Use of TKIs in the management of patients with Ph+ALL: 2nd search results
SEARCH DATE:
January 9, 2009
SUBJECT:
Use of TKIs in the management of patients with Ph+ALL
RESOURCES:
Grey literature search: American Society of Clinical Oncology (ASCO), Centre for International Blood and Marrow Transplant Research (IBMTR),
European Group for Blood and Marrow Transplantation (EBMT), European School of Haematology (ESH), American Society for Blood and Marrow
Transplantation (ASBMT), European Leukemia Net, European Hematology Association/ European Society of Hematology, Canadian Blood and
Marrow Transplant Group.
1. Outcome after frontline therapy with the hyper-CVAD and imatinib mesylate regimen for adults with de novo or minimally treated Philadelphia (Ph) positive
acute lymphoblastic leukemia (ALL). J Clin Oncol 26: 2008 (May 20 suppl; abstr 7019). D. A. Thomas, H. M. Kantarjian, J. E. Cortes, F. Ravandi, S. Faderl,
D. Jones, L. Letvak, R. E. Champlin, S. M. O'Brien
Abstract - No. 7019 2008 ASCO Annual Meeting - Category: Leukemia, Myelodysplasia, and Transplantation - Leukemia
Abstract: Background: Historically, complete remission (CR) rates with hyper-CVAD in de novo adult Ph-ALL were 90% or better; disease recurrence
remained problematic. The selective ABL tyrosine kinase inhibitor (TKI) imatinib was thus incorporated into hyper-CVAD for de novo or minimally treated PhALL. Methods: The final regimen included imatinib 600 mg days 1-14 of induction, 600 mg continuously with courses 2-8, 800 mg during 2 yrs of
maintenance therapy interrupted by intensifications, followed by imatinib indefinitely. Allogeneic stem cell transplant (SCT) was performed in first CR as
feasible. The study accrued from April 2001 to September 2006. Fifty-four pts with imatinib-naive de novo or minimally treated Ph-ALL were treated: 6 were
refractory to 1 induction course and 9 were in CR at start. Median age was 51 yrs (17-84); 52% were male, and 13% had CNS disease. Results: 42 of 45 pts
(93%) with active disease achieved CR (1 CRp, 1 PR, 1 early death). All 6 refractory pts achieved CR. Molecular CR rate (MCR, confirmed by nested PCR)
was 52% overall. Outcome was similar for achievement MCR vs no MCR (prior to SCT) with 3-yr disease-free (DFS) and overall survival (OS) rates of 80%
vs 60% and 62% vs 50%, respectively (p=NS). Sixteen pts (33%) underwent allogeneic SCT in first CR a median of 5 mos from start of therapy (1-13). In the
de novo group, 14 pts with median age 37 yrs had SCT whereas 33 pts with median age 53 yrs did not. 2-yr OS rates were 70% vs 58%, respectively
(p=0.09), with 4 deaths in CR (2 infection, 2 GVHD) after SCT versus 10 deaths in CR (7 infection, 1 pancreatitis, 1 CNS hemorrhage, 1 unknown) after
chemotherapy. With median follow-up of 4 yrs (13-74 mos), 22% pts relapsed within median of 15 mos (8-42), including 2 after SCT without imatinib
maintenance. In the de novo group, 3 of 8 evaluable relapses had non-T315I ABL kinase domain mutations. The addition of imatinib improved outcome
compared with hyper-CVAD alone (irrespective of SCT); overall 3-yr DFS and OS rates were 62% vs 14% and 55% vs 15%, respectively, p<0.001.
Conclusions: Incorporation of second generation TKIs into the hyper-CVAD regimen may further improve on the favorable imatinib experience.
2. A phase I study of INNO-406, a dual inhibitor of Abl and Lyn kinases, in adult patients with Philadelphia chromosome positive (Ph+) chronic myelogenous
leukemia (CML) or acute lymphocytic leukemia (ALL) relapsed, refractory, or intolerant of imatinib. A. R. Craig
Abstract - No. 7046 2007 ASCO Annual Meeting - Category: Leukemia, Myelodysplasia and Transplantation - Leukemia
ournal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 7046 Author(s): A. R. Craig, H. M.
Kantarjian, J. E. Cortes, D. Jones, A. Hochhaus, S. O'Brien, M. Rios, C. Zander, L. Gleich, E. P. Carroll, O. G. Ottmann
Abstract: Background: INNO-406 is an orally available, dual Abl/Lyn kinase inhibitor that is up to 55-times more potent than imatinib in Bcr-Abl cell lines.
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Use of TKIs in the management of patients with Ph+ALL: 2nd search results
Numerous Bcr-Abl mutant proteins (not T315I) are sensitive to INNO-406 in vitro. INNO-406 demonstrates specific Src kinase activity against Lyn kinase.
Methods: In this phase I study, patients with imatinib-resistant or intolerant Philadelphia (Ph+) chromosome- positive leukemias were eligible for treatment
with INNO-406 once a day, orally. Results: 14 pts [median age: 58 yrs (range 18-74); 7 male, 7 female; median CML duration: 53 mo. (range 14-266); and
median time on imatinib 45 months (range 12-129); chronic phase CML (8 pts), accelerated phase CML (2 pts), blast phase CML (1 pt), Ph+ ALL (3 pts);
previous treatment with nilotinib (5 pts), dasatinib (6 pts)] have been enrolled in the following dose cohorts (mg/day): 30 (3 pts), 60 (3), 120 (6) and 240 mg
(2), and have been on treatment between 7 and 123 days. 3 pts remain on study; 10 pts discontinued with disease progression [data unmonitored]. 6 patients
who have completed >1 month of treatment, 3 have evidence of clinical response. Patient 5, a chronic phase CML treated with imatinib for 69 mo. before
developing resistant disease with an Y253H mutation, had a minimal cytogenetic response after 1 month of INNO-406 therapy. Patient 4, an accelerated
phase CML treated with imatinib and nilotinib for 16 and 6 mo., respectively, before becoming intolerant to nilotinib due to thrombocytopenia, has maintained
a complete hematologic response following 4.5 months of INNO-406 therapy at a dose of 120 mg/day. Patient 1, a chronic phase CML treated with imatinib
for 51 mo. before developing resistant disease without a mutation, has maintained stable white cell counts after 4 months of therapy at a dose of 30-60
mg/day, with a 55-fold reduction in Bcr-Abl transcript levels after 1 month of INNO-406 therapy. Conclusions: INNO-406 is well tolerated in patients at a dose
of 240 mg/day, with encouraging evidence of clinical activity in imatinib-resistant and nilotinib-intolerant patients. In the absence of dose limiting toxicity, dose
escalation continues.
3.Sequential imatinib and chemotherapy yield reverse-transcriptase polymerase chain reaction (RT-PCR)-negative peripheral stem cell collections in
Philadelphia (Ph) chromosome positive acute lymphoblastic leukemia (ALL)--Preliminary results of CALGB 10001. M. Wetzler
Abstract - No. 6549 2006 ASCO Annual Meeting - Category: Leukemia, Myelodysplasia and Transplantation - Leukemia Citation: Journal of Clinical
Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 6549 Author(s): M. Wetzler, W. Stock, K. Owzar,
D. A. Sher, E. E. Hoke, C. A. Linker, C. D. Bloomfield, R. A. Larson
Abstract: Background: Ph+ ALL has a short complete remission duration and survival. Allogeneic stem cell transplantation (SCT) is recommended. We
hypothesized that imatinib plus sequential chemotherapy will result in greater leukemia cell cytoreduction than previously achieved with chemotherapy alone,
allowing collection of large numbers of normal hematopoietic stem cells uncontaminated by residual t(9;22) lymphoblasts and thus reduce the likelihood of
relapse after autologous SCT for patients without donors. Methods: Treatment consisted of a 4-5 drug induction regimen followed by imatinib 400 mg BID for
4 weeks, CNS prophylaxis with high-dose methotrexate, another month of imatinib, and ideally allogeneic SCT following fractionated total body irradiation
(FTBI) and etoposide. Those without donors received high-dose cytarabine, etoposide, and G-CSF for stem cell mobilization, leukapheresis, and autologous
SCT after FTBI, etoposide and cyclophosphamide. Imatinib maintenance continues until RT-PCR negative for 12 months. Patients had to be < 60 years old.
Results: 18 patients have enrolled to date; so far 3 underwent allogeneic SCT and 5 completed peripheral stem cell collections of whom 4 have undergone
autologous SCT. Median stem cell yield was 55.74×10 6/kg (range, 34.8-94.4). Peripheral stem cells were assayed from 3 patients for RT-PCR with a
sensitivity of 1:105-106. All 3 samples were negative for BCR-ABL. Of the 3 patients who underwent allogeneic SCT, 1 failed to engraft and died, 1 died due
to respiratory failure on day 70, and 1 relapsed on day 113. Of the 4 patients who underwent autologous SCT, all achieved neutrophil engraftment (>
0.5×109/L) between days 8-10 and platelet engraftment (> 50×109/L) between days 7-17. Two patients relapsed (simultaneous CNS and marrow) on days
164 and 309, and 2 patients are alive in continuous remission on days +297 and +359 following autologous SCT. Conclusions: Sequential imatinib and
chemotherapy can achieve RT-PCR negativity in Ph+ ALL, allowing autologous SCT. Ongoing accrual will evaluate the efficacy of this approach in adults
with Ph+ ALL.
4.Dasatanib (D) in patients (pts) with chronic myelogenous leukemia (CML) in lymphoid blast crisis (LB-CML) or Philadelphia-chromosome positive acute
lymphoblastic leukemia (Ph+ALL) who are imatinib (IM)-resistant (IM-R) or intolerant (IM-I): The CA180015 'START-L' study. S. Coutre
Abstract - No. 6528 2006 ASCO Annual Meeting - Category: Leukemia, Myelodysplasia and Transplantation - Leukemia Citation: Journal of Clinical
Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 6528 Author(s): S. Coutre, G. Martinelli, H.
Dombret, A. Hochhaus, R. Larson, G. Saglio, A. Gollerkeri, A. Apanovitch, O. G. Ottman
Abstract: Background: Dasatinib (D) (BMS-354825) is a multi-targeted kinase inhibitor of BCR-ABL and SRC. Preliminary data from a phase I study suggest
high efficacy of D in IM pretreated pts. Methods: START L is an open label phase II study of D in IM-R or IM-I pts with LB-CML and Ph+ALL conducted at 42
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Use of TKIs in the management of patients with Ph+ALL: 2nd search results
centers worldwide. D was given orally, 70 mg twice a day (bid), with escalation to 100 mg bid for poor response or reductions to 50 mg and 40 mg bid for
toxicity. Pts had weekly blood counts and monthly bone marrow exams, including cytogenetics. The primary endpoint was confirmed (sustained for at least 4
weeks) major hematologic response (MaHR) rates. Results: From January to June 2005, 101 pts were accrued. Data are available on the first 78 treated pts
(42 LB-CML, 36 Ph+ALL). Of the 42 LB-CML pts, 37 were IM-R, 52% were male with median (med) age of 47 years. Prior therapy included IM >600 mg/day
in 52% and stem-cell transplant (SCT) in 33% of pts. Med baseline platelet (plt) count was 32.5/nl, med BM blasts were 82%, Bcr-Abl mutations were seen in
48%, and extramedullary disease (EMD) was seen in 29% of pts. The D dose was reduced in 14%, temporarily interrupted in 33%, and escalated in 26% of
pts. At 6-months, the MaHR rate was 31% including 26% complete hematologic response (CHR), the MCyR rate was 50%, and 17% of pts remained on
study. Of the 36 Ph+ALL pts, 34 were IM-R, 64% were male with med age 46 years. Prior therapy included IM> 600 mg/day in 47% and SCT in 42% of pts.
Baseline plt count was 53.5/nl, med BM blasts were 69%, Bcr-Abl mutations were seen in 47% and EMD was seen in 31% of pts. The D dose was reduced in
28%, temporarily interrupted in 39%, and escalated in 47% of the pts. At 6-months, the MaHR rate was 42% including 31% CHR, the MCyR rate was 58%,
and 33% pts remained on study. Among all 78 pts, grade 3-4 thrombocytopenia and neutropenia was seen in 82% and 76% of pts, respectively. The most
frequent D-related non-hematologic toxicities were diarrhea (30%), nausea (23%), fatigue (19%), rash (17%) and pleural effusion (13%). Conclusions: D is
active in IM pretreated LB-CML and Ph+ALL pts. Data on all 101 pts will be presented at the meeting.
5. Correlation of Clinical Response to BMS-354825 with BCR-ABL Mutation Status in Imatinib-Resistant Patients with Chronic Myeloid Leukemia (CML) and
Philadelphia Chromosome-Associated Acute Lymphoblastic Leukemia (Ph+ ALL). N. Shah Abstract - No. 6521 2005 ASCO Annual Meeting - Category:
Leukemia, Lymphoma, Myeloma, and Transplantation (Adult) - Leukemia
Citation: Journal of Clinical Oncology, 2005 ASCO Annual Meeting Proceedings. Vol 23, No. 16S, Part I of II (June 1 Supplement), 2005: 6521 Author(s): N.
Shah, C. L. Sawyers, H. M. Kantarjian, N. Donato, J. Nicoll, J. Cortes, R. Paquette, F. Huang, E. Clark, M. Talpaz
Abstract: Background: Relapse of CML on imatinib is most often associated with point mutations in the BCR-ABL kinase domain. BMS-354825 is a novel
ABL kinase inhibitor with ≥ 300-fold greater potency than imatinib and preclinical activity against 14 of 15 imatinib resistant BCR-ABL mutants tested. Unlike
imatinib, BMS-354825 binds the ABL kinase domain in both active and inactive conformations, and is thus predicted to have significant activity in most
imatinib-resistant CML and Ph+ ALL cases. Methods: CA180002 is a phase I, dose-escalation study in CML and Ph+ ALL patients resistant or intolerant to
imatinib. Prior to therapy, peripheral blood samples were collected for mutation analysis for correlation with response. Response was assessed by standard
methods. Sixty-three patients are currently evaluable [chronic phase=36, accelerated phase=8, blast phase/Ph+ ALL=19]. Results: Seventeen different
imatinib-resistant point mutations in the BCR-ABL kinase domain were identified in 67% of patients prior to therapy. Complete hematologic remission has
been observed in patients harboring each of these mutations except T315I (5), F317L (1), and D276G (1). The two patients with F317L and D276G have had
partial responses and remain on study. The T315I mutation is highly resistant to BMS-354825 in experimental systems. Nine patients have gone off study
due to progressive disease. Of these, three had T315I detected prior to treatment and two patients had the T315I mutation at the time of disease
progression. Assessment of BCR-ABL kinase inhibition by analysis of phospho-CRKL in patient samples was correlated with response, and loss of BCR-ABL
kinase inhibition was correlated with relapse. Conclusions: Clinical activity of BMS-354825 in imatinib-resistant CML and Ph+ ALL is observed in patients with
a wide range of imatinib-resistant BCR-ABL kinase domain mutations. The exception to date is T315I, which is cross-resistant to both drugs, as predicted
from preclinical studies. This works demonstrates the utility of molecular assessment of tumor early in the clinical evaluation of a targeted inhibitor.
6. Concurrent combination of high dose imatinib and dose-intensive chemotherapy for patients with newly diagnosed Philadelphia-positive acute
lymphoblastic leukemia: Promising preliminary results of JALSG Ph+ALL202 study. N. Usui
Abstract - No. 6538 2004 ASCO Annual Meeting - Category: Adult Leukemia, Lymphoma and Transplantation - Leukemia Citation: Journal of Clinical
Oncology, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 22, No 14S (July 15 Supplement), 2004: 6538 Author(s): N. Usui, M.
Towatari, M. Yanada, J. Takeuchi, F. Yagasaki, A. Takeshita, I. Sugiura, M. Takeuchi, R. Ohno, Japan Adult Leukemia Study Group; JALSG, Tokyo,
Nagoya,Saitama,Hamamatsu,Okayama, Japan
Abstract: Background: Adult patients with Ph+ALL have an extremely poor outcome. In order to improve outcome of patients with Ph+ALL, a phase II trial of
high-dose imatinib and dose-intensive chemotherapy was conducted in newly diagnosed Ph+ALL. Methods: In induction therapy, oral imatinib 600 mg/day
was given from day 8 for 8 weeks (day 63) with dose-intensive chemotherapy consisting of cyclophosphamide (day 1:i.v. 1200 mg/M2), daunorubicin (days 1-
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Use of TKIs in the management of patients with Ph+ALL: 2nd search results
3:i.v. 60 mg/M2), vincristine(days 1,8,15,22: i.v.1.3 mg/M2), prednisolone(days 1-21:p.o. 60 mg/M2). As consolidation therapy, alternating chemotherapy
course [high dose chemotherapy with methotrexate(MTX) (day 1: i.v.1 g/M2) and cytarabine (Ara-C)(days 2 and 3:i.v. 2 g/M2 /q12h) ] and single
administration of oral imatinib (600 mg/day for 4 weeks) were repeated in a total of 8 courses. Risk-adapted intrathecal prophylaxis (MTX+ Ara-C+
dexamethasone) was given. Patients having either related or unrelated HLA-identical donor were permitted to receive allogeneic stem cell transplantation
(SCT). Results: To date, 23 patients with newly diagnosed Ph+ALL have been treated with this protocol from September 2002 to October 2003. Median age
was 40 years (range15-59) and 48 % were male. Twenty-two out of 23 patients (96%) quickly attained CR and one patient died of pulmonary bleeding on day
9. The prospective monitoring of the minimal residual disease by quantitative (real-time) RT-PCR on Day 28 and Day 63 indicated that 16 out of 20 patients
(80%) examined entered molecular remission (defined as BCR-ABL/GAPDH ratio being < 10-5). Allogeneic SCT was performed for 8 patients in CR. Toxicity
profile was similar to that seen with chemotherapy alone. All CR patients were alive even though 2 patients relapsed during consolidation therapy. Therefore,
failure free and overall survival rates at 6 months were 87% and 96%, respectively. Conclusions: Combination treatment of high-dose imatinib with intensive
chemotherapy might increase not only the rate of CR but also the quality of CR in patients with Ph+ ALL.
7. Results of intensive chemotherapy with hyper-CVAD and imatinib mesylate in Philadelphia (Ph) positive acute lymphocytic leukemia (ALL). D. A. Thomas
Abstract - No. 2366 2003 ASCO Annual Meeting - Category: Hematologic Malignancies - Leukemia, Adult Citation: Proc Am Soc Clin Oncol 22: 2003
(abstr 2366) Author(s): D. A. Thomas, G. Garcia-Manero, J. Cortes, S. O'Brien, S. Jeha, M. Andreeff, S. M. Kornblau, L. Letvak, M. Talpaz, H. M. Kantarjian;
M. D. Anderson Cancer Ctr, Houston, TX; Novartis Pharmaceuticals Corporation, East Hanover, NJ
Abstract: The intensive combination chemotherapy program hyper-CVAD in newly diagnosed Ph+ ALL yields complete remission (CR) rates of 90%; but
remissions are brief with median CR duration of 16 months [Kantarjian et al, JCO 18:547, 2000]. The activity of the tyrosine kinase inhibitor imatinib mesylate
in relapsed or refractory Ph+ ALL or chronic myelogenous leukemia in lymphoid blast phase was 20% as a single agent [Druker et al, NEJM 344:1084,
2001]. A phase II trial of imatinib mesylate and hyper-CVAD was conducted in newly diagnosed Ph+ ALL. Imatinib mesylate was given 400 mg days 1-14 of
each course of therapy (fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with high dose methotrexate and ara-C). Riskadapted intrathecal (IT) prophylaxis (either 6 or 8 ITs) were given. Eight intensive courses are then followed by one year of maintenance with imatinib
mesylate 600 mg daily with monthly vincristine and prednisone, in addition to two early and late intensifications with hyper-CVAD and imatinib mesylate. To
date, 18 patients (pts) with Ph+ ALL have been treated with this regimen from April 2001 to November 2002. Thirteen pts had active disease, either newly
diagnosed (n=9) or refractory to one induction course without imatinib mesylate (n=4). Five pts were in CR at study entry after one induction course (all but
one with minimal residual disease detectable either by FISH or quantitative RT-PCR). All pts with active disease at study entry achieved CR (one too early).
After a median follow-up of 1 year (range, 3-18 mos), one primary refractory pt relapsed at 12 mos (bcr-al/abl RT-PCR ratio at 9 months < .05), and one
came off-study after 5 mos for persistent marrow Ph+ metaphases without overt leukemia relapse. Eight pts proceeded to allogeneic bone marrow transplant
(BMT) after median time of 2 months (range, 1-6 mos). One pt relapsed day 149 of BMT (negative by nested PCR mo 2 after BMT). Toxicity profile was
similar to that seen with hyper-CVAD alone. In summary, hyper-CVAD with imatinib mesylate is active, feasible and well tolerated. Longer follow-up is
needed to determine impact on disease-free survival.
8. Phase II study of combination of the hyperCVAD regimen with dasatinib in patients (pts) with newly diagnosed Philadelphia chromosome positive (Ph+)
acute lymphoblastic leukemia (ALL). F. Ravandi Abstract - No. 7020 2008 ASCO Annual Meeting - Category: Leukemia, Myelodysplasia, and
Transplantation - Leukemia Citation: J Clin Oncol 26: 2008 (May 20 suppl; abstr 7020) Author(s): F. Ravandi, S. Faderl, D. A. Thomas, D. Brown, R. Garris,
G. Borthakur, A. Ferrajoli, J. E. Cortes, H. M. Kantarjian, S. M. O'Brien
Abstract: Background: Combination of cytotoxic chemotherapy with imatinib has improved the outcome for pts with Ph+ ALL. Dasatinib is a significantly more
potent BCR-ABL inhibitor and is effective in pts with Ph+ ALL. Methods: Pts with newly diagnosed Ph+ ALL were treated with dasatinib 50 mg po bid for the
first 14 days of each of 8 cycles of alternating hyperCVAD and high dose cytarabine and methotrexate. Pts in CR continue to receive maintenance dasatinib
50 mg po twice daily indefinitely, and vincristine and prednisone monthly for 2 yrs. Results: To date, 20 pts have received a median of 5 cycles (range, 1-8); 8
pts are receiving maintenance in CR. Median age is 55 yrs (range, 23 - 79); 16 pts were > 50 yrs. Median WBC at diagnosis was 4.7 x 109/L (range, 0.8 203.4 x 109/L). Four pts had CNS involvement at diagnosis. Nineteen pts are evaluable for response assessment; one pt is too early. Seventeen pts (90%)
have achieved CR after the first cycle; 2 pts died before response assessment from infections. Fourteen of 17 (82%) pts have achieved cytogenetic (CG) CR
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Use of TKIs in the management of patients with Ph+ALL: 2nd search results
after 1 cycle; 2 had a major CG response (5% and 15% Ph+) and one is unknown (no CG exam on day 21). Five pts (29%) have achieved complete
molecular remission (CMR) after the first cycle with the BCR-ABL/ABL in the other pts ranging from 0.01 to 73.71. Overall, 9 (47%) patients have achieved
CMR and an additional 5 (26%) have achieved a major molecular response (MMR) with the lowest BCR-ABL/ABL ranging from 0 - 10.73. The median time to
neutrophil and platelet recovery for cycle 1 is 18 and 24 days and for subsequent cycles is 15 and 21 days. Grade 3/4 toxicity included GI bleeding,
infections, hypophosphatemia, hypocalcemia, elevated transaminases, and elevated creatinine. With a median follow up of 7 mths (range, 1-15), 16 pts are
alive and 13 are in CR; 2 died during induction, 1 died in CR from an unrelated cardiac event, and 1 died in CR from infection. Two pts have relapsed
(response durations were 54 weeks and 32 weeks); one relapsed with a T315I mutation and had previously achieved a MMR. One pt is too early for
response assessment. Conclusions: The combination of the hyperCVAD regimen with dasatinib can achieve a high CR rate and molecular remissions in pts
with newly diagnosed Ph+ ALL.
9. 12th Congress of the EHA: Friday, June 8, 2007.
Author:
Ottmann, Oliver, Johann Wolfgang Goethe Universitaet, Frankfurt Main, Germany(P)
Co-author(s):
Hochhaus, Andreas, University Heidelberg, Mannheim, Germany
Saglio, Giuseppe, Universita di Torino, Orbassano-Torino, Italy
Paquette, Ron, Universite de Montreal, Montreal, Canada
Simonsson, Bengt, Uppsala University Hospital, Uppsala, Sweden
Porkka, Kimmo, University of Helsinki, Helsinki, Finland
Van Tornout, Jan, Bristol-Myers Squibb Co., Wallingford, United States of America
Apanovitch, AM, Bristol-Myers Squibb Co., Pennington, United States of America
Rousselot, Philippe, Hôpital Saint-Louis, Paris, France
Topic: 21. Acute lymphoblastic leukemia – clinical
Keywords: Acute lymphoblastic leukemia, BCR-ABL, Cytogenetics, Imatinib resistance
Background: Relapsing patients with Ph+ ALL who have previously received treatment with imatinib and/or chemotherapy have a particularly poor prognosis.
Dasatinib is a novel multi-targeted kinase inhibitor of BCR-ABL and SRC family kinases, with in vitro potency some 325-fold greater than imatinib against
BCR-ABL and proven efficacy in this patient population.
Aims: This study was designed to assess the efficacy and safety of dasatinib.
Methods: Phase-II, open-label, international, multicenter study where patients with Ph+ ALL with resistance or intolerance to imatinib were treated with
dasatinib 70 mg BID, administered orally. Dose escalation to 100 mg BID was allowed for inadequate response, and dose reduction to 50 mg or 40 mg BID
for adverse events. All patients provided written informed consent.
Results: From January through July 2005, 46 patients (median age 48 years; 59% male) enrolled and received treatment, 96% of whom were imatinibresistant; 46% had received doses of >600 mg/d per day, and 52% had received imatinib therapy for >/=12 months. Median time from initial diagnosis of Ph+
ALL was 18 months and 37% of patients had undergone prior stem-cell transplantation (SCT). BCR-ABL mutations were present at baseline in 78% of
patients.
With follow-up extending to 18.5 months, the overall major hematologic response rate was 41%. Major cytogenetic response (MCyR) was achieved for 57%
of patients; this was complete in all but one of these patients (54%). Response rates were consistent irrespective of pre-existing BCR-ABL mutations.
Responses were durable with a positive impact on survival; median overall survival (OS) was 8.0 months and 22% of patients remained alive and
progression-free after 1 year of treatment. Outcome was favorable for patients with prior SCT: median OS of 9.0 months (5.8 months for patients without prior
SCT).
Grade 3-4 thrombocytopenia and grade 3-4 neutropenia both occurred in 78% of patients. Most frequent non-hematologic side-effects included diarrhea in
33% of patients (grade 3-4, 9%), pleural effusion in 24% (grade 3-4, 7%), nausea in 22% (no grade 3-4), and pyrexia in 22% (grade 3-4, 2%). The dasatinib
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Use of TKIs in the management of patients with Ph+ALL: 2nd search results
dose was reduced in 30% of patients and interrupted in 43%, primarily due to non-hematologic toxicities. The average median daily dose was 143 mg.
Summary/conclusions: Dasatinib continues to show impressive efficacy in this difficult-to-treat population post-imatinib failure
10. 10th Congress of the EHA: Saturday, June 4, 2005. abstract nr.: 0431
BCR-ABL MUTATIONS IN PATIENTS WITH PHILADELPHIA-POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA (PH ALL) RECEIVING IMATINIB-BASED
THERAPY
Author: H. Pfeifer, Johann Wolfgang Goethe Universität, Frankfurt, Germany
Co-author(s): P. Brueck, Johann Wolfgang Goethe Universität, Frankfurt, GermanyB. Wassmann, Johann Wolfgang Goethe Universität, Frankfurt,
GermanyL. Wunderle, Johann Wolfgang Goethe Universität, Frankfurt, GermanyG. Bug, Johann Wolfgang Goethe Universität, Frankfurt, GermanyT. Hirdes,
Johann Wolfgang Goethe Universität, Frankfurt, GermanyS. Markovic, Johann Wolfgang Goethe Universität, Frankfurt, GermanyD. Badowsky, Johann
Wolfgang Goethe Universität, Frankfurt, GermanyA. Binckebanck, Johann Wolfgang Goethe Universität, Frankfurt, GermanyD. Hoelzer, Johann Wolfgang
Goethe Universität, Frankfurt, GermanyO.G. Ottmann, Johann Wolfgang Goethe Universität, Frankfurt, Germany
Topic: 13. Acute lymphoblastic leukemia
Keywords Only one keyword per text field only: acute lymphoblastic leukemia, bcr-abl, imatinib, kinase domain mutations
Background: Resistance to the Abl kinase inhibitor imatinib has become a critical issue for patients in advanced phases of chronic myelogenous leukemia
(CML) and Ph+ALL. Imatinib-resistance frequently develops as a consequence of point mutations within the Bcr-Abl kinase domain (KD) that prevent imatinib
from binding. In CML patients, more than two dozen mutations have been identified, located primarily in one of three domains referred to as the P-loop, the
catalytic domain and the activation loop. These various mutations differ in the degree of imatinib resistance they confer. In advanced Ph+ALL, mutations
have likewise been associated with clinical resistance, but the pattern and relative abundance of Bcr-Abl resistance mutations emerging in the presence of
imatinib alone or in combination with chemotherapy have not been established.
Aims: To determine the frequency and distribution of mutations of the Abl KD in patients with relapsed/refractory or newly diagnosed Ph+ALL or lymphoid
blast crisis of CML, and their occurrence in relation to imatinib therapy given as single agent versus in combination with chemotherapy.
Methods and patients: In this study, we retrospectively investigated the bcr-abl mutational status at the time of relapse in 64 pts. who were enrolled a) in the
initial phase II trials of imatinib monotherapy for advanced Ph+ALL/ LyBC [n=45], b) in a subsequent GMALL study of elderly pts. with de novo Ph+ALL
receiving imatinib in combination with extended chemotherapy [n=12] or c) in a GMALL study of younger pts. with de novo Ph+ALL receiving imatinib-based
induction therapy [n=7]. Bone marrow and/or PB samples collected at the time of relapse were analyzed by direct sequencing of the abl KD.
Results: Mutations were detected in 39 patients overall (61%). In the phase II trials of imatinib monotherapy, 29/45 patients (64%) developed a mutation; the
frequency of mutations in elderly patients with de novo Ph+ALL receiving parallel imatinib and chemotherapy was 83% (10/12). The overall frequencies of
these mutations were: Y253F/H(n=8; 20%), Q252H(n=4; 10%), E255K(n=13; 33%), G250E(n=4; 10%), M248V(n=2; 5%), in the P-loop region and T315I
(n=8; 20%) - a mutation in a position in direct contact with imatinib. Only 1 mutation (2.5%) in the catalytic domain (F359V) and 1 mutation (2.5%) in the
activation loop (H396R) were observed. In 10 patients (16%) more than one mutation was detected. Comparison of patients with p190bcr/abl and
p210bcr/abl revealed no significant difference in either the frequency (69% vs. 78%) or profile of mutations.
Summary: In Ph+ALL, clinical resistance to imatinib is associated with a high frequency of abl KD mutations, with conspicuous predominance of mutations
located in the P-loop, most of which confer high level resistance to imatinib. In addition, 20% of patients were found to harbor the T315I mutation which
confers absolute resistance to imatinib as well as to other ABL TK inhibitors in clinical development. The mutation profile is comparable in patients with
advanced leukemia treated with imatinib monotherapy and in patients with newly diagnosed Ph+ALL receiving imatinib in combination with chemotherapy.
11. Nilotinib and donor lymphocyte infusion in the treatment of Philadelphia-positive acute lymphoblastic leukaemia relapsing after allogeneic stem cell
transplantation and resistant to imatinib R 1337 M. Tiribelli*, A. Sperotto, A. Candoni, E. Simeone, S. Buttignol, R. Fanin (Udine, IT): 34th Annual Meeting of
the European Group for Blood and Marrow Transplantation 2008.
Allogeneic stem cell transplantation (SCT) is the treatment of choice in adult Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), with long-term
survival of 27-65% when SCT is performed in first complete remission (CR). Nonetheless, many patients relapse after SCT, and the prognosis of these cases
is dismal. Immunotherapy of post-SCT relapse with donor lymphocyte infusion (DLI) is active in chronic myeloid leukemia (CML), while its efficacy is much
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Use of TKIs in the management of patients with Ph+ALL: 2nd search results
lower in ALL. Imatinib is active in relapsed / refractory Ph+ ALL, but responses were usually short lived. Nilotinib is a new ATP-competitive BCR-ABL
inhibitor, 20 to 50-fold more potent that imatinib. We describe the case of a patient with imatinib-resistant post-transplant relapse of ALL, who attained a
complete remission with the combination of nilotinib and DLI.
A 55-years-old man with Ph+ ALL and meningeal involvement received induction and consolidation chemotherapy and CNS radiotherapy, obtaining an
hematologic CR and a MCyR (95% Ph-). The patient then started imatinib (400 mg/day), with a CCyR after 1 month but disease persistence at molecular
level. In January 2006 he underwent a myeloablative (BuCy + ATG) allogeneic SCT from a matched unrelated donor. The patient recovered with a complete
cytogenetic and molecular remission. No GvHD developed in the following months. Five and half months after SCT molecular positivity was detected, rapidly
followed by testicular relapse of ALL. The patient started imatinib 400 mg/day, but rapidly disease progressed with a bone marrow relapse. Salvage
chemotherapy and testicular radiotherapy induced a second hematologic CR, so the patient received a first DLI (0.5 x 10^7/kg), but on day +28 a third
relapse was documented. Treatment with vincristine and dexamethasone attained a partial. In March 2007 the patient started nilotinib at standard dose (800
mg/day). After 3 weeks the patient achieved bone marrow remission and a 1-log reduction of BCR/ABL transcript. Two weeks later a second DLI (10^7/kg)
was administered, that induced a grade I GvHD (skin and liver). At the eight week of nilotinib and 3 weeks after the second DLI, a molecular negativity was
documented. The patient continued a combined therapy with nilotinib and monthly DLI infusion, with sustained complete molecular remission persisting to
date. Our case provide a rationale for the combined use of nilotinib and DLI in the treatment of Ph+ ALL relapsing after transplant and resistant to imatinib.
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