A Pilot Study of the Combination of Nilotinib and Hyper-CVAD for Philadelphia Chromosome Positive Acute Lymphocytic Leukemia and Lymphoid Blast Crisis Chronic Myelogenous Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2144-2144 ◽  
Author(s):  
Edgar Castillo ◽  
Raed Al-Rajabi ◽  
Devesh M. Pandya ◽  
Prakash Varadarajan ◽  
Kevin R Kelly ◽  
...  
Keyword(s):  
Pilot Study ◽  
Complete Remission ◽  
Acute Lymphocytic Leukemia ◽  
Blast Crisis ◽  
Philadelphia Chromosome ◽  
Case Series ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Cell Transplant ◽  
Philadelphia Chromosome Positive

Abstract Abstract 2144 Background: Nilotinib is a second generation bcr-abl tyrosine kinase inhibitor (TKI) that has at least 30 times the potency of Imatinib (IM). Nilotinib has been approved by the FDA for the treatment of adults with chronic myeloid leukemia (CML) in chronic phase (CP) in the frontline, and for CP or accelerated phase (AP) who are either resistant or intolerant to prior therapies, including IM. Philadelphia chromosome positive (Ph+) acute lymphocytic leukemia (ALL) and lymphoid blast crisis of CML (Ly-BC) is aggressive and rapidly fatal. Complete remissions rates are low and have short durability. Relapse is inevitable unless patients (pts) receive an allogeneic stem cell transplant (SCT). The use of TKIs against Ph+ ALL or Ly-BC has shown limited durability of response as single agents. The transient nature of response to TKI is because only some of the blasts are still sensitive to bcr-abl inhibition, while the rest of the clones are not and require the addition of chemotherapy. Hyper-CVAD combined with the first generation TKI, IM is one such chemotherapy regimen that has been used in the management of adults with Ph+ ALL or Ly-BC (Thomas D, et al. Blood, 2004). Despite achieving >90% complete remission (CR) during induction phase, some pts have resistant disease or relapse shortly after attaining remission. We hypothesized that combining nilotinib with hyper-CVAD would achieve greater rates of sustained CR which ultimately translate into lower relapse rates, superior disease free survival, long term survival, and potential cure post SCT. The goal of our pilot case series was to study the feasibility of combining the more potent TKI, nilotinib to hyper-CVAD in pts with Ph+ ALL or Ly-BC, so as to improve the efficacy. Methods: Our case series involves 5 pts at our institution diagnosed with either Ph+ ALL or Ly-BC treated with a combination of hyper-CVAD and nilotinib given orally 400mg twice daily (initiated the day after completion of chemotherapy until the start of next cycle). After completion of eight cycles of chemotherapy, pts received either SCT or maintenance POMP in combination with nilotinib. Supportive care included prophylactic antibiotics, granulocyte colony stimulating factor, and transfusions as needed. None of them had central nervous system (CNS) involvement, but received intrathecal prophylaxis. Clinical characteristics at baseline, safety assessments, and efficacy evaluations including morphologic, cytogenetic, and molecular responses were analyzed. Results: All 5 pts (p190 Ph+ ALL-4, p210 Ly-BC-1; all males; Hispanic-2, Caucasian-3) received the combination for a median of 5 months. The median age was 29 (range 22–72) and the median follow-up period was 14 months. The Ly-BC pt was treated upfront with IM during CP and achieved major molecular remission (MMR) for 39 months, however due to noncompliance, relapsed with progression. All 5 patients achieved complete remission (CR), 60% after the first course. All of them achieved complete cytogenetic remission (CCyR) while 4 achieved MMR. Of the 2 Ph+ ALL pts who completed eight cycles, 1 received SCT and is in MMR for 20 months, while the other pt remains in MMR on POMP-nilotinib maintenance for over 19 months. Another pt is in MMR for 5 months. Two patients relapsed and died: the Ly-BC pt who achieved CR (without MMR) for 3 weeks and another pt that was in CCyR and MMR for 11 months. Most common adverse events included pancytopenia, fever, and infections (with no treatment related life threatening events). Conclusions: Our pilot study is the first to demonstrate the feasibility of combining nilotinib with hyper-CVAD. The results thus far are encouraging and will be expanded into a larger investigator initiated phase II study that can potentially prevent the emergence of resistant clones and improve survival in patients with Ph+ ALL or Ly-BC. Disclosures: Off Label Use: Pilot study of Nilotinib and hyper-CVAD in Ph+ ALL.

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.

Bosutinib (SKI-606) exhibits clinical activity in patients with Philadelphia chromosome positive CML or ALL who failed imatinib

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7006-7006 ◽  
Author(s):  
C. Gambacorti-Passerini ◽  
T. Brummendorf ◽  
H. Kantarjian ◽  
G. Martinelli ◽  
D. Liu ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Phase 1 ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Clinical Activity ◽  
Low Grade ◽  
Imatinib Resistant ◽  
Philadelphia Chromosome Positive

7006 Background: Bosutinib (SKI-606) is an orally available, dual Src/Abl kinase inhibitor. To assess safety and preliminary clinical activity of bosutinib, we conducted a phase 1/2 study in patients (pts) with Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML) or acute lymphocytic leukemia (ALL) who were imatinib resistant/intolerant. Methods: In part 1, 18 pts with imatinib- relapsed/refractory chronic phase (CP) CML received bosutinib 400 mg/day (3 pts), 500 mg/day (3 pts), or 600 mg/day (12 pts). Part 2 was an expanded cohort of 51 pts with all phases of Ph+ CML and ALL dosed at 500 mg daily. Timed blood samples were collected on days 1–3, 15 for PK analysis. Results: Of 69 pts, median age was 59 yrs; 48 were CP; 90% imatinib resistant. Drug-related grade 1/2 adverse events (AEs) occurring in =10% of CP pts: diarrhea (69%), nausea (44%), vomiting (19%), abdominal pain (13%), rash (13%). Grade 3/4 AEs occurring in =5% of CP pts: rash (6%), thrombocytopenia (6%). 17 pts required dose reductions. In evaluable imatinib-resistant CP-CML pts with no prior exposure to other Abl inhibitors, 16/19 (84%) had complete hematologic response (CHR); 4/21 had partial and 7/21 had complete cytogenetic responses for major cytogenetic response (MCyR) rate of 52%. Of 58 pts evaluable for mutations, 13 different imatinib-resistant mutations were found in 32 pts. 12/14 CP pts with non-P-loop mutations and 3/3 with P-loop mutations achieved CHR. 5/11 CP pts with non-P- loop mutations and 1/1 with P-loop mutation achieved MCyR. 4/9 evaluable advanced leukemia pts had CHR, 2 had MCyR. After oral administration, steady state exposure of bosutinib was nearly 2-fold higher than single-dose exposure. Mean elimination half-life was approximately 22–27 hours, supporting a once-daily dosing regimen. Conclusions: Bosutinib was well tolerated in pts with CML, with primarily low-grade gastrointestinal and dermatologic AEs. Bosutinib showed clinical activity in imatinib-resistant pts with cytogenetic responses and CHR across a range of mutations. Durability of response continues to be assessed. [Table: see text]

scholarly journals Analysis of the BCR-ABL protein in Philadelphia chromosome-positive adult acute lymphocytic leukemia

Leukemia ◽  
1997 ◽  
Vol 11 (9) ◽  
pp. 1583-1587 ◽  
Author(s):  
AW Bseiso ◽  
HM Kantarjian ◽  
JQ Guo ◽  
J Cortes ◽  
M Talpaz ◽  
...  
Keyword(s):  
Acute Lymphocytic Leukemia ◽  
Philadelphia Chromosome ◽  
Lymphocytic Leukemia ◽  
Adult Acute Lymphocytic Leukemia ◽  
Philadelphia Chromosome Positive

Efficacy of Nonmyeloablative Hematopoietic Cell Transplant (HCT) in Secondary Myelodysplastic Syndrome (MDS) and Its Impact on the Primary Disease.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 792-792
Author(s):  
F. Kerbauy ◽  
M. Maris ◽  
B. Storer ◽  
D. Maloney ◽  
D. Niederwieser ◽  
...  
Keyword(s):  
Complete Remission ◽  
Local Treatment ◽  
Lymphocytic Leukemia ◽  
The Other ◽  
Myelogenous Leukemia ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Primary Malignancy ◽  
Primary Disease ◽  
Secondary Mds

Abstract Allogeneic HCT is currently the only treatment option with curative potential for secondary MDS. The efficacy of nonmyeloablative HCT in patients (pts) with secondary MDS and its impact on the primary disease is unknown. We analyzed data from 25 patients, 38–74 (median 58) years of age, with secondary MDS who were not candidates for myeloablative HCT. The primary diseases included non-Hodgkin’s lymphoma (NHL) (n=11), chronic lymphocytic leukemia (CLL) (n=5), multiple myeloma (n=2), breast cancer (n=2), acute myelogenous leukemia (n=1), Hodgkin lymphoma (n=1), and other carcinomas (n=3). At the time of HCT, 19 pts (76%), including all with non-hematologic primary malignancies, were in complete remission of the primary underlying malignancy, while 4 patients with CLL and 2 patients with follicular NHL had active disease. Twenty-four patients had received 1–6 (median 2) treatments for the primary disease 0.8–10.8 (median 6.2) years before developing MDS, including autologous HCT in 12 (48%). One patient developed MDS after local treatment for squamous cell carcinoma. The secondary MDS status at HCT was RA(RS) (n=10), RAEB/RAEB-t (n=6) or AML (n=9). The interval from MDS diagnosis to HCT was 0.2–1.5 (median 0.5) years. All pts were conditioned with fludarabine, 90mg/m2 and 2 Gy TBI and received unmodified G-CSF mobilized peripheral blood progenitor cells containing a median 6.2 x106 CD34+ and 2.2 x 108 CD3+ cells/kg from HLA-matched related (n=13) or unrelated (n=12) donors. Postgrafting immunosuppression consisted of cyclosporine and mycophenolate mofetil. All pts had initial donor engraftment at day 28 after HCT, but 2 pts experienced subsequent graft rejections followed by MDS relapse. The incidences of grades II, III and IV acute GVHD were 28%, 12% and 4%, respectively. Fourteen pts (54%) achieved complete remissions of their MDS. Fourteen (56%) patients died; 3 from non-relapse causes and 11 from relapse/progression of MDS. The 1 year estimates of non-relapse mortality, overall and progression free survivals were 17%, 56% and 36%, respectively. The 3-year overall survival was 35% for pts with RA(RS) (n=10) and 29% for patients with more advanced disease. All pts in complete remission of the primary disease at the time of HCT remained in remission of the primary disease after the HCT. Among four pts with active CLL at the time of HCT, one achieved CR after HCT but died from MDS progression, whereas the other 3 had stable disease at the last follow-up. Among 2 pts with active follicular NHL, one achieved CR after HCT but died from progression of MDS and the other pt died on day 7 from multi-organ failure. In summary, nonmyeloablative HCT allowed for development of graft versus tumor effects for MDS. Encouragingly, none of the patients had relapse or progression of their primary malignancy following nonmyeloablative conditioning and post-grafting immunossupression. Additionally, HCT may control the primary disease (CLL and indolent NHL) if active at the time of HCT.

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