: 9-75). None of the pts had morphological relapse. Three pts (33%) had molecular relapse within a median of 6 months (range: 0.8-13.2 months). All 3 resumed TKI therapy: 2 of them regained MMR after a median of 4 months (range: 4.0-4.6 months); third pt continues to respond; the BCR-ABL1 transcripts down from 17.68% to 0.36% after 7 months (Table 2). Six pts remain alive and 3 pts died of disease-unrelated causes. The median TFR was not reached; 3-y TFR was 65% (Figure 1). Though the number of pts was only 9, the duration of CMR had a tendency of successful TFR (P=0.062; HR, 0.09; [95% CI, 0.009-1.119] with duration of CMR for 2 years, and P=0.137; HR, 0.15; [95% CI, 0.01-1.80] with duration of CMR for 3 years, as a binomial variable). The median duration of CMR in pts who relapsed and who did not relapse was 22 months (range, 0-39.9) and 58 months (range, 30.9-140.6), respectively (P= 0.096). Conclusions: Our anecdotal experience reflects the feasibility of stopping TKI in a subset of pts with Ph+ ALL and sustained molecular remissions. Longer follow up and validation of these findings on a larger cohort are highly needed before attempting to discontinue TKI. Disclosures Kantarjian: Astex: Research Funding; Ariad: Research Funding; Jazz Pharma: Research Funding; AbbVie: Honoraria, Research Funding; Cyclacel: Research Funding; Immunogen: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Takeda: Honoraria; Agios: Honoraria, Research Funding; Novartis: Research Funding; Amgen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Konopleva:Ascentage: Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Agios: Research Funding; Ablynx: Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Eli Lilly: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Kisoji: Consultancy, Honoraria; Astra Zeneca: Research Funding; Genentech: Honoraria, Research Funding. O'Brien:Acerta: Research Funding; AbbVie: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Sunesis: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Kite: Research Funding; GlaxoSmithKline: Consultancy; Gilead: Consultancy, Research Funding; Eisai: Consultancy; Celgene: Consultancy; Astellas: Consultancy; Aptose Biosciences, Inc: Consultancy; Amgen: Consultancy; Alexion: Consultancy; TG Therapeutics: Consultancy, Research Funding; Vaniam Group LLC: Consultancy; Verastem: Consultancy; Regeneron: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding. Kadia:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. Jabbour:Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding.

Download Full-text