Ponatinib Treatment in CML and Ph+ ALL Patients: Real-Life Data from the Czech Registries

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5905-5905
Author(s):  
Eva Koriťáková ◽  
Michael Doubek ◽  
Edgar Faber ◽  
Daniela Žáčková ◽  
Jan M. Horáček ◽  
...  
Keyword(s):  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Significant Proportion ◽  
Real Life ◽  
Chronic Phase ◽  
Clinical Activity ◽  
Real World Data ◽  
Abl Kinase ◽  
Number Of Patients ◽  
One Year

Patients with newly diagnosed chronic myeloid leukemia (CML) frequently receive imatinib. Although initial response rates are high, imatinib fails in up to 40% of patients because of disease resistance, frequently because of BCR-ABL kinase domain mutations, or side effects. Patients who discontinue imatinib may have a response to second-generation tyrosine kinase inhibitors (TKIs). Ponatinib (PON) is a potent oral TKI active against unmutated and mutated BCR-ABL kinase. PON is indicated also in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) patients. Clinical activity of PON was confirmed in the phase II PACE trial, however lack of real world data is evident. The aim of this non-interventional study was to analyze data on PON treatment and its efficacy in the Czech patients with CML / Ph+ ALL. The study was designed as a one-off retrospective data collection from 3 national registry databases INFINITY, CAMELIA and DATOOL ALL in the period 2014-2018. In total, the study comprised 27 patients treated with PON at 7 centers; 16 (59.3%) patients were treated for chronic phase (CP) CML, 4 (14.8%) patients for accelerated- or blast-phase (AP/BP) CML and 7 (25.9%) patients for Ph+ ALL. The 16 CP CML patients (68.8% males) had median age at the start of PON treatment 59.7 years (range 28.6-81.4), were heavily pretreated (75% with ≥ 3 TKIs) with median time from diagnosis to start of PON treatment 4.8 (0.2-16.8) years; 37.5% of them had mutations (18.8% with T315l), 75.0% had comorbidities. The 11 AP/BP CML / Ph+ ALL patients (54.5% males) were younger with median age 56.6 (31.2-74.7) years, were less pretreated (36.4% with ≥ 3 TKIs) with a shorter time from diagnosis to start of PON treatment 2.0 (0.4-22.0) years; almost twice as many (72.7%) of them had mutations (54.5% with T315l), 63.6% had comorbidities. The most common reason for switching to ponatinib was hematologic resistance (37.5% of CP CML and 54.5% of AP/BP CML / Ph+ ALL patients). The other most frequent indications were cytogenetic resistance, non-hematologic and hematologic intolerance (18.8%, 12.5% and 12.5% of CP CML patients and 9.1%, 9.1% and 0% of AP/BP CML / Ph+ ALL patients, respectively). Interestingly, starting dose of PON was 45 mg/day as recommended in the product SmPC only in of about half of the patients (43.8% of CP CML and 54.5% of AP/BP CML / Ph+ ALL patients). Median treatment duration was 16.1 (0.8-49.9) months in CP CML patients and only 2.9 (0.2-36.1) months in AP/BP CML / Ph+ ALL patients. Early (in the first 3 months) and late termination of the treatment occurred in 12.5% and 31.3% of CP CML and 54.5% and 27.3% of AP/BP CML / Ph+ ALL patients, respectively. Disease progression was the major reason for treatment termination (50%). In terms of safety, only 1 patient discontinued therapy due to congestive heart failure, and 1 due to vascular adverse event although more than half of the patients had cardiovascular comorbidities and history of cardiovascular disease. PON efficacy was evaluated in 14 CP CML patients and 5 AP/BP CML / Ph+ ALL who were treated beyond 3 months (Figure 1). More than half of CP CML patients achieved MMR (57.1%) and 40% of AP/BP CML / Ph+ ALL achieved undetectable disease. Estimated percentage of CHR, CCyR and MMR in CP CML patients after one year of treatment was 85.7%, 50% and 50%, respectively. Nevertheless, 5 (35.7%), 2 (14.3%) and 1 (7.1%) patients had CHR, CCyR and MMR at start of PON treatment, respectively. In AP/BP CML / Ph+ ALL patients, estimated percentage of CR and CMR after one year was 100% and 40%, respectively. However, 2 patients (20%) had CR at the start of PON treatment. Despite limited number of patients, our analysis confirmed PON efficacy in real-life setting with a significant proportion of heavily pre-treated patients achieving durable molecular responses in both CP and AP/BP CML / Ph+ ALL groups. Our data are comparable to the PACE trial results. This study partially fills the gap in RWE data and significantly contributes to the evaluation of real-life clinical practice in rare disease area. Figure 1. Cumulative incidence of responses on ponatinib treatment in A) CP CML (N=14) and B) AP/BP CML / Ph+ ALL (N=5) patients that continued ponatinib treatment beyond 3 months. Figure 1 Disclosures Žáčková: Bristol Myers Squibb: Consultancy; Novartis: Consultancy; Angelini: Consultancy; Incyte: Consultancy. Kellnerová:Angelini Pharma: Employment.

Combination of the hyperCVAD Regimen with Dasatinib Is Effective in Patients with Relapsed Philadelphia Chromosome (Ph) Positive Acute Lymphoblastic Leukemia (ALL) and Lymphoid Blast Phase Chronic Meyloid Leukemia (CML-LB)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2919-2919 ◽  
Author(s):  
Elias Jabbour ◽  
Susan O’Brien ◽  
Deborah A. Thomas ◽  
Stefan Faderl ◽  
Charles Asa Koller ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Clinical Activity ◽  
High Dose ◽  
Molecular Response ◽  
Blast Phase ◽  
Median Response ◽  
Platelet Recovery ◽  
Abl Kinase

Abstract The dual Src and Abl inhibitor dasatinib is ~325 times more potent in vitro against BCR-ABL kinase activity and has significant clinical activity in patients with imatinibresistant lymphoid blast phase CML (CML-LB) and Ph+ ALL. In this study, patients with relapsed Ph+ ALL or CML-LB received dasatinib 50 mg po bid (or 100 mg daily) for the first 14 days of each of 8 cycles of alternating hyperCVAD and high dose cytarabine and methotrexate. Patients in CR continued to receive dasatinib 50 mg po bid (or 100 mg daily) and vincristine and prednisone monthly for 2 years followed by dasatinib indefinitely. To date 14 patients with relapsed Ph+ ALL or CML-LB have received a median of 3 cycles (range 1–8); 1 patient in complete remission (CR) is receiving maintenance therapy. Median age was 43 years (range 21–69); 4 (29%) patients were older than 50 years. Median WBC at start of treatment was 6.8 × 109/L (range, 0.4 – 27.2 × 109/L). Median blast percentage was 45% (range 0–96%) Three patients had CNS involvement. Median number of previous therapies was 1 (range, 1–4) including hyperCVAD and imatinib, tyrosine kinase inhibitor monotherapy, investigational agents and transplantation. All patients were evaluable for response. 10 patients (71%) achieved CR and 4 patients (29%) achieved CR with incomplete platelet recovery (CRp). Twelve of 14 (86%) patients achieved a major cytogenetic response, complete in 11, 1 (7%) had insufficient metaphases, and 1 (7%) had no response. Overall, 9 (64%) patients had achieved a major molecular response, complete in 5. Median time to neutrophil and platelet recovery during the first course was 18 and 22 days and 18 and 26 days, respectively after subsequent courses. Four patients relapsed after median response duration of 19 weeks (range, 9–38); two of them had acquired ABL kinase domain mutations: One patient lost his baseline mutation, Y253H, and acquired T315I and E450G; the second lost his 3 baseline mutations, Y253H, F359V, and E459K, and acquired T315I.Two patients received an allogeneic transplantation and one patient received a donor lymphocyte infusion. Grade 3 and 4 toxicities included 7 episodes of bleeding (4 GI, 1 GU, and 2 subdural hematomas), 4 episodes of pleural effusions, 2 episodes of pericardial effusions, infections, diarrhea, hypophosphatemia, hypocalcemia, elevated transaminases, and hyperbilirubinemia. With a median follow up of 6 months (range, 1–13 months), 9 patients are alive; 7 in CR/CRp. Two patients died after disease relapse, 1 died post transplant and 2 died in CR/CRp from infections. In conclusion, the hyperCVAD regimen with dasatinib is feasible and effective in patients with relapsed Phpositive ALL and CML-LB.

Imatinib Resistance and/or Intolerance in Clinical Practice in Europe: The “Unmet Needs in CML and Ph+ALL” (UNIC) Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1951-1951 ◽  
Author(s):  
Mauricette Michallet ◽  
Enrica Morra ◽  
Juan Steegmann ◽  
David Marin Costa ◽  
Gert Ossenkoppele ◽  
...  
Keyword(s):  
Chart Review ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Unmet Need ◽  
Chronic Phase ◽  
Medical Chart ◽  
Imatinib Therapy ◽  
Cross Sectional ◽  
Imatinib Resistance ◽  
Number Of Patients

Abstract Imatinib is widely used for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL), and is associated with improved response rates in these patients. However, the management of patients who show resistance or intolerance to imatinib has been identified as an unmet need. The UNIC study aimed to quantify this unmet need. UNIC is a cross-sectional study, with retrospective chart review of patients currently treated for CML or Ph+ALL in Austria, Belgium, France, Italy, Netherlands, Spain, Sweden and UK. Patients were recruited September 2006-March 2007. The study was designed to estimate the proportion of patients ever treated with imatinib and imatinib-treated patients who have experienced imatinib resistance and/or intolerance (primary objectives). A registry was collected of potentially-eligible patients - those aged ≥18 years and treated for CML/Ph+ALL at the participating centers (academic, non-academic, private clinic or other). Case Report Forms (CRFs) were completed for patients who met the inclusion criteria, until the recruitment target was reached. Data were collected at the most recent visit and retrospectively through clinical chart review. Of the 4139 patients in the registry, CRFs were completed for 1716 and analyzable for 1599 (CML, n=1551; Ph+ALL, n=48). Characteristics of the included population were representative of those of the registry. Of the included CML patients, 98% were in chronic phase and 2% were in advanced phases. In total, 1493 (96%) CML and 46 (96%) Ph+ALL patients had received imatinib. By the last observation, 48% of all imatinib-treated patients needed a change in imatinib dose, and >20% discontinued imatinib therapy (CML, 21%; Ph+ALL, 37%). A patient was defined as imatinib resistant if reported as such by the physician in the medical chart, and intolerant to imatinib (or other concurrent treatment) if toxicity led to a change in imatinib use, as reported in the medical chart. Imatinib resistance and treatment intolerance reported during the study are shown in the table. Seven percent of CML and Ph+ALL patients discontinued imatinib due to toxicity. Number (%) of patients [95% confidence interval] according to the physician assessment CML (N=1493) Ph+ALL (N=46) Resistant to imatinib 241 (16.1) [14.3; 18.1] 6 (13.0) [4.9; 26.3] Intolerant to treatment 583 (39.0) [36.6; 41.6] 17 (37.0) [23.2; 52.5] Resistant to imatinib and/or intolerant to treatment 688 (46.1) [43.5; 48.6] 20 (43.5) [28.9; 58.9] Resistant to imatinib and intolerant to treatment 136 (9.1) [7.7; 10.7] 3 (6.5) [1.4; 17.9] This is the largest European observational study of CML/Ph+ALL patients to date. As expected, nearly all patients were exposed to imatinib therapy. Nearly half of all imatinib-treated CML and Ph+ALL patients experienced resistance to imatinib and/or intolerance to treatment including imatinib.

Philadelphia Chromosome-Positive Leukemia Patients Who Harbor Imatinib-Resistant Mutations Have a Higher Likelihood of Developing Additional Mutations Associated with Resistance to Novel Tyrosine Kinase Inhibitors.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 322-322 ◽  
Author(s):  
Simona Soverini ◽  
Alessandra Gnani ◽  
Sabrina Colarossi ◽  
Fausto Castagnetti ◽  
Francesca Palandri ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Median Time ◽  
Kinase Inhibitor ◽  
Selective Pressure ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Abl Kinase ◽  
Time To Relapse

Abstract Resistance to the Bcr-Abl tyrosine kinase inhibitor (TKI) imatinib mesylate (IM) in patients (pts) with chronic myeloid leukemia (CML) and Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) is often caused by selection of point mutations in the Abl kinase domain (KD) altering residues that are directly or indirectly critical for IM binding. Several novel TKIs are now available for IM-resistant pts. In vitro studies have postulated that each of them is likely to retain its own distinct set of insensitive mutations, including novel inhibitor-specific mutations. To assess how Abl KD sequences evolve under the selective pressure of sequential therapy with one or more novel TKIs, we have monitored the mutation status of 101 IM-resistant pts before and during treatment with up to three consecutive novel TKIs (dasatinib, nilotinib, bosutinib). Forty-seven pts had CML in chronic phase; 54 pts had CML in accelerated/blastic phase (AP/BP) or Ph+ ALL. Overall, presence or emergence of TKI-resistant mutations accounted for 90% of cases of dasatinib, nilotinib or bosutinib failure. At the time of IM failure, 55/101 (54%) pts had KD mutations. After switching to a 2nd TKI (n=101 pts), 21/55 (38%) pts who had mutations at baseline as against 8/46 (17%; p=.02) pts who did not have mutations at baseline subsequently relapsed with newly acquired mutations. Median time to relapse was 8 months (range, 3-18). Cloning showed that these mutations could either be acquired by the pre-existing mutated subclone or arise in an independent one. In addition, 15/55 mutated pts did not respond to the 2nd TKI because of the mutation they were harboring at baseline. After switching to a 3rd TKI (n=20 pts), 11/16 mutated pts as against 0/4 non-mutated pts relapsed with newly acquired mutations. Median time to relapse was 3 months (range, 1–5). Switch to a 4th TKI has so far been attempted in 3 mutated pts, but observation time is still too short. Dasatinib failure was associated with the following mutations: T315I, F317L, V299L, T315A, F317I/S/V. Nilotinib failure was associated with the following mutations: Y253H, E255V, T315I, F359C. Bosutinib failure was associated with the following mutations: E255K, T315I, V299L. More detailed analyses will be presented. In summary, the Bcr-Abl kinase is a moving target and pts already harboring mutations, especially those with CML in AP/BP or with Ph+ ALL, have a higher likelihood of developing further mutations under the selective pressure of novel TKIs. It can be hypothesized that in these pts a higher genetic instability may foster rapid emergence of multiple mutations over time within the same or different Bcr-Abl-positive subclones, which are selected or de-selected depending on the sensitivity profile of the specific TKI employed. In this clinical setting combination therapies would probably be more effective than single-agent treatment for long-term disease control. Supported by European LeukemiaNet, AIL, FIRB, COFIN, Fondazione del Monte di Bologna e Ravenna.

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.

scholarly journals Clinical response to larotrectinib in adult Philadelphia chromosome–like ALL with cryptic ETV6-NTRK3 rearrangement

2020 ◽  
Vol 4 (1) ◽  
pp. 106-111 ◽  
Author(s):  
Valentina Nardi ◽  
Nora Ku ◽  
Matthew J. Frigault ◽  
Adrian M. Dubuc ◽  
Harrison Kwei Tsai ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Clinical Response ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Clinical Activity ◽  
Aggressive Therapy ◽  
Key Points

Key Points Larotrectinib has clinical activity in adult Ph-like acute lymphoblastic leukemia with ETV6-NTRK3 rearrangements. ETV6-NTRK3 rearrangements can be cryptic and subclonal in Ph-like ALL at diagnosis and selected for with aggressive therapy.

scholarly journals Homozygous deletions of the p16 tumor-suppressor gene are associated with lymphoid transformation of chronic myeloid leukemia

Blood ◽  
1995 ◽  
Vol 85 (8) ◽  
pp. 2013-2016 ◽  
Author(s):  
H Sill ◽  
JM Goldman ◽  
NC Cross
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tumor Suppressor ◽  
Myeloid Leukemia ◽  
Lymphoblastic Leukemia ◽  
Blast Crisis ◽  
Chronic Phase ◽  
P16 Gene ◽  
Number Of Patients ◽  
Wide Range ◽  
Homozygous Deletions

The p16 gene, also referred to as MTS1, INK4, CDK4I, or CDKN2, at chromosome 9p21 has recently been described as a tumor suppressor that may be involved in a wide range of tumors. We have used a semiquantitative multiplex polymerase chain reaction assay to search for deletions of the p16 gene in 34 patients with chronic myeloid leukemia in blast crisis (CML BC), 19 patients with acute lymphoblastic leukemia (ALL), and 25 patients with acute myeloid leukemia (AML). Homozygous deletions of p16 exons were found in 5 of 10 (50%) patients with CML in lymphoid BC and in 5 (26%) ALL patients, but in only 1 (2%) case with AML. No deletions were found in CML BC of nonlymphoid phenotype. Comparison of chronic phase DNA or remission DNA with acute leukemia DNA in 5 individuals showed that the p16 deletions were acquired and not inherited, directly implicating these lesions in the pathogenesis of the disease. We conclude that functional elimination of the p16 gene, or a closely mapping gene, is involved in a significant number of patients with CML in lymphoid transformation.

Pepsi® or Coke®? Influence of acid on dasatinib absorption

2017 ◽  
Vol 24 (2) ◽  
pp. 156-158 ◽  
Author(s):  
Randall W Knoebel ◽  
Richard A Larson
Keyword(s):  
Drug Administration ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Lymphoblastic Leukemia ◽  
Relevant Literature ◽  
Philadelphia Chromosome ◽  
Gastric Ph ◽  
Abl Kinase ◽  
Carbonated Beverage ◽  
Acid Labile

Dasatinib is a second generation ABL kinase inhibitor used in the management of chronic myeloid leukemia or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Dasatinib's bioavailability is highly dependent on gastric pH. When proton-pump inhibitors (PPIs) are co-administered with dasatinib, absorption is significantly reduced. Cola intake at the time of drug administration has been demonstrated to lead to relevant increases in the bioavailability for other acid labile drugs during PPI treatment. This manuscript reviews the relevant literature supporting a strategy of temporarily lowering the gastric pH with a carbonated beverage at the time of drug administration. The use of cola provides an easy to implement way to significantly improve dasatinib bioavailability, especially during concomitant use of a PPI.

scholarly journals Phenotypic heterogeneity of primitive leukemic hematopoietic cells in patients with chronic myeloid leukemia

Blood ◽  
1992 ◽  
Vol 80 (10) ◽  
pp. 2522-2530 ◽  
Author(s):  
C Udomsakdi ◽  
CJ Eaves ◽  
PM Lansdorp ◽  
AC Eaves
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Philadelphia Chromosome ◽  
Significant Proportion ◽  
Hematopoietic Cells ◽  
Chronic Phase ◽  
Leukemic Cells ◽  
Clonogenic Cell ◽  
Clonogenic Cells

Abstract The peripheral blood of chronic myeloid leukemia (CML) patients with chronic-phase disease and elevated white blood cell (WBC) counts typically contains markedly increased numbers of a variety of neoplastic pluripotent and lineage-restricted hematopoietic progenitors. These include cells detected in standard colony assays as well as their more primitive precursors. The latter are referred to as long-term culture-initiating cells (LTC-IC) because of their ability to generate clonogenic cell progeny detectable after a minimum of 5 weeks incubation on competent fibroblast feeder layers. In this study, we have investigated a number of the properties of the LTC-IC and clonogenic cells present in the blood of such CML patients with high WBC counts. This included an analysis of the light scattering properties of these progenitors, as well as their expression of CD34 and HLA-DR, Rhodamine-123 staining, and in vitro sensitivity to 4- hydroperoxycyclophosphamide. In the case of LTC-IC, the production of different types of lineage-restricted and multipotent progeny was also analyzed. Most of the circulating LTC-IC and clonogenic cells in the CML patients studied (on average approximately 70% and approximately 90%, respectively) showed features of proliferating or activated cells. This is in marked contrast to the majority of progenitors in the blood of normal individuals and most of the LTC-IC in normal marrow, all of which exhibit a phenotype expected of quiescent cells. Interestingly, a significant proportion of the circulating clonogenic cells and LTC-IC in the CML samples studied (on average approximately 10% and approximately 30%, respectively) appeared to be phenotypically similar to normal circulating progenitors, although their absolute numbers were indicative of a neoplastic origin. Both phenotypes of circulating CML clonogenic cells and LTC-IC could be obtained at approximately 10% to 20% purity by differential multiparameter sorting. These findings suggest that expansion of the Philadelphia chromosome-positive clone at the level of the earliest types of hematopoietic cells results from the activation of mechanisms that enable some, but not all, signals that block the cycling of normal stem cells to be bypassed or overcome. In addition, they provide strategies for purifying these primitive leukemic cells that should facilitate further analysis of the mechanisms underlying their abnormal proliferative behavior.

A Pilot Study Evaluating the Safety and Efficacy of Imatinib Given Early after Transplant for High-Risk Philadelphia Chromosome-Postive Leukemias.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1095-1095
Author(s):  
Paul A. Carpenter ◽  
David S. Snyder ◽  
Mary E. Flowers ◽  
Jean E. Sanders ◽  
Paul J. Martin ◽  
...  
Keyword(s):  
Pilot Study ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Dose Intensity ◽  
Antigen Expression ◽  
Myelogenous Leukemia ◽  
Imatinib Therapy ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant

Abstract Patients with Ph+ acute lymphoblastic leukemia (ALL) or chronic myelogenous leukemia (CML) in stages other than first chronic phase (CP1) frequently have recurrent malignancy after allogeneic hematopoietic cell transplant (HCT). Imatinib given after HCT for the treatment of hematological relapse has been of limited success in Ph+ALL but may induce more durable remissions in CML. Hypothesis: We postulated that imatinib might be most effective for preventing hematological relapse after myeloablative HCT if given immediately after engraftment to patients without detectable leukemia, or with leukemia that can be detected only at the molecular level. Study design: A pilot study is ongoing to evaluate the safety and preliminary efficacy of imatinib begun early after myeloablative HCT and continued until post-transplant day 365 (D+365). Study participants became eligible to start imatinib (adults 400 mg/day, children 260 mg/m2/day) if the residual marrow leukemia burden at the time of initial engraftment (ANC>500 on 2 consecutive days) did not exceed >1/20 Ph+ metaphases, >1% aberrant antigen expression on blasts by multidimensional flow, or presence of bcr/abl in >5% interphase nuclei by FISH. The primary endpoint of safety was defined by ability to tolerate imatinib (adults ≥200 mg/day, children ≥100 mg/day) for ≥ 6 days/week until D+90. An attempt was made to administer higher daily doses of imatinib after D+90. Patient characteristics: Ten patients with Ph+ALL (8 CR1, 2 CR2) and 6 patients with CML (2 AP, 2 CP2, 2 CP3) have been enrolled; 13/16 had leukemia detected by molecular or cytogenetic methods at the time of transplant. Median age at transplant was 40 y (range 5–62 y). Stem cell sources were cord blood (n=1), marrow (n=4) or G-mobilized peripheral blood (n=11). Donors were unrelated (n=10) or related (n=6). Results: Imatinib therapy began in 15 patients at a median of 29 days (range 24–39 days) after HCT and has been administered for a median of 299 days (range, 33–380 days). The median of average daily doses during this time period was 400 mg/day (range 389 to 510 mg/day) among adults and 304 mg/m2/day for the 2 children. All patients tolerated imatinib at the intended dose intensity within the first 90 days after HCT. Toxicities (NCI CTC v3.0) possibly attributed to imatinib included grade 1–2 nausea (n=3), grade 1 edema (n=3), grade 1–2 anemia (n=2), and grade 3 neutropenia (n=2). Per protocol, one patient with neutropenia received 2 doses of G-CSF at D+75 and continued imatinib without neutropenia. The second patient was not given G-CSF and imatinib was held for 2 weeks from D+160 until the ANC was >2000. All patients are surviving at a median of 333 days after HCT (range, 68–564), and 14/15 patients have no detectable bcr/abl transcripts in the blood or marrow. Seven patients (4 ALL, 3 CML) have completed imatinib therapy and survive at a median of 467 days after HCT (range, 410–564 days) and 6/7 have no detectable bcr/abl transcripts in blood or marrow. One patient (CML-CP3) with cytogenetic relapse at D+118 had a 4th remission after withdrawal of immunosuppression and continued imatinib but developed hematological relapse at D+429. Conclusions: We conclude that imatinib therapy can be safely prescribed early after myeloablative allogeneic HCT at a dose-intensity comparable to that used in general oncology. Preliminary efficacy data are encouraging and worthy of further study.

Monitoring of Phosphorylated CRKL in Imatinib Resistant Patients with BCR-ABL Positive Leukemias Expressing BCR-ABL Mutants Treated with AMN107.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 497-497
Author(s):  
Paul La Rosée ◽  
Susanne Holm-Eriksen ◽  
Thomas Ernst ◽  
Heiko König ◽  
Philipp Erben ◽  
...  
Keyword(s):  
Phase I ◽  
Direct Sequencing ◽  
Lymphoblastic Leukemia ◽  
Significant Proportion ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Complete Suppression ◽  
Molecular Response ◽  
Imatinib Resistance ◽  
Imatinib Resistant

Abstract AMN107 is a new, highly potent and selective BCR-ABL inhibitor currently in clinical development for the treatment of imatinib-resistant chronic myelogenous leukemia (CML) or Philadelphia positive acute lymphoblastic leukemia ALL (Ph+ALL). Pre-clinical testing has revealed AMN107 to inhibit all but one (T315I) BCR-ABL mutants which have been associated with imatinib resistance. We sought to determine the pharmacodynamic activity of AMN107 by measuring the proportion of phosphorylated CrkL (CrkL-P) as a surrogate of BCR-ABL activity in vivo. Assay validation revealed a CV-value of 13%, which was defined as cut-off value for significant modulation of the Crkl-P/CrkL ratio. A total of 34 patients (median age 61 years, range 35–80) diagnosed with imatinib resistant Ph+ ALL (n=10), CML in chronic phase (n=1), accelerated phase (n=13), myeloid (n=7), or lymphoid blast crisis (n=3) were investigated in a phase I study permitting individual dose escalation (50–1200 mg/day). Proportion of CrkL-P (Crkl-P/total Crkl) was determined by Western blot, ratio BCR-ABL/ABL by quantitative RT-PCR, and mutation status by direct sequencing in 73 peripheral blood or bone marrow samples from baseline and during treatment with AMN107. Median follow up was 89 days (range 13–386). Patients expressed e1a2 (n=7), b2a2 (n=12), b3a2 (n=14), and b2a2&b3a2 (n=1) BCR-ABL transcripts. At baseline, 18 pts exhibited BCR-ABL mutations (P-loop, n=4; T315I, n=3; others, n=11), in 4 pts two different mutations were found in parallel. Prior to treatment with AMN107, the median proportion of CrkL-P indicating BCR-ABL activity was 47% (range 0–69%). Significant reductions of the proportion of CrkL-P were observed from a dose level of 200 mg AMN107/day. CRKL-P (0%) became undetectable during treatment with AMN107 indicating complete suppression of BCR-ABL in 16 pts starting at AMN107 dose levels of 200 (n=1), 400 (n=2), 600 (n=4), 800 (n=8) or 1200 mg/d (n=1). At baseline, patients had unmutated BCR-ABL (n=8), M244V, Y253H, E255K, T315I, M351T, L384M/H396P, A217V/F311L, L324Q/A350V (n=1 each). Undetectability of CrkL-P, correlated with a good molecular response (ratio BCR-ABL/ABL <2%) in 3 pts. We conclude that a minimum of 200 mg of AMN107 is required to induce effective BCR-ABL inhibition in patients. Effectively repressed CrkL phosphorylation in patients lacking molecular response indicates multifactorial resistance mechanisms. Even in patients with BCR-ABL mutations, BCR-ABL may be inactive suggesting alternative signaling pathways that stimulate proliferation. However, treatment with AMN107 is associated with a reduction of the proportion of CrkL-P indicating suppression of BCR-ABL activity in a significant proportion of patients after imatinib resistance. The CrkL phosphorylation status may help to determine alternative treatment strategies including dose optimization in phase I studies.

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